Clinical trial NCT00393679: Evaluation of 4 Artemisinin-based Combinations for Treating Uncomplicated Malaria in African Children
Official title: Evaluation of 4 Artemisinin-based Combinations for Treating Uncomplicated Malaria in African Children
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Fever
Malaria
Keywords: Children 6-59 months
P.falciparum
Haemoglobin
Informed consent
ACT
Lead sponsor: Institute of Tropical Medicine, Belgium
Sponsor class: OTHER
Collaborators: name: Liverpool School of Tropical Medicine
name: East African Network for Monitoring Antimalarial Treatment
name: Centre Muraz
name: University of Calabar
name: Tropical Diseases Research Centre, Zambia
name: University Hospital Tuebingen
name: Albert Schweitzer Hospital
name: Uganda Malaria Surveillance Project
name: Mbarara University of Science and Technology
name: Ministry of Health, Rwanda
name: University of Barcelona
name: Centro de Investigacao em Saude de Manhica
First posted: 2006-10-29
Enrollment: 4112
Sex: ALL
Minimum age (years): 6
Maximum age (years): 59
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: PCR unadjusted treatment failure (TF28U): all treatment failures detected during the active follow up, regardless of genotyping.
timeFrame: Day 28
measure: 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.
timeFrame: Day 28
Secondary outcomes:
measure: 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
timeFrame: Day 63
measure: PCR adjusted treatment failure for the whole period of passive surveillance (TFAPS): TF28A plus all episodes of recurrent parasitaemia identified as recrudescence by genotyping.
timeFrame: Day 28
measure: Fever clearance time.
measure: Asexual parasite clearance time.
measure: Gametocytaemia (prevalence and density) at day 7, 14, 21 and 28 after treatment (for both active follow-ups);
timeFrame: 28 days
measure: Hb changes day 3, 7, 14 and 28 (first and second follow up);
timeFrame: 28 days
measure: Clinical malaria after first active follow-up;
timeFrame: 28 Days
measure: Clinical malaria after second active follow-up;
timeFrame: Up to seven months
measure: TF second clinical episode (D28 and D63);
timeFrame: 63 days
measure: 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).
measure: Safety profiles including significant changes in relevant laboratory values.
timeFrame: Up to seven months
Other outcomes:
Locations:
city: Bobo-Dioulasso
country: Burkina Faso
facility: Centre Muraz/IRSS
city: Lambaréné
country: Gabon
facility: Albert Schweitzer Hospital
city: Manhica
country: Mozambique
facility: Manhiça Health Research Center
city: Calabar
country: Nigeria
facility: Hospital
city: Kigali
country: Rwanda
facility: Mashshesha and Rukara
city: Kampala
country: Uganda
facility: Jinja and Tororo
city: Mbarara
country: Uganda
facility: Mbarara,
city: Ndola
country: Zambia
facility: Tropical Diseases Research Centre, P O Box 71769,
Study officials:
affiliation: Institute of Tropical Medicine Antwerp
name: UmbertoC D'Alessandro, MD MsC PhD
role: STUDY_DIRECTOR
References:
citation: Ravinetto RM, Talisuna A, De Crop M, van Loen H, Menten J, Van Overmeir C, Tinto H, Gonzalez R, Meremikwu M, Nabasuma C, Ngoma GM, Karema C, Adoke Y, Chaponda M, Van Geertruyden JP, D'Alessandro U. Challenges of non-commercial multicentre North-South collaborative clinical trials. Trop Med Int Health. 2013 Feb;18(2):237-41. doi: 10.1111/tmi.12036. Epub 2012 Dec 10.
citation: Four Artemisinin-Based Combinations (4ABC) Study Group. A head-to-head comparison of four artemisinin-based combinations for treating uncomplicated malaria in African children: a randomized trial. PLoS Med. 2011 Nov;8(11):e1001119. doi: 10.1371/journal.pmed.1001119. Epub 2011 Nov 8.