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

Malaria Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00393679
• Other study ID #: 4 ABC
• Secondary ID: IRB Antwerp: 6/4
• Status: Completed
• Phase: Phase 3
• First received: October 27, 2006
• Last updated: January 31, 2014
• Start date: July 2007
• Est. completion date: December 2009

Study information

• Verified date: January 2014
• Source: Institute of Tropical Medicine, Belgium
• Contact: n/a
• Is FDA regulated: No
• Health authority: Belgium: Institutional Review BoardBurkina Faso: Ministry of HealthGabon: Ministry of HealthMozambique: Ministry of Health (MISAU)Nigeria: The National Agency for Food and Drug Administration and ControlRwanda: Ethics CommitteeUganda: Research Ethics CommitteeZambia: Research Ethics Committee
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 4112
• Est. completion date: December 2009
• Est. primary completion date: December 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 6 Months to 59 Months

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Fever
• Malaria

Intervention

Drug:
• amodiaquine-artesunate (ASAQ)
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
• dihydroartemisinin-piperaquine (DHAPQ)
DHAPQ tablets contain either 20/160mg or 40/320mg of dihydroartemisinin (DHA) and piperaquine phosphate (PQ) respectively.
• artemether-lumefantrine (AL)
Tablets containing 20 mg of Artemether and 120 mg of Lumefantrine.
• Lapdap (Chlorproguanil-Dapsone) + artesunate (AS)
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.

Locations

Country	Name	City	State
Burkina Faso	Centre Muraz/IRSS	Bobo-Dioulasso
Gabon	Albert Schweitzer Hospital	Lambaréné
Mozambique	Manhiça Health Research Center	Manhica
Nigeria	Hospital	Calabar
Rwanda	Mashshesha and Rukara	Kigali
Uganda	Jinja and Tororo	Kampala
Uganda	Mbarara,	Mbarara
Zambia	Tropical Diseases Research Centre, P O Box 71769,	Ndola

Sponsors (13)

Lead Sponsor

Collaborator

Institute of Tropical Medicine, Belgium

Albert Schweitzer Hospital, Centre Muraz, Centro de Investigacao em Saude de Manhica, East African Network for Monitoring Antimalarial Treatment, Liverpool School of Tropical Medicine, Mbarara University of Science and Technology, Ministry of Health, Rwanda, Tropical Diseases Research Centre, Zambia, Uganda Malaria Surveillance Project, University Hospital Tuebingen, University of Barcelona, University of Calabar

Countries where clinical trial is conducted

Burkina Faso,  Gabon,  Mozambique,  Nigeria,  Rwanda,  Uganda,  Zambia, 

References & Publications (2)

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.pm — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	PCR unadjusted treatment failure (TF28U): all treatment failures detected during the active follow up, regardless of genotyping.		Day 28	No
Primary	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	No
Secondary	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	No
Secondary	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	No
Secondary	Fever clearance time.			No
Secondary	Asexual parasite clearance time.			No
Secondary	Gametocytaemia (prevalence and density) at day 7, 14, 21 and 28 after treatment (for both active follow-ups);		28 days	No
Secondary	Hb changes day 3, 7, 14 and 28 (first and second follow up);		28 days	No
Secondary	Clinical malaria after first active follow-up;		28 Days	No
Secondary	Clinical malaria after second active follow-up;		Up to seven months	No
Secondary	TF second clinical episode (D28 and D63);		63 days	No
Secondary	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).			Yes
Secondary	Safety profiles including significant changes in relevant laboratory values.		Up to seven months	Yes