Evaluation of 4 Artemisinin-based Combinations for Treating Uncomplicated Malaria in African Children

Study Overview
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Brief Summary
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The main objective is to compare the safety and efficacy of 4 artemisinin-based combinations (ACT) [amodiaquine-artesunate (AQ+AS), dihydroartemisinin-piperaquine (DHAPQ), artemether-lumefantrine (AL) and chlorproguanil/dapsone plus artesunate] for single and repeat treatments of uncomplicated malaria in children. Safety will be determined by registering adverse events and grading, laboratory, and vital signs evaluations. Their incidence will be compared between the different study arms. TO BE NOTED: following GlaxoSmithKline decision to discontinue the clinical development of the fixed-doses combination of Lapdap (Chlorproguanil-Dapsone) and artesunate, the Lapdap plus Artesunate arm was immediately discontinued in this study, on 17th February 2008. A formal amendment has been submitted to all the concerned ECs and competent authorities. The leading EC approved the amendment on 2nd June 2008. TO BE NOTED: since the batches of the study drug DHAPQ expire at the end of October 2008, and because of the unavailability of a new batch of DHAPQ from the manufacturer, the recruitment in the DHAPQ arm had to be discontinued on 30th October 2008. A formal amendment has been submitted to all the concerned ECs and competent authorities.

Official Title
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Evaluation of 4 Artemisinin-based Combinations for Treating Uncomplicated Malaria in African Children

Conditions
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Fever, Malaria

Intervention / Treatment
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* Drug: amodiaquine-artesunate (ASAQ)
* Drug: dihydroartemisinin-piperaquine (DHAPQ)
* Drug: artemether-lumefantrine (AL)
* Drug: Lapdap (Chlorproguanil-Dapsone) + artesunate (AS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and Females aged between 6 months and 59 months inclusive. In the sites where CDA is tested all recruited children will be aged between 12 months and 59 months inclusive (this arm was discontinued on 17th February 2008). This criterion applies only for the recruitment in the first follow up. For the second follow up, children having been included in the first follow up are eligible, regardless of their age. Body weight of 5 Kg and above. Microscopically confirmed, monoinfection of Plasmodium falciparum (parasitaemia ≥ 2,000/μL to 200,000/μL). Fever (axillary temperature at ≥ 37.5°C) or history of fever in the previous 24 hours. Haemoglobin value ≥ 7.0 g/dl; Signed (or thumb-printed whenever parents/guardians are illiterate) informed consent by the parents or guardians. Note the informed consent will be asked only at recruitment and will cover the whole period of the study, including second active follow up and passive case detection. Parents' or guardians' willingness and ability to comply with the study protocol for the duration of the trial. Exclusion Criteria: Participation in any other investigational drug study (antimalarial or others) during the previous 30 days. Known hypersensitivity to the study drugs. Severe malaria. Danger signs: not able to drink or breast-feed, vomiting (> twice in 24hours), recent history of convulsions (>1 in 24h), unconscious state, unable to sit or stand. Presence of intercurrent illness or any condition (cardiac, renal, hepatic diseases) which in the judgement of the investigator would place the subject at undue risk or interfere with the results of the study, including known G6PD deficiency. Severe malnutrition (defined as weight for height <70% of the median NCHS/WHO reference). Ongoing prophylaxis with drugs having antimalarial activity such as cotrimoxazole for the prevention of Pneumocystis carinii pneumonia in children born to HIV+ women.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 59 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>AS-AQ | Drug: amodiaquine-artesunate (ASAQ)<br>* A fix-dose combination tablet containing artesunate-amodiaquine in three different dosages, to be used according to patient age and weight: 25mg/67.5mg; 50mg/135mg; 100mg/270mg<br>* Other names: Coarsucam by Sanofi-Aventis;|
| Experimental: 2<br>DHAPQ TO BE NOTED: since the batches of the study drug DHAPQ expire at the end of October 2008, and because of the unavailability of a new batch of DHAPQ from the manufacturer, the recruitment in the DHAPQ arm had to be discontinued on 30th October 2008. A formal amendment has been submitted to all the concerned ECs and competent authorities. | Drug: dihydroartemisinin-piperaquine (DHAPQ)<br>* DHAPQ tablets contain either 20/160mg or 40/320mg of dihydroartemisinin (DHA) and piperaquine phosphate (PQ) respectively.<br>* Other names: NOTE: batches expire on 31Oct08. Due to unavailability of new batches, recruitment in this arm was discontinued on 30Oct08.;|
| Experimental: 3<br>AL | Drug: artemether-lumefantrine (AL)<br>* Tablets containing 20 mg of Artemether and 120 mg of Lumefantrine.<br>* Other names: Coartem, Riamet by Novartis;|
| Experimental: 4<br>Lapdap + AS TO BE NOTED: following GlaxoSmithKline decision to discontinue the clinical development of the fixed-doses combination of Lapdap (Chlorproguanil-Dapsone) and artesunate, the Lapdap plus Artesunate arm was immediately discontinued in this study, on 17th February 2008. A formal amendment has been submitted to all the concerned ECs and competent authorities.The leading EC approval was obtained on 2nd June 2008. | Drug: Lapdap (Chlorproguanil-Dapsone) + artesunate (AS)<br>* Lapdap tablets contain 15/18.75mg or 80/100mg of Chlorproguanil Hydrochloride and Dapsone, respectively. Arsumax® tablets contain 50mg Artesunate. TO BE NOTED: following GlaxoSmithKline decision to discontinue the clinical development of the fixed-doses combination of Lapdap (Chlorproguanil-Dapsone) and artesunate, the Lapdap plus Artesunate arm was immediately discontinued in this study, on 17th February 2008. A formal amendment has been submitted to all the concerned ECs and competent authorities.The leading EC approval was obtained on 2nd June 2008.<br>* Other names: Arsumax by Sanofi and Guilin.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PCR unadjusted treatment failure (TF28U): all treatment failures detected during the active follow up, regardless of genotyping. |  | Day 28 | 
| PCR adjusted treatment failure up to day 28 (TF28A): all early failures before day 14 plus the recurrent parasitaemias detected at day 14 or later and classified by genotyping as recrudescence. |  | Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PCR unadjusted treatment failure up to day 63 (TF63U): TF28U plus all cases of recurrent parasitaemia (symptomatic or asymptomatic) detected between day 29 and day 63 by passive follow up, regardless of genotyping |  | Day 63 | 
| PCR adjusted treatment failure for the whole period of passive surveillance (TFAPS): TF28A plus all episodes of recurrent parasitaemia identified as recrudescence by genotyping. |  | Day 28 | 
| Fever clearance time. |  |  | 
| Asexual parasite clearance time. |  |  | 
| Gametocytaemia (prevalence and density) at day 7, 14, 21 and 28 after treatment (for both active follow-ups); |  | 28 days | 
| Hb changes day 3, 7, 14 and 28 (first and second follow up); |  | 28 days | 
| Clinical malaria after first active follow-up; |  | 28 Days | 
| Clinical malaria after second active follow-up; |  | Up to seven months | 
| TF second clinical episode (D28 and D63); |  | 63 days | 
| Changes in the frequency of mutations in the dihydrofolate reductase (DHFR) gene at day 0 first follow-up and day re-appearance of parasitaemia (for patients treated with CDA - NOTE that CDA arm was discontinued on 17.02.2008). |  |  | 
| Safety profiles including significant changes in relevant laboratory values. |  | Up to seven months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Children 6-59 months, P.falciparum, Haemoglobin, Informed consent, ACT