Clinical trial NCT00374205: Randomized Trial on Effectiveness of ACTs in Ghana
Official title: A Comparative Assessment of the Effectiveness of Artemether Plus Lumefantrine Versus Artesunate Plus Amodiaquine for the Treatment of Children With Uncomplicated Plasmodium Falciparum Malaria
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Malaria, Falciparum
Keywords: Ghana
Effectiveness
Safety
Drug-Resistance
ACT
Coartem
Arsucam
Lead sponsor: Bernhard Nocht Institute for Tropical Medicine
Sponsor class: OTHER_GOV
Collaborators: name: Presbyterian Health Service (PHS)
name: Kumasi Centre for Collaborative Research (KCCR)
name: School of Medical Sciences Kumasi (SMS/KNUST)
First posted: 2006-09-11
Enrollment: 245
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 purpose of this study is to compare the effectiveness and safety of two Artemisinin Combination Therapies (ACTs) for the treatment of children with uncomplicated Plasmodium falciparum malaria

Detailed description: Childhood mortality related to Plasmodium falciparum malaria is on the rise with more than 1 million deaths per year in Sub-Saharan Africa. In the context of growing drug-resistance to antimalarials health officials are calling for rapid replacement of failing drugs by combining antimalarial drugs. Artemisinin Combination Antimalarial Therapies (ACTs) are in the focus of malaria control programmes and are recommended for first-line treatment in African countries. ACTs have been reported to be highly effective as artemisinin derivatives cause a rapid and substantial decrease in the parasite load when used for treating patients with malaria and resistance to artemisinin is still lacking. However, the short half-lives of artemisinins result in frequent recrudescent infections when used alone and therefore, much interest lays on the choice of the combination partner drug. ACTs also have been proposed as a means of reducing transmission by the reduction of gametocytes and of delaying the spread of drug resistance and prolonging the therapeutic life span of. Nevertheless, drug resistance of parasites to the respective partner drug is a matter of concern. Artesunate-amodiaquine (AQ) and artemether-lumefantrine (AL) are two registered fixed-dose artemisinin combination chemotherapies used in Africa which are GMP-manufactured at industrial scale. There is still limited data from randomised, controlled trials to support the general effectiveness of these two ACTs in Africa, including Ghana. More data is needed to compare these two therapies to make evidence-based first-line treatment decisions. Importantly, it is difficult to predict how combination therapy may affect the spread of drug resistance and monitoring drug resistance markers should be embedded in these trials to guide drug policy decision.

The aim of this open-labelled, randomised drug trial is to compare the effectiveness and safety of artesunate-amodiaquine (Arsucam®) against artemether plus lumefantrine (Coartem®) for the treatment of children under five years of age with uncomplicated Plasmodium falciparum malaria.

Eligibility criteria: Inclusion Criteria:

* Male and female outpatients aged 6 months to 59 months
* Absence of severe malnutrition
* A slide-confirmed P. falciparum asexual parasitaemia between 2,000/µl and 200,000/µl
* A measured axillary temperature ≥ 37.5 °C or rectal/tympanic temperature ≥ 38.0 °C
* Absence of general danger signs (unable to drink; repeated vomiting; recent history of convulsions; lethargic or unconscious state; unable to stand up or to sit)
* Ability to tolerate oral therapy
* Permanent residence in study area
* Informed consent by the legal representative of the subject, if possible, the parents

Exclusion Criteria:

* Adequate anti-malarial treatment within the previous 7 days
* Antibiotic treatment for a current infection
* Previous participation in a clinical trial
* Haemoglobin \< 5 g/dl
* Leucocyte count: \> 15000/µl
* Mixed plasmodial infection
* Severe malaria as defined by WHO recommendations
* Any other severe underlying disease (cardiac, renal, hepatic diseases, malnutrition, known HIV infection) or concomitant disease masking assessment of response
* History of allergy or intolerance against trial medication

Primary outcomes:
measure: Clinical and PCR-controlled parasitological cure rate at day 28
timeFrame: 28 days
Secondary outcomes:
measure: Clinical and PCR-controlled parasitological cure rate at day 14
timeFrame: 14 days
measure: Effect on anaemia
timeFrame: 28 days
measure: Molecular Drug Resistance Markers
timeFrame: 28 days
measure: Recrudescence and Reinfection
timeFrame: 28 days
measure: Effects on Gametocytemia
timeFrame: 28 days
measure: Acceptance of Therapies
timeFrame: 7 days
measure: Incidences of malaria episodes over a follow-up period of 1 year
timeFrame: 12 months
Other outcomes:
Locations:
city: Agogo
country: Ghana
facility: Agogo Presbyterian Hospital
state: Asante Akim North District
Study officials:
affiliation: School of Medical Science (SMS), Kwame Nkrumah University of Science and Technology (KNUST), Kumasi, Ghana
name: Daniel Ansong, MD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Mutabingwa TK, Anthony D, Heller A, Hallett R, Ahmed J, Drakeley C, Greenwood BM, Whitty CJ. Amodiaquine alone, amodiaquine+sulfadoxine-pyrimethamine, amodiaquine+artesunate, and artemether-lumefantrine for outpatient treatment of malaria in Tanzanian children: a four-arm randomised effectiveness trial. Lancet. 2005 Apr 23-29;365(9469):1474-80. doi: 10.1016/S0140-6736(05)66417-3.
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citation: Martensson A, Stromberg J, Sisowath C, Msellem MI, Gil JP, Montgomery SM, Olliaro P, Ali AS, Bjorkman A. Efficacy of artesunate plus amodiaquine versus that of artemether-lumefantrine for the treatment of uncomplicated childhood Plasmodium falciparum malaria in Zanzibar, Tanzania. Clin Infect Dis. 2005 Oct 15;41(8):1079-86. doi: 10.1086/444460. Epub 2005 Sep 13.
citation: Sidhu AB, Uhlemann AC, Valderramos SG, Valderramos JC, Krishna S, Fidock DA. Decreasing pfmdr1 copy number in plasmodium falciparum malaria heightens susceptibility to mefloquine, lumefantrine, halofantrine, quinine, and artemisinin. J Infect Dis. 2006 Aug 15;194(4):528-35. doi: 10.1086/507115. Epub 2006 Jul 11.