Efficacy and tolerability of artesunate-amodiaquine (Camoquin plus®) versus artemether-lumefantrine (Coartem®) against uncomplicated Plasmodium falciparum malaria: multisite trial in Senegal and Ivory Coast

Authors


Corresponding Author Babacar Faye, Department of Parasitology, Faculty of Medicine, Cheikh Anta Diop University, BP 5005, 16949 Dakar Fann, Senegal. Tel.: +221 33 8251998; Fax: +221 33 3253668; E-mail: bfaye67@yahoo.fr

Summary

Objective  To compare, in a phase IV trial, the efficacy and tolerability of artesunate-amodiaquine (Camoquin plus®) dosed at 300 and 600 mg of amodiaquine per tablet to artemether-lumefantrine (Coartem®) for the treatment of Plasmodium falciparum uncomplicated malaria in Ivory Cost and Senegal.

Method  Multisite, randomised, open-labelled study in patients over the age of 7 years. The primary endpoint for efficacy was adequate clinical and parasitological response (ACPR) at day 28. The secondary endpoints were fever and parasite clearance and gametocyte carriage in each treatment group. Drug tolerability was assessed comparing adverse events and modification of biological parameters between D0 and D7. Data were analysed on an intention-to-treat and per protocol basis.

Results  We included 322 patients; 316 patients completed the monitoring to D28 (155 in AS + AQ group and 161 in AL group). In ITT analysis, an ACPR corrected rate of 97.4% was observed in AS + AQ group versus 97% in AL group (= 0.99). No parasite recrudescence was observed in AS + AQ arm. All patients in both groups had a fever and parasite clearance at D2. Gametocytes had disappeared by D14 in the AL group and by D21 in the AS + AQ group. No serious adverse events were observed. Minor adverse events were significantly more frequent in the AS + AQ arm. Biological parameters between D0 and D7 did not show any significant statistical variations except for anaemia.

Conclusion  This study demonstrates the efficacy and tolerability of AS + AQ for uncomplicated Plasmodium falciparum malaria treatment in African patients over the age of 7 years.

Introduction

Malaria is a major endemic disease caused by parasites in the tropical regions of the world with more than 2 billion people exposed to it, 300–500 million of new clinical cases and 1–2 million deaths every year. More than 90% of these deaths occur in Africa, mainly among children. Since 2001, WHO suggests to use artemisinin combination therapies (ACT) to treat P. falciparum uncomplicated malaria (WHO 2001). Many artesunate+amodiaquine combination therapies are formulated as 100 mg of amodiaquine and 50 mg of artesunate per tablet, which requires rather many tablets to be taken per day. To improve treatment compliance, Pfizer Laboratories developed two new formulations with 300/600 mg of amodiaquine per tablet and 100/200 mg of artesunate per tablet for malaria case management in children up to 7 years of age and in adults.

In this study, conducted from September 2007 to January 2008, we compared the efficacy and tolerability of this newly formulated artesunate plus amodiaquine (Camoquin Plus®; Pfizer Pharma, Dakar, Senegal) to artemether plus lumefantrine (Coartem®; Novartis Pharma AG, Basel, Switzerland) in the treatment of uncomplicated malaria among patients over 7 years of age.

Methods

Study site

In Senegal, the study was carried out in Guediawaye health district, 16 km from Dakar. In Ivory Coast, the study was undertaken in the General Hospital of Bonoua and in the community level urban health structure of Anonkoua-Kouté. The Department of Parasitology, Faculty of Medicine, Cheikh Anta Diop University of Dakar coordinated the study.

Study population

Patients with the following criteria were enrolled: age >7 years; axillary temperature above 37.5 °C; P. falciparum parasite density between 1.000 and 100.000 asexual forms/μl of blood (Senegal) and 2.000 and 200.000 asexual forms/μl of blood (Ivory Cost). Informed consent was obtained from each of the participants or his/her legal representative. Patients were excluded if they had signs of severe malaria (WHO 2000).

The protocol was reviewed and approved by the “Conseil National de Recherche en Santé“(CNRS) which is the national ethics committee in Senegal and the the “Comité National d’Ethique des Sciences de la Vie et de la Santé” (CNESVS) of Ivory Coast.

Study procedures

This was a multicentre open randomised clinical trial, phase IV comparing 3-day regimens of AS + AQ and AL, with 28 days follow-up. Patients were enrolled, weighed and randomised in blocks of 10 to receive AS + AQ or AL.

The number of patients to be included in this study was determined using Epi info 2000 software. On the basis of previous studies, the cure rate of AL was estimated at 95% (Ndayiragije et al. 2004; Martin et al. 2006). The maximal difference acceptable for the AS + AQ to be considered as clinically non-inferior is 5% (absolute value in percentage). For a statistical power of 80% (β = 20%), a risk α = 5%, and using 95% a confidence level, the sample size for each arm was 150 patients (75 patients per arm in each country).

All doses were administered at the health post, under direct supervision of the investigators. In the event of vomiting within the 30 minutes after taking the drug, the dose was repeated. Patients who kept vomiting were withdrawn.

The drug dosages of the study were the following: for AS + AQ, two dosages were used in the study. Children aged 7–14 years received 1 tablet of amodiaquine (300 mg of amodiaquine) and one tablet of artesunate (100 mg of artesunate) per day in a single dose for 3 days. The daily dose among adults (up to 14 years old) was one amodiaquine tablet (600 mg) and one artesunate tablet (200 mg) in a single dose for 3 days. AL was administered twice a day according to the patient’s weight for 3 days.

Study participants were examined in the study clinic 1, 2, 3, 7, 14, 21 and 28 days after enrolment or at any time if they did not feel well. Thick films were carried out during these visits. Quinine was given in case of treatment failure.

Blood for thick and thin smears was obtained by finger prick on Day 1, 2, 3, 7, 14, 21 and 28. Blood smears were stained with Giemsa, and 200 leucocytes were read. Assuming a total leukocyte count of 8000/l, parasite density was determined as the number of asexual parasites x 8000/200. The slide readers were kept blinded to the treatment allocated.

To distinguish recrudescence from new infection in case of treatment failure, four drops of blood were collected on filter paper on day 0 and on the day the parasitemia recurred. The parasite was genotyped by nested PCR to compare two polymorphic genetic markers from Plasmodium falciparum: Merozoïte Surface Protein (MSP) genes 1 and 2.

Tolerability and safety assessment

All adverse events were closely monitored during each scheduled visit. Adverse events were defined as occurring new events or worsening from baseline after administration of treatment. Patients were interviewed by the investigators to assess adverse events and were also examined by a physician. All signs noted during the interview and clinical examination were reported.

Haematology and biochemical tests were carried out at enrolment and Day 7 to evaluate haemoglobin, creatinin, aspartate amino transferase (ASAT), alanine amino transferase (ALAT) and bilirubin parameters. Biological abnormalities were noted.

Data analysis

Data were captured and analysed using Epi info 2000 software. The Intention-to-treat (ITT) and per protocol (PP) analyses were performed. ITT included all randomised participants who took at least one full dose and had one post-baseline efficacy assessment without major protocol violations as wrong dosage, wrong use of non-assigned drug by mistake and co infection with other malaria species. Patients with major protocol violations and patients lost to follow up or withdrawn (because of an adverse event or to the use of another drug with antimalarial activity or withdrawal consent) were considered as treatment failures. The per protocol analysis included patients who received the three doses and had no major protocol violation up to the day 28. Those lost to follow up or withdrawing consent were excluded from the per protocol analysis.

The primary endpoint was adequate clinical and parasitological response (ACPR). The secondary endpoints were comparison of fever and parasite clearance, gametocyte carriage after treatment and tolerability of the two regimens.

Data were analysed by estimations of difference in proportions corresponding to a 95% confidence interval. Groups were compared using chi-square test or Fisher exact test for qualitative outcome and Student’s t-test for quantitative outcome when applicable. Otherwise, non-parametric tests (Mann–Whitney, Kruskall–Wallis) were used. A p value (two-sided) <0.05 was considered statistically significant.

Results

Trial profile

Of 886 patients screened, 322 patients meeting the inclusion criteria participated in the trial: 159 in the AS + AQ group and 163 in the AL group. Two cases of withdrawal of consent (one case in each group) and three lost to follow up, all in the AS + AQ arm were registered. A patient from the AL group who received quinine after inclusion was excluded from the study for protocol violation. The global trial profile of patients in the study is summarised in Figure 1.

Figure 1.

 Trial profile.

At inclusion, the two groups were similar regarding age, gender, weight, axillary temperature, parasite density and gametocyte carriage (Table 1). The average age was 12.2 ± 9 in AS+AQ group and 18.3 ± 11 in AL group (P = 0.15). Average weight was 43 ± 18 in AS + AQ group and 44.6 ± 18 in AL group (P = 0.29). The sex ratio was not significantly different: 1.25 in AS + AQ group and 1.05 in Al group (P = 0.69). On the whole, both groups of patients were comparable at the inclusion as far as socio-demographic parameters are concerned.

Table 1.   General features of patients at the inclusion
ParametersAS + AQALP value
Mean age16.2 ± 918.3 ± 110.15
Mean weight43 ± 1844. 6 ± 180.29
Sex ratio m/f 1.25 1.050.69
Axillary Temperature (°C)38.14 ± 1.3138.15 ± 1.280.99
Mean parasitic density28439308170.73
Gametocyte carriers5 (3.1%)5 (3%)1

Regarding biological data at inclusion, no significant statistical difference was observed in haemoglobin, creatinin and bilirubin rates (Table 4). We did not observe any significant statistical difference in ALAT and ASAT average rates among the two groups (P = 0.11).

Table 4.   biological parameters between J0 and J7
Biological parametersCamoquin plus® (n = 160)PCoartem® (n = 162)P
J0J7J0J7
Haemoglobin average rate(g/dl)11.1710.60.0211.311.030.11
Anaemia (Hb <11g/dl) (%)36.867.5<10−330.939.30.10
ALAT average rate(UI/l)282812725.80.56
Patients with normal ALAT (%)85.685.6183.386.40.43
ASAT average rate(UI/l)31.4330.50.7331.327.80.10
Patients with normal ASAT (%)82.581.90.8880.287.70.06
Mean bilirubin6.55.90.355.65.70.86
Mean creatinin5.35.20.864.85.10.59
Patients with high creatinin (>13) (%)8.76.90.536.26.80.82

Therapeutic efficacy

The ACPR in ITT analysis at D28 was 95.6% in the AS + AQ group and 95.7% in the AL group (P = 0.97) (Table 2). Treatment failure was noted in 3 patients in the AS+AQ group (1.8%) and in 5 patients in the AL group (3%). After PCR, three patients were classified as having recrudescence, all in the AL group. The ACPR corrected was 97.4% for the AS + AQ arm and 98.2% for the AL arm (P = 0.99).

Table 2.   Treatment outcome at D28
OutcomeArtesunate Amodiaquine (AS + AQ)Artemether- Lumefantrine (AL)P value
Intention to treat analysis
 Enrolled patients159163 
 Patients seen at day 28155/159 (97.5%)161/163 (98.7%)0.73
 Missing  4/159 (2.5%)  2/163 (1.2%)0.75
 Crude parasitological failure at day 28  3/159 (1.8%)  5/163 (3.6%)
 PCR adjusted failure rate at day 28  0/159 (0%)  3/163 (1.8%)0.30
 PCR adjusted Cure rate at day 28155/159 (97.4%)160/163 (98.2%)0.31
Per-protocol analysis
 Patients seen at day 28155161 
 Crude parasitological failure day 28  3/155 (1.9%)  5/161 (3.1%)
 PCR adjusted failure rate day 28  0/155 (0%)  3/161 (1.9)
 PCR adjusted failure rate day 28155/155 (100%)158/161 (98.10%)0.07

In PP analysis, the ACPR at D28 was 98.1% for AS + AQ and 96.8% for AL (P = 0.74). After PCR correction, ACPR was 100% for AS + AQ and 98.1% among patients treated with AL (P = 0.25). All patients in both groups achieved complete fever and parasite clearance were obtained on D2.

At inclusion, 3.1% and 3%, respectively, in the AS + AQ and AL groups carried gametocytes. The same proportion was observed on D1 and D2; complete gametocyte clearance was obtained at D21 for patients treated with AS + AQ and D14 for those treated with AL (Figure 2).

Figure 2.

 Evolution of gametocytes carriage.

Tolerability and safety

Overall, the clinical tolerance of the drugs in the study was good in both treatment groups. No patient in the study presented a serious adverse event, although 50 patients in the AS + AQ group (31.2%) and 49 patients in the AL group (30.2%) did presented at least one adverse event (P = 0.88). Adverse events were more frequent in the AS + AQ group. The difference was statistically significant for abdominal pain, nausea/vomiting and dizziness (Table 3).

Table 3.   Adverse events reported from D0 to D28
SymptomsAS + AQ (n = 159)AL (n = 163)P value
  1. Significant values are given in bold.

Headache44 (27.5%)41 (25.3%)0.65
Abdominal pain41 (25.6%)26 (16%)0.03
Nausea -Vomiting50 (31.2%)27 (16.6%)0.02
Asthénie12 (7.5%)9 (5.5%)0.47
Dizziness18 (11.2%)6 (3.7%)0.009

Anaemia was more frequent, and the average rate of haemoglobin was low on D7 in the AS + AQ group (P = 0.02). Patients with high creatinin decreased in AS + AQ group at D7. No significant statistical variations were noted for the other biochemical parameters (Table 4).

Discussion

Rapid and effective case management is a key for malaria control. This requires not only the proper diagnosis of cases but also the administration of efficient antimalarial drugs. The rates of ACPR at D28 during this study in ITT and PP analysis demonstrate the good efficacy of AS + AQ for the treatment of uncomplicated malaria in adult. ACPR in IT was 97.4% for AS + AQ and 98.2% for the comparator: AL (P = 0.99). In PP, this ACPR corrected was 100% for AS + AQ versus 98.1% for AL (P = 0.25).

These results confirm the data previously published in other similar clinical trials in Senegal (Brasseur et al. 2007; Faye et al. 2007) and in Africa in general evaluating this combination (Oyakhirome et al. 2007; Falade et al. 2008; Sirima et al. 2009).

Fever and parasitemia disappear rapidly. After 48 h of the first administration of the drugs, fever and parasite clearance was complete in the two groups. This is a basic property of ACTs (Adjei et al. 2008; Juma et al. 2008).

Both treatments had an action on the gametocyte carriage; and there was a gradual elimination of gametocytes in both arms. However, the antigametocyte action was more effective and quick during the treatment with AL. The artemisinin derivates antigametocyte action was demonstrated in other studies (Martin et al. 2006; Oyakhirome et al. 2007; Kobbe et al. 2008, Ménard et al. 2008).

Both treatments were clinically and biologically well tolerated by patients with comparable profiles. Minor adverse events were noted in each treatment arm. However, it seems that they are more frequently observed with AS + AQ combination. Nausea, vomiting, abdominal pains and dizziness were frequently reported by patients who received amodiaquine. The frequency of these adverse events could be attributable to the specific presentation of this AS + AQ combination. These are tablets containing 600 or 300 mg of amodiaquine and tablets of 100 or 200 mg of artesunate, in a single daily dose. This formulation has the advantage of reducing the number of tablets, but it may increase adverse events. A study in Senegal has shown that it is possible to reduce these side effects by dividing the daily dose (Ndiaye et al. 2008).

Our study confirmed the good efficacy and the tolerability of artesunate-amodiaquine combination treatment of Plasmodium falciparum uncomplicated malaria in African adults. It also demonstrates the non-inferiority of AS + AQ dosed at 300 and 600 mg of amodiaquine per tablet in one dose per day versus AL in two doses per day. However, adverse events, although mild, are more frequent with this formulation. To achieve equally good results in normal circumstances, where the treatment is not supervised, good compliance on the part of patients is required. This new formulation, with fewer tablets per dose, may lead to better compliance.

Acknowledgements

We are grateful to all the patients who agreed to participate in the study and the medical staff in the health structures involved for facilitating the study on their site. The investigations were financially supported by Pharmaceutical lab PFIZER, West Africa who also supplied the antimalarial drugs used for this study.

Ancillary