To establish efficacy and safety of artesunate/lumefantrine fixed-dose combination (FDC) in comparison with artemether/lumefantrine FDC in treatment of uncomplicated Plasmodium falciparum malaria.
To establish efficacy and safety of artesunate/lumefantrine fixed-dose combination (FDC) in comparison with artemether/lumefantrine FDC in treatment of uncomplicated Plasmodium falciparum malaria.
Confirmed cases of uncomplicated P. falciparum malaria were randomly assigned to receive artesunate (100 mg)/lumefantrine (480 mg) (ASLF FDC) or artemether (80 mg)/lumefantrine (480 mg) (AMLF FDC) tablets for 3 days. Patients were followed up on Day 7, 14, 21 and 28.
Of the 158 enrolled patients, 144 completed the study. Seventy-three patients (94.8%) from the ASLF group and 71 patients (94.7%) from the AMLF group showed parasite clearance within 48 h. The mean parasite clearance time was 25.40 ± 14.82 h in the ASLF group and 24 ± 13.32 h in the AMLF group (P = 0.542). All patients showed gametocyte clearance by Day 7 and remained gametocyte free till Day 28. Sixty-five patients (84.4%) from the ASLF group and 56 patients (74.7%) from the AMLF group were afebrile within 24 h. The mean fever clearance time was 17.38 ± 12.33 h in the ASLF group and 17.2 ± 12.01 h in the AMLF group (P = 0.929). There was one early treatment failure in the AMLF group as per WHO criteria. Improvement in haemoglobin and haematocrit was comparable in both the treatment groups. In the ASLF group, of the 25 (32.47%) patients anaemic at baseline, only seven (9.09%) reported anaemia on Day 28, while in the AMLF group, of the 14 (18.67%) patients anaemic at baseline, only four (5.33%) reported anaemia on Day 28. Both study medications were well tolerated.
Artesunate (100 mg)/lumefantrine (480 mg) fixed-dose combination could add one more option to currently available artemisinin combinations in treatment of uncomplicated P. falciparum malaria.
Mesurer l'efficacité et la sécurité de combinaisons à dose fixe (CDF) d'artésunate/luméfantrine comparées à celles de la CDF d'artéméther/luméfantrine dans le traitement du paludisme non compliqué à P lasmodium falciparum.
Les cas confirmés de paludisme non compliqué à P . falciparum ont été randomisés pour recevoir soit des comprimés d'artésunate (100 mg)/luméfantrine (480 mg) (ASLF-CDF) ou d'artéméther (80 mg)/luméfantrine (480 mg) (AMLF-CDF) pendant 3 jours. Les patients ont été suivis jusqu'aux jours 7, 14, 21 et 28.
Sur les 158 patients inscrits, 144 ont terminé l’étude. L’élimination des parasites a été observée dans les 48 heures chez 73 patients (94,8%) du groupe ASLF et 71 (94,7%) du groupe AMLF. Le temps moyen de clairance parasitaire était de 25,40 ± 14,82 h dans le groupe ASLF et 24 ± 13,32 h dans le groupe AMLF (P = 0,542). Tous les patients ont montré une clairance des gamétocytes au jour 7 et en sont restés exempts jusqu'au jour 28. 65 patients (84,4%) du groupe ASLF et 56 patients (74,7%) du groupe AMLF étaient non fébriles endéans les 24 heures. La durée moyenne pour la clairance de la fièvre était de 17,38 ± 12,33 h dans le groupe ASLF et 17,2 ± 12,01 h dans le groupe AMLF (P = 0,929). Il y a eu 1 cas d’échec thérapeutique précoce dans le groupe AMLF selon les critères de l’OMS. L'amélioration dans le taux d'hémoglobine et dans l'hématocrite était comparable dans les deux groupes de traitement. Dans le groupe ASLF, sur 25 (32,47%) patients anémiques au départ, seuls 7 (9,09%) ont rapporté de l'anémie au jour 28, alors que dans le groupe AMLF, sur 14 (18,67%) patients anémiques au départ, seuls 4 (5,33%) ont rapporté de l'anémie au jour 28. Les deux types de médicaments de l’étude ont été bien tolérés.
La CDF d’ASLF pourrait être une option additionnelle dans les combinaisons à base d'artémisinine actuellement disponibles dans le traitement du paludisme non compliqué à P . falciparum.
Establecer la eficacia y la seguridad de las combinaciones de dosis fija (CDF) de artesunato + lumefantrina, comparada con la CDF artemeter+lumefantrina en el tratamiento de la malaria no complicada por P lasmodium falciparum.
Los casos confirmados de malaria no complicada por P . falciparum fueron asignados de forma aleatoria para recibir pastillas de artesunato (100 mg)/lumefantrina (480 mg) (CDF-ASLF) o artemeter (80 mg)/lumefantrina (480 mg) (CDF-AMLF) durante 3 días. Se realizó un seguimiento a los pacientes en los días 7, 14, 21 y 28.
De los 158 pacientes incluidos en el estudio, 144 lo completaron. 73 pacientes (94.8%) del grupo ASLF y 71 pacientes (94.7%) del grupo AMLF estaban limpios de parásitos a las 48 h. El tiempo medio para la ausencia de parásitos era de 25.40 ± 14.82 h en el grupo ASLF y de 24 ± 13.32 h en el grupo AMLF (P = 0.542). Todos los pacientes estaban libres de gametocitos en el Día 7 y continuaban así hasta el Día 28. 65 pacientes (84.4) del grupo ASLF y 56 pacientes (74.7%) del grupo AMLF estuvieron afebriles dentro de las primeras 24 h. El tiempo medio para no tener fiebre era de 17.38 ± 12.33 h en el grupo ASLF y 17.2 ± 12.01 h en el grupo AMLF (P = 0.929). Hubo 1 fallo temprano en el tratamiento dentro del grupo AMLF según criterios de la OMS. La mejoría en la hemoglobina y el hematocrito era comparable en ambos grupos de tratamiento. En el grupo ASLF, de los 25 (32.47%) pacientes anémicos antes del tratamiento, solo 7 (9.09%) reportaron anemia a Día 28, mientras que en el grupo AMLF de los 14 (18.67%) pacientes anémicos antes de recibir tratamiento, solo 4 (5.33%) reportaron anemia a Día 28. Ambas medicaciones utilizadas en el estudio fueron bien toleradas.
La CDF ASLF podría ser una opción más a las combinaciones de artemisinina actualmente disponibles para el tratamiento de la malaria no complicada por P . falciparum.
Malaria remains one of the largest global healthcare problems of the 21st century (Krudsood et al. 2003). Of the four species, Plasmodium falciparum is the most dangerous parasite with increasing morbidity and mortality in tropical regions (Looareesuwan et al. 1999). Each year 1.5–2.7 million cases of malaria result in death (Day 1996). Resistance to commonly used antimalarials such as chloroquine and sulphadoxine/pyrimethamine poses major challenges to malaria control (Kabanywanyi et al. 2007); thus, WHO (2010) recommends the use of artemisinin combination therapies (ACTs) as the first-line treatment of malaria.
A combination antimalarial therapy, usually consisting of a fast-acting, short half-life antimalarial and more slowly acting agent with a longer half-life, is recommended for treatment of P. falciparum malaria (Miller et al. 2006). Artemisinin derivatives are noted for rapid reduction in parasite biomass (Falade et al. 2008). For the ACTs to be highly effective in a 3-day regimen, the terminal elimination half-life of atleast one drug component must exceed 24 h (Nosten & White 2007). Lumefantrine, having a longer elimination half-life (approximately 4.5 days) (Omari et al. 2009), has a slower onset of action and clears the residual parasites (Premji et al. 2008). Based on this consideration, artemether–lumefantrine (AMLF), artesunate–amodiaquine, artesunate–sulphadoxine–pyrimethamine, artesunate–sulphamethoxypyrazine–pyrimethamine or artesunate–mefloquine are some of the combinations that are proven to be safe and effective (Brockman et al. 2000; Von Seidlein et al. 1998, 2000; Adjuik et al. 2002).
Of the available derivatives, artesunate has the favourable pharmacological profile for use in ACT treatment of uncomplicated malaria. The hemisuccinate group in the molecule confers water solubility and relatively high oral bioavailability. It is rapidly and quantitatively converted in vivo to the potent active metabolite dihydroartemisinin (Davis et al. 2005), the most active schizonticidal metabolite. Artemisinin, dihydroartemisinin and artemether are all poorly water soluble, that is, absorption is slower and less complete. Thus, artesunate could provide an advantage over other artemisinins (Li & Weina 2010). In a combination of artesunate and lumefantrine, artesunate, being a fast-acting drug, will quickly reduce the parasite biomass and resolve clinical symptoms, while long-acting lumefantrine may prevent recrudescence. This dual effect will eventually reduce the selective pressure on the parasite to develop resistance.
In view of the potential benefits of artesunate and lumefantrine, this study aims to assess the comparative safety and efficacy of artesunate (100 mg)/lumefantrine (480 mg) fixed-dose combination (FDC) with AMLF FDC in the treatment of uncomplicated P. falciparum malaria.
This was a randomised, double-blind, double-dummy, comparative, multicentric, phase III study conducted at six centres in India, namely IPGMER/SSKM Hospital, Kolkata; Surat Municipal Institute of Medical Education & Research, Surat; Smt. BK Shah Medical College & Dhiraj Hospital, Vadodara; Government Medical College & New Civil Hospital, Surat; LTMMC & Municipal General Hospital, Mumbai; and Sheth VS General Hospital, Ahmedabad. The study was approved by the regulatory authority and hospital ethics committee of each centre and was conducted according to Good Clinical Practices Guidelines and Declaration of Helsinki.
Patients of either sex aged between 18 and 65 years, with a body weight >40 kg and diagnosed of uncomplicated P. falciparum malaria were included. Clinically, malaria was confirmed by positive blood smear with asexual parasite density between 1000 and 100 000/μl, axillary temperature ≥37.5 °C and/or history of fever during last 24 h and any three of the following signs and symptoms of uncomplicated malaria: chills, nausea, vomiting, headache, malaise, diarrhoea and anorexia.
Patients were excluded if they had severe malaria or mixed malarial infections. Patients with a family history of congenital prolongation of QTc interval, cardiac dysrhythmias, bradycardia, severe cardiac disease or electrolyte imbalance were excluded from study. Patients with recent myocardial infarction, stroke, unstable angina, a history of coronary artery bypass surgery or transient ischaemic attack in past 6 months were excluded from the study, as were patients with a systolic BP >180 mmHg and/or diastolic BP >110 mmHg, abnormal renal and liver function, blood related disorders and neurological disorders. Patients using concomitant medication, which may interact with study drugs or known to be metabolised by CYP2D6, were excluded. Patients with a history of hypersensitivity to study drugs, HIV, hepatitis or syphilis infection, alcohol or other substance abuse and those who had participated in any other clinical trial within 30 days prior to screening/enrolment in this study were not enrolled. Women who were pregnant, lactating or of child-bearing age and not using medically accepted means of birth control were also excluded.
All patients were provided with an oral explanation about the study and study drugs, and all patients gave written consent to participate in the study prior to performing any study-related procedure. Blood samples were collected for presence of parasite and other laboratory investigations. Both thick and thin blood smear examination was performed. Approximately 1 μl of blood was used to prepare the thick smears. A qualified pathologist at each site performed the microscopic examination. At least 50 fields were reviewed before a negative result was reported.
Confirmed cases of uncomplicated P. falciparum malaria satisfying the eligibility criteria were enrolled and randomised to artesunate 100 mg/lumefantrine 480 mg (ASLF FDC) or artemether 80 mg/lumefantrine 480 mg (AMLF FDC) (Lumerax®, Ipca Laboratories Limited) groups. Patients were hospitalised for next 4 days and received treatment on the 0th, 8th, 24th, 36th, 48th and 60th h along with high fatty food. In case if patient vomited the first dose (0th h) within 1 h of administration, the full dose was readministered. If vomiting persisted, the patient was excluded from the trial. Standard anti-emetics and antipyretics were permitted to prevent any associated nausea, vomiting and fever, respectively. Patients were examined every 12 and 6 h during hospitalisation for presence of parasites and fever, respectively. Patients were discharged 24 h after the last dose and were followed up on Day 7, 14, 21 and 28 for clinical and safety evaluation. Physical examination and vital signs were recorded daily during hospitalisation and at each follow-up visit. At each visit, details of concomitant medications, if any, were captured and blood sample was collected for haemoglobin and haematocrit estimation. Microscopic examination of blood smear was performed for parasite count and gametocyte carriage for symptomatic patients. Further evaluations were performed for patients reporting any adverse event (AE).
Patients were randomly allocated to receive treatment with either ASLF FDC or AMLF FDC as per the computer-generated block randomisation. The number of blocks was calculated at each centre, based on the block size and number of patients recruited at each centre.
A double-blind and double-dummy design was adopted for this study. Along with the active drug of the respective group, a matching placebo of the other active drug was given to the patients to maintain blinding. Each site was provided with a sealed envelope that contained individual patient envelopes with the details of treatment allocation. These envelopes were to be opened only in case of emergency or serious adverse event (SAE). The study drug was administered either by a study investigator or medically qualified personnel.
Efficacy outcome measures were parasite clearance time (PCT), as assessed by measuring the time from the first dose until the first total and continued disappearance of asexual parasite forms for at least an additional 24 h. Thick and thin blood smear (venous blood sampling) was examined for malaria parasites every 12 h until negative during hospitalisation and then at the follow-up visit if the patient was symptomatic. Gametocyte carriage in the peripheral blood smear was assessed along with parasitaemia. The clinical signs and symptoms of malaria were evaluated at each visit.
Fever clearance time (FCT) was assessed by measuring the time from the first dose until the first time the body temperature dropped and remained <37.5 °C for at least another 48 h. It included patients who had a body temperature of >37.5 °C at baseline. Body temperature was recorded every 6 h during hospitalisation and subsequently at each follow-up visit. Parasite reduction during the first 48 h (measured as number of patients with a negative blood smear on Day 2 and Day 3) was also evaluated.
The 28-day cure rate, defined as proportion of patients with clearance of parasitaemia within 3 days of initiation of study treatment, without subsequent treatment failure within 28 days, was also determined. Change in haemoglobin and haematocrit from baseline until the end of study was evaluated.
At the end of the study, response to therapy based on patient's overall response to the study drugs was observed and categorised as per criteria given by WHO (2006). Early treatment failure (ETF) was defined as development of danger signs or severe malaria on Day 1, Day 2 or Day 3, in presence of parasitaemia; parasitaemia on Day 2 higher than on Day 0 irrespective of axillary temperature; axillary temperature ≥37.5 °C on Day 3 in the presence of parasitaemia; parasitaemia on Day 3 was ≥25% of count on Day 0. Late treatment failure (LTF) was defined as development of danger signs or severe malaria after Day 3 in the presence of parasitaemia, without previously meeting any of the criteria of ETF; presence of parasitaemia and axillary temperature ≥37.5 °C (or history of fever) on any day from Day 4 to Day 28, without previously meeting any of the criteria of ETF; presence of parasitaemia on any day from Day 7 to Day 28 and axillary temperature <37.5 °C, without previously meeting any of the criteria of ETF or late clinical failure. Adequate clinical and parasitological response (ACPR) was defined as absence of parasitaemia on Day 28 irrespective of axillary temperature without previously meeting any of the criteria of ETF or LTF.
Safety evaluation was based on AEs reported during the study and changes in the laboratory parameters. AEs were categorised by the investigator according to intensity as mild, moderate or severe. At each visit, reported AEs, clinical state of patient and details of concomitant medications, if any were captured. Changes in the laboratory parameters were assessed by obtaining blood and urine samples at baseline and 24 h after the last dose administration for routine haematology, biochemistry and routine urinalysis.
The trial was designed as a non-inferiority study. Assuming a 5% failure rate in AMLF group and a maximum allowable inferiority of 10% for the ASLF group compared with AMLF, a sample size of 72 patients per group was required with 80% power and 95% confidence.
Descriptive statistics were used to compare the demographic characteristics of the study population and their initial clinical and biological characteristics. Data were presented in terms of mean ± SD and/or median (range) for continuous variables and percentage for categorical variables. All patients were compared at baseline for homogeneity using t-test or Mann–Whitney U-test for continuous variables and chi-square test for categorical variables.
Efficacy was evaluated using modified intension-to-treat (ITT) analysis that included all randomised patients who participated at least until Day 3. Efficacy parameters were PCT, FCT, resolution of clinical signs and symptoms and gametocyte clearance. Continuous data were compared by t-test or Mann–Whitney U-test. Categorical data were analysed by chi-square test or Fisher's exact test, as appropriate.
Safety data were evaluated using ITT analysis that included all patients who gave written informed consent for participation in study. Safety parameters were AEs and changes in laboratory parameters. For all statistical tests, the significance level was set at 0.05. Statistical analysis was performed using SAS 9.2.
Between July 2009 and January 2012, 263 patients presenting with signs and symptoms of malaria were screened, of whom 158 eligible patients were enrolled in the study and 105 excluded. Eligible patients were randomised to receive either ASLF FDC (n = 80) or AMLF FDC (n = 78). Of the 158 patients, 144 patients completed the 28-day follow-up. Figure 1 provides the details of screening, enrolment, treatment and follow-up. The Day 7 LTF case in AMLF was symptomatic throughout the study, and parasitaemia was observed at 0, 12, 24, 36, 48, 60 and 72 h. Also, gametocyte carriage was observed in this patient till the last visit.
Both treatment groups were similar with respect to baseline demography and disease characteristics, except for average pulse rate, which was higher in the AMLF group than in the ASLF group (89.87 ± 10.11 vs. 94.05 ± 11.14; P = 0.017), but the difference was not clinically significant (Table 1). Baseline clinical signs and symptoms of malaria were similar in both the groups and reflected the underlying malaria infection. Commonly reported signs and symptoms were fever, chills and headache. Fever was reported by all patients in both groups. Anorexia was reported in significantly more number of patients randomised to ASLF group [ASLF: 25 (31.25%), AMLF: 13 (16.67%); P = 0.031]. Other reported signs and symptoms were nausea, malaise, vomiting, myalgia, diarrhoea, abdominal cramps and arthralgia.
|Parameters||Artesunate 100 mg + lumefantrine 480 mg (N = 80)||Artemether 80 mg + lumefantrine 480 mg (N = 78)||P-value|
|Age (years)b (range)||32.79 ± 11.14 (18–60)||32.49 ± 10.01 (18–65)||0.862|
|Height (cm)b (range)||161.3 ± 7.08 (134–176)||161.29 ± 6.42 (150–174)||0.993|
|Weight (kg)b (range)||57.9 ± 8.62 (42–90)||58.08 ± 8.14 (41.9–84)||0.894|
|BMI (kg/m2)b (range)||22.3 ± 3.36 (16.14 - 31.89)||22.42 ± 3.52 (15.21 - 34.52)||0.846|
|Pulse rate (beats/min)b (range)||89.87 ± 10.11 (72–120)||94.05 ± 11.14 (72–140)||0.017|
|Respiration rate (breaths/min)b (range)||18.10 ± 1.91 (16–26)||18.51 ± 2.43 (16–28)||0.258|
|Systolic blood pressure (mmHg)b (range)||114.81 ± 11.85 (90–170)||112.92 ± 9.2 (90–130)||0.289|
|Diastolic blood pressure (mmHg)b (range)||74.47 ± 6.63 (60–90)||74.8 ± 5.61 (60–86)||0.739|
|Body temperature (°F)b (range)||100.69 ± 1.4 (97–103)||100.87 ± 1.25 (98.4–103)||0.454|
|Parasite density (parasite count/μl)c (range)||14357.2 [10746.18, 19181.6] (1000–115000)||10811.09 [7941.6, 14717.3] (240–67000)||0.078|
|Patients with parasitesd|
|<5000/μl||19 (23.75)||24 (30.77)||0.104|
|≥5000 and <15 000/μl||9 (11.25)||5 (6.41)|
|≥15 000 and <30 000/μl||21 (26.25)||30 (38.46)|
|≥30 000/μl||31 (38.75)||19 (24.36)|
|Gametocyte carriaged||10 (12.50)||10 (12.82)||0.924|
|Presence of hepatomegalyd||4 (5.00)||4 (5.13)||0.969|
|Presence of splenomegalyd||6 (7.50)||5 (6.41)||0.789|
|Sign and symptomsd|
|Fever||80 (100)||78 (100)||0.999|
|Chills||76 (95.00)||70 (89.74)||0.086|
|Headache||60 (75.00)||58 (74.36)||0.897|
|Nausea||38 (47.50)||33 (42.31)||0.457|
|Malaise||37 (46.25)||32 (41.03)||0.553|
|Vomiting||23 (28.75)||23 (29.49)||0.989|
|Anorexia||25 (31.25)||13 (16.67)||0.031|
|Myalgia||15 (18.75)||19 (24.36)||0.364|
|Diarrhoea||6 (7.50)||4 (5.13)||0.383|
|Abdominal cramps||4 (5.00)||3 (3.85)||0.739|
|Arthralgia||3 (3.75)||4 (5.13)||0.673|
Efficacy was assessed by comparing PCT, FCT and 28-day cure rate.
Patients from both treatment groups showed rapid clearance of parasites (Table 2). No significant difference was observed in the proportion of aparasitaemic patients on Day 1 in the two treatment groups [70.13 vs. 72% from ASLF and AMLF group, respectively (P = 0.790)]. At the end of Day 3, 76 patients from the ASLF group and 72 patients from the AMLF group showed complete parasite clearance. The median PCT100 in both the treatment groups was 24 h (Table 3).
|No. of patients with||Artesunate 100 mg + lumefantrine 480 mg (N = 77) n (%)||Artemether 80 mg + lumefantrine 480 mg (N = 75) n (%)||P-value|
|After 12 h||29 (37.66)||31 (41.33)||0.643|
|After 24 h||54 (70.13)||54 (72.00)||0.799|
|After 36 h||69 (89.61)||69 (92.00)||0.611|
|After 48 h||73 (94.81)||71 (94.67)||0.969|
|After 60 h||76 (98.70)||72 (96.00)||0.298|
|After 72 h||76 (98.70)||72 (96.00)||0.298|
|After 6 h||28 (36.36)||32 (42.67)||0.427|
|After 12 h||43 (55.84)||45 (60.00)||0.604|
|After 18 h||57 (74.03)||58 (77.33)||0.635|
|After 24 h||65 (84.42)||56 (74.67)||0.136|
|After 48 h||77 (100.0)||75 (100.0)||0.999|
|After 72 h||77 (100.0)||75 (100.0)||0.999|
|After 12 h||12 (15.58)||6 (8.00)||0.148|
|After 24 h||8 (10.39)||6 (8.00)||0.647|
|After 48 h||5 (6.49)||4 (5.33)||0.793|
|After 72 h||4 (5.19)||3 (4.00)||0.752|
|Day 7||0 (0.00)||0 (0.00)||–|
|Day 14||0 (0.00)||0 (0.00)||–|
|Day 21||0 (0.00)||0 (0.00)||–|
|Day 28||0 (0.00)||0 (0.00)||–|
|Parameters||Artesunate 100 mg + lumefantrine 480 mg (N = 77) n (%)||Artemether 80 mg + lumefantrine 480 mg (N = 75) n (%)||P-value|
|Fever clearance timea|
|Mean ± SD||17.38 ± 12.33||17.2 ± 12.01||0.929|
|Median (95% CI)||12 (14.58–20.18)||18 (14.44–19.96)||0.986|
|Gametocyte clearance timea|
|Mean ± SD||21.66 ± 35.04||17.28 ± 25.9||0.383|
|Median (95% CI)||12 (12–168)||12 (12–168)||0.201|
|Mean ± SD||25.40 ± 14.82||24 ± 13.32||0.542|
|Median (95% CI)||24 (22.04–28.77)||24 (20.91–27.09)||0.697|
Using the formula proposed by Stepniewska et al. 2010, for a true positivity rate of <3%, n should not exceed [(n + 60)/26], where n is number of patients with parasitaemia on Day 3 for patient sample size >50, the proportion is 2.54 [(1 + 60)/24] for artesunate–lumefantrine group, 2.63 [(3 + 60)/24] for AMLF group and 2.67 [(4 + 60)/24] for total population.
The rate of parasite clearance was similar in both treatment groups: >99% of parasites were cleared within 48 h. There was no significant difference between the groups with respect to percentage reduction in mean parasite count during hospitalisation.
The mean (±SD) FCT was 17.38 ± 12.33 h in the ASLF group and 17.2 ± 12.01 h in the AMLF group. The mean and median FCT was comparable in both treatment groups (P > 0.05) (Table 3). It was observed that 84.42% of patients from the ASLF group and 74.67% of patients from the AMLF group were afebrile within 24 h. By 48 h, all patients were afebrile, demonstrating rapid fever clearance ability of both the treatments. Both groups were comparable with respect to percentage of patients showing fever clearance at 6, 12, 18, 24, 48 and 72 h (Table 2).
The 28-day cure rate revealed 100% efficacy in per protocol (PP) population. Both modified ITT and PP analysis for 28-day cure rates did not demonstrate any significant difference between the treatment groups. In the ITT population, there was 1 ETF in AMLF group as per WHO criteria. There was no late parasitological or clinical failure in the treatment groups. There was comparable improvement in clinical status of the patients in both the treatment groups.
Gametocyte carriage rates in both treatment groups were similar at baseline. At 12 h, two new cases of gametocyte carriage were reported in the ASLF group, but in the subsequent hours, a fall in the number of gametocyte carriers was observed. Median gametocyte clearance time was 12 h in both treatment groups. All patients showed gametocyte clearance by Day 7 and remained gametocyte free till Day 28. There was no significant difference in patients with presence of gametocytes in both the treatment groups at 24, 48 and 72 h (Table 2).
At the end of therapy, patients in both treatment groups showed comparable improvement in haemoglobin levels (Figure 2). In the ASLF group, of the 25 (32.47%) patients anaemic (Hb < 11 gm/dl) at baseline, only seven (9.09%) reported anaemia on Day 28, while in AMLF group, of the 14 (18.67%) patients anaemic at baseline, only four (5.33%) reported anaemia on Day 28 (Table 4). The median anaemia recovery time was 2 days in the ASLF and 1.5 days in the AMLF group.
|Outcome||Artesunate 100 mg + lumefantrine 480 mg (N = 77)||Artemether 80 mg + lumefantrine 480 mg (N = 75)||P-valuea|
|No. of patients with Hb < 11 gm/dLc|
|Baseline||25 (32.47)||14 (18.67)||0.051|
|End of therapy||7 (9.09)||4 (5.33)||0.371|
|Recovery time from anaemiad (in days)||2 (1.58 – 8.53)||1.5 (0.59 – 6.81)||0.299|
Both treatments were well tolerated, and no SAE was reported. A total of seven AEs (6 in ASLF and 1 in AMLF) were reported by five patients (4 in ASLF and 1 in AMLF; P = 0.188) during the study. The AEs comprised headache (3 in ASLF group) and fever (2 in ASLF group and 1 in AMLF group). Vomiting was reported by one patient in the ASLF group. All AEs were mild and did not have any casual relationship with study drugs. No significant difference was observed with respect to the incidence of AEs reported in two treatment groups. Also, no clinically significant changes were observed in any of the routine biochemical parameters or the routine urine examination from baseline till end of therapy.
Both artesunate and lumefantrine have been available for some time for treatment of malaria. However, to the best of our knowledge, to date there are no data available with ASLF combination for the treatment of uncomplicated P. falciparum malaria. This was probably the first clinical study that evaluated the comparative efficacy and safety of ASLF FDC in a randomised, double-blind, double-dummy, comparative, multicentric study in Indian patients with P. falciparum malaria. By demonstrating the non-inferiority of the therapeutic efficacy and safety of ASLF with respect to AMLF, this study shows that ASLF could be an effective alternative for the treatment of uncomplicated P. falciparum malaria.
WHO (2010) recommends that artemisinin-based combination therapies be used for the treatment of uncomplicated P. falciparum malaria. The advantages of adding artemisinin derivatives are as follows: rapid killing of parasites, prevention of ETF, reduction in the parasite biomass and gametocytocidal activity (Looareesuwan et al. 1999). ACTs combine a derivative of the natural product artemisinin, an extremely potent and fast-acting antimalarial endoperoxide, with a longer-lasting partner drug that continues to reduce the parasite biomass after the short-lived artemisinin has dropped below therapeutic levels. Artemisinin derivatives act rapidly against asexual blood stage parasites to alleviate symptoms and have the additional beneficial effect of killing gametocytes and therefore decreasing parasite transmission (Greenwood et al. 2008).
All enrolled patients were almost equally distributed between the two treatment groups with regard to demography and baseline disease characteristics. The baseline clinical signs and symptoms were comparable in both the groups except of anorexia that was significantly high in ASLF group.
The ACPR is an outcome that measures treatment response over a clinically relevant period. In the present study, all patients responded satisfactorily to the 2 treatment regimens with similarly high level of efficaciousness, that is, 100% cure in both the treatment groups in the modified ITT population, while 100% in the ASLF and 98.7% in AMLF group in PP population.
The expectation that artesunate and artemether would produce a rapid reduction in parasites during the initial stages of treatment and that lumefantrine would then prevent reappearance during the follow-up period was well supported by the efficacy data, with a median PCT of 24 h and concomitant resolution of fever (median FCT was 12 and 18 h in ASLF and AMLF group, respectively). Further, complete gametocyte clearance was observed on Day 7 and followed the similar pattern on both treatment groups.
The effect of ASLF combination observed in this study on gametocyte carriage is also consistent with the results of the studies conducted with AMLF combination previously (Sowunmi et al. 2007). The various other parameters (% reduction in mean parasites, proportion of patients with parasite clearance within 48 h, parasite and fever clearance in 24 h and time to fever clearance in evaluable patients) were comparable in both the treatment groups. Also, there was no significant difference in anaemia recovery time between two treatment groups.
As mentioned by Stepniewska et al. 2010, for a true positivity rate of <3%, n (number of patients with parasitaemia) should not exceed (n + 60)/24. In our study, n did not exceed the proportion for ASLF group, whereas n exceeded the proportion for AMLF group and the total population, indicating more detailed investigations.
The AEs reported in this study were same as those generally expected in malaria patients with antimalarial medications (Miller et al. 2006). No patient experienced any SAE during the trial. The reported AEs were mild, required symptomatic treatment or resolved on their own. Clinical improvement was immediate upon initiation of treatment, and complete resolution of signs and symptoms by end of the therapy indicates the effectives of both the treatments. Also, both treatments showed improvement in haemoglobin and haematocrit levels at the end of the study, that is, Day 28. The changes in the other laboratory investigations in either treatment group were not clinically significant. Both medications were well tolerated and showed overall good response.
In conclusion, ASLF FDC was not inferior to AMLF FDC in the treatment of uncomplicated P. falciparum malaria in Indian patients. The two artemisinin-containing combinations showed a good safety profile and were well tolerated. Because artesunate 100 mg/lumefantrine 480 mg FDC provided an effective, sustained and well-tolerated parasite clearance and clinical improvement, similar to widely accepted AMLF combination, ASLF could add one more option to currently available artemisinin combinations in the treatment of uncomplicated P. falciparum malaria.
This study was funded by Ipca Laboratories Ltd., Mumbai, India. We thank Ravikiran Payghan and Anita Parihar, for their technical support in coordinating the study-related activities at all the sites; Kumar Naidu and Avinash Mule for statistical analysis and data management for this study; and Shruti Kulkarni, Pankaj Wadibhasme and Prashant Nawal for help with drafting this manuscript. Authors would also like to thank Dr. Dipak Idani and Dr. Jigar Mehta, who were study co-investigators at Surat Municipal Institute of Medical Education and Research, Surat; and Smt. BK Shah Medical College and Dhiraj Hospital, Vadodara, respectively.