Evaluation of 4 Artemisinin-Based Combinations for Treating Uncomplicated Malaria in African Children - Full Text View

Sponsors and Collaborators:	Institute of Tropical Medicine, Belgium Liverpool School of Tropical Medicine East African Network for Monitoring Antimalarial Treatment Centre Muraz University of Calabar Tropical Diseases Research Centre, Ndola, Zambia University Hospital Tuebingen Albert Schweitzer Hospital, Netherlands Uganda Malaria Surveillance Project,Kampala,Uganda Mbarara University of Science and Technology Programme National Lutte contre le Paludisme,Kigali,Rwanda University of Barcelona Manhica Research Centre, Mozambique
Information provided by:	Institute of Tropical Medicine, Belgium
ClinicalTrials.gov Identifier:	NCT00393679

Purpose

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.

Condition	Intervention	Phase
Fever Malaria	Drug: amodiaquine-artesunate (ASAQ) Drug: dihydroartemisinin-piperaquine (DHAPQ) Drug: artemether-lumefantrine (AL) Drug: Lapdap (Chlorproguanil-Dapsone) + artesunate (AS)	Phase III

MedlinePlus related topics: Fever Malaria

Drug Information available for: Artesunate Artemisinin Artemether Dihydroquinghaosu Piperaquine Benflumetol Dapsone Amodiaquine Amodiaquine hydrochloride Chlorproguanil

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Safety/Efficacy Study
Official Title:	Evaluation of 4 Artemisinin-Based Combinations for Treating Uncomplicated Malaria in African Children

Further study details as provided by Institute of Tropical Medicine, Belgium:

Primary Outcome Measures:

PCR unadjusted treatment failure (TF28U): all treatment failures detected during the active follow up, regardless of genotyping. [ Time Frame: Day 28 ] [ Designated as safety issue: No ]
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. [ Time Frame: Day 28 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

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 [ Time Frame: Day 63 ] [ Designated as safety issue: No ]
PCR adjusted treatment failure for the whole period of passive surveillance (TFAPS): TF28A plus all episodes of recurrent parasitaemia identified as recrudescence by genotyping. [ Time Frame: Day 28 ] [ Designated as safety issue: No ]
Fever clearance time. [ Designated as safety issue: No ]
Asexual parasite clearance time. [ Designated as safety issue: No ]
Gametocytaemia (prevalence and density) at day 7, 14, 21 and 28 after treatment (for both active follow-ups); [ Time Frame: 28 days ] [ Designated as safety issue: No ]
Hb changes day 3, 7, 14 and 28 (first and second follow up); [ Time Frame: 28 days ] [ Designated as safety issue: No ]
Clinical malaria after first active follow-up; [ Time Frame: 28 Days ] [ Designated as safety issue: No ]
Clinical malaria after second active follow-up; [ Time Frame: Up to seven months ] [ Designated as safety issue: No ]
TF second clinical episode (D28 and D63); [ Time Frame: 63 days ] [ Designated as safety issue: No ]
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). [ Designated as safety issue: Yes ]
Safety profiles including significant changes in relevant laboratory values. [ Time Frame: Up to seven months ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	5100
Study Start Date:	July 2007
Estimated Study Completion Date:	December 2009
Estimated Primary Completion Date:	July 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Experimental AS-AQ	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
2: Experimental 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) DHAPQ tablets contain either 20/160mg or 40/320mg of dihydroartemisinin (DHA) and piperaquine phosphate (PQ) respectively.
3: Experimental AL	Drug: artemether-lumefantrine (AL) Tablets containing 20 mg of Artemether and 120 mg of Lumefantrine.
4: Experimental 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) 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.

Eligibility

Ages Eligible for Study:	6 Months to 59 Months
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00393679

Contacts

Contact: Umberto D'Alessandro, MD, MSc, PhD	+32 32476354	UDAlessandro@itg.be
Contact: Jean-Pierre Van geertruyden, MD MSc	+32 32476363	jpvangeertruyden@itg.be

Locations

Burkina Faso
Centre Muraz/IRSS	Recruiting
Bobo-Dioulasso, Burkina Faso
Principal Investigator: Serge P Diagbouga, MD
Gabon
Albert Schweitzer Hospital	Recruiting
Lambaréné, Gabon
Principal Investigator: Pierre-Blaise Matsiegui
Mozambique
Manhiça Health Research Center	Active, not recruiting
Manhica, Mozambique
Nigeria
Hospital	Recruiting
Calabar, Nigeria
Contact: Martin Meremikwu, MD
Principal Investigator: Martin Meremikwu
Rwanda
Mashshesha and Rukara	Active, not recruiting
Kigali, Rwanda
Uganda
Mbarara,	Active, not recruiting
Mbarara, Uganda
Jinja and Tororo	Active, not recruiting
Kampala, Uganda
Zambia
Tropical Diseases Research Centre, P O Box 71769,	Recruiting
Ndola, Zambia
Contact: Modest Mulenga, MD MsC PhD
Principal Investigator: Modest Mulenga, MD MsC PhD

Sponsors and Collaborators

Institute of Tropical Medicine, Belgium

Liverpool School of Tropical Medicine

East African Network for Monitoring Antimalarial Treatment

Centre Muraz

University of Calabar

Tropical Diseases Research Centre, Ndola, Zambia

University Hospital Tuebingen

Albert Schweitzer Hospital, Netherlands

Uganda Malaria Surveillance Project,Kampala,Uganda

Mbarara University of Science and Technology

Programme National Lutte contre le Paludisme,Kigali,Rwanda

University of Barcelona

Manhica Research Centre, Mozambique

Investigators

Study Director:

UmbertoC D'Alessandro, MD MsC PhD

Institute of Tropical Medicine, Antwerp

More Information

Responsible Party:	Institute of Tropical Medicine, Belgium ( Prof. Umberto D'Alessandro )
Study ID Numbers:	4 ABC, IRB Antwerp: 6/40/187
Study First Received:	October 27, 2006
Last Updated:	October 30, 2008
ClinicalTrials.gov Identifier:	NCT00393679
Health Authority:	Belgium: Institutional Review Board; Burkina Faso: Ministry of Health; Gabon: Ministry of Health; Mozambique: Ministry of Health (MISAU); Nigeria: The National Agency for Food and Drug Administration and Control; Rwanda: Ethics Committee; Uganda: Research Ethics Committee; Zambia: Research Ethics Committee

Keywords provided by Institute of Tropical Medicine, Belgium:

Children 6-59 months
P.falciparum
Haemoglobin
Informed consent
ACT

Study placed in the following topic categories:

Artesunate
Benflumetol
Protozoan Infections
Artemether-lumefantrine combination
Amodiaquine
Clotrimazole
Miconazole
Artemisinine
Tioconazole
Malaria

Artemether
Folic Acid
Fever
Piperaquine
Artemisinins
Chloroguanide
Dapsone
Parasitic Diseases
Dihydroquinghaosu
Chlorproguanil

Additional relevant MeSH terms:

Antimetabolites
Anti-Infective Agents
Antiprotozoal Agents
Molecular Mechanisms of Pharmacological Action
Antiplatyhelmintic Agents
Coccidiosis
Anthelmintics
Enzyme Inhibitors
Folic Acid Antagonists
Schistosomicides

Pharmacologic Actions
Antimalarials
Anti-Bacterial Agents
Antiparasitic Agents
Antifungal Agents
Therapeutic Uses
Amebicides
Coccidiostats
Leprostatic Agents

ClinicalTrials.gov processed this record on January 16, 2009