Dihydroartemisinin-piperaquine for treating uncomplicated Plasmodium falciparum malaria

  • Review
  • Intervention

Authors


Abstract

Background

The World Health Organization (WHO) recommends Artemisinin-based Combination Therapy (ACT) for treating uncomplicated Plasmodium falciparum malaria. This review aims to assist the decision-making of malaria control programmes by providing an overview of the relative effects of dihydroartemisinin-piperaquine (DHA-P) versus other recommended ACTs.

Objectives

To evaluate the effectiveness and safety of DHA-P compared to other ACTs for treating uncomplicated P. falciparum malaria in adults and children.

Search methods

We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL) published in The Cochrane Library; MEDLINE; EMBASE; LILACS, and the metaRegister of Controlled Trials (mRCT) up to July 2013.

Selection criteria

Randomized controlled trials comparing a three-day course of DHA-P to a three-day course of an alternative WHO recommended ACT in uncomplicated P. falciparum malaria.

Data collection and analysis

Two authors independently assessed trials for eligibility and risk of bias, and extracted data. We analysed primary outcomes in line with the WHO 'Protocol for assessing and monitoring antimalarial drug efficacy’ and compared drugs using risk ratios (RR) and 95% confidence intervals (CI). Secondary outcomes were effects on gametocytes, haemoglobin, and adverse events. We assessed the quality of evidence using the GRADE approach.

Main results

We included 27 trials, enrolling 16,382 adults and children, and conducted between 2002 and 2010. Most trials excluded infants aged less than six months and pregnant women.

DHA-P versus artemether-lumefantrine

In Africa, over 28 days follow-up, DHA-P is superior to artemether-lumefantrine at preventing further parasitaemia (PCR-unadjusted treatment failure: RR 0.34, 95% CI 0.30 to 0.39, nine trials, 6200 participants, high quality evidence), and although PCR-adjusted treatment failure was below 5% for both ACTs, it was consistently lower with DHA-P (PCR-adjusted treatment failure: RR 0.42, 95% CI 0.29 to 0.62, nine trials, 5417 participants, high quality evidence). DHA-P has a longer prophylactic effect on new infections which may last for up to 63 days (PCR-unadjusted treatment failure: RR 0.71, 95% CI 0.65 to 0.78, two trials, 3200 participants, high quality evidence).

In Asia and Oceania, no differences have been shown at day 28 (four trials, 1143 participants, moderate quality evidence), or day 63 (one trial, 323 participants, low quality evidence).

Compared to artemether-lumefantrine, no difference was seen in prolonged QTc (low quality evidence), and no cardiac arrhythmias were reported. The frequency of other adverse events is probably similar with both combinations (moderate quality evidence).

DHA-P versus artesunate plus mefloquine

In Asia, over 28 days follow-up, DHA-P is as effective as artesunate plus mefloquine at preventing further parasitaemia (PCR-unadjusted treatment failure: eight trials, 3487 participants, high quality evidence). Once adjusted by PCR to exclude new infections, treatment failure at day 28 was below 5% for both ACTs in all eight trials, but lower with DHA-P in two trials (PCR-adjusted treatment failure: RR 0.41 95% CI 0.21 to 0.80, eight trials, 3482 participants, high quality evidence). Both combinations contain partner drugs with very long half-lives and no consistent benefit in preventing new infections has been seen over 63 days follow-up (PCR-unadjusted treatment failure: five trials, 2715 participants, moderate quality evidence).

In the only trial from South America, there were fewer recurrent parastaemias over 63 days with artesunate plus mefloquine (PCR-unadjusted treatment failure: RR 6.19, 95% CI 1.40 to 27.35, one trial, 445 participants, low quality evidence), but no differences were seen once adjusted for new infections (PCR-adjusted treatment failure: one trial, 435 participants, low quality evidence).

DHA-P is associated with less nausea, vomiting, dizziness, sleeplessness, and palpitations compared to artesunate plus mefloquine (moderate quality evidence). DHA-P was associated with more frequent prolongation of the QTc interval (low quality evidence), but no cardiac arrhythmias were reported.

Authors' conclusions

In Africa, dihydroartemisinin-piperaquine reduces overall treatment failure compared to artemether-lumefantrine, although both drugs have PCR-adjusted failure rates of less than 5%. In Asia, dihydroartemisinin-piperaquine is as effective as artesunate plus mefloquine, and is better tolerated.

Résumé scientifique

La dihydroartémisinine-pipéraquine pour le traitement du paludisme à Plasmodium falciparum non compliqué

Contexte

L'Organisation Mondiale de la Santé (OMS) recommande les combinaisons thérapeutiques à base d'artémisine (CTA) pour le traitement du paludisme à Plasmodium falciparum non compliqué. Cette revue vise à aider la prise de décision des programmes de contrôle du paludisme en fournissant une synthèse des effets relatifs de la dihydroartémisinine-pipéraquine (DHA-P) par rapport à d'autres CTA recommandées.

Objectifs

Évaluer l'efficacité et l'innocuité de la DHA-P par rapport à d'autres CTA pour le traitement du paludisme à P. falciparum non compliqué chez l'adulte et l'enfant.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre spécialisé du groupe Cochrane sur les maladies infectieuses ; le registre Cochrane des essais contrôlés (CENTRAL), publié dans la Bibliothèque Cochrane; MEDLINE ; EMBASE ; LILACS et le méta-registre des essais contrôlés (mECR) jusqu'à juillet 2013.

Critères de sélection

Essais contrôlés randomisés comparant un traitement de trois jours de DHA-P à un traitement alternatif de CTA de trois jours recommandé par l'OMS dans le paludisme P. à falciparum non compliqué.

Recueil et analyse des données

Deux auteurs ont indépendamment évalué l'éligibilité des essais et le risque de biais et extrait les données. Nous avons analysé les critères de jugement principaux en parallèle avec le «protocole de l'OMS pour évaluer l'efficacité et la surveillance de médicaments antipaludiques » et comparé les médicaments à l'aide des risques relatifs (RR) et l'indice de confiance (IC) à 95%. Les critères de jugement secondaires étaient les effets sur les gamétocytes, l'hémoglobine et les effets indésirables. Nous avons évalué la qualité des preuves en utilisant l'approche GRADE.

Résultats principaux

Nous avons inclus 27 essais, portant sur 16 382 adultes et enfants et réalisés entre 2002 et 2010. La plupart des essais excluaient les enfants âgés de moins de six mois et les femmes enceintes.

La DHA-P par rapport à l'artéméther-luméfantrine

En Afrique, suite à un suivi de 28 jours, la DHA-P est supérieure à l'artéméther-luméfantrine dans la prévention d'autres parasitémies (échec de traitement PCR-non ajusté : RR 0,34, IC à 95% 0,30 à 0,39, neuf essais, 6 200 participants, preuves de haute qualité) et bien que l'échec de traitement PCR-non ajusté était inférieur à 5 % pour les CTA, il était systématiquement plus faible avec la DHA-P (échec de traitement PCR-non ajusté : RR 0,42, IC à 95% 0,29 à 0,62, neuf essais, 5 417 participants, preuves de haute qualité). La DHA-P apporte un effet prophylactique de plus longue durée sur de nouvelles infections qui peuvent durer jusqu'à 63 jours (échec de traitement PCR-non ajusté : RR 0,71, IC à 95 % 0,65 à 0,78, deux essais, 3200 participants, preuves de haute qualité).

En Asie et en Océanie, aucune différence n'a été démontrée à 28 jours (quatre essais, 1 143 participants, preuves de qualité modérée), ni à 63 jours (un essai, 323 participants, preuves de faible qualité).

Par rapport à l'artéméther-luméfantrine, aucune différence n'était observée lors de QTc prolongée (preuves de faible qualité) et aucune arythmie cardiaque n'a été rapportée. La fréquence des autres effets indésirables est probablement similaire avec les deux combinaisons (preuves de qualité modérée).

La DHA-P par rapport à l'artésunate + la méfloquine

En Asie, après un suivi de 28 jours, la DHA-P est aussi efficace que l'artésunate + la méfloquine dans la prévention d'autres parasitémies (échec de traitement PCR-non ajusté : huit essais, 3 487 participants, preuves de haute qualité). Après avoir été ajusté par la PCR pour exclure de nouvelles infections, l'échec du traitement au 28ème jour était inférieur à 5 % pour les deux CTA dans les huit essais, mais réduisait avec la DHA-P dans deux essais (échec de traitement PCR-non ajusté: RR IC à 0,41 95% 0,21 à 0,80, huit essais, 3 482 participants, preuves de haute qualité). Les deux combinaisons contiennent des médicaments partenaires à durée de demi-vie très longue et aucun bénéfice notable pour prévenir de nouvelles infections n'a été observé après 63 jours de suivi (échec de traitement PCR-non ajusté: cinq essais, 2 715 participants, preuves de qualité modérée).

Dans le seul essai en Amérique du Sud, il y avait une réduction de la récurrence de parasitémies après 63 jours avec l'artésunate + la méfloquine (échec de traitement PCR-non ajusté : RR 6,19, IC à 95% 1,40 à 27,35, un essai, 445 participants, preuves de faible qualité), mais aucune différence n'a été observée après avoir été ajustés pour de nouvelles infections (échec de traitement PCR-non ajusté : Un essai, 435 participants, preuves de faible qualité).

La DHA-P est associée à moins de nausées, de vomissements, d'étourdissements, de perte de sommeil et de palpitations par rapport à l'artésunate + la méfloquine (preuves de qualité modérée). La DHA-P était associée à des prolongations plus fréquentes de l'intervalle QTc (preuves de faible qualité), mais aucune arythmie cardiaque n'a été rapportée.

Conclusions des auteurs

En Afrique, la dihydroartémisinine-pipéraquine réduit dans l'ensemble l'échec du traitement par rapport à l'artéméther-luméfantrine, bien que les deux médicaments aient des taux d'échec PCR-ajustés inférieurs à 5 %. En Asie, la dihydroartémisinine-pipéraquine est aussi efficace que l'artésunate + la méfloquine et est mieux tolérée.

Plain language summary

Dihydroartemisinin-piperaquine for treating uncomplicated malaria

This review summarises trials evaluating the effects of dihydroartemisinin-piperaquine (DHA-P) compared to other artemisinin-based combination therapies recommended by the World Health Organization. After searching for relevant trials up to July 2013, we included 27 randomized controlled trials, enrolling 16,382 adults and children and conducted between 2002 and 2010.

What is uncomplicated malaria and how might dihydroartemisinin-piperaquine work

Uncomplicated malaria is the mild form of malaria which usually causes a fever, with or without headache, tiredness, muscle pains, abdominal pains, nausea, and vomiting. If left untreated, uncomplicated malaria can develop into severe malaria with kidney failure, breathing difficulties, fitting, unconsciousness, and eventually death.

DHA-P is one of five artemisinin-based combination therapies the World Health Organization currently recommends to treat malaria. These combinations contain an artemisinin component (such as dihydroartemisinin) which works very quickly to clear the malaria parasite from the person's blood, and a longer acting drug (such as piperaquine) which clears the remaining parasites from the blood and may prevent new infections with malaria for several weeks.

What the research says

DHA-P versus artemether lumefantrine

In studies of people living in Africa, both DHA-P and artemether-lumefantrine are very effective at treating malaria (high quality evidence). However, DHA-P cures slightly more patients than artemether-lumefantrine, and it also prevents further malaria infections for longer after treatment (high quality evidence). DHA-P and artemether-lumefantrine probably have similar side effects (moderate quality evidence).

DHA-P versus artesunate plus mefloquine

In studies of people living in Asia, DHA-P is as effective as artesunate plus mefloquine at treating malaria (moderate quality evidence). Artesunate plus mefloquine probably causes more nausea, vomiting, dizziness, sleeplessness, and palpitations than DHA-P (moderate quality evidence).

Overall, in some people, DHA-P has been seen to cause short term changes in electrocardiographs tracing the conduction of the heart rhythm (low quality evidence), but these small changes on the electrocardiograph resolved within one week without serious consequences.

Résumé simplifié

La dihydroartémisinine-pipéraquine pour le traitement du paludisme non compliqué

Cette revue résume les essais évaluant les effets de la dihydroartémisinine-pipéraquine (DHA-P) par rapport à d'autres traitements combinés à base d'artémisinine qui sont recommandés par l'Organisation Mondiale de la Santé. Après avoir recherché des essais pertinents jusqu'en juillet 2013, nous avons inclus 27 essais contrôlés randomisés portant sur 16 382 adultes et enfants et réalisés entre 2002 et 2010.

Qu'est-ce que le paludisme non compliqué et comment la dihydroartémisinine-pipéraquine pourrait-elle fonctionner

Le paludisme non compliqué est la forme légère de paludisme qui provoque généralement de la fièvre, avec ou sans maux de tête, de la fatigue, des douleurs musculaires, des douleurs abdominales, des nausées et des vomissements. S'il n'est pas traité, le paludisme non compliqué peut se développer en paludisme sévère avec une insuffisance rénale, des difficultés respiratoires, des pertes de connaissance et éventuellement des décès.

La DHA-P est l'un des cinq traitements combinés à base d'artémisinine qui est actuellement recommandé par l'Organisation Mondiale de la Santé pour traiter le paludisme. Ces combinaisons contiennent de l'artémisinine (tel que la dihydroartémisinine) qui agit très rapidement pour éliminer le parasite du paludisme dans le sang d'une personne, ainsi qu'un médicament à action plus longue (tel que la piperaquine) qui élimine les parasites restants dans le sang et pourrait prévenir de nouvelles infections au paludisme pendant plusieurs semaines.

Ce que disent les recherches

La DHA-P par rapport à l'artéméther-luméfantrine

Dans les études portant sur des patients vivant en Afrique, la DHA-P et l'artéméther-luméfantrine sont très efficaces pour le traitement du paludisme (preuves de haute qualité). Cependant, la DHA-P cure légèrement plus de patients que l'artéméther-luméfantrine et prévient également d'autres infections au paludisme pendant une durée plus longue après le traitement (preuves de haute qualité). La DHA-P et l'artéméther-luméfantrine ont probablement des effets secondaires semblables (preuves de qualité modérée).

La DHA-P par rapport à l'artésunate + la méfloquine

Dans les études portant sur des patients vivant en Asie, la DHA-P est aussi efficace que l'artésunate + la méfloquine dans le traitement du paludisme (preuves de qualité modérée). L'artésunate + la méfloquine entraînent probablement davantage de nausées, de vomissements, d'étourdissements, de perte de sommeil et de palpitations que la DHA-P (preuves de qualité modérée).

Dans l'ensemble, chez certaines personnes, la DHA-P entraînait des changements à court terme dans les électrocardiographiques qui traçaient la conduction du rythme cardiaque (preuves de faible qualité), mais ces petits changements sur les électrocardiographiques régressaient en l'espace d'une semaine sans conséquences graves.

Notes de traduction

Traduit par: French Cochrane Centre 15th June, 2014
Traduction financée par: Financeurs pour le Canada : Instituts de Recherche en Santé du Canada, Ministère de la Santé et des Services Sociaux du Québec, Fonds de recherche du Québec-Santé et Institut National d'Excellence en Santé et en Services Sociaux; pour la France : Ministère en charge de la Santé

Summary of findings(Explanation)

Summary of findings for the main comparison. Dihydroartemisinin-piperaquine versus Artemether-lumefantrine for uncomplicated P. falciparum malaria in Africa
  1. 1 No serious risk of bias: Trials are generally at low risk of bias. Exclusion of studies at high or unclear risk of selection bias or detection bias did not change the result.
    2 No serious inconsistency: The trials all had similar results and statistical heterogeneity was low.
    3 No serious indirectness: The trials were conducted in different transmission settings in East, West and Southern Africa. Most studies were limited to children.
    4 No serious imprecision: Both limits of the 95% CI imply appreciable benefit, and the overall meta-analysis is adequately powered to detect this result.
    5 No serious imprecision: Although there is a benefit in favour of DHA-P, PCR-adjusted treatment failure was below 5% with both drugs.
    6 No serious inconsistency: At this timepoint there is more inconsistency between trials. Both show a benefit with DHA-P but there is variation in the size of this benefit.
    7 Seven studies from East, West and Southern Africa reported outcomes at day 42. At this timepoint DHA-P still had an advantage over AL6 on PCR-unadjusted treatment failure (RR 0.60, 95% CI 0.53 to 0.67, seven studies, 3301, high quality evidence), and PCR-adjusted treatment failure (RR 0.58, 95% CI 0.41 to 0.81, seven studies, 2559 participants, moderate quality evidence).
    8 No serious inconsistency: Statistical heterogeneity was low.
    9 No serious imprecision: Both ACTs performed well in these two trials with low levels of treatment failure.

Dihydroartemisinin-piperaquine versus Artemether-lumefantrine for uncomplicated P. falciparum malaria in Africa
Patient or population: Patients with uncomplicated P. falciparum malaria
Settings: Malaria endemic settings in Africa
Intervention: Dihydroartemisinin-piperaquine (DHA-P)
Comparison: Artemether-lumefantrine (AL6)
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(trials)
Quality of the evidence
(GRADE)
Assumed riskCorresponding risk
AL6 DHA-P

Treatment failure

Day 28

PCR-unadjusted RR 0.34
(0.30 to 0.39)
6200
(9 trials)
⊕⊕⊕⊕
high 1,2,3,4
23 per 100 8 per 100
(7 to 9)
PCR-adjusted RR 0.42
(0.29 to 0.62)
5417
(9 trials)
⊕⊕⊕⊕
high 1,2,3,5
3 per 100 1 per 100
(1 to 2)

Treatment failure

Day 63

PCR-unadjusted RR 0.71
(0.65 to 0.78)
3200
(2 trials)
⊕⊕⊕⊕
high 1,3,4,6,7
45 per 100 32 per 100
(29 to 35)
PCR-adjusted RR 0.72
(0.50 to 1.04)
2097
(2 trials)
⊕⊕⊕⊕
high 1,3,7,8,9
6 per 100 4 per 100
(3 to 6)
*The basis for the assumed risk (for example, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.,
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

Malaria is a febrile illness caused by infection with the protozoan parasite Plasmodium, which is transmitted from person to person by the bite of infected female Anopheles mosquitoes. Five Plasmodium species are capable of causing malaria in humans, of which P. falciparum is responsible for over 90% of malaria cases and almost all of the malaria deaths worldwide (WHO 2012).

Uncomplicated malaria is the mild form of the disease which typically presents as a fever, with or without associated headache, tiredness, muscle pains, abdominal pains, rigors (severe shivering), nausea, and vomiting. If left untreated P. falciparum malaria can rapidly develop into severe malaria with consequent renal failure (kidney failure), pulmonary oedema (fluid in the lungs), convulsions (fitting), coma, and eventually death (WHO 2010; Sinclair 2012). A clinical diagnosis of malaria can be confirmed by detection of the malaria parasite in the patient's blood. This has traditionally been done by light microscopy but increasingly rapid diagnostic tests are being used (Abba 2011).

Resistance of P. falciparum to the traditional antimalarial drugs (such as chloroquine, sulfadoxine-pyrimethamine, amodiaquine, and mefloquine) is a growing problem and is thought to have contributed to increased malaria mortality in recent years (WHO 2010). Chloroquine resistance has now been documented in all regions except Central America and the Caribbean. There is high-level resistance to sulfadoxine-pyrimethamine throughout South East Asia and increasingly in Africa, and mefloquine resistance is common in the border areas of Cambodia, Myanmar, and Thailand (WHO 2010; WWARN 2013).

To combat the spread of resistance, the World Health Organization (WHO) now recommends that P. falciparum malaria is always treated using a combination of two drugs that act at different biochemical sites within the parasite (WHO 2010). If a parasite mutation producing drug resistance arises spontaneously during treatment, the parasite should then be killed by the partner drug, thus reducing or delaying the development of resistance and increasing the useful lifetime of the individual drugs (White 1996; White 1999). The current drug combinations all include a short-acting artemisinin derivative (such as artesunate, artemether, or dihydroartemisinin), partnered with a longer-acting drug in combinations known as 'Artemisinin-based Combination Therapies' (ACTs).

Description of the intervention

The WHO recommends five ACTs for treating uncomplicated P. falciparum malaria: dihydroartemisinin-piperaquine (DHA-P); artesunate plus mefloquine (AS+MQ); artemether-lumefantrine - six doses regimen (AL6); artesunate plus amodiaquine (AS+AQ); and artesunate plus sulfadoxine-pyrimethamine (AS+SP) (WHO 2010).

Dihydroartemisinin is the active metabolite of the artemisinin derivatives, and produces faster relief of clinical symptoms and faster clearance of parasites from the blood than other antimalarial drugs (McIntosh 2000; Adjuik 2004; WHO 2010). When used as a monotherapy, the short half-life of the artemisinin derivatives (and rapid elimination from the blood) means that patients must take the drug for at least seven days (Meshnick 1996; Adjuik 2004). Failure to complete the course, due to the rapid improvement in clinical symptoms, can lead to high levels of treatment failure even in the absence of drug resistance. The long-acting partner drug in ACTs therefore allows the artemisinin component to be taken for a shorter duration (White 1999), and the current recommendation is for three days of the artemisinin-derivative to cover two asexual parasite life-cycles (Adjuik 2004; WHO 2010).

The artemisinin derivatives also reduce the development of gametocytes (the sexual form of the P. falciparum parasite that is capable of infecting mosquitoes) and consequently the carriage of gametocytes in the peripheral blood (Price 1996; Targett 2001). This reduction in infectivity has the potential to reduce the post-treatment transmission of malaria (particularly in areas of low or seasonal transmission), which may have important public health benefits (WHO 2010).

Artemisinin and its derivatives are generally reported as being safe and well-tolerated, and the safety profile of ACTs may be largely determined by the partner drug (Nosten 2007; WHO 2010). Animal studies of artemisinin derivatives have reported neurotoxicity (brain damage), but this has not been seen in human studies (Price 1999). Animal studies have also shown adverse effects on the early development of the fetus, and consequently the use of artemisinin derivatives in pregnant women has so far been restricted to the second and third trimesters and continues to be evaluated (Nosten 2007). Other reported adverse events include gastrointestinal (GI) disturbance (stomach upset), dizziness, tinnitus (ringing in the ears), neutropenia (low levels of white blood cells), elevated liver enzymes (a marker for liver damage), and electrocardiographic (ECG) abnormalities (changes in cardiac conduction) (Nosten 2007). The incidence of type 1 hypersensitivity (allergic) reactions is reported to be approximately 1 in 3000 patients (Nosten 2007).

Piperaquine is a bisquinoline antimalarial whose mode of action is thought to be similar to that of chloroquine (a 4-aminoquinolone) (Keating 2012). In vitro studies have shown it is effective against chloroquine-resistant P. falciparum, although there are reports of some cross-resistance (Keating 2012). Piperaquine has a very long elimination half-life of between two to three weeks, similar to mefloquine but longer than lumefantrine or amodiaquine, and consequently could be expected to provide a long period of post-treatment prophylaxis (Davis 2005; Keating 2012).

In a previous review of DHA-P, Myint 2007 noted an association between DHA-P and prolongation of the QT interval in two small observational trials (Karunajeewa 2004: N = 62, and Ashley 2004a THA; N = 32). Prolonged QT interval is a cardiac conduction defect which can sometimes lead to fatal arrhythmias.

Assessment of antimalarial drug efficacy

The WHO recommends that first-line antimalarials should have a treatment failure rate of less than 10%, and that failure rates higher than 10% should trigger a change in treatment policy (WHO 2010). Treatment failure can be classified as:

Early treatment failure:

  • the development of danger signs or severe malaria on days 1, 2, or 3 in the presence of parasitaemia;

  • parasitaemia on day 2 higher than on day 0;

  • parasitaemia and axillary temperature > 37.5 °C on day three;

  • parasitaemia on day 3 > 20% of count on day 0.

or late treatment failure:

  • development of danger signs, or severe malaria, after day three with parasitaemia;

  • presence of P. falciparum parasitaemia and axillary temperature > 37.5 °C on or after day 4;

  • presence of P. falciparum parasitaemia after day 7.

The late reappearance of P. falciparum parasites in the blood can be due to failure of the drug to completely clear the original parasite (a recrudescence) or due to a new infection, which is especially common in areas of high transmission. A molecular genotyping technique called polymerase chain reaction (PCR) can be used in clinical trials to distinguish between recrudescence and new infection, giving a clearer picture of the efficacy of the drug and its post-treatment prophylactic effect (White 2002; Cattamanchi 2003).

The WHO recommends a minimum follow-up period of 28 days for antimalarial efficacy trials, but longer follow-up may be required for antimalarials with long elimination half-lives (White 2002; Bloland 2003). This is because treatment failure due to true recrudescence of malaria parasites may be delayed until the drug concentration falls below the minimum concentration required to inhibit parasite multiplication, which may be beyond 28 days. The WHO recommends 42 days follow-up for trials involving lumefantrine and piperaquine and 63 days for mefloquine trials (WHO 2010).

Why it is important to do this review

This review aims to assist national decision-making by providing a concise summary of the benefits and harms of DHA-P in comparison to the other recommended ACTs. Other information that is also important when selecting national first or second-line ACTs includes:

  • the appropriateness of the partner drug within a locality, based on regional and national overviews of drug resistance and the intensity of malaria transmission;

  • the simplicity of the treatment regimen (co-formulated products are generally preferred as they reduce the availability and use of monotherapy, which may in turn reduce the development of resistance); and

  • the cost (since the ACT is likely to represent a large percentage of the annual health expenditure in highly endemic countries).

Objectives

To evaluate the effectiveness and safety of DHA-P compared to other ACTs for the treatment of uncomplicated P. falciparum malaria in adults and children.

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials (RCTs). We excluded quasi-RCTs.

Types of participants

Adults and children (including pregnant women and infants) with symptomatic, microscopically confirmed, uncomplicated P. falciparum malaria.

We also included trials that recruited participants with P. vivax co-infection.

Types of interventions

Intervention

A three-day course of DHA-P.

Control

A three-day course of an alternative WHO recommended ACT.

Types of outcome measures

Primary outcomes

Total failure at days 28, 42, and 63; PCR-adjusted and PCR-unadjusted.

Secondary outcomes
  • Gametocyte carriage at day 7 or 14 (preference for day 14 in data analyses);

  • Gametocyte development (negative at baseline and positive at follow-up);

  • Change in haemoglobin from baseline (minimum 28 day follow-up).

Adverse events
  • Deaths occurring during follow-up;

  • Serious adverse events (life threatening, causing admission to hospital, or discontinuation of treatment);

  • Haematological and biochemical adverse effects (for example, neutropenia, liver toxicity);

  • Early vomiting;

  • Other adverse events.

Search methods for identification of studies

Electronic searches

We searched the following databases up to 29 July 2013 using the search terms detailed in Table 1: Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL) published in The Cochrane Library; MEDLINE; EMBASE; LILACS. We also examined the metaRegister of Controlled Trials (mRCT) using the search terms 'malaria' and 'arte* OR dihydroarte*'.

Table 1. Detailed search strategy
  1. aCochrane Infectious Diseases Group Specialized Register.
    bSearch terms used in combination with the search strategy for retrieving trials developed by The Cochrane Collaboration (Lefebvre 2008); upper case: MeSH or EMTREE heading; lower case: free text term.

Search set CIDG SRa CENTRAL MEDLINEb EMBASEb LILACSb
1malariamalariamalariamalariamalaria
2arte*arte*arte*arte*arte*
3dihydroarte*dihydroarte*dihydroarte*dihydroarte*dihydroarte*
4amodiaq*amodiaq*amodiaq*amodiaq$amodiaq$
5lumefantrinelumefantrinelumefantrinelumefantrinelumefantrine
6Coartem*Coartem*Coartem*Coartem$Coartem$
7mefloquinemefloquinemefloquinemefloquinemefloquine
82 or 32 or 32 or 32 or 32 or 3
94 or 5 or 6 or 74 or 5 or 6 or 74 or 5 or 6 or 74 or 5 or 6 or 74 or 5 or 6 or 7
101 and 8 and 91 and 8 and 91 and 8 and 91 and 8 and 91 and 8 and 9
11 — —Limit 10 to humansLimit 10 to human —

Searching other resources

We contacted individual researchers working in the field, organizations including the WHO, and pharmaceutical companies involved in the manufacture of DHA-P (Atlantic, Guilin, Holleykin, HolleyPharm) for information on unpublished trials. In addition, reference lists of all trials identified by the methods described above were checked.

Data collection and analysis

Selection of studies

Babalwa Zani (BZ) and Michael Gathu (MG) independently reviewed the results of the literature search, obtained full-text copies of all potentially relevant trials and checked each trial report for evidence of multiple publications from the same data set.

BZ and MG also independently assessed each trial for inclusion using an eligibility form based on the inclusion criteria and resolved any disagreements through discussion or, where necessary, by consultation with David Sinclair (DS). We contacted trial authors when further information was necessary. We listed the ineligible trials and the reasons for their exclusion in the 'Characteristics of excluded studies' table.

Data extraction and management

BZ and MG independently extracted data on trial characteristics including methods, participants, interventions, outcomes, dose, and drug ratios of the combinations using a pre-tested data extraction form. We also recorded the number of participants randomized and analysed in each treatment group for each outcome and reported the loss to follow-up in each group.

For dichotomous outcomes, we recorded the number of participants experiencing the event and the total number of participants in each treatment group. For continuous outcomes, the arithmetic means and standard deviations for each treatment group together with the numbers of participants in each group were extracted. Where trials reported the data using geometric means, we recorded this information and extracted standard deviations on the log scale. Where trials gave median values, we extracted medians and ranges.

Primary outcome

Our primary analyses drew on the WHO's protocol for assessing and monitoring antimalarial drug efficacy (Bloland 2003). This protocol has been used to guide most efficacy trials since its publication in 2003, even though it was designed to assess the level of antimalarial resistance in the study area rather than for comparative trials. As a consequence, a high number of randomized participants are excluded from the final efficacy outcome as losses to follow-up or voluntary or involuntary withdrawals. For this reason we conducted a series of sensitivity analyses to restore the integrity of the randomization process and test the robustness of the results to this methodology (For a summary of the methodology and sensitivity analysis see Table 2).

Table 2. Primary outcome measure (Total failure)
  1. aNote: participants who were found to not satisfy the inclusion criteria after randomization are removed from all calculations.
    bPCR: polymerase chain reaction.
    c'Excluded' means removed from the calculation.
    dTo re-classify all indeterminate or missing PCR results as treatment failures in the PCR-adjusted analysis.
    eTo re-classify all PCR-confirmed new infections as treatment successes in the PCR-adjusted analysis. (This analysis may overestimate efficacy as PCR is not wholly reliable and some recrudescences may be falsely classified as new infections. Also some participants may have proceeded to develop a recrudescence after the new infection.)
    fTo re-classify all exclusions after enrolment (losses to follow-up, withdrawn consent, other antimalarial use, or failure to complete treatment) as treatment failures. For PCR-unadjusted total failure, this represents a true worse-case scenario.
    gTo re-classify all exclusions after enrolment (losses to follow-up, withdrawn consent, other antimalarial use, or failure to complete treatment) as treatment successes.

AnalysisParticipantsPCRb-unadjustedPCR-adjusted
NumeratorDenominatorNumeratorDenominator
Primary analysisExclusions after enrolmentaExcludedcExcludedExcludedExcluded
Missing or indeterminate PCRIncluded as failuresIncludedExcludedExcluded
New infectionsIncluded as failuresIncludedExcludedExcluded
Sensitivity analysis 1dAs 'Primary analysis' except: missing or indeterminate PCRIncluded as failuresIncluded
Sensitivity analysis 2eAs 'Sensitivity analysis 1' except: new infectionsIncluded as successesIncluded
Sensitivity analysis 3fAs 'Sensitivity analysis 2' except: exclusions after enrolmentIncluded as failuresIncludedIncluded as failuresIncluded
Sensitivity analysis 4gAs 'Sensitivity analysis 2' except: exclusions after enrolmentIncluded as successesIncludedIncluded as successesIncluded
PCR-unadjusted total failure

We calculated PCR-unadjusted total failure (P. falciparum) as the sum of early treatment failures and late treatment failures (without PCR adjustment). The denominator excluded participants for whom an outcome was not available (for example, those who were lost to follow-up, withdrew consent, took other antimalarials, or failed to complete treatment) and those participants who were found not to fulfil the inclusion criteria after randomization.

PCR-adjusted total failure

We defined PCR-adjusted total failure (P. falciparum) as the sum of early treatment failures, and late treatment failures due to PCR-confirmed recrudescence. Participants with indeterminate PCR results, missing PCR results, or PCR-confirmed new infections were treated as involuntary withdrawals and excluded from the calculation. The denominator excluded participants for whom an outcome was not available (for example, those who were lost to follow-up, withdrew consent, took other antimalarials, or failed to complete treatment) and those participants who did not fulfil the inclusion criteria after randomization.

These primary outcomes relate solely to failure due to P. falciparum. For both PCR-unadjusted and PCR-adjusted total failure, we retained participants who developed confirmed P. vivax infection during follow-up in the calculation if they were treated with chloroquine and continued in follow-up. They were classified as treatment successes if they did not subsequently develop P. falciparum parasitaemia. We excluded from the calculation those participants who developed P. vivax parasitaemia and were removed from the trial's follow-up.

Assessment of risk of bias in included studies

BZ and MG independently assessed the risk of bias for each trial using 'The Cochrane Collaboration's tool for assessing the risk of bias' (Higgins 2008) and resolved differences of opinion through discussion with DS. We followed the guidance to assess whether adequate steps were taken to reduce the risk of bias across six domains: sequence generation; allocation concealment; blinding (of participants, personnel, and outcome assessors); incomplete outcome data; selective outcome reporting; and other sources of bias.

For sequence generation and allocation concealment, we reported the methods used. For blinding, we described who was blinded and the blinding method. For incomplete outcome data, we reported the percentage and proportion of participants lost to follow-up. For selective outcome reporting, any discrepancies between the methods used and the results were stated in terms of the outcomes measured or the outcomes reported. For other biases, we described any other trial features that could have affected the trial result (for example, if the trial was stopped early).

We categorized our risk of bias judgements as 'low', 'high', or 'unclear'. Where risk of bias was unclear, we attempted to contact the trial authors for clarification and resolved any differences of opinion through discussion.

Measures of treatment effect

We analysed the data using Review Manager (RevMan) and presented and combined dichotomous data using risk ratios (RR). For continuous data summarized by arithmetic means and standard deviations, we combined data using mean differences. RRs and mean differences were accompanied by 95% confidence intervals (CI). We reported medians and ranges in tables.

Unit of analysis issues

We split trials including more than two comparison groups and analysed as individual pair-wise comparisons. When conducting meta-analysis, we ensured that participants and cases in the placebo group were counted only once, by dividing the placebo cases and participants evenly between the intervention groups.

Dealing with missing data

If data from the trial reports were insufficient, unclear, or missing, we attempted to contact the trial authors for additional information. If the missing data rendered the result uninterpretable, we excluded the data from the meta-analysis and clearly stated the reason for exclusion. We explored the potential effects of missing data through a series of sensitivity analyses (Table 2).

Assessment of heterogeneity

We assessed heterogeneity between trials by inspecting the forest plots, applying the Chi² test with a 10% level of statistical significance, and using the I² statistic with a value of 50% to denote moderate levels of heterogeneity.

Assessment of reporting biases

The possibility of publication bias was assessed by examining funnel plots for asymmetry. We noted that funnel plot asymmetry could also be caused by differences in methodological quality or heterogeneity.

Data synthesis

To aid interpretation, we gave the included trials identity codes including the first author, the year of publication, and the three-letter international country code or two-letter continent code (for trials conducted in more than one country). We listed trials in forest plots in chronological order of the year the trial was completed.

Using pair-wise comparisons we directly compared treatments. For outcomes that were measured at different time points, we stratified the analysis by the time point. The primary outcome analysis was also stratified by geographical region as a crude marker for differences in transmission and resistance patterns.

We performed meta-analysis within geographic regions where appropriate after assessment and investigation of heterogeneity. In the first instance, we used a fixed-effects model and applied a random-effects model when the Chi² test P value was less than 0.1 or the I² statistic greater than 50%.

Quality of evidence

We assessed the quality of evidence across each outcome measure using the GRADE approach. The quality rating across studies has four levels: high, moderate, low, or very low. RCTs are initially categorized as high quality but can be downgraded after assessment of five criteria: risk of bias, consistency, directness, imprecision, and publication bias. Similarly, observational studies are initially categorized as low quality and can be downgraded by the same criteria, but in exceptional circumstances may be upgraded by three further criteria; large effect size, all plausible confounders would act to reduce the effect size, and evidence of a dose-response effect (Guyatt 2008).

Subgroup analysis and investigation of heterogeneity

We investigated potential sources of heterogeneity through a series of analyses, sub-grouping the trials by: geographical region, intensity of malaria transmission (low to moderate versus high malaria transmission), known parasite resistance, allocation concealment, participant age, and drug dose (comparing regimens where there are significant variations in drug dose).

Sensitivity analysis

We conducted a series of sensitivity analyses to investigate the robustness of the methodology used in the primary analysis. The aim was to restore the integrity of the randomization process by adding excluded groups back into the analysis in a stepwise fashion (see Table 2 for details).

Results

Description of studies

See the Characteristics of included studies and Characteristics of excluded studies section.

Results of the search

We conducted the searches up to 29 July 2013 and identified 90 trials in total. After screening titles and abstracts, we obtained full text copies of 49 trials. Of these, 34 trials met the inclusion criteria and we excluded 15 trials (Figure 1). We included 27 trials as primary references and retained seven trials as secondary references for additional data on secondary outcomes and adverse events. One of the 26 trials had two different recruitment settings which we split and considered as two separate trials (Ashley 2004a THA; Ashley 2004b THA). One trial (Borrmann 2011 KEN (a)) is pending as we await data for a separate recruitment period from the trial authors.

Figure 1.

Study flow diagram.

Included studies

We included 27 trials, enrolling 16,382 participants and conducted between 2002 and 2010.

Twelve trials were conducted in Africa; Uganda (three trials), Kenya (three trials), Sudan (one trial), Rwanda (one trial), Burkina Faso (one trial), and three multi-centre trials with sites in Kenya, Uganda, Rwanda, Mozambique, Zambia, Gabon, Burkina Faso, Nigeria, Senegal, Côte d’Ivoire, and Cameroon (Bassat 2009 AF; The 4ABC Study 2011 AF; Yavo 2011 AF). Fourteen trials were conducted in Asia and Oceania; Thailand (five trials), Myanmar (two trials), Laos (one trial), Vietnam (one trial), Cambodia (one trial), Indonesia (two trials), Papua New Guinea (one trial); and one multi-centre trial had sites in Thailand, Laos, and India (Valecha 2010 AS). Only one trial was from South America (Peru).

The African trials focused on children, while Asian trials included older populations and excluded children below one year of age. All trials excluded pregnant and lactating women.

Eleven trials compared DHA-P with AS+MQ, 16 trials compared DHA-P with AL, four trials compared DHA-P with ASAQ, and one trial compared DHA-P with AS+SP. Some trials had more than two arms and compared multiple ACTs.

Three trials (Hasugian 2007 IDN; Ratcliff 2007 IDN; Karunajeewa 2008 PNG) conducted in Asia and Oceania included participants with P. vivax mono-infection at baseline. For our primary analysis we obtained data from the trial authors for only those participants who had P. falciparum or mixed infection (P. falciparum and P. vivax) at baseline. Arinaitwe 2009 UGA had an unusual trial design where participants were followed up for more than one episode of malaria. We used data from all malaria episodes in our primary analysis.

We listed the trial details of the included studies in the 'Characteristics of included studies' table.

Excluded studies

The reasons for exclusion are in the 'Characteristics of excluded studies' table.

Risk of bias in included studies

For a summary of the 'Risk of bias' assessments, see Figure 2.

Figure 2.

Risk of bias summary: review authors' judgements about each risk of bias item for each included trial.

Allocation

Nine trials were at low risk of selection bias, with adequate methods for both generation of the randomization sequence and allocation concealment. A further 18 studies were at unclear risk of selection bias due to inadequate descriptions of their methods. For primary outcomes we conducted a sensitivity analysis including only the trials with adequate allocation concealment.

Blinding

Eighteen trials blinded the microscopists to treatment allocation and so were at low risk of performance and detection bias for the primary outcomes. Only four of the included trials blinded the outcome assessors for adverse events.

Incomplete outcome data

We reported the proportion of participants in each treatment arm for whom an outcome was not available and conducted sensitivity analyses to test the possible effect of these losses. Four trials were at high risk of bias due to high dropout rates (> 15%).

Selective reporting

Due to the varying half-lives of drugs, the choice of which day to measure outcomes can influence the comparative effects of the ACTs. If an ACT with a long half-life (DHA-P or AS+MQ) is compared to a drug with a short half-life (AS+AQ or AS+SP), day 28 outcomes may underestimate PCR-adjusted failure with the long half-life drug. At later time points (day 42 and 63), drugs with long half-lives are likely to appear superior in preventing new infections (PCR-unadjusted failure) which represents a prophylactic effect. We noted this while interpreting the data but did not consider this a source of trial bias.

Other potential sources of bias

Pharmaceutical companies provided financial support or study drugs in 13 trials. In the two large trials of the new Eurartesim® formulation (Bassat 2009 AF & Valecha 2010 AS), the pharmaceutical company was fully involved in the design, conduct and analysis of the trials, In one of these (Bassat 2009 AF), it is stated that an independent author had access to the primary dataset and took responsibility for the analyses. We judged this trial to be at unclear risk of bias. In the second trial, this additional safety measure was not described and we judged the trial to be at high risk of bias.

Effects of interventions

See: Summary of findings for the main comparison Dihydroartemisinin-piperaquine versus Artemether-lumefantrine for uncomplicated P. falciparum malaria in Africa

Comparison 1. DHA-P versus artesunate plus mefloquine

We found 11 trials, 10 in Asia and one in South America, that assessed this comparison; conducted between 2002 and 2009.

Allocation concealment was at 'low risk of bias' in only two trials (Mayxay 2006 LAO; Grande 2007 PER). Five trials blinded laboratory staff (outcome assessors) to treatment allocation (Ashley 2004a THA; Ashley 2004b THA; Ashley 2005 THA; Smithuis 2010 MMR; Valecha 2010 AS). Patients were unblinded in all trials, and only one trial blinded outcome assessors for adverse effects (The 4ABC Study 2011 AF).

Total failure

In Asia over 63 days follow-up, recurrent parasitaemias (including both recrudescences and new infections) occurred in less than 15% of all participants, with no differences in PCR-unadjusted treatment failure between groups (day 28: eight trials, 3487 participants, Analysis 1.1; day 42: seven trials, 3421 participants, Analysis 1.3; Day 63: five trials, 2715 participants, Analysis 1.5).

Once adjusted by PCR to exclude new infections, treatment failure at day 28 was below 5% for both ACTs in all eight trials for which data was available (eight trials, 3482 participants, Analysis 1.2). Two of the eight trials, conducted in Thailand at trial sites with multi-drug resistant P. falciparum, found slightly higher levels of recrudescence following AS+MQ and statistically significant benefits with DHA-P (Ashley 2005 THA; Valecha 2010 AS). Recrudescences remained low in both groups over 63 days of follow-up (day 42: six trials, 2901 participants, Analysis 1.4; day 63: five trials, 2500 participants, Analysis 1.6).

In the one trial from South America, only day 63 data was available (Analysis 1.5; Analysis 1.6). Recrudescences and new infections were very rare with both treatments, but new infections were lower with AS+MQ (RR 6.19, 95% CI 1.40 to 27.35, one trial, 445 participants, Analysis 1.5).

Gametocytes

AS+MQ appears to clear gametocytes from the peripheral blood quicker than DHA-P (Gametocyte carriage on Day 7: RR 1.99, 95% CI 1.57 to 2.51, three trials, 2270 participants, Analysis 1.7; Day 14: RR 5.11, 95% CI 3.26 to 7.99, three trials, 2249 participants, Analysis 1.7). In addition, the number of participants who developed detectable gametocytes (after being negative at baseline) was low in both groups, but lowest with AS+MQ (RR 3.06, 95% CI 1.13 to 8.33, three trials, 1234 participants, Analysis 1.8). Five trials reported additional data on gametocyte carriage which could not be pooled and are presented in Table 3.

Table 3. DHA-P versus AS+MQ: Additional secondary outcomes data
  1. Hb - Haemoglobin
    HCT - Haematocrit

OutcomeStudy IDMeasureDHA-PAS+MQP valueComment
Gametocyte carriage Grande 2007 PERPerson gametocytemia weeks per 1000 person weeks32.524.90.31 
Mayxay 2006 LAOProportion with gametocytes at any timepoint after treatment (on or after day 7)9/1103/1100.07 
Person gametocytemia weeks per 1000 person weeks--> 0.05Mean across all groups was 0.10 (95% CI 0.03 to 0.20). No difference between groups (published data).
Smithuis 2006 MMRGametocyte incidence at day 718/1885/2180.01 
Gametocyte incidence at day 143/1681/2120.12 
Person gametocytemia weeks per 1000 person weeks--0.03Gametocyte carriage in DHA-P group was higher than in AS+MQ group (published data). Figures not given.
Smithuis 2010 MMRPerson gametocytemia weeks per 1000 person weeks112.829.5Not statedData presented are for fixed-dose AS+MQ combination.
Valecha 2010 ASPerson gametocytemia weeks per 1000 person weeks

20.2

(130/6420)

7.4

(23/3108)

0.01Published data in paper presented as "person gametocytemia weeks per 100 person weeks".
Anaemia Ashley 2004b THAMedian decrease in HCT by day 76.3%9.4%0.21"Mean decrease in HCT up to day 7 then recovery in all groups".
Ashley 2005 THAAbsolute changes in HCT---"Mean decrease in HCT up to day 7 then recovery in all groups".
Janssens 2007 KHMMean HCT at day 6340.0 % (3.7)40.2% (3.8)Not stated"Patients in both treatment groups showed similar haematological
recovery during the 63-day follow-up period".
Mayxay 2006 LAOMean HCT days 7 to 42Not statedNot stated> 0.05"the mean hematocrit after treatment did not significantly differ between groups".
Smithuis 2006 MMRMean haemoglobin at day 2810.4 g/dL10.5 g/dL0.65Data presented are for supervised treatment groups.
Proportion anaemic (Hb < 10 g/dL) on day 2856/15259/1560.85Data presented are for supervised treatment groups.
Smithuis 2010 MMRMean increase in haemoglobinNot statedNot stated> 0.05"The mean increase of haemoglobin was similar among the treatment groups".
Valecha 2010 ASMean increase in Hb from day 0 to day 63 in g/dL1.28 ± 2.221.42 ± 2.120.30 
Anaemia

Seven trials reported a variety of measures of haematological changes between baseline and the last day of follow-up which we could not pool. None of the individual trials reported differences between groups (see Table 3).

Adverse events

There was no difference in the frequency of serious adverse events (eight trials, 3522 participants, Analysis 1.9; see Appendix 2 for details of serious adverse events).

Nine trials reported some measure of early vomiting (vomiting related to drug administration) and there was no difference shown in any trial (nine trials, 4114 participants, Analysis 1.10). However, subsequent nausea and vomiting were consistently more common with AS+MQ (Nausea: RR 0.68, 95% CI 0.60 to 0.78, nine trials, 4531 participants; vomiting: RR 0.59, 95% CI 0.47 to 0.75, five trials, 2744 participants, Analysis 1.10). Diarrhoea was more common with DHA-P (RR 1.46, 95% CI 1.05 to 2.04, five trials, 2217 participants, Analysis 1.10).

AS+MQ was consistently associated with increased dizziness (RR 0.72, 95% CI 0.66 to 0.78, nine trials, 4531 participants), and sleeplessness (RR 0.49, 95% CI 0.40 to 0.60, six trials, 2551 participants, Analysis 1.11), and increases in headache (four trials), fatigue (two trials), nightmares (one trial), and anxiety (one trial) are reported in the few trials that recorded them (Analysis 1.11).

Palpitations were also more common with AS+MQ (RR 0.61, 95% CI 0.45 to 0.82, three trials, 1175 participants, Analysis 1.12), but only one trial performed routine ECGs in both treatment groups (Valecha 2010 AS). In this trial there was a baseline imbalance in the prevalence of borderline prolonged QTc (431 to 450 ms in children and adult men/451 to 470 ms in adult women), using Bazett's correction method (16.6% DHA-P versus 12.2% AS+MQ, P = 0.066; authors' own figures), but not Fridericia's method (2.9% DHA-P versus 1.6% AS+MQ, P > 0.05; authors' own figures).

On day 2, a higher proportion of participants treated with DHA-P had borderline prolonged QTc by both correction methods (Bazett's: 21.4% DHA-P versus 16.3% AS+MQ, P = 0.043; Fridericia's: 13.0% DHA-P versus 5.3% AS+MQ, P < 0.001; authors' own figures). There was also a statistically significant increase in the prevalence of prolonged QTc with DHA-P (> 450 ms in children and adult men, and > 470 ms in adult women), using Bazett's method but not Fridericia's method (one trial, 1148 participants, Analysis 1.12). No consequent arrhythmias were noted, and these differences were no longer present at day seven (for additional data see Table 4).

Table 4. DHA-P versus AS+MQ/AL6: QTc measurements
  1. 1 In this analysis the direction of effect is reversed. These figures have been confirmed as correct by the study authors.
    2 Figures not presented in paper: Taken from Analysis 4.13.
    N/R - Not reported
    QTcB - QT interval corrected for rate and gender using Bazett's method.
    QTcF - Qt interval corrected for rate and gender using Fridericia's method.

Study IDNo. of participantsDayOutcomeCorrection
method
DHA-P
(%)
AS+MQ
(%)
P value
Valecha 2010 AS1150At baselineBorderline QTc (431 to 450ms)QTcB16.612.10.066
QTcF2.91.6>0.05
Day 2Borderline QTc (431 to 450ms)QTcB21.416.30.043
QTcF13.05.3<0.001
Prolonged QTc (> 450ms)QTcB8.64.20.007
QTcF4.75.3< 0.0011
QTc increase > 60 msQTcB0.90.8> 0.05
QTcF4.62.9< 0.001
Day 7No differences between groups N/RN/R> 0.05
 DHA-P
(%)
AL6
(%)
P value
Bassat 2009 AF1553At baselineBorderline QTc (431-450ms) N/RN/R 
Day 2Borderline QTc (431-450ms)QTcB29.119.8< 0.001
QTcF1.01.20.76
Prolonged QTc (> 450ms)QTcB9.16.90.152
QTcF0.20.20.992
QTc > 500 msQTcB0.190.39> 0.05
QTcFN/RN/R 
QTc increase > 60 msQTcB2.72.0> 0.05
QTcFN/RN/R 
Day 7No differences between groups N/RN/R> 0.05

Four trials conducted biochemical monitoring for either renal or hepatic adverse events. Monitoring was adequate in three trials (Ashley 2004a THA; Tran 2004 VNM; Grande 2007 PER), and inadequate in one (Valecha 2010 AS), but incompletely reported in all four trials. No clinically important toxicities were reported (see Table 5).

Table 5. DHA-P versus AS+MQ: Biochemical monitoring and adverse events
  1. 1 Judged as adequate given that no clinically important abnormalities were seen at day 7. Longer follow-up is therefore probably unnecessary.
    2 Judged as incomplete as data were not presented. Only a text summary was given.
    3 Judged as inadequate as biochemical abnormalities are likely to occur earlier than day 28.

    LFT = Liver Function Tests

    U&E = Urea and electrolytes

Study IDNo. of participantsTestsDays testedDays reported  Days tested adequate to detect adverse events?For adequate testing, was reporting complete? Results as presented in the paper
Ashley 2004a THA134U&E, LFTsDays 0 and 7NoneAdequate1Incomplete 2"No biochemical evidence of toxicity was observed".
Grande 2007 PER522U&E, LFTsDays 0 and 7NoneAdequate1Incomplete2"No patient had abnormal liver and renal function test results of clinical significance, both at entry and at day 7".
Tran 2004 VNM243LFTsDays 3,7,28NoneAdequate1Incomplete2"There were no significant differences between the three groups in the results of liver function tests done on all patients on days 3, 7, and 28".
Valecha 2010 AS1150Not clearly statedDays 0, 28, 63NoneInadequate3Incomplete2"Other than elevated liver parameters, as might be expected in this population, there were no relevant changes in biochemistry parameters".'
Sensitivity analysis

As described in the methods section, we undertook a series of sensitivity analyses to test the robustness of our results to different analysis plans. An example of these is given in Analysis 1.14 & Analysis 1.15. In general, the method of analysis did not change the significance of results and so the remaining sensitivity analyses were deleted.

Comparisons 2 and 3: DHA-P dosing concerns

Two dosing regimens were commonly used in clinical trials of DHA-P versus AS+MQ, which give the same total dose, but divided into three or four doses, given over three days (see Table 6). One trial (Ashley 2005 THA) directly compared the three-dose regimen with the four-dose regimen and found no difference at any time point (one trial, 318 participants, Analysis 2.1; Analysis 2.2).

Table 6. DHA-P versus AS+MQ dosing regimens
Study IDYear of studyAge limitsDHA-PAS+MQ
Ashley 2004a THA2003> 14 yrs6 mg/kg DHA + 48 mg/kg P in 4 divided doses at 0, 8, 24, and 48 hrs4 mg/kg AS once daily for 3 days + 8 mg/kg MQ once daily for 3 days.
Ashley 2004b THA20031 to 65 yrs6 mg/kg DHA + 48 mg/kg P in 4 divided doses at 0, 8, 24, and 48 hrs4 mg/kg AS once daily for 3 days + 8 mg/kg MQ once daily for 3 days.
Ashley 2005 THA20051 to 65 yrs6.4 mg/kg DHA and 51.2 mg/kg P in 4 divided doses at 0, 8, 24, and 48 hrs or 3 divided doses at 0, 24, and 48 hrs4 mg/kg AS once daily for 3 days + 8 mg/kg MQ once daily for 3 days.
Grande 2007 PER20055 to 60 yrsTotal dose: 6.3 mg/kg DHA and 50.4 mg/kg PQP in 3 divided doses, given once daily for 3 days4 mg/kg AS once daily for 3 days + 8 mg/kg MQ once daily for 3 days.
Janssens 2007 KHM2003> 1 yr

Adult total dose: 6 mg/kg DHA and + 48 mg/kg P in 4 divided doses at 0, 8, 24, and 48 hrs

Children total dose: 6.4 mg/kg DHA + 51.2 mg/kg P in 4 divided doses at 0, 8, 24, and 48 hrs

Adults: 100 mg AS plus 500 mg MQ twice daily on day 0, 200 mg AS once daily on days 1 and 2.

Children: 4 mg/kg AS once daily for 3 days + 25 mg/kg MQ in 2 equal doses on day 0.

Mayxay 2006 LAO2004> 1 yr6.3 mg/kg DHA + 50.4 mg/kg P in 3 divided doses, once daily for 3 days4 mg/kg AS once daily for 3 days + 15 mg MQ base/kg on day 1 and 10 mg base/kg on day 2.
Smithuis 2006 MMR2004> 1 yr6.3 mg/kg DHA + 50.4 mg/kg P in 3 divided doses, once daily for 3 days

4 mg/kg AS once daily for 3 days.

25 mg MQ base/kg as a single dose on day 0.

Smithuis 2010 MMR2009> 1 yr2.5 mg/kg DHA + 20 mg/kg P daily, given once daily for 3 days

Fixed combination: 4 mg/kg AS + 8.8 mg/kg MQ daily, once daily for 3 days.

Loose combination: 4 mg/kg AS once daily for 3 days + 25 mg base/kg MQ as a single dose on day 0.

Tangpukdee 2005 THANot stated> 14 yrs6 mg/kg DHA + 45 mg/kg P in 3 divided doses, given once daily for 3 days4 mg/kg AS once daily for 3 days + 8 mg/kg MQ once daily for 3 days.
Tran 2004 VNM2002> 2 yrs

40 mg/320 mg tablets
Adults: 2 tablets at 0, 6, 24, and 48 hrs

Children < 15 yrs: 1 tablet at 0, 6, 24, and 48 hrs

4 mg/kg AS once daily for 3 days + 25 mg base/kg MQ as 2 divided doses 6 hrs apart on day 3.
Valecha 2010 AS20073m to 65 yrs (≥18 yrs in India)DHA: 2.25 mg/kg DHA + 18 mg/kg P daily dose for 3 days4mg/kg AS once daily for 3 days + MQ none on day 0, then 15 mg/kg once on day 1 and 10 mg/kg once on day 2

In comparisons comparing DHA-P to AS+MQ, six trials used the three-dose regimen, four trials used the four-dose regimen, and one trial used both. Stratifying the analysis by dosing regimen did not reveal any important differences in efficacy between the two regimens (Analysis 3.1 to Analysis 3.6).

Comparison 4. DHA-P versus artemether-lumefantrine (six doses)

We found fifteen trials which assessed this comparison; eleven in Africa, three in Asia and one in Oceania; conducted between 2005 and 2011. Eleven of the fifteen trials included children only.

Allocation concealment was at low risk of bias in eight trials (Kamya 2007 UGA; Ratcliff 2007 IDN; Zongo 2007 BFA; Yeka 2008 UGA; Arinaitwe 2009 UGA; Bassat 2009 AF; The 4ABC Study 2011 AF; Yavo 2011 AF). Ten out of 14 trials blinded laboratory staff to treatment allocation.

Total failure

In Africa, PCR-unadjusted treatment failure at day 28 was consistently lower with DHA-P (RR 0.34, 95% CI 0.30 to 0.39, nine trials, 6200 participants, Analysis 4.1). After PCR adjustment to exclude new infections, treatment failure at Day 28 was below 5% with both ACTs in all nine trials, but was consistently lowest with DHA-P (RR 0.42, 95% CI 0.29 to 0.62, nine trials, 5417 participants, Analysis 4.2). Six trials continued follow-up until day 42, and two until day 63. DHA-P appears to have a longer post-treatment prophylactic effect than AL6 in keeping with its longer elimination half-life (Day 42 PCR-unadjusted treatment failure: RR 0.60, 95% CI 0.53 to 0.67, seven trials, 3301 participants, Analysis 4.3; Day 63 PCR-unadjusted treatment failure: RR 0.71, 95% CI 0.65 to 0.78, two trials, 3200 participants, Analysis 4.5).

In Asia and Oceania, PCR-unadjusted treatment failure at day 28 was similar between treatments (four trials, 1143 participants, Analysis 4.1), and with no statistically significant differences after PCR adjustment (three trials, 925 participants, Analysis 4.2). Of note, PCR-adjusted treatment failure at day 28 was above 10% in those treated with DHA-P in the one trial from Papua New Guinea (Karunajeewa 2008 PNG), but this has not been seen elsewhere. No differences were seen in PCR-unadjusted or PCR-adjusted treatment failure at day 42 (two trials, 572 participants, Analysis 4.3; Analysis 4.4), or day 63 (one trial, 323 participants, Analysis 4.5; Analysis 4.6).

Gametocytes

SIx trials, all from Africa, reported the development of gametocytes in those negative at baseline. The results were highly heterogenous and we could not pool them (six trials, 1968 participants) heterogeneity: Chi² test, P = 0.001, I² = 78%, Analysis 4.7). Carriage of gametocytes during the first two weeks was higher with DHA-P (RR 4.32, 95% 1.48 to 12.63, four trials, 1537 participants, Analysis 4.8), but lower with DHA-P during weeks three to six; a finding which may reflect the lower treatment failure rates with DHA-P at later time points (Analysis 4.8). Bassat 2009 AF reports that person-gametocyte weeks was higher in those treated with DHA-P (see Table 7).

Table 7. DHA-P versus AL6: Additional secondary outcomes data
  1. Hb - Haemoglobin

OutcomeTrial IDMeasureDHA-PAL6P valueComment
Gametocyte carriage Bassat 2009 AFPerson gametocytemia weeks per 1000 person weeks43.9721.430.005 
Smithuis 2010 MMRPerson gametocytemia weeks per 1000 person weeks112.858.2Not stated 
Ratcliff 2007 IDNPerson gametocytemia weeks per 1000 person weeks--Not significantFigures not given.
Karunajeewa 2008 PNGPost-treatment gametocytemia--No differenceFigures not given.
Anaemia Yeka 2008 UGAMean increase in Hb (g/dL)1.75 ± 1.81.66 ± 2.00.63 
Mens 2008 KENFinal mean Hb level (mmol/L)7.15 ± 1.076.79 ± 1.24Not significant 
Arinaitwe 2009 UGAMean Hb recovery (g/dL)0.62 ± 1.680.56 ± 1.580.41 
Agarwal 2013 KENMean Hb increase from baseline in patients not re-infected11.6 g/dL9.8 g/dLNot statedP value for difference in mean Hb increase in re-infected patients and those not re-infected is given as 0.9.
Mean Hb increase from baseline in re-infected patients11.1 g/dL9.9 g/dLNot stated

In Asia, Karunajeewa 2008 PNG and Ratcliff 2007 IDN report no differences in gametocyte carriage between groups but did not give figures, while Smithuis 2010 MMR reports higher gametocyte carriage with DHA-P (see Table 7).

Anaemia

Six trials reported changes in haemoglobin from baseline to the last day of follow-up (day 28 or 42). There is a trend towards a small benefit with DHA-P which may not be of clinical significance (six trials, 3529 participants, Analysis 4.9).

Adverse events

No difference has been shown in the frequency of serious adverse events, although the trend is towards a small increase in serious adverse events with DHA-P (nine trials, 7246 participants, Analysis 4.10, see Appendix 2 for details of serious adverse events).

DHA-P is associated with a higher frequency of early vomiting (drug-related vomiting), which just reached statistical significance (RR 1.69, 95% CI 1.00 to 2.83, four trials, 2969 participants, Analysis 4.11), but there was no difference in vomiting overall (nine trials, 6761 participants, Analysis 4.11).

Compared to AL6, DHA-P was also associated with a slightly higher frequency of pruritis (RR 1.74, 95% CI 1.03 to 2.92, five trials, 2033 participants, Analysis 4.14), but there were no differences in any other clinical side effects (Analysis 4.11 to Analysis 4.14).

Only one trial conducted ECG monitoring on participants in both treatment groups (Bassat 2009 AF). On day 2, a higher proportion of participants treated with DHA-P had borderline raised QTc intervals (431 to 450 ms) when corrected by Bazett's method (29.1% DHA-P versus 19.8% AL6, P < 0.001; authors' own figures), but not Fridericia's method (1.0% DHA-P versus 1.2% AL6, P = 0.76; authors' own figures). There were no differences in the proportion of patients with prolonged QTc interval (> 450 ms), using either Bazett's or Fridericia's method (one trial, 1548 participants, Analysis 4.13) or reported at day 7 (see Table 4 for additional data).

Three trials conducted biochemical monitoring for either renal or hepatic adverse events (Bassat 2009 AF; The 4ABC Study 2011 AF; Yavo 2011 AF). Monitoring was adequate in all three trials but incompletely reported in one trial. No clinically important toxicities were reported (see Table 8).

Table 8. DHA-P versus AL6: Biochemical monitoring and adverse events
  1. 1 Adequate given that no clinically important abnormalities were seen.
    2 Incomplete as trial authors did not present data and only gave a text summary.
    3 Complete as trial authors presented data for the two days tested.

Trial IDNo. of participantsTestsDays testedDays reported  Days tested adequate to detect adverse events?For adequate testing, was reporting complete? Results as presented in the paper
Bassat 2009 AF1553LFTs and renal functionDays 3, 28, and 42NoneAdequate1Incomplete 2"...altered liver enzymes (ALT)... was similar between the two treatment groups".
The 4ABC Study 2011 AF2701LFT and renal functionDays 7 and 28Days 7 and 28Adequate1Complete3"The median levels of alanine aminotransferase and creatinine before treatment, as well as the proportion of patients with values above the normal range (both clinically and non-clinically significant, the latter not shown), were similar between the four study arms, and this did not change during the follow-ups at day 7 and 28".
Yavo 2011 AF384LFTsDays 0 and 4Baseline and day 4Adequate1Complete3"In DP group from the beginning of the treatment to day 4, there was a decrease of the mean of AST and a small increase of ALT mean, while in the AL group, AST and ALT means increased. However, these variations were not significantly different. The decrease of the mean of creatinin from the beginning of the treatment to day 4 was not significant in the DP group but was significant in the AL group. In the two groups, the bilirubin decrease was significant".

Comparison 5. DHA-P versus artesunate plus amodiaquine

We found four trials which assessed this comparison; two in Africa and two in Asia; conducted between 2004 and 2009.

Allocation concealment was assessed as low risk of bias in two trials (Hasugian 2007 IDN; The 4ABC Study 2011 AF) and unclear in the other two. In all four trials laboratory staff were blinded to treatment allocation.

Total failure

In Africa, PCR-unadjusted treatment failure at day 28 was lower following treatment with DHA-P in both trials (RR 0.49, 95% CI 0.41 to 0.59, two trials, 2800 participants, Analysis 5.1). After PCR-adjustment to exclude new infections, the difference between treatments was no longer statistically significant, but treatment failure was below 5% following treatment with DHA-P in both trials, and above 5% following AS+AQ in Rwanda (two trials, 2486 participants, Analysis 5.2). One trial followed participants up to day 63 (The 4ABC Study 2011 AF), and found no differences in PCR-unadjusted or PCR-adjusted treatment failure at this time point (one trial, 2292 participants, Analysis 5.5; Analysis 5.6).

In Asia, PCR-unadjusted treatment failure at day 28 was lower following treatment with DHA-P (RR 0.38 95% CI 0.18 to 0.77, two trials, 482 participants, Analysis 5.1), and remained lower after PCR-adjustment although the number of events was very low (RR 0.08, 95% CI 0.01 to 0.40, two trials, 466 participants, Analysis 5.2). One trial followed participants up to day 42 (Hasugian 2007 IDN), and one to day 63 (Smithuis 2010 MMR), when the differences remained statistically significant in favour of DHA-P (Analysis 5.3 to Analysis 5.6).

Gametocytes

Two trials reported no statistically significant differences in gametocyte carriage during follow-up but did not report the data (see Table 9).

Table 9. DHA-P versus AS+AQ: Additional secondary outcomes data
  1. Hb - Haemoglobin
    PCV - Packed cell volume
    Neutropenia - neutrophil count < 1000/µL

OutcomeTrial IDMeasureDHA-PAS+AQP valueComment
Gametocyte carriage Karema 2006 RWAGametocyte prevalence--Not significantFigures not given.
Hasugian 2007 IDNPost-treatment gametocyte carriage--No differenceFigures not given.
Anaemia Karema 2006 RWAMean PCV at baseline31.5 ± 4.931.0 ± 5.5No difference 
Mean PCV at day 1433.4 ± 3.634.0 ± 3.70.08 
Hasugian 2007 IDNProportion of patients with anaemia at day 7--0.02"Although there was no significant difference in haemoglobin levels between treatment groups at the time of admission, the rates of anemia at days 7 and 28 were significantly higher in AS+AQ recipients".
Proportion of patients with anaemia at day 28--0.006
Smithuis 2010 MMRMean increase in haemoglobinNot statedNot stated> 0.05"The mean increase of haemoglobin was similar among the treatment groups".
Anaemia

Two trials reported no difference between PCV and haemoglobin levels respectively between the treatment groups (Karema 2006 RWA; Smithuis 2010 MMR; see Table 9). Hasugian 2007 IDN found that the prevalence of anaemia at day 7 (P = 0.02) and 28 (P = 0.006) was higher with AS+AQ (authors' own figures); this may be attributed to the recurrence of parasitaemia with both P. falciparum and P. vivax being higher in the AS+AQ group.

Adverse events

The frequency of serious adverse events was lower with DHA-P, and despite few events, this reached statistical significance (RR 0.40 95% CI 0.19 to 0.87, two trials, 2805 participants, Analysis 5.7, see Appendix 2 for details of serious adverse events). The 4ABC Study 2011 AF reported 15 serious adverse events in 1003 participants treated with AS+AQ versus 10/1468 with DHA-P. The exact nature of these serious adverse events was unclear, but the authors reported no differences in serious adverse events classified as possibly, probably, or definitely related to the trial drug (4/1003 versus 4/1468).

Hasugian 2007 IDN and Smithuis 2010 MMR found no difference in the number of participants with early vomiting (two trials, 650 participants, Analysis 5.8).

Pyrexia was the only adverse event that was statistically more common with DHA-P (RR 1.18 95% CI 1.02 to 1.37, one trial, 2471 participants, Analysis 5.9).

Two trials conducted biochemical monitoring for renal or hepatic adverse events (Karema 2006 RWA; Smithuis 2010 MMR). Monitoring was adequate in both trials but incompletely reported in one trial. No clinically important toxicities were reported (see Table 10).

Table 10. DHA-P versus AS+AQ: Biochemical monitoring and adverse events
  1. 1 Adequate given that no clinically important abnormalities were seen.
    2 Incomplete as trial authors did not present data and only gave a text summary.
    3 Complete as trial authors presented data for the two days tested.

Study IDNo. of participntsTestsDays testedDays reported  Days tested adequate?  For adequate testing, was reporting complete? Results as presented in the paper
Karema 2006 RWA762LFTs at one site onlyDays 0 and 14NoneAdequate1Incomplete 2"No hepatotoxicity was observed, although analyses were performed at one site only (data not shown)".
The 4ABC Study 2011 AF2701LFT and renal functionDays 7 and 28Days 7 and 28Adequate1Complete3"The median levels of alanine aminotransferase and creatinine before treatment, as well as the proportion of patients with values above the normal range (both clinically and non-clinically significant, the latter not shown), were similar between the four study arms, and this did not change during the follow-ups at day 7 and 28".

Comparison 6. DHA-P versus artesunate plus sulfadoxine-pyrimethamine

One trial conducted in Oceania in 2007 assessed this comparison (Karunajeewa 2008 PNG). The trial authors did not describe any attempt to conceal allocation. Laboratory staff were blinded to treatment allocation.

Total failure

At day 28 PCR-adjusted treatment failure was > 10% in both groups (Analysis 6.2).

There were no statistically significant differences in treatment failure between the two arms (one trial, 223 participants, Analysis 6.1 to Analysis 6.4)

Gametocytes

No significant differences in gametocyte carriage during follow-up were reported (figures not reported).

Anaemia

Trial authors reported haemoglobin levels remained similar in both groups throughout follow-up (figures not reported).

Adverse events

Monitoring for adverse events was undertaken but no differences between the groups were reported.

Discussion

For summaries of the main results for efficacy see; Summary of findings for the main comparison; Table 11; Table 12; Table 13; Table 14; Table 15), and for adverse effects see Appendix 3.

Table 11. Dihydroartemisinin-piperaquine compared to Artemether-lumefantrine for uncomplicated P. falciparum malaria in Asia and Oceania
  1. 1 No serious risk of bias: Trials are generally at low or unclear risk of bias. Exclusion of trials as high risk of selection bias or detection bias did not change the result.
    2 No serious inconsistency: Statistical heterogeneity was low.
    3 No serious indirectness: The trials were conducted in adults and children in Indonesia, Thailand, Papua New Guinea, and Myanmar.
    4 Downgraded by 1 for serious imprecision: The 95% CI is wide and includes appreciable differences between drugs.
    5 No serious risk of bias: This single trial is generally at low risk of bias.
    6 Downgraded by 1 for serious indirectness: This single trial is from Myanmar. The results may not be easily generalized to elsewhere.
    7 Two trials from Indonesia and Papua New Guinea reported outcomes at Day 42. At this timepoint there was no difference in PCR unadjusted or PCR adjusted treatment failure (two trials, 572 participants, low quality evidence).

Dihydroartemisinin-piperaquine compared to Artemether-lumefantrine for uncomplicated P. falciparum malaria in Asia
Patient or population: Patients with uncomplicated P. falciparum malaria
Settings: Asia and Oceania
Intervention: Dihydroartemisinin-piperaquine (DHA-P)
Comparison: Artemether-lumefantrine (AL6)
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(trials)
Quality of the evidence
(GRADE)
Assumed riskCorresponding risk
AL6 DHA-P

Treatment failure

Day 28

PCR-unadjusted RR 0.97
(0.64 to 1.47)
1143
(4 trials)
⊕⊕⊕⊝
moderate 1,2,3,4
7 per 100 7 per 100
(4 to 10)
PCR-adjusted RR 2.01
(0.81 to 5.03)
925
(3 trials)
⊕⊕⊕⊝
moderate 1,2,3,4
1 per 100 3 per 100
(1 to 7)

Treatment failure

Day 63

PCR-unadjusted RR 0.94
(0.47 to 1.88)
323
(1 trial)
⊕⊕⊝⊝
low 4,5,6,7
9 per 100 8 per 100
(4 to 17)
PCR-adjusted RR 1.00
(0.14 to 7.01)
298
(1 trial)
⊕⊕⊝⊝
low 4,5,6,7
1 per 100 1 per 100
(0 to 7)
*The basis for the assumed risk (for example, the median control group risk across trials) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
Table 12. Dihydroartemisinin-piperaquine compared to Artesunate plus mefloquine for treating uncomplicated P. falciparum malaria in Asia
  1. 1 No serious risk of bias: Trials are generally at low risk of selection bias and detection bias. Exclusion of trials as high or unclear risk of bias did not change the result.
    2 No serious inconsistency: Six trials found very few recurrent parasitaemia in both groups. Two trials primarily conducted in Thailand in areas with multi-drug resistance found an increased risk of recurrent parasitaemia with AS+MQ.
    3 No serious indirectness: The trials were conducted in adults and children in Vietnam, Thailand, Cambodia, Myanmar, India, and Laos.
    4 No serious imprecision: The overall result is of no significant difference between treatments. However, where there is P. falciparum resistance to mefloquine, DHA-P may be superior.
    5 No serious imprecision: The overall result is of a statistically significant benefit with DHA-P although this benefit may only be present where there is resistance to mefloquine.
    6 Downgraded by one for serious inconsistency: Of the five trials, one from Thailand in 2005 found a statistically significant benefit with DHA-P, one from Myanmar in 2009 found a benefit with DHA-P, and three found no difference.
    7 No serious indirectness: The trials were conducted in adults and children in Thailand, Cambodia, Myanmar, India, and Laos.
    8 No serious imprecision: The overall result is of no significant difference between treatments. Although some trials found statistically significant differences, these may not be clinically important.
    9 No serious inconsistency: There is a small amount of variability between trials, with only one trial showing a statistically significant benefit with DHA-P.

Dihydroartemisinin-piperaquine compared to Artesunate plus mefloquine for treating uncomplicated P. falciparum malaria in Asia
Patient or population: Patients with treating uncomplicated P. falciparum malaria
Settings: Endemic settings in Asia
Intervention: Dihydroartemisinin-piperaquine (DHA-P)
Comparison: Artesunate plus mefloquine (AS+MQ)
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(trials)
Quality of the evidence
(GRADE)
Assumed riskCorresponding risk
AS+MQ DHA-P

Treatment failure

Day 28

PCR-unadjusted RR 1.02
(0.28 to 3.72)
3487
(8 trials)
⊕⊕⊕⊕
high 1,2,3,4
2 per 100 2 per 100
(1 to 8)
PCR-adjusted RR 0.41
(0.21 to 0.8)
3467
(8 trials)
⊕⊕⊕⊕
high 1,2,3,5
1 per 100 0 per 100
(0 to 1)

Treatment failure

Day 63

PCR-unadjusted RR 0.84
(0.69 to 1.03)
2715
(5 trials)
⊕⊕⊕⊝
moderate 1,6,7,8
12 per 100 10 per 100
(8 to 13)
PCR-adjusted RR 0.5
(0.3 to 0.84)
2500
(5 trials)
⊕⊕⊕⊕
high 1,7,8,9
3 per 100 2 per 100
(1 to 3)
*The basis for the assumed risk (for example, the median control group risk across trials) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
Table 13. Dihydroartemisinin-piperaquine compared to Artesunate plus mefloquine for uncomplicated P. falciparum malaria in South America
  1. 1 No serious risk of bias: This trial is at low risk of selection bias and unclear risk of detection bias.
    2 Downgraded by 1 for serious indirectness: This findings of this single trial are not easily generalized to other South American countries.
    3 Downgraded by 1 for serious imprecision: Although this result reached statistical significance the number of events is very low, and there is a high possibility that this is a chance finding.
    4 Downgraded by 1 for serious imprecision: There were too few events in this single trial to confidently exclude important effects.

Dihydroartemisinin-piperaquine compared to Artesunate plus mefloquine for uncomplicated P. falciparum malaria in South America
Patient or population: Patients with uncomplicated P. falciparum malaria
Settings: Endemic settings in South America
Intervention: Dihydroartemisinin-piperaquine (DHA-P)
Comparison: Artesunate plus mefloquine (AS+MQ)
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(trials)
Quality of the evidence
(GRADE)
Assumed riskCorresponding risk
AS+MQ DHA-P

Treatment failure

Day 28

PCR-unadjusted-Data unavailable-
--
PCR-adjusted-Data unavailable-
--

Treatment failure

Day 63

PCR-unadjusted RR 6.19
(1.4 to 27.35)
445
(1 trial)
⊕⊕⊝⊝
low 1,2,3
1 per 100 6 per 100
(1 to 24)
PCR-adjusted RR 9.55
(0.52 to 176.35)
435
(1 trial)
⊕⊕⊝⊝
low 1,2,4
0 per 100 0 per 100
(0 to 0)
*The basis for the assumed risk (for example, the median control group risk across trials) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
Table 14. Dihydroartemisinin-piperaquine compared to Artesunate plus amodiaquine for uncomplicated P. falciparum malaria in Africa
  1. 1 No serious risk of bias: Trials are generally at low risk of bias. Exclusion of trials as high or unclear risk of selection bias or detection bias did not change the result.
    2 No serious inconsistency: The trials had similar results and statistical heterogeneity was low.
    3 No serious indirectness: The trials were conducted in children in different transmission settings in Burkina Faso, Gabon, Nigeria, Rwanda, Uganda, Zambia, and Mozambique.
    4 No serious imprecision: Both limits of the 95% CI imply appreciable benefit.
    5 Downgraded by 1 for serious imprecision: The findings did not reach statistical significance.
    6 No serious risk of bias: This finding is only reported in one trial which was at low risk of bias.
    7 Downgraded by 1 for serious imprecision: There 95% CI are wide and include what might be important differences.
    8 No data were presented for day 42.

Dihydroartemisinin-piperaquine compared to Artesunate plus amodiaquine for uncomplicated P. falciparum malaria in Africa
Patient or population: Patients with uncomplicated P. falciparum malaria
Settings: Africa
Intervention: Dihydroartemisinin-piperaquine (DHA-P)
Comparison: Artesunate plus amodiaquine (AS+AQ)
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(trials)
Quality of the evidence
(GRADE)
Assumed riskCorresponding risk
AS+AQDHA-P

Treatment failure

Day 28

PCR-unadjusted RR 0.49
(0.41 to 0.59)
2800
(2 trials)
⊕⊕⊕⊕
high 1,2,3,4
20 per 100 10 per 100
(8 to 12)
PCR-adjusted RR 0.67
(0.42 to 1.06)
2486
(2 trials)
⊕⊕⊕⊝
moderate 1,2,3,5
4 per 100 2 per 100
(2 to 4)

Treatment failure

Day 63

PCR-unadjusted RR 0.96
(0.86 to 1.07)
2292
(1 trial)
⊕⊕⊕⊝
moderate 3,6,7,8
37 per 100 35 per 100
(32 to 39)
PCR-adjusted RR 1.8
(0.85 to 3.83)
1506
(1 trial)
⊕⊕⊕⊝
moderate 3,6,7,8
2 per 100 3 per 100
(1 to 6)
*The basis for the assumed risk (for example, the median control group risk across trials) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
Table 15. Dihydroartemisinin-piperaquine compared to Artesunate plus amodiaquine for treating uncomplicated P. falciparum malaria in Asia
  1. 1 No serious risk of bias: Trials are generally at low risk of bias. Exclusion of trials as high or unclear risk of selection bias or detection bias did not change the result.
    2 No serious inconsistency: The trials all had similar results and statistical heterogeneity was low.
    3 No serious indirectness: The trials were conducted in adults and children in Indonesia and Myanmar.
    4 Downgraded by 1 for serious imprecision: Although this result reached statistical significance there are limited data, with few events. Larger trials are needed to have full confidence in this result.
    5 No serious risk of bias: This finding is only reported in one trial which was generally at low risk of bias.
    6 Downgraded by 1 for serious indirectness: This trial was from a single setting in Myanmar, and may not be easily generalized to elsewhere.
    7 One trial from Indonesia conducted in 2007 presented day 42 outcomes and at this timepoint there was still an advantage on PCR-unadjusted treatment failure with DHA-P (RR 0.27, 95% CI 0.10 to 0.72, one trial, 152 participants, moderate quality evidence), and PCR-adjusted treatment failure (RR 0.10, 95% CI 0.01 to 0.81, one trial, 141 participants, moderate quality evidence).

Dihydroartemisinin-piperaquine compared to Artesunate plus amodiaquine for treating uncomplicated P. falciparum malaria in Asia
Patient or population: Patients with treating uncomplicated P. falciparum malaria
Settings: Asia
Intervention: Dihydroartemisinin-piperaquine (DHA-P)
Comparison: Artesunate plus amodiaquine (AS+AQ)
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(trials)
Quality of the evidence
(GRADE)
Assumed riskCorresponding risk
AS+AQDHA-P

Treatment failure

Day 28

PCR-unadjusted RR 0.38
(0.18 to 0.77)
482
(2 trials)
⊕⊕⊕⊝
moderate 1,2,3,4
11 per 100 4 per 100
(2 to 8)
PCR-adjusted RR 0.08
(0.01 to 0.4)
466
(2 trials)
⊕⊕⊕⊝
moderate 1,2,3,4
8 per 100 1 per 100
(0 to 3)

Treatment failure

Day 63

PCR-unadjusted RR 0.49
(0.27 to 0.89)
304
(1 trial)
⊕⊕⊝⊝
low 4,5,6,7
19 per 100 9 per 100
(5 to 17)
PCR-adjusted RR 0.14
(0.03 to 0.59)
278
(1 trial)
⊕⊕⊝⊝
low 4,5,6,7
10 per 100 1 per 100
(0 to 6)
*The basis for the assumed risk (for example, the median control group risk across trials) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of main results

DHA-P versus artemether lumefantrine

In Africa, during 28 days follow-up, DHA-P is superior to AL6 at preventing further parasitaemia (high quality evidence), and although PCR-adjusted treatment failure was below 5% for both ACTs it was consistently lower with DHA-P (high quality evidence). DHA-P has a longer prophylactic effect on new infections which may last for up to 63 days (high quality evidence).

In Asia and Oceania, no differences in treatment failure have been shown at day 28 (moderate quality evidence), or day 63 (low quality evidence).

DHA-P and AL6 appear to have similar adverse effect profiles (moderate quality evidence). DHA-P was associated with borderline prolongation of QTc interval but no difference was seen in prolonged QTc (low quality evidence) and no cardiac arrhythmias were reported.

DHA-P versus artesunate plus mefloquine

In Asia, during 28 days follow-up, DHA-P is as effective as AS+MQ at preventing further parasitaemia (high quality evidence). Once adjusted by PCR to exclude new infections, treatment failure at day 28 was below 5% for both ACTs in all eight trials, but lower with DHA-P in two trials from sites with multi-drug resistant P. falciparum (high quality evidence). Both combinations contain partner drugs with very long half-lives and no consistent difference in preventing new infections has been seen between drugs over 63 days follow-up (moderate quality evidence).

In the only trial from South America, there were fewer recurrent parasitaemias over 63 days with AS+MQ (low quality evidence), but there was no difference between treatments once adjusted by PCR for new infections (low quality evidence).

Compared to AS+MQ, DHA-P is associated with reduced nausea, vomiting, dizziness, sleeplessness, and palpitations (moderate quality evidence). The only notable adverse event associated with DHA-P was an increased frequency of prolongation of the QTc interval (low quality evidence), however no cardiac arrhythmias were reported in these trials.

Overall completeness and applicability of evidence

DHA-P is one of the most studied ACTs, and we included 27 trials in this review, which enrolled 16,382 adults and children with uncomplicated malaria. Notably, these trials excluded infants aged less than six months and pregnant women, and further safety data is required for these groups.

The efficacy of DHA-P against uncomplicated P. falciparum malaria in adults and children however is now well established, and although there is only limited data from South America, it is likely that the findings of this review can be applied worldwide.

Despite the high efficacy against asexual parasitaemia, DHA-P appears to have a reduced efficacy against gametocytes. Compared to DHA-P, both AS+MQ and AL6 reduce the carriage of gametocytes during the first 14 days post-treatment. This deficiency has been discussed in the literature, and it is likely due to a relative underdosing of the artemisinin derivative in the combination. The clinical significance of this effect remains unclear as gametocyte carriage is only an indirect measure of transmission potential. Furthermore, any increased risk of transmission in the early period after treatment may be offset by the later improved prophylactic effect of DHA-P.

DHA-P has been available and in use for several years despite the lack of a WHO prequalified formulation manufactured according to Good Manufacturing Practices Standards (GMP), and concerns about the stability and shelf-life of the dihydroartemisinin combination (Jansen 2010; Schmatz 2010). However, the Eurartesim® formulation evaluated by Bassat 2009 AF and Valecha 2010 AS has now been registered and approved for use by the European Medicines Agency (EMA) (European Medicines Agency 2011).

The potential for prolongation of the QTc interval is the most notable adverse effect. This was noted in the EMA's report where they advised that DHA-P should not be used in people who have, or are at risk of, QTc interval prolongation or cardiac arrhythmias, and should not be taken with other drugs which prolong the QTc interval (European Medicines Agency 2011). No participants were reported to have experienced confirmed cardiac arrhythmias in these studies.

Systematic reviews in infectious diseases also need to consider the possibility of changing drug effects over time as drug resistance patterns change and develop. In this review, we partially explored this possibility by presenting all forest plots with trials arranged in chronological order, but we found no evidence of a decline in efficacy over time. However, a systematic review may not be the most appropriate way to examine these effects, as RCTs tend to be conducted for new drugs with little research interest once they are well established. Selection of first and second line antimalarials should therefore take into account other knowledge on antimalarial resistance, such as that produced by the WorldWide Antimalaria Resistance Network (WWARN 2013).

Quality of the evidence

We assessed the quality of the evidence in this review using the GRADE approach and presented the evidence in six summary of findings tables for efficacy (Summary of findings for the main comparison; Table 12; Table 13; Table 11; Table 14; Table 15), and in three summary of findings tables for adverse events (in Appendix 3).

The evidence that DHA-P is at least as effective as AS+MQ in Asia was of high quality. There was some statistical heterogeneity, with two trials (predominantly from trial sites in Thailand) finding slightly higher levels of treatment failure with AS+MQ. This may be a consequence of resistance to mefloquine in the area and was not considered sufficient to downgrade the evidence.

The evidence for superiority of DHA-P over AL6 in Africa was of high quality, with no reason to downgrade for risk of bias, inconsistency, indirectness, or imprecision. It should be noted that both DHA-P and AL6 performed better than the WHO standard of 5% PCR-adjusted treatment failure at day 28 in all trials. The choice between DHA-P and AL6 may therefore be based more on considerations of adherence and cost, rather than efficacy.

We also assessed the quality of evidence on comparative adverse effects and presented these in Appendix 3. In general, the evidence was of moderate to low quality, meaning we can have reasonable confidence in some of these effects.

Agreements and disagreements with other studies or reviews

We found three recent systematic reviews of DHA-P (Keating 2012; Naing 2013 & WWARN 2013b), and reviewed the public assessment report of Eurartesim® by the EMA (European Medicines Agency 2011).

The most recent systematic review (Naing 2013) includes 26 of the 27 trials we included in this review and reaches very similar conclusions: "DHA-P is non-inferior to other currently used ACTs such as AS+MQ and AL6" and "the better safety profile of DHA-P and once-daily dosage improves adherence. For these reasons, DHA-P has the potential to become a first-line antimalarial drug".

The second review (Keating 2012) is more narrative and focuses on the Eurartesim® formulation registered with the EMA. The review contains an extensive discussion of the effects of the formulation on the QTc interval, and the author concludes that "there are currently no data signalling that DHA-P is associated with clinically significant arrhythmias". Similarly, the EMA public report concludes that "Treatment emergent QTc prolongation was asymptomatic in all cases", and "The magnitude of QTc prolongation is reduced if dosing occurs between meals". Conditional for registration, the pharmaceutical company agreed to undertake further post-marketing evaluation of the effects of DHA-P on the QTc interval and the potential for arrhythmias (European Medicines Agency 2011).

The third review (WWARN 2013b) was based on individual patient data from 24 published and two unpublished studies. The analysis paid particular attention to the relationship between age, the drug dose administered, and treatment efficacy. The authors report that treatment failure following DHA-P was highest in young children (aged between one and five years), and conclude that this is related to significant underdosing of both dihydroartemisinin and piperaquine in this age group, and to different pharmacokinetics in young children. On this basis, some further dose optimization of this combination is underway.

Authors' conclusions

Implications for practice

In Africa, DHA-P seems to reduce treatment failure compared to AL6, although it should be noted that AL6 also performed above the WHO standard of 95% cure rate in all these trials. DHA-P therefore represents an effective alternative with a simplified dosing regimen, and a longer post-treatment prophylactic effect.

In Asia, DHA-P appears to be as effective as the widely used AS+MQ, and is better tolerated. This may promote DHA-P to become the first line treatment option.

Implications for research

The efficacy of DHA-P is now well established. Future research should concentrate on safety surveillance, particularly in infants and pregnant women, and further appraisal of the potential effects on cardiac conduction.

Acknowledgements

We acknowledge the contributions of Paul Garner and Hasifa Bukirwa to the development of the original protocol and thank Vittoria Lutje for conducting the searches.

The authors are grateful to the Cochrane Editorial Unit, who helped with data extraction during a review updating pilot programme in 2010. This document is an output from a project funded by UKaid from the UK Government for the benefit of developing countries. The views expressed are not necessarily those of the Department for International Development (DFID).

Data and analyses

Download statistical data

Comparison 1. Dihydroartemisinin-piperaquine versus Artesunate plus mefloquine
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Total failure (P. falciparum) Day 28 PCR-unadjusted8 Risk Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Asia83487Risk Ratio (M-H, Random, 95% CI)1.02 [0.28, 3.72]
2 Total failure (P. falciparum) Day 28 PCR-adjusted8 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 Asia83482Risk Ratio (M-H, Fixed, 95% CI)0.41 [0.21, 0.80]
3 Total failure (P. falciparum) Day 42 PCR-unadjusted7 Risk Ratio (M-H, Random, 95% CI)Subtotals only
3.1 Asia73421Risk Ratio (M-H, Random, 95% CI)0.90 [0.54, 1.50]
4 Total failure (P. falciparum) Day 42 PCR-adjusted6 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
4.1 Asia62901Risk Ratio (M-H, Fixed, 95% CI)0.48 [0.26, 0.88]
5 Total failure (P. falciparum) Day 63 PCR-unadjusted6 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
5.1 Asia52715Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.69, 1.03]
5.2 South America1445Risk Ratio (M-H, Fixed, 95% CI)6.19 [1.40, 27.35]
6 Total failure (P. falciparum) Day 63 PCR-adjusted6 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
6.1 Asia52500Risk Ratio (M-H, Fixed, 95% CI)0.50 [0.30, 0.84]
6.2 South America1435Risk Ratio (M-H, Fixed, 95% CI)9.55 [0.52, 176.35]
7 Gametocyte carriage3 Risk Ratio (M-H, Random, 95% CI)Subtotals only
7.1 Gametocyte carriage day 032322Risk Ratio (M-H, Random, 95% CI)1.07 [0.66, 1.73]
7.2 Gametocyte carriage day 732270Risk Ratio (M-H, Random, 95% CI)1.99 [1.57, 2.51]
7.3 Gametocyte carriage day 1432249Risk Ratio (M-H, Random, 95% CI)5.11 [3.26, 7.99]
7.4 Gametocyte carriage day 2132218Risk Ratio (M-H, Random, 95% CI)9.44 [0.80, 110.80]
7.5 Gametocyte carriage day 2832199Risk Ratio (M-H, Random, 95% CI)9.55 [1.80, 50.61]
8 Gametocyte development (in those negative at baseline)31234Risk Ratio (M-H, Fixed, 95% CI)3.06 [1.13, 8.33]
9 Serious adverse events (including deaths)83522Risk Ratio (M-H, Fixed, 95% CI)1.20 [0.59, 2.42]
10 Other adverse events: Gastrointestinal10 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
10.1 Early vomiting94114Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.71, 1.15]
10.2 Nausea94531Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.60, 0.78]
10.3 Vomiting52744Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.47, 0.75]
10.4 Anorexia63497Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.73, 1.02]
10.5 Diarrhoea52217Risk Ratio (M-H, Fixed, 95% CI)1.46 [1.05, 2.04]
10.6 Abdominal pain73887Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.82, 1.20]
11 Other adverse events: Neuro-psychiatric9 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
11.1 Headache42039Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.64, 1.00]
11.2 Dizziness94531Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.66, 0.78]
11.3 Sleeplessness62551Risk Ratio (M-H, Fixed, 95% CI)0.49 [0.40, 0.60]
11.4 Fatigue2872Risk Ratio (M-H, Fixed, 95% CI)0.41 [0.23, 0.73]
11.5 Nightmares1220Risk Ratio (M-H, Fixed, 95% CI)0.09 [0.01, 0.69]
11.6 Anxiety1522Risk Ratio (M-H, Fixed, 95% CI)0.10 [0.03, 0.33]
11.7 Blurred vision1464Risk Ratio (M-H, Fixed, 95% CI)0.49 [0.24, 1.02]
11.8 Tinnitus1220Risk Ratio (M-H, Fixed, 95% CI)0.4 [0.13, 1.24]
12 Other adverse events: Cardio-respiratory4 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
12.1 Palpitations31175Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.45, 0.82]
12.2 Cough11148Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.54, 1.19]
12.3 Dyspnoea1220Risk Ratio (M-H, Fixed, 95% CI)0.3 [0.08, 1.06]
12.4 Prolonged QT interval (reported as adverse events)11148Risk Ratio (M-H, Fixed, 95% CI)1.27 [0.72, 2.24]
12.5 Prolonged QT interval (Bazett's correction)11148Risk Ratio (M-H, Fixed, 95% CI)2.05 [1.20, 3.49]
12.6 Prolonged QT interval (Fridericia's correction)11148Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.52, 1.52]
13 Other adverse events: Musculoskeletal/dermatological4 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
13.1 Arthralgia11148Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.60, 1.65]
13.2 Myalgia11148Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.63, 1.70]
13.3 Urticaria2719Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.15, 2.35]
13.4 Pruritis2872Risk Ratio (M-H, Fixed, 95% CI)0.65 [0.26, 1.60]
13.5 Rash1220Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.01, 8.09]
14 Sensitivity analysis: Total failure Day 63 PCR-unadjusted4 Risk Ratio (M-H, Random, 95% CI)Subtotals only
14.1 Total failure (P. falciparum) Day 63 PCR-unadjusted41627Risk Ratio (M-H, Random, 95% CI)0.94 [0.52, 1.70]
14.2 Total failure Day 63 PCR-unadjusted (losses to follow-up included as failures)41801Risk Ratio (M-H, Random, 95% CI)0.95 [0.65, 1.38]
14.3 Total failure Day 63 PCR-unadjusted (losses to follow-up included as successes)41801Risk Ratio (M-H, Random, 95% CI)0.94 [0.52, 1.68]
15 Sensitivity analysis: Total failure Day 63 PCR-adjusted4 Risk Ratio (M-H, Random, 95% CI)Subtotals only
15.1 Total failure (P. falciparum) Day 63 PCR-adjusted41497Risk Ratio (M-H, Random, 95% CI)0.57 [0.17, 1.83]
15.2 Total failure Day 63 PCR-adjusted (indeterminate PCR included as failures)41508Risk Ratio (M-H, Random, 95% CI)0.67 [0.32, 1.39]
15.3 Total failure Day 63 PCR-adjusted (new infections included as successes)41627Risk Ratio (M-H, Random, 95% CI)0.67 [0.34, 1.35]
15.4 Total failure Day 63 PCR-adjusted (losses to follow-up included as failures)41801Risk Ratio (M-H, Random, 95% CI)0.93 [0.67, 1.30]
15.5 Total failure Day 63 PCR-adjusted (losses to follow-up included as successes)41801Risk Ratio (M-H, Random, 95% CI)0.67 [0.34, 1.33]
Analysis 1.1.

Comparison 1 Dihydroartemisinin-piperaquine versus Artesunate plus mefloquine, Outcome 1 Total failure (P. falciparum) Day 28 PCR-unadjusted.

Analysis 1.2.

Comparison 1 Dihydroartemisinin-piperaquine versus Artesunate plus mefloquine, Outcome 2 Total failure (P. falciparum) Day 28 PCR-adjusted.

Analysis 1.3.

Comparison 1 Dihydroartemisinin-piperaquine versus Artesunate plus mefloquine, Outcome 3 Total failure (P. falciparum) Day 42 PCR-unadjusted.

Analysis 1.4.

Comparison 1 Dihydroartemisinin-piperaquine versus Artesunate plus mefloquine, Outcome 4 Total failure (P. falciparum) Day 42 PCR-adjusted.

Analysis 1.5.

Comparison 1 Dihydroartemisinin-piperaquine versus Artesunate plus mefloquine, Outcome 5 Total failure (P. falciparum) Day 63 PCR-unadjusted.

Analysis 1.6.

Comparison 1 Dihydroartemisinin-piperaquine versus Artesunate plus mefloquine, Outcome 6 Total failure (P. falciparum) Day 63 PCR-adjusted.

Analysis 1.7.

Comparison 1 Dihydroartemisinin-piperaquine versus Artesunate plus mefloquine, Outcome 7 Gametocyte carriage.

Analysis 1.8.

Comparison 1 Dihydroartemisinin-piperaquine versus Artesunate plus mefloquine, Outcome 8 Gametocyte development (in those negative at baseline).

Analysis 1.9.

Comparison 1 Dihydroartemisinin-piperaquine versus Artesunate plus mefloquine, Outcome 9 Serious adverse events (including deaths).

Analysis 1.10.

Comparison 1 Dihydroartemisinin-piperaquine versus Artesunate plus mefloquine, Outcome 10 Other adverse events: Gastrointestinal.

Analysis 1.11.

Comparison 1 Dihydroartemisinin-piperaquine versus Artesunate plus mefloquine, Outcome 11 Other adverse events: Neuro-psychiatric.

Analysis 1.12.

Comparison 1 Dihydroartemisinin-piperaquine versus Artesunate plus mefloquine, Outcome 12 Other adverse events: Cardio-respiratory.

Analysis 1.13.

Comparison 1 Dihydroartemisinin-piperaquine versus Artesunate plus mefloquine, Outcome 13 Other adverse events: Musculoskeletal/dermatological.

Analysis 1.14.

Comparison 1 Dihydroartemisinin-piperaquine versus Artesunate plus mefloquine, Outcome 14 Sensitivity analysis: Total failure Day 63 PCR-unadjusted.

Analysis 1.15.

Comparison 1 Dihydroartemisinin-piperaquine versus Artesunate plus mefloquine, Outcome 15 Sensitivity analysis: Total failure Day 63 PCR-adjusted.

Comparison 2. Dihydroartemisinin-piperaquine dose analysis: 3 dose versus 4 dose regimen
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Total failure PCR-unadjusted1318Risk Ratio (M-H, Fixed, 95% CI)1.72 [0.84, 3.53]
1.1 Day 631318Risk Ratio (M-H, Fixed, 95% CI)1.72 [0.84, 3.53]
2 Total failure PCR-adjusted1292Risk Ratio (M-H, Fixed, 95% CI)0.56 [0.05, 6.09]
2.1 Day 631292Risk Ratio (M-H, Fixed, 95% CI)0.56 [0.05, 6.09]
Analysis 2.1.

Comparison 2 Dihydroartemisinin-piperaquine dose analysis: 3 dose versus 4 dose regimen, Outcome 1 Total failure PCR-unadjusted.

Analysis 2.2.

Comparison 2 Dihydroartemisinin-piperaquine dose analysis: 3 dose versus 4 dose regimen, Outcome 2 Total failure PCR-adjusted.

Comparison 3. Dihydroartemisinin-piperaquine dose analysis (versus Artesunate plus mefloquine)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Total failure Day 28 PCR-unadjusted83644Risk Ratio (M-H, Random, 95% CI)0.78 [0.25, 2.41]
1.1 DHA-P 4 doses41075Risk Ratio (M-H, Random, 95% CI)0.56 [0.10, 3.14]
1.2 DHA-P 3 doses52569Risk Ratio (M-H, Random, 95% CI)0.98 [0.19, 5.07]
2 Total failure Day 28 PCR-adjusted83633Risk Ratio (M-H, Random, 95% CI)0.50 [0.15, 1.65]
2.1 DHA-P 4 doses41067Risk Ratio (M-H, Random, 95% CI)0.79 [0.10, 6.11]
2.2 DHA-P 3 doses52566Risk Ratio (M-H, Random, 95% CI)0.39 [0.08, 1.94]
3 Total failure Day 42 PCR-unadjusted73578Risk Ratio (M-H, Random, 95% CI)0.82 [0.51, 1.31]
3.1 DHA-P 4 doses3957Risk Ratio (M-H, Random, 95% CI)0.80 [0.50, 1.28]
3.2 DHA-P 3 doses52621Risk Ratio (M-H, Random, 95% CI)0.89 [0.40, 1.99]
4 Total failure Day 42 PCR-adjusted63046Risk Ratio (M-H, Random, 95% CI)0.49 [0.20, 1.18]
4.1 DHA-P 4 doses3903Risk Ratio (M-H, Random, 95% CI)0.62 [0.14, 2.82]
4.2 DHA-P 3 doses42143Risk Ratio (M-H, Random, 95% CI)0.43 [0.12, 1.48]
5 Total failure Day 63 PCR-unadjusted63317Risk Ratio (M-H, Random, 95% CI)0.93 [0.62, 1.40]
5.1 DHA-P 4 doses31019Risk Ratio (M-H, Random, 95% CI)0.81 [0.59, 1.10]
5.2 DHA-P 3 doses42298Risk Ratio (M-H, Random, 95% CI)1.22 [0.52, 2.90]
6 Total failure Day 63 PCR-adjusted63072Risk Ratio (M-H, Random, 95% CI)0.57 [0.28, 1.15]
6.1 DHA-P 4 doses3908Risk Ratio (M-H, Random, 95% CI)0.42 [0.17, 1.04]
6.2 DHA-P 3 doses42164Risk Ratio (M-H, Random, 95% CI)0.85 [0.26, 2.77]
Analysis 3.1.

Comparison 3 Dihydroartemisinin-piperaquine dose analysis (versus Artesunate plus mefloquine), Outcome 1 Total failure Day 28 PCR-unadjusted.

Analysis 3.2.

Comparison 3 Dihydroartemisinin-piperaquine dose analysis (versus Artesunate plus mefloquine), Outcome 2 Total failure Day 28 PCR-adjusted.

Analysis 3.3.

Comparison 3 Dihydroartemisinin-piperaquine dose analysis (versus Artesunate plus mefloquine), Outcome 3 Total failure Day 42 PCR-unadjusted.

Analysis 3.4.

Comparison 3 Dihydroartemisinin-piperaquine dose analysis (versus Artesunate plus mefloquine), Outcome 4 Total failure Day 42 PCR-adjusted.

Analysis 3.5.

Comparison 3 Dihydroartemisinin-piperaquine dose analysis (versus Artesunate plus mefloquine), Outcome 5 Total failure Day 63 PCR-unadjusted.

Analysis 3.6.

Comparison 3 Dihydroartemisinin-piperaquine dose analysis (versus Artesunate plus mefloquine), Outcome 6 Total failure Day 63 PCR-adjusted.

Comparison 4. Dihydroartemisinin-piperaquine versus Artemether-lumefantrine
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Total failure (P. falciparum) Day 28 PCR-unadjusted13 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 Africa96200Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.30, 0.39]
1.2 Asia and Oceania41143Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.64, 1.47]
2 Total failure (P. falciparum) Day 28 PCR-adjusted12 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 Africa95417Risk Ratio (M-H, Fixed, 95% CI)0.42 [0.29, 0.62]
2.2 Asia and Oceania3925Risk Ratio (M-H, Fixed, 95% CI)2.01 [0.81, 5.03]
3 Total failure (P. falciparum) Day 42 PCR-unadjusted9 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
3.1 Africa73301Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.53, 0.67]
3.2 Asia and Oceania2572Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.65, 1.17]
4 Total failure (P. falciparum) Day 42 PCR-adjusted9 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
4.1 Africa72559Risk Ratio (M-H, Fixed, 95% CI)0.58 [0.41, 0.81]
4.2 Asia and Oceania2468Risk Ratio (M-H, Fixed, 95% CI)1.69 [0.75, 3.83]
5 Total failure (P. falciparum) Day 63 PCR-unadjusted3 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
5.1 Africa23200Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.65, 0.78]
5.2 Asia1323Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.47, 1.88]
6 Total failure (P. falciparum) Day 63 PCR-adjusted3 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
6.1 Africa22097Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.50, 1.04]
6.2 Asia1298Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.14, 7.01]
7 Gametocyte development (in those negative at baseline)6 Risk Ratio (M-H, Random, 95% CI)Totals not selected
8 Gametocyte carriage4 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
8.1 Gametocyte carriage day 1 to 1441537Risk Ratio (M-H, Fixed, 95% CI)4.32 [1.48, 12.63]
8.2 Gametocyte carriage day 15 to 2841516Risk Ratio (M-H, Fixed, 95% CI)0.21 [0.06, 0.72]
8.3 Gametocyte carriage day 29 to 422650Risk Ratio (M-H, Fixed, 95% CI)0.28 [0.13, 0.61]
9 Anaemia8 Mean Difference (IV, Fixed, 95% CI)Subtotals only
9.1 Mean haemoglobin (g/dL) at baseline86599Mean Difference (IV, Fixed, 95% CI)-0.04 [-0.09, 0.01]
9.2 Mean haemoglobin (g/dL) at day 281134Mean Difference (IV, Fixed, 95% CI)0.36 [-0.03, 0.75]
9.3 Mean haemoglobin (g/dL) at day 421375Mean Difference (IV, Fixed, 95% CI)0.30 [-0.02, 0.62]
9.4 Mean change in haemoglobin (g/dL) from baseline to day 2822185Mean Difference (IV, Fixed, 95% CI)0.19 [0.03, 0.34]
9.5 Mean change in haemoglobin (g/dL) from baseline to day 422835Mean Difference (IV, Fixed, 95% CI)0.26 [0.00, 0.51]
10 Serious adverse events (including deaths)97246Risk Ratio (M-H, Fixed, 95% CI)1.58 [0.93, 2.68]
11 Other adverse events: Gastrointestinal12 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
11.1 Early vomiting42969Risk Ratio (M-H, Fixed, 95% CI)1.69 [1.00, 2.83]
11.2 Vomiting96761Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.89, 1.20]
11.3 Nausea2547Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.36, 3.76]
11.4 Diarrhoea74889Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.81, 1.09]
11.5 Abdominal pain5911Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.65, 1.08]
11.6 Anorexia53834Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.80, 1.08]
12 Other adverse events: Neuro-psychiatric6 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
12.1 Headache2309Risk Ratio (M-H, Fixed, 95% CI)1.21 [0.90, 1.63]
12.2 Sleeplessness2547Risk Ratio (M-H, Fixed, 95% CI)2.07 [0.69, 6.16]
12.3 Dizziness2547Risk Ratio (M-H, Fixed, 95% CI)1.67 [0.67, 4.15]
12.4 Sleepiness1384Risk Ratio (M-H, Fixed, 95% CI)2.85 [0.12, 69.49]
12.5 Weakness51812Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.89, 1.27]
13 Other adverse events: Cardio-respiratory6 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
13.1 Cough54342Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.95, 1.09]
13.2 Coryza2832Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.89, 1.07]
13.3 Prolonged QTc interval (reported as adverse events)11548Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.51, 1.90]
13.4 Prolonged QTc interval (Bazett's correction)11548Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.91, 1.92]
13.5 Prolonged QTc interval (Fridericia's correction)11548Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.09, 10.81]
14 Other adverse events: Musculoskeletal/dermatological5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
14.1 Pruritis52033Risk Ratio (M-H, Fixed, 95% CI)1.74 [1.03, 2.92]
14.2 Face oedema1384Risk Ratio (M-H, Fixed, 95% CI)2.85 [0.12, 69.49]
Analysis 4.1.

Comparison 4 Dihydroartemisinin-piperaquine versus Artemether-lumefantrine, Outcome 1 Total failure (P. falciparum) Day 28 PCR-unadjusted.

Analysis 4.2.

Comparison 4 Dihydroartemisinin-piperaquine versus Artemether-lumefantrine, Outcome 2 Total failure (P. falciparum) Day 28 PCR-adjusted.

Analysis 4.3.

Comparison 4 Dihydroartemisinin-piperaquine versus Artemether-lumefantrine, Outcome 3 Total failure (P. falciparum) Day 42 PCR-unadjusted.

Analysis 4.4.

Comparison 4 Dihydroartemisinin-piperaquine versus Artemether-lumefantrine, Outcome 4 Total failure (P. falciparum) Day 42 PCR-adjusted.

Analysis 4.5.

Comparison 4 Dihydroartemisinin-piperaquine versus Artemether-lumefantrine, Outcome 5 Total failure (P. falciparum) Day 63 PCR-unadjusted.

Analysis 4.6.

Comparison 4 Dihydroartemisinin-piperaquine versus Artemether-lumefantrine, Outcome 6 Total failure (P. falciparum) Day 63 PCR-adjusted.

Analysis 4.7.

Comparison 4 Dihydroartemisinin-piperaquine versus Artemether-lumefantrine, Outcome 7 Gametocyte development (in those negative at baseline).

Analysis 4.8.

Comparison 4 Dihydroartemisinin-piperaquine versus Artemether-lumefantrine, Outcome 8 Gametocyte carriage.

Analysis 4.9.

Comparison 4 Dihydroartemisinin-piperaquine versus Artemether-lumefantrine, Outcome 9 Anaemia.

Analysis 4.10.

Comparison 4 Dihydroartemisinin-piperaquine versus Artemether-lumefantrine, Outcome 10 Serious adverse events (including deaths).

Analysis 4.11.

Comparison 4 Dihydroartemisinin-piperaquine versus Artemether-lumefantrine, Outcome 11 Other adverse events: Gastrointestinal.

Analysis 4.12.

Comparison 4 Dihydroartemisinin-piperaquine versus Artemether-lumefantrine, Outcome 12 Other adverse events: Neuro-psychiatric.

Analysis 4.13.

Comparison 4 Dihydroartemisinin-piperaquine versus Artemether-lumefantrine, Outcome 13 Other adverse events: Cardio-respiratory.

Analysis 4.14.

Comparison 4 Dihydroartemisinin-piperaquine versus Artemether-lumefantrine, Outcome 14 Other adverse events: Musculoskeletal/dermatological.

Comparison 5. Dihydroartemisinin-piperaquine versus Artesunate plus amodiaquine
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Total failure (P. falciparum) Day 28 PCR-unadjusted4 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 Africa22800Risk Ratio (M-H, Fixed, 95% CI)0.49 [0.41, 0.59]
1.2 Asia2482Risk Ratio (M-H, Fixed, 95% CI)0.38 [0.18, 0.77]
2 Total failure (P. falciparum) Day 28 PCR-adjusted4 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 Africa22486Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.42, 1.06]
2.2 Asia2466Risk Ratio (M-H, Fixed, 95% CI)0.08 [0.01, 0.40]
3 Total failure (P. falciparum) Day 42 PCR-unadjusted1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
3.1 Asia1152Risk Ratio (M-H, Fixed, 95% CI)0.27 [0.10, 0.72]
4 Total failure (P. falciparum) Day 42 PCR-adjusted1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
4.1 Asia1141Risk Ratio (M-H, Fixed, 95% CI)0.10 [0.01, 0.81]
5 Total failure (P. falciparum) Day 63 PCR-unadjusted2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
5.1 Africa12292Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.86, 1.07]
5.2 Asia1304Risk Ratio (M-H, Fixed, 95% CI)0.49 [0.27, 0.89]
6 Total failure (P. falciparum) Day 63 PCR-adjusted2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
6.1 Africa11506Risk Ratio (M-H, Fixed, 95% CI)1.80 [0.85, 3.83]
6.2 Asia1278Risk Ratio (M-H, Fixed, 95% CI)0.14 [0.03, 0.59]
7 Serious adverse events (including deaths)22805Risk Ratio (M-H, Fixed, 95% CI)0.40 [0.19, 0.87]
8 Other adverse events: Gastrointestinal3 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
8.1 Early vomiting2650Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.44, 1.56]
8.2 Vomiting12471Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.62, 1.01]
8.3 Nausea1316Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.62, 1.61]
8.4 Diarrhoea22787Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.83, 1.27]
8.5 Abdominal pain1316Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.51, 1.65]
8.6 Anorexia22787Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.72, 1.13]
9 Other adverse events: Neuro-psychiatric1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
9.1 Headache1316Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.14, 6.75]
9.2 Sleeplessness1316Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.44, 1.41]
10 Other adverse events: Cardio-respiratory2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
10.1 Cough12471Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.91, 1.15]
10.2 Palpitations1316Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.58, 1.35]
Analysis 5.1.

Comparison 5 Dihydroartemisinin-piperaquine versus Artesunate plus amodiaquine, Outcome 1 Total failure (P. falciparum) Day 28 PCR-unadjusted.

Analysis 5.2.

Comparison 5 Dihydroartemisinin-piperaquine versus Artesunate plus amodiaquine, Outcome 2 Total failure (P. falciparum) Day 28 PCR-adjusted.

Analysis 5.3.

Comparison 5 Dihydroartemisinin-piperaquine versus Artesunate plus amodiaquine, Outcome 3 Total failure (P. falciparum) Day 42 PCR-unadjusted.

Analysis 5.4.

Comparison 5 Dihydroartemisinin-piperaquine versus Artesunate plus amodiaquine, Outcome 4 Total failure (P. falciparum) Day 42 PCR-adjusted.

Analysis 5.5.

Comparison 5 Dihydroartemisinin-piperaquine versus Artesunate plus amodiaquine, Outcome 5 Total failure (P. falciparum) Day 63 PCR-unadjusted.

Analysis 5.6.

Comparison 5 Dihydroartemisinin-piperaquine versus Artesunate plus amodiaquine, Outcome 6 Total failure (P. falciparum) Day 63 PCR-adjusted.

Analysis 5.7.

Comparison 5 Dihydroartemisinin-piperaquine versus Artesunate plus amodiaquine, Outcome 7 Serious adverse events (including deaths).

Analysis 5.8.

Comparison 5 Dihydroartemisinin-piperaquine versus Artesunate plus amodiaquine, Outcome 8 Other adverse events: Gastrointestinal.

Analysis 5.9.

Comparison 5 Dihydroartemisinin-piperaquine versus Artesunate plus amodiaquine, Outcome 9 Other adverse events: Neuro-psychiatric.

Analysis 5.10.

Comparison 5 Dihydroartemisinin-piperaquine versus Artesunate plus amodiaquine, Outcome 10 Other adverse events: Cardio-respiratory.

Comparison 6. Dihydroartemisinin-piperaquine versus Artesunate plus sulfadoxine-pyrimethamine
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Total failure (P. falciparum) Day 28 PCR-unadjusted1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 Oceania1223Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.62, 1.64]
2 Total failure (P. falciparum) Day 28 PCR-adjusted1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 Oceania1195Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.46, 2.22]
3 Total failure (P. falciparum) Day 42 PCR-unadjusted1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
3.1 Oceania1215Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.74, 1.45]
4 Total failure (P. falciparum) Day 42 PCR-adjusted1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
4.1 Oceania1161Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.39, 1.51]
Analysis 6.1.

Comparison 6 Dihydroartemisinin-piperaquine versus Artesunate plus sulfadoxine-pyrimethamine, Outcome 1 Total failure (P. falciparum) Day 28 PCR-unadjusted.

Analysis 6.2.

Comparison 6 Dihydroartemisinin-piperaquine versus Artesunate plus sulfadoxine-pyrimethamine, Outcome 2 Total failure (P. falciparum) Day 28 PCR-adjusted.

Analysis 6.3.

Comparison 6 Dihydroartemisinin-piperaquine versus Artesunate plus sulfadoxine-pyrimethamine, Outcome 3 Total failure (P. falciparum) Day 42 PCR-unadjusted.

Analysis 6.4.

Comparison 6 Dihydroartemisinin-piperaquine versus Artesunate plus sulfadoxine-pyrimethamine, Outcome 4 Total failure (P. falciparum) Day 42 PCR-adjusted.

Appendices

Appendix 1. Adverse event monitoring

DHA-P versus Artesunate plus mefloquine
Trial IDSample SizeBlindingClinical symptoms monitoringBiochemistryHaematologicalECG
Ashley 2004a THA134Open labelInpatient monitoring until day 28U&E, LFT on days 0 and 7FBC on days 0 and 7None
Ashley 2004b THA356Open labelDaily review until parasites cleared then weekly until day 63U&E, LFT on days 0 and 7 (DHA-P group only)

FBC on days 0 and 7

(DHA-P group only)

Days 0 and 7 (DHA-P group only)
Ashley 2005 THA499Open labelClinical examination and symptom enquiry daily until parasites cleared then weekly until day 63NoneHaematocrit daily until parasites cleared then weekly until day 63None
Grande 2007 PER522Open labelClinical assessment daily until day 3 then weekly until day 63U&E, LFT on days 0 and 7,FBC, PCV days 0 and 7, PCV days 14 and 63None
Janssens 2007 KHM464Open labelClinical examination and symptom questionnaire days 0, 1, 2, and 3NoneNoneNone
Mayxay 2006 LAO220Open labelDaily review until parasites cleared then weekly until day 42NoneNoneNone
Smithuis 2006 MMR652Open labelSymptom questionnaire at days 0, 1, 2, 3, and 7NoneNoneNone
Smithuis 2010 MMR491Open labelReview weekly for 9 weeksNoneNoneNone
Tangpukdee 2005 THA180Open labelInpatient monitoring until day 28. Assessed using non-suggestive questioning.NoneNoneNone
Tran 2004 VNM243Open labelReview at days 0, 2, and 7LFTs on days 3, 7 and 28NoneNone
Valecha 2010 AS1150Open labelClinical review until parasites cleared then weekly until day 63.Blood and urine samples 0, 28, 63 and on the day of any recurrent parasitaemia.NoneDays 0, 2, 7, 28, 63 and on the day of any recurrent parasitaemia.
DHA-P versus Artemether-lumefantrine
Trial IDSample SizeBlindingClinical symptoms monitoringBiochemistryHaematologicalECG
Adam 2010 SDN160

Open

label

Review at days 1, 2, 3, 7, 14, 21, and 28.NoneNoneNone
Agarwal 2013 KEN274Open labelClinical assessment on days 1, 2, 3, 7, 14, 21, 28, 35, and 42 after enrolment or at any day if ill.NoneNoneNone
Arinaitwe 2009 UGA

671

treated

episodes

Open

label

Review at days 0, 2, 3, 7, 14, 21, 28 after each episode for 1 year.NoneNoneNone
Bassat 2009 AF1548

Open

label

In-patient review throughout the dosing period then weekly till day 42.LFT and renal function at days 3, 28, and 42 and at clinician's requestFBC at days 3, 28 and 4212-lead ECG at days 0, 2, and 7
Kamya 2007 UGA421

Double

blind

Clinical assessment daily till day 3 then weekly until day 42.NoneNoneNone
Karunajeewa 2008 PNG250Open labelClinical assessment on days 0, 1, 2, 3, 7, 14, 28, and 42.NoneNoneNone
Krudsood 2007 THA191Open labelIn-patient review daily until day 28.NoneNoneNone
Mens 2008 KEN146Open labelReview on days 0, 1, 2, 3, 7, 14, and 28.NoneNoneNone
Ratcliff 2007 IDN774Open labelReview and symptom questionnaire daily until fever and parasites cleared then weekly until day 42.NoneNone None
Sawa 2013 KEN298Single blindClinical examination on days 1, 2, 3, 7, 14, 28, and 42.NoneNoneNone
The 4ABC Study 2011 AF2,701Single blindClinical assessment on days 1, 2, 3, 7, 14, 21, and 28.LFT and renal function at days 7 and 28FBC at days 3, 7, 14, and 28None
Yavo 2011 AF384Open labelClinical assessment on days 1, 2, 3, 4, 7, 14, 21, and 28.LFT at baseline and day 4NoneNone
Yeka 2008 UGA414Single blindReview daily till day 3 then weekly until day 42.NoneNone None
Zongo 2007 BFA375Open labelAssessment daily until day 3 then weekly until day 42.NoneNoneNone
DHA-P versus Artemether plus amodiaquine
Trial IDSample SizeBlindingClinical symptoms monitoringBiochemistryHaematologicalECG
Hasugian 2007 IDN334Open labelClinical assessment daily until afebrile then weekly until day 42.NoneNoneNone
Karema 2006 RWA504Open labelClinical assessment on days 0, 1, 2, 3, 7, 14, 21, and 28.Differential WBC count (and LFT at one site only) at days 0 and 14NoneNone
Smithuis 2010 MMR316Open labelReview weekly for 9 weeks.NoneNoneNone
The 4ABC Study 2011 AF2477Single blindClinical assessment on days 1, 2, 3, 7, 14, 21, and 28.Liver and renal function tests at days 7 and 28FBC at days 3, 7, 14, and 28None
DHA-P versus artesunate plus sulfadoxine-pyrimethamine
Trial IDSample SizeBlindingClinical symptoms monitoringBiochemistryHaematologicalECG
Karunajeewa 2008 PNG245Open labelClinical assessment on days 0, 1, 2, 3, 7, 14, 28, and 42NoneNoneNone

Appendix 2. Serious adverse event descriptions

DHA-P versus Artesunate plus mefloquine
Trial IDNumber of participantsBlindingComment
Ashley 2004a THA134Open labelNo serious adverse events observed.
Ashley 2004b THA356Open labelNo serious adverse events observed.
Ashley 2005 THA499Open label4/166 serious events with AS+MQ (death, severe anaemia, febrile convulsion, coagulopathy) and 11/333 with DHA-P (2 deaths, bacterial sepsis, febrile convulsion, leptospirosis, haematemesis, nephritic syndrome, severe anaemia, respiratory infection, epigastric pain, and vomiting).
Grande 2007 PER522Open label3 serious drug related events with AS+MQ requiring stopping treatment (encephalopathy, anxiety and arrhythmia, palpitations, and chest pain).
Janssens 2007 KHM464Open labelNo serious adverse events observed.
Mayxay 2006 LAO220Open labelOne neuropsychiatric reaction in AS+MQ group.
Smithuis 2006 MMR652Open labelNo serious adverse events reported in the first 7 days.
Smithuis 2010 MMR491Open labelNot reported.
Tangpukdee 2005 THA180Open labelNo serious adverse events observed.
Tran 2004 VNM243Open label12 events (10 vomiting, 2 dizziness) described as significant in AS+MQ group and none with DHA-P (P = 0.002).
Valecha 2010 AS1150Open label12/767 events described as serious in DHA-P group (6 deemed related to drug: 2 cases of anaemia, 1 viral infection, 1 Wolf-Parkinson-White syndrome, 1 convulsion, 1 encephalitis), 3/381 in AS+MQ group (all deemed related to drug: 1 anaemia, 1 convulsion, 1 encephalitis).
DHA-P versus Artemether-lumefantrine
Trial IDNumber of participantsBlindingComment
Adam 2010 SDN160

Open

label

All AE described as mild.
Agarwal 2013 KEN274Open label1/137 with DHA-P, 2/137 with AL (all severe malaria and attributed to new infections).
Arinaitwe 2009 UGA671 treated episodes

Open

label

3/320 with DHA-P, 1/351 with AL6 (all due to development of severe anaemia).
Bassat 2009 AF1548

Open

label

18/1038 with DHA-P and 5/510 with AL6 (P = 0.2490. One death occurred in each group but the other SAEs are not described.
Kamya 2007 UGA421

Double

blind

4/211 with DHA-P, 2/210 with AL, all judged to be unrelated to study meds (3 febrile convulsions, otitis media, asthma attack, pyomyositis).
Karunajeewa 2008 PNG250Open label Overall comment: No treatment withdrawals were attributable to adverse events related to a study drug.
Krudsood 2007 THA191Open label Overall comment: No significant differences are noted between the treatments.
Mens 2008 KEN146Open labelOne patient treated with DHA-P died on day 14. Assessed as unrelated to treatment.
Ratcliff 2007 IDN774Open labelOne death 60 days after treatment. Cause not known.
Sawa 2013 KEN298Single blind Overall comment: No adverse events reported.
The 4ABC Study 2011 AF2701Single blind10/1468 with DHA-P compared to 6/1225 with AL6. The only ones described are one death due to diarrhoeal disease in the DHA-P group and three deaths in the AL group (two severe malaria and one unknown cause). None were related to treatment.
Yavo 2011 AF384Open labelNone reported.
Yeka 2008 UGA414Single blind2/215 with AL, 5/199 with DHA-P, all judged unrelated to study meds (2 convulsions, 2 pyomyositis, vomiting, severe anaemia, dehydration).
Zongo 2007 BFA375Open labelNone observed.
Bassat 2009 AF1548

Open

label

No difference in QT prolongation.
DHA-P versus Artesunate plus amodiaquine
Trial IDNumber of participantsBlindingComment
Hasugian 2007 IDN334Open label3 with AS+AQ (2 vomiting, 1 ataxia), none with DHA-P.
Karema 2006 RWA504Open labelNot reported (one seizure with AS+AQ).
Smithuis 2010 MMR316Open labelNot reported.
The 4ABC Study 2011 AF2477Single BlindOccurence more frequent in AS+AQ group (15/1003 in the AS+AQ group versus 10/1468 in the DHA-P group). The only ones described are one severe malaria case in AS+AQ group and one death due to diarrhoeal disease in DHA-P group.
DHA-P versus artesunate plus sulfadoxine-pyrimethamine
Trial IDNumber of participantsBlindingComment
Karunajeewa 2008 PNG245Open label Overall comment: No treatment withdrawals were attributable to adverse events related to a study drug.

Footnotes

AE = adverse event; AL6 = artemether-lumefantrine; AQ = amodiaquine; AS = artesunate; DHA-P = dihydroartemisinin-piperaquine; ECG: electrocardiogram; MQ = mefloquine; QT = interval between the Q and T waves of an ECG; SAE = serious adverse event; SP = sulfadoxine-pyrimethamine.

Appendix 3. Adverse events GRADE tables

Dihydroartemisinin-piperaquine compared to Artesunate plus mefloquine for treating uncomplicated P. falciparum malaria
Patient or population: Patients with uncomplicated P. falciparum malaria
Settings: Malaria endemic areas
Intervention: Dihydroartemisinin-piperaquine (DHA-P)
Comparison: Artesunate plus mefloquine (AS+MQ)
Outcomes Number of participants having adverse events (95% CI) No of participants
(trials)
Quality of the evidence
(GRADE)
AS+MQ DHA-P
Serious adverse events (including deaths) 8 per 1000 9 per 1000
(4 to 18)
3522
(8 trials)
moderate 1,2,3,4
Gastroenterological Early vomiting 7 per 100 6 per 100
(5 to 8)
4114
(9 trials)
moderate 2,3,5,6
Nausea 20 per 100 14 per 100
(12 to 16)
4531
(9 trials)
moderate 3,5,7,8
Vomiting 13 per 100 8 per 100
(6 to 10)
2744
(5 trials)
moderate 3,5,7,8
Anorexia 15 per 100 13 per 100
(11 to 15)
3497
(6 trials)
low 3,5,7,9
Diarrhoea 6 per 100 8 per 100
(6 to 11)
2217
(5 trials)
moderate 3,5,7,8
Abdominal pain 11 per 100 11 per 100
(9 to 13)
3887
(7 trials)
moderate 3,5,7,10
Neuro-psychiatric Headache 12 per 100 10 per 100
(8 to 12)
2039
(4 trials)
low 3,5,8,11
Dizziness 36 per 100 26 per 100
(24 to 28)
4531
(9 trials)
moderate 3,5,7,8
Sleeplessness 21 per 100 10 per 100
(8 to 13)
2551
(6 trials)
moderate 3,5,7,8
Fatigue 8 per 100 3 per 100
(2 to 6)
872
(2 trials)
low 5,7,12
Nightmares 10 per 100 1 per 100
(0 to 7)
220
(1 trial)
low 5,12
Anxiety 11 per 100 1 per 100
(0 to 4)
522
(1 trial)
low 5,12
Blurred vision 9 per 100 4 per 100
(2 to 9)
464
(1 trial)
low 5,12
Tinnitus 9 per 100 4 per 100
(1 to 11)
220
(1 trial)
low 5,12
Cardio-respiratory Palpitations 18 per 100 11 per 100
(8 to 15)
1175
(3 trials)
moderate 3,5,7,8
Cough 10 per 100 8 per 100
(5 12)
1148
(1 trial)
low 5,9
Dyspnoea 9 per 100 3 per 100
(1 to 10)
220
(1 trial)
low 5,13
Prolonged QT interval
(adverse event)
4 per 100 5 per 100
(3 to 9)
1148
(1 trial)
low 9,14,15
Prolonged QT interval
(Bazett's correction)
4 per 100 9 per 100
(5 to 15)
1148
(1 trial)
low 5,9,15
Prolonged QT interval
(Fridericia's correction)
5 per 100 4 per 100
(3 to 8)
1148
(1 trial)
low 5,9,15
Musculoskeletal/
dermatological
Arthralgia 6 per 100 5 per 100
(3 to 9)
1148
(1 trial)
moderate 5,10,14
Myalgia 6 per 100 6 per 100
(4 to 10)
1148
(1 trial)
moderate 5,10,14
Urticaria 2 per 100 1 per 100
(0 to 4)
719
(2 trials)
low 5,13
Pruritis 3 per 100 2 per 100
(1 to 4)
872
(2 trials)
low 5,13
Rash 1 per 100 0 per 100
(0 to 7)
220
(1 trial)
low 5,13
The assumed risk of adverse events in the AS+MQ group is an average risk across trials. The corresponding risk with DHA-P (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval.
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
1 No serious risk of bias: Only eight of the 11 trials made any comment on serious adverse events. None of these eight trials were blinded.
2 No serious inconsistency: None of the eight trials found statistically significant differences.
3 No serious indirectness: These trials recruited both adults and children, and were conducted in Asia and South America.
4 Downgraded by 1 for imprecision: These trials do not exclude the possibility of rare but clinically important adverse effects.
5 Downgraded by 1 for serious risk of bias: All trials were open label.
6 No serious imprecision: The 95% CI around the absolute effect is narrow and excludes clinically important differences.
7 No serious inconsistency: This finding was consistent across trials with no significant statistical heterogeneity.
8 No serious imprecision: The result is statistically significant and the meta-analysis is adequately powered to detect this effect.
9 Downgraded by 1 for serious imprecision: This result does not reach statistical significance.
10 No serious imprecision: The finding is of no difference between treatments and the sample size is adequately powered to detect differences if they existed.
11 Downgraded by 1 for serious inconsistency: There is moderate heterogeneity between trials.
12 Downgraded by 1 for serious indirectness: Only two trials have assessed this outcome.
13 Downgraded by 1 for imprecision: Limited data available and the result is not statistically significant.
14 Downgraded by 1 for serious risk of bias: This trial is unblinded. Only a few of the recorded prolonged QT intervals were registered as adverse events which removed the statistical significance. The reasons for this are unclear.
15 No serious indirectness: This single large trial was conducted in adults and children in Thailand, Laos, and India.
Dihydroartemisinin-piperaquine compared to Artemether-lumefantrine for uncomplicated P. falciparum malaria
Patient or population: Patients with uncomplicated P. falciparum malaria
Settings: Malaria endemic areas
Intervention: Dihydroartemisinin-piperaquine (DHA-P)
Comparison: Artemether-lumefantrine (AL6)
Outcomes Number of participants having adverse events (95% CI) No of participants
(trials)
Quality of the evidence
(GRADE)
AL6 DHA-P
Serious adverse events (including deaths) 6 per 1000 10 per 1000
(6 to 17)
7022
(8 trials)
moderate 1,2,3,4
Gastroenterological Early vomiting 2 per 100 3 per 100
(2 to 5)
2695
(3 trials)
moderate 2,3,5,6
Vomiting 9 per 100 9 per 100
(8 to 11)
6761
(9 trials)
moderate 2,3,5,6
Nausea 2 per 100 2 per 100
(1 to 7)
547
(2 trials)
low 2,3,5,7
Diarrhoea 12 per 100 12 per 100
(10 to 14)
4889
(7 trials)
moderate 2,3,5,6
Abdominal pain 19 per 100 16 per 100
(12 to 20)
911
(5 trials)
low 2,3,5,8
Anorexia 15 per 100 14 per 100
(12 to 17)
3834
(5 trials)
moderate 2,3,5,6
Neuro-psychiatric Headache 27 per 100 33 per 100
(25 to 44)
309
(2 trials)
low 2,3,5,8
Sleeplessness 1 per 100 3 per 100
(1 to 9)
547
(2 trials)
low 2,3,5,7
Dizziness 3 per 100 4 per 100
(2 to 11)
547
(2 trials)
low 3,5,7
Sleepiness 0 per 100 0 per 100
(0 to 0)
384
(1 trial)
low 2,3,5,7
Weakness 17 per 100 18 per 100
(15 to 21)
1812
(5 trials)
moderate 2,3,5,6
Cardio-respiratory Cough 42 per 100 42 per 100
(40 to 45)
4342
(5 trials)
moderate 2,3,5,6
Coryza 68 per 100 66 per 100
(60 to 72)
832
(2 trials)
low 1,2,3,8
Prolonged QT interval
(adverse event)
3 per 100 2 per 100
(1 to 5)
1548
(1 trial)
low 8,10,11
Prolonged QT interval
(Bazett's correction)
7 per 100 9 per 100
(6 to 11)
1548
(1 trial)
low 5,8,11
Prolonged QT interval
(Fridericia's correction)
0 per 100 0 per 100
(0 to 2)
1548
(1 trial)
low 5,8,11
Musculoskeletal/
dermatological
Pruritis 2 per 100 4 per 100
(2 to 6)
2033
(5 trials)
moderate 2,3,5,6
Facial oedema 0 per 100 0 per 100
(0 to 0)
384
(1 trial)
low 2,3,5,7
*The basis for the assumed risk (for example, the median control group risk across trials) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk ratio.
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 No serious risk of bias: All but one of the trials are open label. However, we did not down grade for this outcome.
2 No serious inconsistency: The finding is consistent across all trials. Statistical heterogeneity is low.
3 No serious indirectness: Trials were mainly conducted in children in Africa, with few trials in Asia or in adults.
4 Downgraded by 1 for serious imprecision: No statistically significant difference was detected between treatments. However the current sample size does not exclude the possibility of rare but clinically important differences.
5 Downgraded by 1 for risk of bias: The majority of trials are open label.
6 No serious imprecision: The finding is of no effect and the CIs around the absolute effect excludes clinically important differences.
7 Downgraded by 1 for serious imprecision: There are limited data.

8 Downgraded by 1 for serious imprecision: The result does not reach statistical significance.
9 No serious imprecision: The total number of participants is high and findings are precise.
10 Downgraded by 1 for serious risk of bias: This trial is unblinded. Only a few of the recorded prolonged QT intervals were registered as adverse events which removed the statistical significance. The reasons for this are unclear.
11 No serious indirectness: This single trial was conducted in children in Uganda, Kenya, Mozambique, Zambia, and Burkina Faso.

Dihydroartemisinin-piperaquine compared to Artesunate plus amodiaquine for uncomplicated P. falciparum malaria
Patient or population: Patients with uncomplicated P. falciparum malaria
Settings: Malaria endemic areas
Intervention: Dihydroartemisinin-piperaquine (DHA-P)
Comparison: Artesunate plus amodiaquine (AS+AQ)
Outcomes Number of participants having adverse events (95% CI) No of participants
(trials)
Quality of the evidence
(GRADE)
AS+AQ DHA-P
Serious adverse events (including deaths) 2 per 100 1 per 100
(0 to 1)
2805
(2 trials)
moderate 1,2,3,4
Gastrointestinal Early vomiting 6 per 100 5 per 100
(3 to 10)
650
(2 trials)
low 3,5,6,7
Vomiting 11 per 100 8 per 100
(7 to 11)
2471
(1 trial)
moderate 7,8,9,10
Nausea 17 per 100 17 per 100
(11 to 28)
316
(1 trial)
moderate 5,9,11,12
Diarrhoea 11 per 100 11 per 100
(9 to 14)
2787
(2 trials)
moderate 2,3,12,13
Abdominal pain 13 per 100 12 per 100
(7 to 21)
316
(1 trial)
low 5,7,9,11
Anorexia 11 per 100 10 per 100
(8 to 12)
2787
(2 trials)
low 2,3,7,13
Neuro-psychiatric Headache 1 per 100 1 per 100
(0 to 9)
316
(1 trial)
low 5,9,11,14
Sleeplessness 14 per 100 11 per 100
(6 to 20)
316
(1 trial)
low 5,7,9,11
Cardio-respiratory Cough 31 per 100 32 per 100
(28 to 36)
2471
(1 trial)
moderate 7,8,9,10
Palpitations 23 per 100 20 per 100
(13 to 30)
316
(1 trial)
low 5,7,9,11
*The basis for the assumed risk (for example, the median control group risk across trials) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk ratio.
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
1 No serious risk of bias: Only one of the two trials was blinded. However, we did not downgrade for this outcome.
2 No serious inconsistency: The finding is consistent across all trials. Statistical heterogeneity is low.
3 No serious indirectness: Trials were mainly conducted in children in Africa and Asia, with few Asian adults.
4 Downgraded by 1 for serious imprecision: The number of events is low despite the findings reaching statistical significance and the total number of participants being high.
5 Downgraded by 1 for risk of bias: The trial that reported this finding was open-label
6 No serious inconsistency: The finding is consistent across all trials. Statistical heterogeneity can be explained by difference in definition of early vomiting.
7 Downgraded by 1 for serious imprecision: The result does not reach statistical significance.
8 No serious risk of bias: The trial that reported this outcome had low risk of bias for blinding of adverse events.
9 No serious inconsistency: This outcome was only reported in one trial.
10 No serious indirectness: This trial was mainly conducted in children in Africa.
11 No serious indirectness: The trial was mainly conducted in children and adults in Asia.
12 No serious imprecision: The finding is of no effect but the CIs around the absolute effect excludes clinically important differences.
13 Downgraded by 1 for risk of bias: Only one trial was blinded for adverse events.
14 Downgraded by 1 for serious imprecision: There are limited data and the 95% CI is wide.

Contributions of authors

DS, BZ, SD, and PO developed the protocol as used in Sinclair 2009. For this update, BZ and MG reviewed the reference list, extracted data, and entered it into Review Manager (RevMan). BZ, MG, and DS conducted the analyses, constructed summary of findings tables, and evaluated the quality of evidence using the GRADE approach. All authors reviewed and edited the final draft.

Declarations of interest

None known.

Differences between protocol and review

This review was originally incorporated in a larger review of ACTs (Sinclair 2009). In this review we have included additional appraisal and GRADE assessments of adverse effects.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Adam 2010 SDN

Methods

Trial design: An open label RCT

Follow-up: Temperature and blood smears on days 1, 2, 3, 7, 14, 21, and 28. Haemoglobin concentrations (Hb) measured on days 0 and 28.

Adverse event monitoring: Participants requested to attend the health centre any time they felt unwell. During follow-up participants were asked about the presence of adverse effects that might be expected from treatment (for example, nausea, vomiting). These were considered treatment-related if they had not been reported at the participant's first presentation.

Participants

Number of participants: 160

Inclusion criteria: Age ≥ 6 months, uncomplicated P. falciparum mono-infection, axillary temperature > 37.5°C or a history of fever within the preceding 24 hrs, able to take oral treatment, informed consent.

Exclusion criteria: Severe or complicated malaria, severe concomitant pathology or other illness needing medical follow-up incompatible with the trial, allergy to one of the trial drugs, use of one of the trial drugs in the preceding 28 days, pregnancy.

Interventions

1. DHA-P, fixed dose combination, 40 mg/320 mg adult tablets, 20 mg/160 mg children's tablets (Duo-Cotecxin: Beijing)

  • 5 to 9 kg half an adult tablet (or 1 children's tablet) each day for 3 days

  • 10 to 19.9 kg 1 adult tablet (or 2 children's tablets) each day for 3 days

  • 20 to 40 kg 2 adult tablets (or 4 children's tablets) each day for 3 days

  • > 40 kg 3 adult tablets (or 6 children's tablet) each day for 3 days

  • (Equivalent to daily doses of about 2.4 mg dihydroartemisinin/kg and 20 mg piperaquine/kg)

2. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg (Coartem: Novartis)

  • 5 to 14 kg 1 tablet twice daily for 3 days

  • 15 to 24 kg 2 tablets twice daily for 3 days

  • 25 to 34 kg 3 tablets twice daily for 3 days

  • ≥ 35 kg 4 tablets twice daily for 3 days

All doses were supervised.

Outcomes
  1. ACPR at day 28, PCR-adjusted and PCR-unadjusted

  2. Gametocyte carriage

  3. Adverse events

Not included in this review:

  1. Fever clearance time

  2. Parasite clearance time

Notes

Country: Sudan

Setting: Elmouraf health centre, Sinnar

Transmission: Unstable transmission

Resistance: "Multiple drug resistance"

Dates: Dec 2009 to Feb 2010

Funding: Beijing Holley-Cotec Pharmaceuticals

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Block-randomization using a concealed envelope system was used to allocate each patient to one of the two treatment arms". Block size was unclear.
Allocation concealment (selection bias)Unclear riskUsed concealed envelopes, unclear if they were sequentially numbered or opaque.
Blinding for microscopy outcomes (performance bias and detection bias)Low risk"all the slides were double-checked blindly".
Blinding for adverse events (performance and detection bias)High riskTrial described as "open".
Incomplete outcome data (attrition bias)
All outcomes
Low riskLow losses to follow-up in both groups (6.3% DHA-P versus 7.5% AL6).
Selective reporting (reporting bias)Low riskThe WHO recommends 42 day follow-up in studies of AL6. Day 28 outcomes may underestimate treatment failure with AL6.
Other biasUnclear riskThe role of the trial sponsor was not described.

Agarwal 2013 KEN

Methods

Trial design: An open label RCT

Follow-up: Followed up for 42 days and asked to return on days 1, 2, 3, 7, 14, 21, 28, 35, and 42 after enrolment or at any day if ill. Clinical assessment and blood smear at each visit. Hb measured on days 0, 7, 14, 28, and 42.

Adverse event monitoring: Not reported. "Adverse events investigated and addressed".

Participants

Number of participants: 274

Inclusion criteria: Children aged 6 to 59 months with axillary temperature ≥ 37.5 °C or history of fever in preceding 48 hrs, weight ≥ 5.0 kg, parasitaemia, residing within 10 km of Siaya District Hospital, written informed consent.

Exclusion criteria: Lethargy, convulsions, persistent vomiting, inability to drink, signs of severe malaria, severe anaemia (Hb < 5 g/dL), known hypersensitivity to trial drugs, presence of chronic medical conditions, treatment with any anti-malarial in preceding two weeks, previous enrolment in any malaria trial, severe malnutrition (weight-for-age ≤ 3 standard deviations below mean for gender according to WHO standards).

Interventions

1. DHA-P, fixed dose combination, 20 mg/160 mg tablets (DuoCotexin: Beijing Holley-Cotec)

  • 5 to 6 kg: one half tablet daily

  • 7 to 9 kg: one tablet daily

  • 10 to 14 kg: two tablets on day 0 then one tablet on days 1 and 2

  • 15 to 19 kg: two tablets daily

2. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg (Coartem: Novartis)

  • 5 to 14 kg 1 tablet twice daily for 3 days

  • 15 to 24 kg 2 tablets twice daily for 3 days

  • 25 to 34 kg 3 tablets twice daily for 3 days

All doses, except AL evening doses, administered under direct supervision.

Outcomes
  1. ACPR at days 28 and 42, PCR-unadjusted and PCR-adjusted

  2. Mean change in Hb from baseline to day 28

  3. Adverse events

Not included in this review:

  1. Fever clearance

  2. Parasite clearance

Notes

Country: Kenya

Setting: district hospital in western Kenya

Transmission: Holoendemic with high transmission and two seasonal peaks, April to July and November to December

Resistance: Not reported

Dates: Oct 2010 to Aug 2011

Funding: KEMRI/CDC Research and Public Health Collaboration, Beijing Holley-Cotec provided DHA-P free of charge.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"children were block randomized in fixed blocks of ten to treatment".
Allocation concealment (selection bias)Unclear riskNone described.
Blinding for microscopy outcomes (performance bias and detection bias)Low risk"All microscopists were blinded to the treatment arm".
Blinding for adverse events (performance and detection bias)Unclear riskNo other blinding reported.
Incomplete outcome data (attrition bias)
All outcomes
High riskPercentage withdrawn from analysis high in both treatment groups (17.5% DHA-P versus 18.2% AL).
Selective reporting (reporting bias)Low riskAll WHO outcomes reported.
Other biasLow riskNo other forms of bias identified.

Arinaitwe 2009 UGA

Methods

Trial design: An open label RCT

Follow-up: Blood smears taken on days 0, 2, 3, 7, 14, 21, and 28 after each episode and any time they felt ill. Follow-up continued for up to one year.

Adverse event monitoring: Clinicians assessed participants for adverse events using standardized criteria at each follow-up visit. Passive monitoring was carried out for up to 63 days after treatment. Adverse events were defined as any untoward medical occurrence, regardless of its suspected relationship to the trial drugs, as per International Conference of Harmonization guidelines. Adverse events were graded as mild, moderate, severe, or life threatening.

Participants

Number of participants: 232, with 671 episodes of uncomplicated falciparum malaria treated. All episodes treated were included in the analysis.

Inclusion criteria: For enrolment in the trial cohort: age 6 weeks to 12 months, HIV status of mother and child documented, living within a 30 km radius of the trial clinic, currently breast-feeding if HIV exposed, and informed consent including consent to come to the trial clinic for any illness and avoid medications given outside of the trial. For randomization: uncomplicated malaria diagnosed by positive blood smear after documented fever of ≥ 38.0 °C or history of fever in the past 24 hrs, age ≥ 4 months, weight ≥ 5 kg.

Exclusion criteria: Active medical problems requiring inpatient evaluation. For withdrawal from trial cohort: movement outside trial area, inability to tolerate trial drugs, withdrawal of informed consent, inability to be located for > 60 days, or inability to adhere to trial procedures and schedule.

Interventions

1. DHA-P, fixed dose combination, 40 mg/320 mg tablets (Duocotecxin: Holley Pharm)

  • Target daily dose 6.4 mg/kg dihydroartemisinin and 51.2 mg/kg piperaquine given in three equally divided daily doses to the nearest quarter tablet.

2. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg (Coartem: Novartis)

  • 5 to 14 kg 1 tablet twice daily for 3 days

  • 15 to 24 kg 2 tablets twice daily for 3 days

Only the first daily dose supervised. Subsequent episodes of malaria occurring > 14 days after a previous episode were treated with the assigned trial drug.

Outcomes
  1. Recurrent falciparum parasitaemia at day 28, 42, 63, PCR-unadjusted and PCR-adjusted

  2. Gametocyte carriage

  3. Mean change in Hb from baseline to day 28

  4. Adverse events

Not included in this review:

  1. Incidence of malaria after randomization

  2. Fever clearance

  3. Parasite clearance

Notes

Country: Uganda

Setting: Enrolled from local antenatal clinics in Tororo

Transmission: High transmission

Resistance: Not reported

Dates: Aug 2007 to Jul 2008

Funding: Doris Duke Charitable Foundation and Puget Sound Partners in Global Health. Holleypharm provided DHA-P free of charge.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"A randomization list was computer generated by an off-site investigator".
Allocation concealment (selection bias)Low risk"Sequentially numbered, sealed envelopes containing the treatment group assignments were prepared from the randomization list. The study nurse assigned treatment numbers sequentially and allocated treatment by opening the envelope corresponding to the treatment number".
Blinding for microscopy outcomes (performance bias and detection bias)Low riskNo blinding of microscopists reported, but all slides were re-read by a second microscopist, and a third microscopist resolved discrepancies.
Blinding for adverse events (performance and detection bias)High riskDescribed as "open-label".
Incomplete outcome data (attrition bias)
All outcomes
Low riskSimilar low drop out in both groups (1.7% DHA-P versus 1.6% AL6).
Selective reporting (reporting bias)Low riskAll listed outcomes reported.
Other biasLow riskThis trial randomized individuals to an ACT and then followed them up through multiple treatment episodes. The data presented is for the all malaria episodes reported during the trial period.

Ashley 2004a THA

Methods

Trial design: A 3-arm RCT

Follow-up: All patients admitted to hospital for 28 days, oral temperature taken every 6 hrs, parasite counts 12-hourly until negative then daily for 28 days

Adverse event monitoring: Adverse events defined as signs or symptoms that occurred or became more severe after treatment started. All patients had full blood counts, urea, electrolytes, creatinine, and liver function tests at days 0 and 7.

Participants

Number of participants: 134

Inclusion criteria: Age > 14 yrs, weight > 40 kg, symptoms of malaria, P. falciparum parasitaemia, informed consent.

Exclusion criteria: Pregnancy or lactation, signs or symptoms of severe malaria, > 4% of red blood cells parasitized, contraindication to mefloquine, treatment with mefloquine in the previous 60 days, sulphonamides or 4-aminoquinolones present in urine on admission.

Interventions

1. DHA-P, fixed dose combination (Artekin: Holleykin)

  • Total dose: 6 mg/kg DHA and 48 mg/kg P in 4 divided doses at 0, 8, 24, and 48 hrs

2. Artesunate plus mefloquine, loose combination (Artesunate: Guilin, Mequin: Atlantic)

  • AS 4 mg/kg once daily for 3 days

  • MQ 8 mg/kg once daily for 3 days

All doses were supervised.

Outcomes
  1. Cure rate at day 28, all reappearances of parasites presumed to be recrudescences as patients hospitalized for duration

  2. Adverse events

Not included in this review:

  1. Fever clearance time

  2. Parasite clearance time

Notes

Country: Thailand

Setting: Bangkok Hospital for Tropical Diseases

Transmission: Low transmission

Resistance: Multiple-drug resistance

Dates: Jul 2002 to Apr 2003

Funding: Mahidol University, Tak Malaria Initiative Project, supported by Bill and Melinda Gates Foundation, Wellcome Trust of Great Britain.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"The randomisation was computer generated (STATA; version 7; Statacorp)". Randomized in blocks of six.
Allocation concealment (selection bias)Unclear risk"The treatment allocation was concealed in sealed envelopes labelled with the study code", unclear if these were sequentially numbered or opaque.
Blinding for microscopy outcomes (performance bias and detection bias)Low risk"Laboratory staff reading the blood smears had no knowledge of the treatment received".
Blinding for adverse events (performance and detection bias)Unclear riskNo other blinding described.
Incomplete outcome data (attrition bias)
All outcomes
Low riskSimilar loss to follow-up in all groups (10.6% DHA-P versus 11.9% AS+MQ).
Selective reporting (reporting bias)Low riskThe WHO recommends 63 days follow-up in studies of AS+MQ. Day 28 outcomes are likely to underestimate treatment failure with AS+MQ and DHA-P.
Other biasLow riskNo other sources of bias identified.

Ashley 2004b THA

Methods

Trial design: A RCT

Follow-up: Temperature and blood smears daily until clearance of fever and parasites, then weekly attendance until day 63

Adverse event monitoring: Adverse events defined as signs or symptoms that occurred or became more severe after treatment started. A subset of 55 patients in the DHA-P group had full blood counts, urea, electrolyte, creatinine and liver function tests at days 0 and 7. Thirty-two patients from the DHA-P group also had ECG monitoring before and after treatment.

Participants

Number of participants: 355

Inclusion criteria: Age 1 to 65 yrs, symptomatic P. falciparum parasitaemia, informed consent

Exclusion criteria: Pregnancy or lactation, signs or symptoms of severe malaria, > 4% of red blood cells parasitized, contraindication to mefloquine, treatment with mefloquine in the previous 60 days

Interventions

1. DHA-P, fixed dose combination (Artekin: Holleykin)

  • Total dose: 6 mg/kg DHA and 48 mg/kg P in 4 divided doses at 0, 8, 24, and 48 hrs

2. Artesunate plus mefloquine, loose combination (Artesunate: Guilin, Mequin: Atlantic)

  • AS 4 mg/kg once daily for 3 days

  • MQ 8 mg/kg once daily for 3 days

All doses were supervised.

Outcomes
  1. Cure rate at day 63, PCR-adjusted and PCR-unadjusted

  2. P. vivax during follow-up, and mean time to reappearance

  3. Gametocyte development during follow-up

  4. Mean haematocrit at days 0 and 7

  5. Adverse events

Not included in this review:

  1. Fever clearance time

  2. Parasite clearance time

Notes

Country: Thailand

Setting: Four clinics on the Thai-Myanmar border

Transmission: Unstable low and seasonal transmission

Resistance: Multiple-drug resistance

Dates: Jul 2002 to Apr 2003

Funding: Wellcome Trust of Great Britain

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"The randomisation was computer generated (STATA; version 7; Statacorp)". Randomized in blocks of 9.
Allocation concealment (selection bias)Unclear risk"The treatment allocation was concealed in sealed envelopes labelled with the study code", unclear if these were sequentially numbered or opaque.
Blinding for microscopy outcomes (performance bias and detection bias)Low risk"Laboratory staff reading the blood smears had no knowledge of the treatment received".
Blinding for adverse events (performance and detection bias)Unclear riskNo other blinding described.
Incomplete outcome data (attrition bias)
All outcomes
Low riskSimilar losses to follow-up in all groups (12.8% DHA-P versus 13.6% AS+MQ).
Selective reporting (reporting bias)Low riskAll WHO outcomes reported.
Other biasLow riskNo other sources of bias identified.

Ashley 2005 THA

Methods

Trial design: A 3-arm RCT

Follow-up: Temperature and blood smears daily until clearance of fever and parasites, then weekly attendance for examination, symptom enquiry, malaria smear and haematocrit until day 63

Adverse event monitoring: Adverse events defined as signs or symptoms that occurred or became more severe after treatment started. Symptoms were screened at each visit

Participants

Number of participants: 499

Inclusion criteria: Age 1 to 65 yrs, symptomatic P. falciparum mono-infection or mixed infections, informed consent

Exclusion criteria: Pregnancy or lactation, signs or symptoms of severe malaria, > 4% of red blood cells parasitized, treatment with mefloquine in the previous 60 days

Interventions

1. DHA-P, fixed dose combination (Artekin: Holleykin)

  • Total dose: 6.4 mg/kg DHA and 51.2 mg/kg P in 4 divided doses at 0, 8, 24, and 48 hrs

2. DHA-P, fixed dose combination (Artekin: Holleykin)

  • Total dose: 6.4 mg/kg DHA and 51.2 mg/kg P in 3 divided doses at 0, 24, and 48 hrs

3. Artesunate plus mefloquine, loose combination (Artesunate: Guilin, Mequin: Atlantic)

  • AS 4 mg/kg once daily for 3 days

  • MQ 8 mg/kg once daily for 3 days

All doses supervised.

Outcomes
  1. Cure rate at day 63, PCR-adjusted and PCR-unadjusted

  2. P. vivax during follow-up, and mean time to reappearance

  3. Gametocyte development during follow-up

  4. Mean haematocrit at days 0 and 7

  5. Adverse events

Not included in this review:

  1. Fever clearance time

  2. Parasite clearance time

Notes

Country: Thailand

Setting: Six clinics on the Thai-Myanmar border

Transmission: Unstable low and seasonal transmission

Resistance: Multiple-drug resistance

Dates: Nov 2004 to Jun 2005

Funding: DnDi, European Union International Co-operation programme, Médecins sans Frontières, WHO/TDR, Wellcome Trust of Great Britain

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"The randomisation list was generated using STATA; version 7 (Stata)". Randomized in blocks of nine.
Allocation concealment (selection bias)Unclear risk"The treatment allocation was concealed in sealed envelopes labelled with the study code", unclear if these were sequentially numbered or opaque.
Blinding for microscopy outcomes (performance bias and detection bias)Low risk"Laboratory staff reading the blood smears had no knowledge of the treatment received".
Blinding for adverse events (performance and detection bias)Unclear riskNo other blinding described.
Incomplete outcome data (attrition bias)
All outcomes
Low riskLosses to follow-up were low in all groups (4.2% DHA-P versus 4.8% AS+MQ).
Selective reporting (reporting bias)Low riskAll WHO outcomes reported. Two patients were considered to be early treatment failures by the reviewers and reclassified as such. This was not clearly stated in the paper.
Other biasLow riskNo other sources of bias identified.

Bassat 2009 AF

Methods

Trial design: An open label RCT (non-inferiority).

Follow-up: Children were kept at the health facility for the three day treatment period, and then returned on days 7, 14, 21, 28, 35, and 42, and any time symptoms occurred, for clinical assessment and blood smears. Haematological and biochemical assessments were carried out at enrolment, days 3, 28, and 42 and at clinician request.

Adverse event monitoring: Monitoring and recording of adverse events was carried out throughout the trial. A 12-lead ECG was performed at enrolment and on days 2 and 7 to assess any QT/QTc interval prolongation.

Participants

Number of participants: 1553

Inclusion criteria: Uncomplicated malaria, age 6 to 59 months, body weight > 5 kg, fever (axillary temperature ≥ 37.5 °C) or history of fever in the preceding 24 hrs, microscopically confirmed P. falciparum mono-infection, asexual parasite densities between 2,000 and 200,000/μL, informed consent

Exclusion criteria: severe malaria or other danger signs, acute malnutrition (weight for height < 70% of the median National Center for Health Statistics/WHO reference), any other concomitant illness or underlying disease, contra-indication to trial drugs, ongoing antimalarial prophylaxis, ECG abnormality requiring urgent management

Interventions

1. DHA-P, fixed dose combination, 40 mg/320 mg tablets and 20 mg/160 mg tablets (Eurartesim®, Sigma-Tau)

  • Daily dose of 2.25 mg/kg dihydroartemisinin and 18 mg/kg piperaquine, rounded up to the nearest half tablet

2. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg (Coartem: Novartis)

  • 5 to 14 kg 1 tablet twice daily for 3 days

  • 15 to 24 kg 2 tablets twice daily for 3 days

  • 25 to 34 kg 3 tablets twice daily for 3 days

All doses were supervised.

Outcomes
  1. Adequate clinical and parasitological response on days 14, 28, and 42, PCR-adjusted and PCR-unadjusted

  2. Gametocyte presence and clearance

  3. Hb changes from baseline to day 28

  4. Adverse events

Not included in this review:

  1. Fever clearance time

  2. Parasite clearance time

Notes

Country: Burkina Faso, Kenya, Mozambique, Uganda, and Zambia

Setting: Four rural sites and one peri-urban site.

Transmission: Malaria mesoendemic at all sites. Two sites had high transmission in one period of the year (Jun to Dec or Nov to May), three others had perennial malaria with two sites having two peak seasons and one with marked seasonality (Oct to Apr)

Resistance: Documented resistance to chloroquine ranged from 35% in Burkina Faso to 81% in Uganda

Dates: Aug 2005 to Jul 2006

Funding: Medicine for Malaria Venture and Sigma-Tau I.F.R. SpA (Rome).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"A randomisation list stratified by country was generated by an independent off site contract research organisation".
Allocation concealment (selection bias)Low risk"Each treatment allocation concealed in opaque sealed envelopes that were opened only after the patient’s recruitment".
Blinding for microscopy outcomes (performance bias and detection bias)Low risk"assessment of the primary end-point were made by staff blinded to the treatment assignment and before availability of the PCR results".
Blinding for adverse events (performance and detection bias)High riskDescribed as 'open label'. ECG assessment were interpreted in a blinded manner.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNumber excluded from primary analysis similar between groups (7.5% DHA-P versus 9.7% AL6).
Selective reporting (reporting bias)Low riskAll outcomes listed in the trial protocol were assessed.
Other biasUnclear risk"Employees of Sigma-Tau participated in study design, data entry, collection and analysis of data". "An author independent of the sponsor, Umberto D’Alessandro, had access to the primary dataset and takes responsibility for the analyses and manuscript as a whole".

Grande 2007 PER

Methods

Trial design: An open-label RCT

Follow-up: Days 0, 1, 2, 3, 7, 14, 21, 28, 35, 42, 49, 56, and 63 or any other day they became ill, for a clinical assessment and malaria film. PCV measurement day 0, 7, 14 and 63. P. vivax treated with CQ.

Adverse event monitoring: Assessed at each follow-up visit, an adverse event defined as any unfavourable and unintended sign, symptom or disease temporally associated with the drug administered. Complete blood count, liver, and renal function tests at days 0 and 7.

Participants

Number of participants: 522

Inclusion criteria: Age 5 to 60 yrs, fever > 37.5 °C or history of fever in the previous 24 hrs, P. falciparum mono-infection 1000 to 200,000/µL.

Exclusion criteria: Pregnancy or lactation, severe malaria, any concomitant illness or underlying disease, contraindication to any of the trial drugs, history of treatment with mefloquine in the previous 60 days or chloroquine, primaquine or quinine in previous 14 days.

Interventions

1. DHA-P, fixed dose combination (Artekin: Holleykin)

  • Total dose: 6.3 mg/kg DHA and 50.4 mg/kg PQP in 3 divided doses, given once daily for 3 days

2. Artesunate plus mefloquine, loose combination (Artesunate: Guilin, Lariam: Hoffman La-Roche)

  • AS 4 mg/kg once daily for 3 days

  • MQ 8 mg/kg once daily for 3 days

All doses were supervised.

Outcomes
  1. Day 63 cure rate PCR-adjusted and PCR-unadjusted

  2. P. vivax during follow-up

  3. Gametocyte prevalence at day 0, 7, 14, 21, and 28

  4. Gametocyte development during follow-up

  5. Adverse events

Not included in this review:

  1. Fever clearance

  2. Parasite clearance

Notes

Country: Peru

Setting: Nine rural health posts

Transmission: Low malaria transmission

Resistance: High CQ and SP resistance

Dates: July 2003 to July 2005

Funding: Directorate-General for Development and Cooperation of the Belgian Government

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Randomized in blocks of 10". No further details given.
Allocation concealment (selection bias)Low risk"Sealed opaque envelopes were opened only after the final decision to recruit the patient had been made".
Blinding for microscopy outcomes (performance bias and detection bias)Unclear riskNo comment on blinding of laboratory staff.
Blinding for adverse events (performance and detection bias)High riskAn open-label trial.
Incomplete outcome data (attrition bias)
All outcomes
Low riskSimilar loss to follow-up in both groups (8.7% DHA-P versus 5.9% AS+MQ).
Selective reporting (reporting bias)Low riskAll WHO outcomes reported.
Other biasLow riskNo other sources of bias identified.

Hasugian 2007 IDN

Methods

Trial design: An open label RCT

Follow-up: Daily until fever and parasites cleared then weekly until day 42, for a physical examination, a symptom questionnaire and malaria film. Hb measured on days 0, 7, and 28.

Adverse event monitoring: Assessed at each follow-up visit

Participants

Number of participants: 340

Inclusion criteria: Age > 1 yr, weight > 5 kg, slide confirmed malaria (P. falciparum, P. vivax or both), fever or history of fever in the preceding 48 hrs

Exclusion criteria: Pregnancy or lactation, danger signs or signs of severe malaria, > 4% red blood cells parasitized, concomitant disease that required hospital admission

Interventions

1. DHA-P, fixed dose combination (Artekin: Holley)

  • Total dose: 6.75 mg/kg DHA and 54 mg/kg PQP in 3 divided doses given once daily for 3 days

2. Artesunate plus amodiaquine, loose combination (Arsumax: Guilin, Flavoquine: Aventis)

  • AS 4 mg/kg once daily for 3 days

  • AQ 10 mg/kg once daily for 3 days

All doses supervised

Outcomes
  1. Parasitological failure on days 42 and 28, PCR-adjusted and PCR-unadjusted

  2. Parasitological failure with P. vivax on days 42 and 28

  3. Gametocyte carriage after treatment

  4. Anaemia at days 0, 7, and 28

  5. Adverse events

Not included in the review:

  1. Fever clearance

  2. Parasite clearance

Notes

Country: Indonesia

Setting: Rural clinics

Transmission: Unstable

Resistance: Chloroquine and SP resistance

Dates: Jul 2005 to Dec 2005

Funding: Wellcome Trust - National Health and Medical Research Council.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"A randomisation list was generated in blocks of 20 by an independent statistician".
Allocation concealment (selection bias)Low risk"Treatment allocation concealed in an opaque, sealed envelope that was opened once the patient had been enrolled".
Blinding for microscopy outcomes (performance bias and detection bias)Low risk"All slides were read by a certified microscopist who was blinded to treatment allocation".
Blinding for adverse events (performance and detection bias)High riskAn open-label trial.
Incomplete outcome data (attrition bias)
All outcomes
High riskThe primary outcome data are unpublished data including only participants with P. falciparum mono or co-infection at baseline. High losses to follow-up in both groups at day 42 (21% DHA-P versus 24.5 % AL6), moderate at day 28 (16.6% DHA-P versus 18.8 % AL6).
Selective reporting (reporting bias)Low riskAll WHO outcomes reported. Day 42 outcomes may underestimate failure with DHA-P due to its long half-life.
Other biasLow riskNo other sources of bias identified.

Janssens 2007 KHM

Methods

Trial design: An open label RCT

Follow-up: Monitored daily until fever and parasites cleared then weekly to day 63. Temperature, symptom questionnaire, malaria film, and haematocrit at each visit.

Adverse event monitoring: An adverse event defined as any new sign or symptom appearing after treatment started. At each visit a symptom questionnaire was completed.

Participants

Number of participants: 464

Inclusion criteria: Age > 1 yr, axillary temp > 37.5 °C or history of fever, signs and symptoms of uncomplicated malaria, P. falciparum mono or mixed infections, written informed consent

Exclusion criteria: Pregnancy or lactation, signs or symptoms of severe malaria, > 4% red blood cells parasitized, a history of convulsions or neuropsychiatric disorder, treatment with mefloquine in the past 60 days.

Interventions

1. DHA-P, fixed dose combination, 40 mg/320 mg tablets (Artekin: Holleykin)

  • Adult total dose: 6 mg/kg DHA and 48 mg/kg P in 4 divided doses, given at 0, 8, 24, and 48 hrs

  • Children total dose: 6.4 mg/kg DHA + 51.2 mg/kg P in 4 divided doses, given at 0, 8, 24, 48 hrs

2. Artesunate plus mefloquine, loose combination (Artesunate: Guilin, Mefloquine: Mepha)

  • Adults: 100 mg AS plus 500 mg MQ twice daily on day 0, then 200 mg AS once daily on day 1 and day 2

  • Children: AS 4 mg/kg once daily for 3 days plus 25 mg/kg MQ split into 2 doses on day 0

All doses supervised.

Outcomes
  1. Cure rate at days 63, 42, and 28, PCR-adjusted and PCR-unadjusted

  2. P. vivax parasitaemia during follow-up

  3. Mean haematocrit at day 0 and 63

  4. Adverse effects

Not included in the review:

  1. Fever clearance

  2. Parasite clearance

Notes

Country: Cambodia

Setting: Rural health centres and outreach malaria clinics

Transmission: Low and seasonal

Resistance: Multiple-drug resistance

Dates: Oct 2002 to March 2003

Funding: Médecins sans Frontières

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Computer generated randomisation (STATA version 8, Statacorp)".
Allocation concealment (selection bias)Unclear risk"Treatment allocations were concealed in sealed envelopes". No further details.
Blinding for microscopy outcomes (performance bias and detection bias)Unclear riskNo comment on blinding of laboratory staff.
Blinding for adverse events (performance and detection bias)High riskAn open-label trial.
Incomplete outcome data (attrition bias)
All outcomes
Low riskLosses to follow-up balanced and low in both groups (9.3% DHA-P versus 10% AS+MQ).
Selective reporting (reporting bias)Low riskAll WHO outcomes reported.
Other biasLow riskNo other sources of bias identified.

Kamya 2007 UGA

Methods

Trial design: A single blind (outcome assessors) RCT

Follow-up: Standardized history and examination and malaria film on days 0, 1, 2, 3, 7, 14, 21, 28, 35, 42 and any other day they felt unwell. Hb measured at day 0 and day 42 or day of failure. Anaemia was treated with ferrous sulphate and anthelminthics according to IMCI guidelines.

Adverse event monitoring: Assessed for any new or worsening event at each visit. An adverse event defined as any untoward medical occurrence, irrespective of its suspected relationship to the trial medications.

Participants

Number of participants: 509

Inclusion criteria: Age 6 months to 10 yrs, weight > 5 kg, axillary temp > 37.5 °C or history of fever in the past 24 hrs, P. falciparum mono-infection 2000 to 200,000/µL, informed consent

Exclusion criteria: Danger signs or signs of severe malaria, evidence of concomitant febrile illness, history of serious side effects to trial medication

Interventions

1. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg tablets (Coartem: Novartis)

  • 5 to 14 kg 1 tablet twice daily for 3 days

  • 15 to 24 kg 2 tablets twice daily for 3 days

  • 25 to 34 kg 3 tablets twice daily for 3 days

  • > 35 kg 4 tablets twice daily for 3 days

2. DHA-P, fixed dose combination, 40 mg/320 mg tablets (Duocotexin: HolleyPharm)

  • Total dose: DHA 6.4 mg/kg + P 51.2 mg/kg in 3 divided doses, given once daily for 3 days

  • Plus placebo tablet in the evening to simulate twice daily dosing

All doses supervised. All participants received a glass of milk after each dose

Outcomes
  1. Risk of treatment failure at day 42, PCR-adjusted and unadjusted

  2. Non falciparum species during follow-up

  3. Gametocyte development during follow-up

  4. Mean increase in Hb at last day of follow-up

  5. Adverse events

Not included in the review:

  1. Fever clearance

  2. Parasite clearance

Notes

Country: Uganda

Setting: Rural health centre

Transmission: Perennial holoendemic malaria with very high transmission intensity

Resistance: Not reported

Dates: Mar 2006 to July 2006

Funding: US Centres for Disease Control, Malaria Consortium Drugman, DFID, DHA-P supplied by HolleyPharm

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"A randomisation list was computer generated by an off-site investigator".
Allocation concealment (selection bias)Low risk"Sequentially numbered, sealed envelopes containing the treatment group assignments were prepared from the randomisation list".
Blinding for microscopy outcomes (performance bias and detection bias)Low risk"Study physicians and laboratory personnel involved in assessing outcomes were blinded to treatment assignments".
Blinding for adverse events (performance and detection bias)Low riskPlacebos were used to blind participants to treatment allocation. Trial physicians were also blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskLow losses to follow-up in both groups (0.9% AL6 versus 0.9% DHA-P). A large number of participants were excluded after randomization for failing to meet the entry criteria.
Selective reporting (reporting bias)Low riskAll WHO outcomes reported. Day 42 outcomes may underestimate failure with DHA-P due to its long half-life.
Other biasLow riskNo other sources of bias identified.

Karema 2006 RWA

Methods

Trial design: A 3-arm open label RCT

Follow-up: History, clinical signs and symptoms, and malaria film on days 0, 1, 2, 3, 7, 14, 21, and 28 and any other day they felt unwell. PCV measured at days 0 and 14.

Adverse event monitoring: An adverse event defined as any unfavourable and unintended sign associated temporally with the use of the drug administered. Differential WBC count (and liver function tests at 1 site only) assessed at days 0 and 14.

Participants

Number of participants: 762

Inclusion criteria: Age 12 to 59 months, weight > 10 kg, axillary temp > 37.5 °C or history of fever in the preceding 24 hrs, P. falciparum mono-infection 2000 to 200,000/µL.

Exclusion criteria: Severe malaria, any other concomitant illness or underlying disease, known allergy to trial drugs, clear history of adequate antimalarial treatment in the previous 72 hrs, PCV < 15%.

Interventions

1. DHA-P, fixed dose combination, 40 mg/320 mg tablets (Artekin: Holleypharm)

  • Total dose: DHA 4.8 to 9.3 mg/kg + P 38.4 to 73.8 mg/kg in 3 divided doses, given once daily for 3 days

2. Artesunate plus amodiaquine, loose combination (Arsumax: Sanofi)

  • AS 4 mg/kg once daily for 3 days

  • AQ 10 mg/kg once daily for 3 days

All doses supervised

Outcomes
  1. ACPR at day 28, PCR-adjusted and PCR-unadjusted

  2. Gametocyte prevalence during follow-up

  3. Mean PCV at baseline and day 14

  4. Adverse events

Not included in this review:

  1. Fever clearance

  2. Parasite clearance

Notes

Country: Rwanda

Setting: Peri-urban and rural health centres

Transmission: Not reported

Resistance: Not reported

Dates: Oct 2003 to Apr 2004

Funding: Belgian Development Co-operation in collaboration with the Prince Leopold Institute of Tropical Medicine. DHA-P provided by Holleypharm

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Randomly allocated in blocks of 15", computer generated sequence (information from author).
Allocation concealment (selection bias)Unclear risk"Allocation of treatment was concealed until final recruitment'. No further details.
Blinding for microscopy outcomes (performance bias and detection bias)Low risk"Laboratory technicians reading malaria slides did not know the treatment received".
Blinding for adverse events (performance and detection bias)High riskAn open-label trial.
Incomplete outcome data (attrition bias)
All outcomes
Low riskVery low losses to follow-up in all groups (0.8% DHA-P versus 0.4% AS+AQ).
Selective reporting (reporting bias)Low riskAll WHO outcomes reported. Day 28 outcomes may underestimate failure with DHA-P due to its long half-life.
Other biasLow riskNo other sources of bias identified.

Karunajeewa 2008 PNG

Methods

Trial design: A 4-arm open label RCT

Follow-up: Standardized follow-up including temperature and malaria film on days 0, 1, 2, 3, 7, 14, 28, and 42. Drug levels assayed on day 7.

Adverse event monitoring: None described

Participants

Number of participants: 372

Inclusion criteria: Age 0.5 to 5 yrs, axillary temp > 37.5 °C or history of fever in the preceding 24 hrs, > 1000/µL asexual P. falciparum or > 250/µL asexual P. vivax,P. ovale, or P. malariae, informed consent

Exclusion criteria: Features of severe malaria, evidence of another infection or coexisting condition including malnutrition, intake of trial drug in previous 14 days.

Interventions

1. Artesunate plus sulfadoxine-pyrimethamine, loose combination (Sanofi-Aventis, Roche)

  • AS 4 mg/kg once daily for 3 days

  • SP 25/1.25 mg/kg once on the first day

2. DHA-P, fixed dose combination, 40 mg/320 mg tablets (Beijing Holley-Cotec)

  • DHA 2.5 mg/kg once daily for 3 days

  • P 20 mg/kg once daily for 3 days

3. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg tablets (Novartis), given with milk

  • A 1.7 mg/kg twice daily for 3 days

  • L 10 mg/kg twice daily for 3 day

All doses supervised except the evening dose of AL6

Outcomes
  1. ACPR (P. falciparum) at days 28 and 42, PCR-adjusted and PCR-unadjusted

  2. ACPR (P. vivax) at day 42

  3. Gametocyte prevalence during follow-up

  4. Adverse events

Not included in this review:

  1. Fever clearance

  2. Parasite clearance

  3. Drug levels day 7

Notes

Country: Papua New Guinea

Setting: Health centres

Transmission: Holoendemic

Resistance: CQ and SP

Dates: Apr 2005 to Jul 2007

Funding: WHO Western Pacific Region, Rotary against Malaria in Papua New Guinea, National Health and Medical Research Council of Australia

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Computer-generated randomised assignment with blocks of 24 for each site".
Allocation concealment (selection bias)Unclear riskNot described.
Blinding for microscopy outcomes (performance bias and detection bias)Low riskMicroscopists were unaware of treatment assignments.
Blinding for adverse events (performance and detection bias)High riskAn open label trial.
Incomplete outcome data (attrition bias)
All outcomes
Low riskModerate losses to follow-up in all groups (11.5% AS+SP versus 13.0% DHA-P versus 14.2% AL6).
Selective reporting (reporting bias)Low riskAll WHO outcomes reported. Day 42 outcomes may underestimate failure with DHA-P due to its long half-life.
Other biasLow riskNo other sources of bias identified.

Krudsood 2007 THA

Methods

Trial design: An open label RCT

Follow-up: Blood smears every 12 hrs until found to be negative and daily for 28 days. Haematological and biochemical samples, and urine examined on day 0, 1 and 3 and weekly for the 4 weeks trial period.

Adverse event monitoring: Regular physical examinations were conducted and assessment was done using non-suggestive questioning by investigators

Participants

Number of participants: 191

Inclusion criteria: Male and female patients with uncomplicated malaria confirmed by positive falciparum asexual blood smear, age ≥ 13 years, body weight ≥ 35kg, ability to take oral medication, agreement to stay in hospital for at least 28 days, informed consent

Exclusion criteria: Pregnant or lactating women, severe malaria per WHO criteria, vomiting not allowing oral medication, concomitant systemic disease or disorder other than malaria requiring therapy, history of ingestion of antimalarials in preceding 14 days or with sulphonamides or 4-aminoquinolones in urine.

Interventions

1. DHA-P, fixed dose combination, 40 mg/320 mg tablets (Artekin: Holleypharm)

  • Daily dose: DHA 2.0 mg/kg + P 15 mg/kg, given once daily for 3 days

2. Artemether-lumefantrine, fixed dose combination (Coartem: Novartis)

  • Daily dose: A 1.6 mg/kg + L 9.6 mg/kg, given twice daily for 3 days

All doses supervised

Outcomes
  1. Cure rate at day 28, PCR-unadjusted

  2. Adverse events

Not included in this review:

  1. Fever clearance

  2. Parasite clearance

Notes

Country: Thailand

Setting: Hospital for tropical diseases

Transmission: "No known malaria transmission"

Resistance: Some resistance to P. falciparum reported in Southeast Asia reported

Dates: Nov 2005 to June 2006

Funding: Mahidol University Research Grant

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported in the trial.
Allocation concealment (selection bias)Unclear riskNot reported.
Blinding for microscopy outcomes (performance bias and detection bias)Unclear riskBlinding of microscopists not reported.
Blinding for adverse events (performance and detection bias)High riskTrial is 'open-label'.
Incomplete outcome data (attrition bias)
All outcomes
High riskLoss to follow-up in one treatment group was high (15.5% DHA-P versus 13.8% AL6).
Selective reporting (reporting bias)Low riskAll listed outcomes are reported.
Other biasLow riskNo other sources of bias identified.

Mayxay 2006 LAO

Methods

Trial design: An open label RCT

Follow-up: Temperature was measured every 6 hrs and patient reviewed daily until fever and parasites cleared then weekly until day 42 or anytime they felt unwell. At each visit a malaria film and haematocrit measurement was taken.

Adverse event monitoring: Potential adverse events were recorded at each visit

Participants

Number of participants: 220

Inclusion criteria: Age > 1 year, axillary temp > 37.5 °C or history of fever in the previous 3 days, P. falciparum mono-infection 1000 to 200,00/µL, were likely to stay in hospital until parasite clearance and complete 42 days follow-up, informed consent

Exclusion criteria: Pregnancy or lactation, signs of severe malaria, antimalarials in the previous 3 days, contraindications to the trial drugs

Interventions

1. DHA-P, fixed dose combination, 40 mg/320 mg tablets (Artekin: Holleykin)

  • Total dose: DHA 6.3 mg/kg + P 50.4 mg/kg in 3 divided doses, given once daily for 3 days

2. Artesunate plus mefloquine, loose combination (Artesunate: Guilin, Lariam: Roche)

  • AS 4 mg/kg once daily for 3 days

  • MQ 15 mg base/kg on day 1 and 10 mg base/kg on day 2

All doses supervised.

Outcomes
  1. Cure rate at day 42, PCR-adjusted and PCR-unadjusted

  2. P. vivax during follow-up

  3. Adverse events

Not included in the review:

  1. Fever clearance time

  2. Parasite clearance time

  3. Gametocyte carriage after treatment

Notes

Country: Lao People's Democratic Republic (Laos)

Setting: District clinic

Transmission: Not reported

Resistance: Not reported

Dates: May 2004 to Sept 2004

Funding: Western Pacific Regional office of WHO, Wellcome Trust of Great Britain, Artekin provided by Holleykin Pharmaceuticals

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Randomized in blocks of 10". No further details given.
Allocation concealment (selection bias)Low risk"The treatment choice was kept in a sealed opaque envelope, which was opened only after the decision to recruit".
Blinding for microscopy outcomes (performance bias and detection bias)Unclear riskNo comment on blinding of laboratory staff.
Blinding for adverse events (performance and detection bias)High riskAn open-label trial.
Incomplete outcome data (attrition bias)
All outcomes
Low riskLow losses to follow-up in both groups (3.6% DHA-P versus 1.8% AS+MQ).
Selective reporting (reporting bias)Low riskThe WHO recommends 63 days follow-up in studies of AS+MQ. Day 42 outcomes are likely to overestimate the efficacy of the two drugs.
Other biasLow riskNo other sources of bias identified.

Mens 2008 KEN

Methods

Trial design: An open label RCT

Follow-up: Malaria film and Hb level on days 0, 1, 2, 3, 7, 14, and 28, plus QT-NASBA for detection of sub-microscopic gametocytaemia

Adverse event monitoring: Adverse events were recorded at each visit in the case record form. An adverse event defined as any unfavourable and unintended sign.

Participants

Number of participants: 146

Inclusion criteria: Age 6 months to 12 years, axillary temp > 37.5 °C or history of fever, P. falciparum mono-infection 1000 to 200,000/µL, informed consent

Exclusion criteria: Severe malaria, any other underlying illness

Interventions

1. DHA-P, fixed dose combination, 20 mg/160 mg tablets (Sigma-Tau)

  • 4 to 7 kg ½ tablet once daily for 3 days

  • 7 to 13 kg 1 tablet once daily for 3 days

  • 13 to 24 kg 2 tablets once daily for 3 days

  • 24 to 35 kg 4 tablets once daily for 3 days

2. Artemether-lumefantrine, fixed dose combination, 20/120 mg tablets (Novartis)

  • 5 to 14 kg 1 tablet twice daily for 3 days

  • 15 to 24 kg 2 tablets twice daily for 3 days

  • 25 to 34 kg 3 tablets twice daily for 3 days

All doses supervised and given with a glass of milk.

Outcomes
  1. Recurrent parasitaemia at day 28, PCR-adjusted and PCR-unadjusted

  2. Gametocyte prevalence during follow-up

  3. Mean Hb at day 28

  4. Adverse events

Not included in this review:

  1. Fever clearance

  2. Parasite clearance

Notes

Country: Kenya

Setting: Health centre

Transmission: High transmission

Resistance: Not reported

Dates: Apr 2007 to Jul 2007

Funding: The Knowledge and Innovation Fund, Koninklijk Instituut voor de Tropen/Royal Tropical Institute. DHA-P provided free of charge by Sigma-Tau.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"A computer generated randomisation list".
Allocation concealment (selection bias)Unclear riskNone described.
Blinding for microscopy outcomes (performance bias and detection bias)Low riskMicroscopists were blinded to treatment allocation.
Blinding for adverse events (performance and detection bias)Unclear riskNo other blinding described.
Incomplete outcome data (attrition bias)
All outcomes
Low riskLow losses to follow-up in both groups (8.2% DHA-P versus 8.2% AL6).
Selective reporting (reporting bias)Low riskThe WHO recommends 42 days follow-up in studies of AL6. Day 28 outcomes may underestimate treatment failure with AL6 and DHA-P.
Other biasLow riskNo other sources of bias identified.

Ratcliff 2007 IDN

Methods

Trial design: An open-label RCT

Follow-up: A symptom questionnaire, physical examination, malaria film and Hb measurement daily until fever and parasites cleared then weekly to day 42

Adverse event monitoring: A symptom questionnaire at each visit

Participants

Number of participants: 774

Inclusion criteria: Weight > 10 kg, fever or a history of fever in the preceding 48 hrs, slide confirmed malaria (P. falciparum, P. vivax or mixed infections)

Exclusion criteria: Pregnancy or lactation, danger signs or signs of severity, parasitaemia > 4%, concomitant disease requiring hospital admission

Interventions

1. DHA-P, fixed dose combination, 40 mg/320 mg tablets (Artekin: Holleykin)

  • Total dose: DHA 6.75 mg/kg + P 54 mg/kg in 3 divided doses, given once daily for 3 days

2. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg tablets (Coartem: Novartis)

  • 10 to 15 kg 1 tablet twice daily for 3 days

  • 15 to 25 kg 2 tablets twice daily for 3 days

  • 25 to 35 kg 3 tablets twice daily for 3 days

  • > 35 kg 4 tablets twice daily for 3 days

Only the first dose of each day was supervised. All participants advised to take each dose with a biscuit or milk.

Outcomes
  1. Parasitological failure at days 42 and 28, PCR-adjusted and PCR-unadjusted

  2. P. vivax during follow-up

  3. Gametocyte carriage after treatment

  4. Anaemia during follow-up

  5. Adverse events

Not included in the review:

  1. Fever clearance

  2. Parasite clearance

Notes

Country: Indonesia

Setting: Rural outpatient clinics

Transmission: Unstable

Resistance: Multiple-drug resistance

Dates: Jul 2004 to Jun 2005

Funding: Wellcome Trust UK and National Health and Medical Research Council Australia

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"A randomisation list was generated in blocks of 20 patients by an independent statistician".
Allocation concealment (selection bias)Low risk"With each treatment allocation concealed in an opaque sealed envelope". No further details given.
Blinding for microscopy outcomes (performance bias and detection bias)Low riskThe microscopists were blinded to treatment allocation.
Blinding for adverse events (performance and detection bias)High riskAn open label trial.
Incomplete outcome data (attrition bias)
All outcomes
High riskThe primary outcome data are unpublished data including only participants with P. falciparum mono or co-infection at baseline. Losses to follow-up were high in both groups at day 42 (28.4 % DHA-P versus 25.6 % AL6) and moderate at day 28 (19% DHA-P versus 17.6% AL6).
Selective reporting (reporting bias)Low riskAll WHO outcomes reported. Day 42 outcomes may underestimate failure with DHA-P due to its long half-life.
Other biasLow riskNo other sources of bias identified.

Sawa 2013 KEN

Methods

Trial design: RCT

Follow-up: Clinical assessment on days 1, 2, 3, 7, 14, 28, and 42 and any other time when child became ill. Blood smears taken on all follow-up days except day 1.

Adverse event monitoring: Not reported

Participants

Number of participants: 298

Inclusion criteria: Microscopically confirmed P. falciparum infection with asexual parasite density of 1,000 to 200,000 parasites/µL, tympanic temperature of ≥ 37.5 °C or history of fever in preceding 24 hrs, age 6 months to 10 years, informed consent

Exclusion criteria: Hb level of < 5 g/dL, presence of any other Plasmodium species, presence of other febrile disease, severe malaria, history of adverse events with trial drugs

Interventions

1. DHA-P, fixed dose combination, 40 mg/320 mg tablets (Duocotexin: Holley Pharm)

  • Total dose: DHA 6.4 mg/kg + P 51.2 mg/kg in 3 equally divided doses, given once daily for 3 days

  • Dose rounded off to nearest half tablet

2. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg tablets (Coartem: Novartis)

  • Half tablet per 5 kg body weight

  • Dose rounded to nearest half tablet

All doses were supervised. All participants advised to take each dose with fatty food to facilitate absorption.

Outcomes
  1. Parasitological efficacy at days 42 and 28, PCR-adjusted and PCR-unadjusted

  2. Gametocyte carriage after treatment

Not included in the review:

  1. Malaria transmission to mosquitoes

Notes

Country: Kenya

Setting: Community setting

Transmission: Moderate transmission intensity

Resistance: None reported

Dates: Apr to Jun 2009

Funding: Grants from the European Community’s Seventh Framework Programme and the Bill and Melinda Gates Foundation

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"A randomization list was generated for different age strata (<2 years, 2–5 years, and 5–10 years), using MS Excel".
Allocation concealment (selection bias)Unclear riskAllocation concealment is not reported.
Blinding for microscopy outcomes (performance bias and detection bias)Low risk"Except for those involved in administering medication, all staff members engaged in the trial were blinded to the treatment arm to which each child was assigned".
Blinding for adverse events (performance and detection bias)Low riskAll staff blinded were except those administering drugs.
Incomplete outcome data (attrition bias)
All outcomes
Low riskLow number of patients without outcomes in both groups (DHA-P 7.6%, AL6 5.2%).
Selective reporting (reporting bias)Low riskAll WHO outcomes are reported.
Other biasLow riskNo other sources of bias identified.

Smithuis 2006 MMR

Methods

Trial design: A 4-arm open-label RCT

Follow-up: A symptom questionnaire, malaria film, and gametocyte count on days 0, 1, 2, 3, 7, 14, 21, 28, 35, and 42. Hb was measured on days 0 and 28.

Adverse event monitoring: A symptom questionnaire at each visit

Participants

Number of participants: 652

Inclusion criteria: Age > 1 year, axillary temperature > 37.5 °C or history of fever in the previous 48 hrs, P. falciparum mono-infection 500 to 100,000 parasites/µL or co-infection with P. vivax, informed consent.

Exclusion criteria: Pregnancy, signs of severe malaria, signs or symptoms of other diseases, history of taking mefloquine in the previous 2 months or any other antimalarial in the previous 48 hrs, history of psychiatric disease.

Interventions

1. DHA-P, fixed dose combination, 40 mg/320 mg tablets (Artekin: Holleykin)

  • Total dose: DHA 6.3 mg/kg + P 50.4 mg/kg in 3 divided doses, given once daily for 3 days

  • Supervised

2. DHA-P, fixed dose combination, 40 mg/320 mg tablets (Artekin: Holleykin)

  • Total dose: DHA 6.3 mg/kg + P 50.4 mg/kg in 3 divided doses, given once daily for 3 days

  • Unsupervised

3. Artesunate plus mefloquine, loose combination (artesunate: Guilin, Lariam: Hoffman-La Roche)

  • AS 4 mg/kg once daily for 3 days

  • MQ 25 mg base/kg as a single dose on day 0

  • Supervised

4. Artesunate plus mefloquine, loose combination (artesunate: Guilin, Lariam: Hoffman-La Roche)

  • AS 4 mg/kg once daily for 3 days

  • MQ 25 mg base/kg as a single dose on day 0

  • Unsupervised

Outcomes
  1. Failure Rate at days 42 and 28, 42 PCR-unadjusted and PCR-adjusted

  2. P. vivax during follow-up and median time to appearance

  3. Gametocyte carriage at days 0, 7, 14, 21, and 28

  4. Mean change in Hb from day 0 to day 28

  5. Adverse events

Not included in the review:

  1. Fever clearance

  2. Parasite clearance

  3. New gametocyte appearance at day 7 and day 14

Notes

Country: Myanmar

Setting: Rural village tracts

Transmission: Seasonal with peaks in the monsoon season Nov to Jan and sometimes in the early monsoon, May to June

Resistance: Very high rates of CQ and SP resistance

Dates: Nov 2003 to Feb 2004

Funding: Médecins sans Frontières (Holland)

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskUnmarked and sealed envelopes, containing the treatment allocation were drawn from a box.
Allocation concealment (selection bias)Unclear risk"Unmarked and sealed envelopes". No further details given.
Blinding for microscopy outcomes (performance bias and detection bias)Unclear riskNo comment on blinding of laboratory staff.
Blinding for adverse events (performance and detection bias)High riskAn open label trial.
Incomplete outcome data (attrition bias)
All outcomes
Low riskVery low losses to follow-up in both groups.
Selective reporting (reporting bias)Low riskThe WHO recommends 63 days follow-up in studies of AS+MQ. Day 42 outcomes are likely to overestimate the efficacy of the two drugs.
Other biasLow riskNo other sources of bias identified.

Smithuis 2010 MMR

Methods

Trial design: A 5-arm open-label RCT

Follow-up: Assessment done weekly for 9 weeks and at any other time they became ill. Hb was only measured on day 63.

Adverse event monitoring: Specific procedures not reported.

Participants

Number of participants: 811

Inclusion criteria: Acute uncomplicated malaria (parasite density 500 – 200,000 parasites/µL) or mixed infection, weight > 5 kg, age > 6 months, informed consent

Exclusion criteria: Pregnancy, severe malaria, severe acute malnutrition (weight-for-height below 70% of median with or without symmetrical peripheral oedema), history of antimalarial treatment within preceding 48 hrs, history of taking mefloquine in past 8 weeks, known history of hypersensitivity to trial drugs.

Interventions

1. DHA-P, fixed dose combination, 40 mg/320 mg adult tablets, 20 mg/160mg children's tablets

  • DHA 2.5 mg/kg + P 20 mg/kg daily, given once daily for 3 days

  • Supervised

2. Artemether-lumefantrine, fixed dose combination, 20 mg/120mg tablets

  • A 3.3 mg/kg + L 19.8 mg/kg daily, twice daily for 3 days

  • Only first dose was supervised

  • Patients were advised to take some fatty food. Mothers were encouraged to breastfeed treated infants before each dose

3. Artesunate amodiaquine, fixed dose combination, 25 mg/67.5mg tablets, 50 mg/135 mg tablets, 100 mg/270mg tablets

  • AS 4 mg/kg + AQ 10.8 mg base/kg daily, once daily for 3 days

  • Supervised

4. Artesunate plus mefloquine, fixed dose combination, 25 mg/55 mg tablets, 100mg/220mg tablets

  • AS 4 mg/kg + MQ 8.8 mg/kg daily, once daily for 3 days

  • Supervised

5. Artesunate plus mefloquine, loose combination

  • AS 4 mg/kg once daily for 3 days

  • MQ 25 mg base/kg as a single dose on day 0

  • Supervised

  • Dose rounded off to nearest quarter tablet

For children, tablets were crushed and syrup added.

Outcomes
  1. Recurrence of P. falciparum after antimalarial treatment on days 28 and 63 PCR-unadjusted and PCR-adjusted

  2. P. vivax during follow-up and median time to appearance

  3. Gametocyte carriage at days 0, 7, 14, 21, and 28

  4. Mean change in Hb from day 0 to day 28

  5. Adverse events

Not included in the review:

  1. New gametocyte appearance at day 7

  2. Gametocyte carriage after single dose of primaquine

Notes

Country: Myanmar

Setting: Three clinics in Rakhine state

Transmission: Seasonal and generally low

Resistance: No resistance reported

Dates: Dec 2008 to Mar 2009

Funding: Médecins sans Frontières (Holland) and the Wellcome Trust Mahidol University Oxford Tropical Medicine Research Programme

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"random assignment was achieved by patients drawing an envelope from a box after enrolment".
Allocation concealment (selection bias)Unclear risk"Treatment allocations were put in sealed envelopes in blocks of 50 for each age-group".
Blinding for microscopy outcomes (performance bias and detection bias)Low risk"Microscopists examining blood films were unaware of treatment allocation".
Blinding for adverse events (performance and detection bias)High riskDescribed as "open-label".
Incomplete outcome data (attrition bias)
All outcomes
Low riskLow losses to follow-up in each treatment group (AA 3.2%, AL6 5.6%, AM-F 4.1%, AM-L 7.5%, DP 3.7%).
Selective reporting (reporting bias)Unclear riskSome WHO outcomes are not reported (for example, LTF, ETF).
Other biasLow riskNo other sources of bias identified.

Tangpukdee 2005 THA

Methods

Trial design: An open label RCT

Follow-up: The patients were admitted to hospital for 28 days. Clinical evaluation and parasite counts were performed 12-hourly until parasites cleared then daily for 28 days.

Adverse event monitoring: Assessed daily using non-suggestive questioning. Side effects were defined as signs and symptoms which occurred or became more severe after treatment started. Routine haematology, biochemistry, and urinalysis were conducted and baseline and weekly during follow-up.

Participants

Number of participants: 180

Inclusion criteria: Age >14 years, weight > 40 kg, P. falciparum on blood smear, ability to take oral medicines, agree to stay in hospital for 28 days, informed consent

Exclusion criteria: Pregnancy or lactation, severe malaria, severe vomiting, concomitant systemic diseases, other antimalarials in the previous 14 days or the presence of sulphonamides or 4-aminoquinolones in the urine

Interventions

1. DHA-P, fixed dose combination, 40 mg/320 mg tablets (Artekin: Holleykin)

  • Total dose: DHA 6 mg/kg + P 45 mg/kg in 3 divided doses, given once daily for 3 days

2. Artesunate plus mefloquine, loose combination

  • AS 4 mg/kg once daily for 3 days

  • MQ 8 mg/kg once daily for 3 days

All doses supervised

Outcomes
  1. Cure rate at day 28. PCR analysis not performed as all patients hospitalised for duration of follow-up, so all recurrent parasitaemias presumed to be recrudescence

  2. Adverse events

Not included in the review:

  1. Fever clearance time

  2. Parasite clearance time

Notes

Country: Thailand

Setting: Bangkok Hospital for Tropical Diseases

Transmission: Low

Resistance: Multiple-drug resistance

Dates: Not given

Funding: Mahidol University Research Grant, Artekin supplied by Holleykin Pharmaceuticals

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Randomly treated at a ratio of 1:2". No further details given.
Allocation concealment (selection bias)Unclear riskNone described.
Blinding for microscopy outcomes (performance bias and detection bias)Unclear riskNo comment on blinding of laboratory staff.
Blinding for adverse events (performance and detection bias)High riskAn open label trial.
Incomplete outcome data (attrition bias)
All outcomes
Low riskLosses to follow-up were low and similar between groups (10.8% DHA-P versus 10% AS+MQ).
Selective reporting (reporting bias)Low riskDay 28 outcomes may overestimate the efficacy of drugs with long half-lives such as AS+MQ and DHA-P.
Other biasLow riskNo other sources of bias identified.

The 4ABC Study 2011 AF

Methods

Trial design: An open label multicenter RCT

Follow-up: The patients were admitted to hospital for 3 days in some facilities while in some, they were kept for only 1h to check for vomiting. They were asked to return on days 3, 7, 14, 21, and 28. Clinical assessment and blood smears taken at each visit and when clinically judged to be necessary. Haematological samples were taken at enrolment and on days 3, 7, 14, and 28. Samples for biochemistry tests (liver and renal function) were taken at enrolment and on days 7 and 28.

Adverse event monitoring: Monitored throughout the trial. Method of monitoring not specified.

Participants

Number of participants: 4116

Inclusion criteria: Suspected uncomplicated malaria, age 6 to 59 months, body weight > 5 kg, microscopically confirmed P. falciparum mono-infection with asexual parasite density between 2,000 and 200,000/µL, fever (axillary temperature ≥ 37.5 °C) or history of fever in preceding 24 hrs, Hb ≥ 7.0 g/dL, informed consent.

Exclusion criteria: Participation in another investigational drug trial in previous 30 days, known hypersensitivity to study drugs, severe malaria or other danger signs for example not able to breast-feed or drunk, vomiting (more than twice in 24 hrs), recent history of convulsions (more than once in 24 hrs), unconscious state, unable to stand or sit, severe malnutrition (weight for height < 70% of median National Center for Health Statistics/WHO reference) or other concomitant illness or underlying disease, contra-indication to receive trial drugs, or ongoing prophylaxis with drugs having antimalarial activity.

Interventions

1. DHA-P, fixed dose combination, 40 mg/320 mg adult tablets, 20 mg/160 mg paediatric tablets (Eurartesim®: Sigma Tau)

  • DHA 2.25 mg/kg + P 18 mg/kg daily, given once daily for 3 days

  • Dose rounded off to nearest half tablet

2. Artemether-lumefantrine, fixed dose combination (Coartem: Novartis)

  • 5 to 14 kg 1 tablet twice daily for 3 days

  • 15 to 24 kg 2 tablets twice daily for 3 days

  • 25 to 34 kg 3 tablets twice daily for 3 days

  • Administered with a fatty food (for example, milk or groundnuts)

3. Artesunate-amodiaquine, fixed dose combination, 25 mg/67.5 mg tablets, 50 mg/135 mg tablets, 100 mg/270 mg tablets (Coarsucam: Sanofi Aventis)

  • AS 2.8-5.5 mg/kg + AQ 7.5-15 mg/kg, given once daily for 3 days

  • < 9 kg 1 tablet of 25 mg/67.5 mg formulation per day

  • 9 to 17.9kg 1 tablet of 50 mg/135 mg formulation per day

  • 18 to 35.9kg 1 tablet of 100 mg/270 mg formulation per day

All doses supervised.

Outcomes
  1. ACPR at day 28, PCR-unadjusted and PCR-adjusted

  2. ACPR at day 63, PCR-unadjusted and PCR-adjusted

  3. Presence and clearance of gametocytes

  4. Hb changes from baseline to days 3, 7, 14, and 28

  5. Adverse events

Not included in the review:

  1. Fever clearance time

  2. Parasite clearance time

Notes

Country: Seven sub-Saharan African countries (Burkina Faso, Gabon, Nigeria, Rwanda, Uganda, Zambia, and Mozambique)

Setting: We were unable to identify the trial sites as rural, urban or health facilities

Transmission: Varied across trial regions. Trial regions in Gabon and Nigeria had perennial and high malaria transmission; trial regions in Burkina Faso and Rwanda had seasonal but high transmission; trial regions in Zambia included areas with seasonal, mesoendemic transmission; trial regions in Mozambique had perennial, mesoendemic transmission; Jinja and Tororo trial regions in Uganda had perennial, low transmission while Mbarara in Uganda had mesoendemic transmission. .

Resistance: All sites had notable CQ and SP resistance. CQ resistance ranged from 24% in Burkina Faso to 100% in Gabon while SP resistance ranged from 4% in Burkina Faso to 49% in Jinja, Uganda.

Dates: Jul 2007 to Jun 2009

Funding: European Developing Countries Clinical Trials Partnership (EDCTP) and the Medicine for Malaria Venture (MMV).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"A randomization list was produced for each recruiting site by the National Institute for Health Research Medicines for Children Research Network Clinical Trials Unit, University of Liverpool, UK".
Allocation concealment (selection bias)Low risk"Each treatment allocation concealed in opaque sealed envelopes that were opened only after the patient’s recruitment".
Blinding for microscopy outcomes (performance bias and detection bias)Low riskTrial is described as "open-label" but the clinician or other staff following up the patient and assessing the end points blinded to the treatment assignment whenever possible.
Blinding for adverse events (performance and detection bias)Low risk"the clinician or other staff following up the patient and assessing the end points blinded to the treatment assignment whenever possible".
Incomplete outcome data (attrition bias)
All outcomes
Low riskLow loss to follow-up in each treatment group (3.5% ASAQ, 2.5% DHA-P, 2.4% AL6).
Selective reporting (reporting bias)Low riskAll WHO outcomes are reported.
Other biasLow riskNo other sources of bias identified.

Tran 2004 VNM

Methods

Trial design: An open label RCT

Follow-up: Malaria film on days 0, 2, and 7. Participants followed up to day 56 but further details not described

Adverse event monitoring: Not described

Participants

Number of participants: 243

Inclusion criteria: Age > 2 yrs, microscopically confirmed uncomplicated P. falciparum malaria

Exclusion criteria: Pregnancy, evidence of organ dysfunction, unable to tolerate oral medication, unable to return for follow-up, resident in Dac O for > 2 years

Interventions

1. DHA-P, fixed dose combination, 40 mg/320 mg tablets (Artekin: Holleykin)

  • Adults: 2 tablets at 0, 6, 24, and 48 hrs

  • Children < 15 yrs: 1 tablet at 0, 6, 24, and 48 hrs

2. Artesunate plus mefloquine, loose combination (artesunate: Guilin, Lariam: Hoffman-La Roche)

  • AS 4 mg/kg once daily for 3 days

  • MQ 25 mg base/kg as 2 divided doses 6 hrs apart on day 3

Outcomes
  1. Parasitological failure at days 42 and 28, PCR-adjusted and PCR-unadjusted

  2. Adverse events

Not included in this review:

  1. Fever clearance

  2. Parasite clearance

Notes

Country: Vietnam

Setting: Health station

Transmission: Low and seasonal

Resistance: Multiple-drug resistance

Dates: Nov 2001 to Mar 2002

Funding: Wellcome Trust of Great Britain

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Patients were randomly allocated one of three treatments in a ratio of 2:2:1". No further details given.
Allocation concealment (selection bias)Unclear risk"Drugs were kept in identically numbered opaque envelopes". No further details.
Blinding for microscopy outcomes (performance bias and detection bias)Unclear riskNo comment on blinding of laboratory staff.
Blinding for adverse events (performance and detection bias)High riskAn open label trial.
Incomplete outcome data (attrition bias)
All outcomes
Low risk"There were no losses to follow-up".
Selective reporting (reporting bias)Unclear riskIt is unclear from the paper whether it is only clinical failure that is being reported.
Other biasLow riskNo other sources of bias identified.

Valecha 2010 AS

Methods

Trial design: An open-label (non-inferiority) RCT

Follow-up: Particiopants were managed as outpatients unless local practice dictated otherwise (some centres used hospital stays of between 3 and 28 days). Outpatients were asked to return on days 1, 2, 3, 7, 14, 21, 28, 35, 42, 49, 56, and 63, and any time they felt unwell. Blood smears were performed at each visit.

Adverse event monitoring: Blood and urine samples were taken for analysis on days 0, 28, 63 (if abnormal on day 28) and on the day of any recurrent parasitaemia. Twelve-lead ECGs were performed at days 0, 2, 7, 28 (if abnormal on day 7), 63 and on the day of any recurrent parasitaemia.

Participants

Number of participants: 1150

Inclusion criteria: Age 3 months to 65 years (≥18 years in India), P. falciparum mono-infection (80 to 200,000 parasites/µL) or mixed infection, weight ≥ 5 kg, fever (≥ 37.5 °C) or history of fever, informed consent.

Exclusion criteria: Severe malaria, treatment with MQ in the 60 days before screening, treatment with DHA-P in the 3 months before screening, > 4% parasitised red blood cells, pregnancy or lactation.

Interventions

1. DHA-P, fixed dose combination, adult tablets 40 mg/320 mg, child tablets 20 mg/160 mg (Eurartesim®: Sigma Tau)

  • One dose daily for 3 days

  • 2.25 mg/kg DHA and 18 mg/kg piperaquine per dose

  • Dose rounded up to the nearest half tablet

2. Artesunate plus mefloquine, loose dose combination, AS 50mg tablets, MQ 250 mg tablets (Mepha Ltd)

  • AS 4mg/kg once daily for 3 days

  • MQ none on day 0, then 15 mg/kg once on day 1 and 10 mg/kg once on day 2

All doses supervised.

Outcomes
  1. Cure rate at days 28, 42, and 63, PCR corrected and uncorrected

  2. Mean change in Hb day 0 to day 63

  3. Gametocyte carriage

  4. Person-gametocyte-weeks

  5. Adverse events

Not included in this review:

  1. Fever clearance

  2. Parasite clearance

Notes

Country: Thailand (six sites), Laos (two centres), and India (three centres).

Setting: Hospitals and research units.

Transmission: Varied across trial regions. Trial regions in Thailand had unstable, low and seasonal malaria transmission; trial regions in Laos had seasonal transmission with a peak just after the heavy rainy months of July to August; trial regions in India included areas with perennial transmission, perennial transmission with a seasonal peak from June to September, and transmission active in post monsoon months.

Resistance: All sites had notable CQ resistance (estimates of 28 day treatment failure at the Indian sites ranged from 32% to 67% between 2002 and 2007). The Thai sites also had multi-drug resistant P. falciparum.

Dates: Jun 2005 to Feb 2007.

Funding: Medicines for Malaria Venture, Sigma Tau, and Oxford University.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"The randomisation list was generated by an external contract research organisation (MDS Pharma Services) using the plan procedure of SAS (Cary, NC, USA)".
Allocation concealment (selection bias)Unclear risk

"Randomisation was conducted under blinded conditions: the blind to the investigator and patient in the randomisation process was maintained by the use of sealed envelopes".

Envelopes are not described as opaque.

Blinding for microscopy outcomes (performance bias and detection bias)Low risk"Evaluation of the PCR test results was blinded".
Blinding for adverse events (performance and detection bias)High riskTrial is described as "open label".
Incomplete outcome data (attrition bias)
All outcomes
Low riskProportion of participants not completing the trial was low in both groups (6.6% DHA-P versus 6.0% AS+MQ).
Selective reporting (reporting bias)Low riskAll listed outcomes reported.
Other biasHigh risk"A committee representing members of the DHA-PQP Joint Development Team and trial site Principal Investigators developed the protocol. Sigma Tau conducted the study, collected and analysed data. All authors had access to the primary data and take responsibility for data reporting accuracy and completeness. The corresponding author had responsibility for the final decision to submit for publication".

Yavo 2011 AF

Methods

Trial design: An open-label (non-inferiority) RCT

Follow-up: Clinical and physical assessment and blood smears taken on follow-up days 1, 2, 3, 4, 7, 14, 21, and 28 after swallowing first antimalarial. Haematological and biochemical assessment conducted at baseline and on day 4.

Adverse event monitoring: Recorded on the case report forms and graded as mild, moderate or severe.

Participants

Number of participants: 384

Inclusion criteria: At least 2 years of age, P. falciparum mono-infection with parasitaemia from 2,000 to 200,000/µL of blood in Cameroon and Côte d’Ivoire and 1,000 to 100,000/µL of blood in Sénégal, fever with axillary temperature ≥ 37.5 °C, written informed consent

Exclusion criteria: History of side-effects to trial drugs, evidence of concomitant febrile illness, severe malaria or danger signs, treatment with 4-amino quinolones, SP, MG or halofantrine in previous 7 days or quinine, artemisinin or cyclins in previous 3 days, pregnancy or nursing, ongoing antimalarial treatment

Interventions

1. DHA-P, fixed dose combination, 40 mg/320 mg tablets (Duocotecxin: Beijing Holley-Cotect Pharmaceutical Co.)

  • One dose daily for 3 days

  • 5 to 9 kg half tablet

  • 10 to 14 kg ¾ tablet

  • 15 to 19 kg 1 tablet

  • 20 to 24 kg 1¼ tablets

  • 25 to 29 kg 1 ½ tablets

  • 30 to 34 kg 1 ¾ tablets

  • 35 to 39 kg 2 tablets

  • 40 to 44 kg 2 ¼ tablets

  • 45 to 49 kg 2 ½ tablets

  • ≥ 50 kg 3 tablets

  • Dose rounded up to the nearest quarter tablet

2. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg (Coartem: Novartis)

  • 5 to 14 kg 1 tablet twice daily for 3 days

  • 15 to 24 kg 2 tablets twice daily for 3 days

  • 25 to 34 kg 3 tablets twice daily for 3 days

  • > 35 kg 4 tablets twice daily for 3 days

All doses supervised.

Outcomes
  1. ACPR at day 28, PCR-adjusted and PCR-unadjusted

  2. Mean change in Hb day 0 to day 63

  3. Change in gametocyte carrier status

  4. Adverse events

Not included in this review:

  1. Fever clearance

  2. Parasite clearance

Notes

Country: Senegal, Côte d’Ivoire, Cameroon

Setting: health facilities

Transmission: Not reported

Resistance: "CQ and SP resistance reported in most parts of the continent"

Dates: November 2006 to May 2008

Funding: Beijing Holley-Cotec Pharmaceutical Co. Ltd which also supplied DHA-P free of charge

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"In each study site computer generated randomization codes were prepared by an independent individual".
Allocation concealment (selection bias)Low risk"These codes were enclosed in sequentially numbered opaque sealed envelopes, each of which contained the treatment allocation".
Blinding for microscopy outcomes (performance bias and detection bias)Unclear riskBlinding of microscopists not described.
Blinding for adverse events (performance and detection bias)High riskTrial described as "open label".
Incomplete outcome data (attrition bias)
All outcomes
Low riskLow percentage of patients without outcomes (3.0% in DHA-P and 2.1% in AL6).
Selective reporting (reporting bias)Low riskAll WHO outcomes are reported. Day 28 outcomes may underestimate effect of DHA-P.
Other biasLow riskNo other sources of bias identified.

Yeka 2008 UGA

Methods

Trial design: A single blind RCT

Follow-up: Standardized history, physical exam, and malaria film on days 0, 1, 2, 3, 7, 14, 21, 28, 35, and 42 and any other day they were unwell. Hb on days 0 and 42 or the day of failure. Anaemia was treated with ferrous sulphate and anthelmintics according to IMCI guidelines.

Adverse event monitoring: Assessed at each visit including neurological examination. Adverse events described as any untoward medical occurrence.

Participants

Number of participants: 461

Inclusion criteria: Age 6 months to 10 yrs, weight > 5 kg, axillary temp > 37.5 °C or history of fever in the previous 24 hrs, P. falciparum mono-infection 2000 to 200,000/µL, informed consent

Exclusion criteria: Danger signs or evidence of severe malaria, concomitant febrile illness, history of serious side effects to the trial medications

Interventions

1. DHA-P, fixed dose combination, 40 mg/320 mg tablets (Duocotexin: HolleyPharm)

  • Total dose: DHA 6.4 mg/kg + P 51.2 mg/kg in 3 divided doses, given once daily for 3 days

  • Plus placebo in the evenings to simulate twice daily dosing

2. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg tablets (Coartem: Novartis)

  • 5 to 14 kg 1 tablet twice daily for 3 days

  • 15 to 24 kg 2 tablets twice daily for 3 days

  • 25 to 34 kg 3 tablets twice daily for 3 days

  • > 35 kg 4 tablets twice daily for 3 days

All doses supervised and given with a glass of milk

Outcomes
  1. ACPR at day 42, PCR-adjusted and PCR-unadjusted

  2. Gametocytes development during follow-up

  3. Mean increase in Hb at last day of follow-up

  4. Adverse events

Not included in this review:

  1. Fever clearance

  2. Parasite clearance

Notes

Country: Uganda

Setting: Health centre

Transmission: Moderate transmission

Resistance: Not stated

Dates: Aug 2006 to Apr 2007

Funding: CDC, DfID, DHA-P supplied by Holleypharm, AL6 supplied by Uganda Ministry of Health

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"A randomisation list was computer generated by an off-site investigator".
Allocation concealment (selection bias)Low risk"Sealed opaque envelopes containing the study number and assigned treatment were secured in a locked cabinet".
Blinding for microscopy outcomes (performance bias and detection bias)Low risk"Only the study nurse was aware of assignments. All other study personnel were blinded".
Blinding for adverse events (performance and detection bias)Low risk"Patients were not informed of their treatment regimen". "Only the study nurse was aware of assignments and adverse events assessed by clinicians. All other study personnel were blinded".
Incomplete outcome data (attrition bias)
All outcomes
Low riskLow losses to follow-up in both groups (1.4% DHA-P versus 1.5% AL6).
Selective reporting (reporting bias)Low riskAll WHO outcomes reported. Day 42 outcomes may underestimate treatment failure with DHA-P due to its long half-life.
Other biasLow riskNo other sources of bias identified.

Zongo 2007 BFA

Methods

Trial design: A 3-arm RCT

Follow-up: A standardized history, examination, and malaria film on days 0, 1, 2, 3, 7, 14, 21, 28, 35, and 42. Hb measured on days 0 and 42 or day of clinical failure. Children with Hb < 10 g/dL were treated with ferrous sulphate and antihelminthic treatment.

Adverse event monitoring: Assessed at each visit. Adverse events defined as untoward medical occurrences.

Participants

Number of participants: 580

Inclusion criteria: Age > 6 months, weight > 5 kg, axillary temp > 37.5 °C or history of fever in the last 24 hrs, P. falciparum mono-infection 2000 to 200,000/µL, the ability to participate in 42 days follow-up, informed consent.

Exclusion criteria: Danger signs or signs of severe malaria, history of serious adverse effects related to trial medications, evidence of concomitant febrile illness, antimalarial use other than chloroquine in previous two weeks, Hb < 5 g/dL.

Interventions

1. DHA-P, fixed dose combination, 40 mg/320 mg tablets (Duocotexin: HolleyPharm)

  • Total dose: DHA 6.4 mg/kg + PQP 51.2 mg/kg in 3 divided doses, given once daily for 3 days

2. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg tablets (Coartem: Novartis)

  • 5 to 14 kg 1 tablet twice daily for 3 days

  • 15 to 24 kg 2 tablets twice daily for 3 days

  • 25 to 34 kg 3 tablets twice daily for 3 days

  • > 35 kg 4 tablets twice daily for 3 days

3. Amodiaquine plus sulfadoxine-pyrimethamine, loose combination (Flavoquine: Aventis, Fansidar: Roche)

  • AQ 10 mg/kg once daily on days 0 and 1, then 5 mg/kg once on day 2

  • SP 25/1.25 mg/kg on day 0

All doses supervised

Outcomes
  1. Risk of treatment failure at days 42 and 28, PCR-adjusted and PCR-unadjusted

  2. Gametocyte development during follow-up

  3. Hb (mean g/dL) on day 0 and last day of follow-up

  4. Adverse events

Not included in this review:

  1. Fever clearance

  2. Parasite clearance

Notes

Country: Burkino Faso

Setting: Health dispensaries

Transmission: Holoendemic, transmission principally in the rainy season May to Oct

Resistance: Not reported

Dates: Not reported

Funding: Doris Duke Charitable Foundation, Holley Cotec Pharmaceuticals, International Atomic Energy Agency, National Budget of the Institut de Recherche en Sciences de la Sante

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Randomly assigned on the basis of a computer-generated code provided by an off-site investigator".
Allocation concealment (selection bias)Low risk"Referred for treatment allocation by a study nurse not involved in enrolment or assessment of treatment outcomes".
Blinding for microscopy outcomes (performance bias and detection bias)High risk"The study was not blinded".
Blinding for adverse events (performance and detection bias)High riskAs above.
Incomplete outcome data (attrition bias)
All outcomes
Low riskLow losses to follow-up in all groups (8% DHA-P versus 6.4% AL6 versus 8.2% AQ+SP).
Selective reporting (reporting bias)Low riskAll WHO outcomes reported. Day 42 outcomes may underestimate treatment failure with DHA-P due to its long half-life.
Other biasLow riskNo other sources of bias identified.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Chinh 2009Comparison not relevant to this review: two fixed-dose combinations of DHA-P were compared.
Guo 1990Conference presentation. Comparison not relevant to this review: artesunate versus piperaquine.
Gupta 2010Molecular genotyping analysis based on Kamya 2007 UGA and Yeka 2008 UGA. Contains no new efficacy data.
Karema 2005Conference presentation of Karema 2006 RWA.
Somé 2010Polymorphism selection analysis based on Zongo 2007a BFA. Contains no new efficacy data.
Song 2011 KHMComparison not relevant to this review: DHA-P-phosphate (2 day dosage) versus artemether-lumefantrine.
Sutanto 2013Comparison not relevant to this review: DHA-P + primaquine versus DHA-P.
Tarning 2008Pharmacokinetic analysis based on Ashley 2005 THA. Contains no new efficacy data.
Thanh 2009Quasi-RCT.
Tjitra 2012Comparison not relevant to this review: Artemisinin-naphthoquine versus DHA-P.
Tran 2012Comparison not relevant to this review: AS monotherapy versus DHA-P.
Verret 2011Nutritional status analysis based on Arinaitwe 2009 UGA. Contains no new efficacy data.
Wang 2008Quasi-RCT.
Yeka 2013A comparison of DHA-P versus artemether-lumefantrine as rescue treatments based on The 4ABC Study 2011 AF. Contains no new efficacy data.

Characteristics of studies awaiting assessment [ordered by study ID]

Borrmann 2011 KEN (a)

Methods

Trial design: A non-inferiority RCT

Follow-up: Clinical assessment and blood smears taken on days 0, 1, 2, and 3 then weekly until day 63 and finally on day 84.

Adverse event monitoring: Monitoring done on days 0, 1, 2, and 3 then weekly until day 63 and finally on day 84.

Participants

Number of participants: 474

Inclusion criteria: Uncomplicated malaria, age 6 to 59 months, body weight ≥ 5kg, microscopically confirmed falciparum mono-infection with asexual parasite density of 2,000 to 200,000 µL, reported or documented axillary temperature ≥ 37.5 °C, informed consent

Exclusion criteria: Known allergies, severe malaria or danger signs, ECG abnormalities that require urgent management, participation in another investigational drug study within previous 30 days.

Interventions

1. DHA-P, fixed dose combination, 40 mg/320 mg tablets and 20 mg/160 mg tablets (Eurartesim®, Sigma-Tau)

  • Daily dose of 2.25 mg/kg dihydroartemisinin and 18 mg/kg piperaquine, given once daily for 3 days, rounded up to the nearest half tablet

2. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg (Coartem: Novartis)

  • A 2 mg/kg twice daily for 3 days

  • L 12 mg/kg twice daily for 3 days

All doses were supervised.

Outcomes
  1. 28-day cure rate, PCR-adjusted and PCR-unadjusted

  2. Risk of recrudescent primary or secondary (re-) infections

  3. Gametocyte carrier rate

  4. Hb recovery

Not included in this review:

  1. Fever clearance time

  2. Parasite clearance time

Notes

Country: Kenya

Setting: One hospital site.

Transmission: Perennial with peaks trailing two typical annual rainy seasons

Resistance: None reported

Dates: Sep 2005 to Apr 2008

Funding: DFG and MMV grants, European Developing Countries Clinical Trials Partnership (EDCTP) and the Wellcome Trust

Characteristics of ongoing studies [ordered by study ID]

Tekete 2012 AF

Trial name or titleEDCTP Longitudinal study
Methods

Trial design: An open-label RCT

Follow-up: Patients will receive same study drug for subsequent episodes of uncomplicated malaria for up to 2 years after first randomization. Haematology, biochemistry and clinical safety will be assessed over this two year period.

Participants

Number of participants: 4032

Inclusion criteria: Acute uncomplicated malaria, age > 6 months, weight ≥ 5 kg with no clinical sign of severe malnutrition, axillary temp > 37.5 °C, oral/rectal/tympanic temperature > 38 °C or history of fever in the last 24 hrs, microscopically confirmed P. falciparum with parasite density less than 200,000/µL, ability to swallow oral medication, no documented malaria treatment in preceding 2 weeks or 4 weeks for re-inclusion, the ability to participate in the scheduled follow-up visits, written informed consent

Exclusion criteria: Signs and symptoms of severe/complicated malaria, severe vomiting (more than 3 times in preceding 24hrs) or inability to tolerate oral medication, severe diarrhoea (3 or more watery stools per day), known history of clinically significant disorders such as cardiovascular (QTc interval > 450 ms), respiratory (including active tuberculosis), history of jaundice, renal, hepatic, gastrointestinal, immunological (including active HIV), neurological, endocrine, or other major psychiatric disorders, history of convulsions or other abnormality (including recent head trauma), Hb < 7 g/dL, concomitant febrile illness, hypersensitivity to study drugs, use of any other antimalarial in preceding 2 weeks before enrolment, pregnant or lactating women, known or suspected chronic alcohol abuse, active Hepatitis A, B or C, liver function tests > 2 times upper limit of normal, known significant renal impairment indicated by serum creatinine more than 1.5 x ULN

Interventions

1. DHA-P, fixed dose combination, adult tablets 40 mg/320 mg, child tablets 20 mg/160 mg (Eurartesim®: Sigma Tau)

  • One dose daily for 3 days

2. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg tablets (Coartem: Novartis)

  • Dose based on body weight between 2 to 4 tablets/day

  • Children given dispersible tablets

  • Once daily for 3 days

3. Artesunate-Amodiaquine, fixed dose combination, 3 strengths: 25 mg/67.5 mg, 50 mg/135 mg, 100 mg/270 mg (Winthrop: Sanofi-aventis)

  • Once daily for 3 days

4, Artesunate-Amodiaquine, fixed dose combination (Pyramax: Shin Poong)

  • Dose based on body weight between 1 to 4 tablets/sachets per day

  • Once daily for 3 days

Outcomes
  1. Incidence rate of malaria

  2. Repeated treatment safety over 2 years

  3. Efficacy of study drugs according to WHO guidelines

Starting date01 June 2011
Contact informationPrincipal investigator - Dr Abdoulaye Djimde - adjimde@mrtcbko.org
Notes

Country: Burkino Faso (2 centres), Mali (1 centre), Guinea (1 centre)

Dates: 01 June 2011 to 29 June 2014

Funding: Medicines for Malaria Venture and European & Developing Countries Clinical Trials Partnership (EDCTP)

Ancillary