Randomized Trial on Effectiveness of ACTs in Ghana

Malaria, Falciparum Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00374205
• Other study ID #: 01KA22062006
• Status: Terminated
• Phase: Phase 4
• First received: September 8, 2006
• Last updated: November 26, 2007
• Start date: September 2006
• Est. completion date: October 2007

Study information

• Verified date: November 2007
• Source: Bernhard Nocht Institute for Tropical Medicine
• Contact: n/a
• Is FDA regulated: No
• Health authority: Ghana: Ministry of HealthGermany: Ethics Commission
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 245
• Est. completion date: October 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 6 Months to 59 Months

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

• Malaria
• Malaria, Falciparum

Intervention

Drug:
• Artesunate plus Amodiaquine
Artesunate 50 mg and Amodiaquine 153 mg co-blister tablets: 3 days once daily weight-adjusted dosing according to manufacturer
• Artemether-Lumefantrine
Artemether 20 mg/Lumefantrine 120mg fixe-dose-combination tablets: 3 days twice daily weight-adjusted dosing according to manufacturer

Locations

Country	Name	City	State
Ghana	Agogo Presbyterian Hospital	Agogo	Asante Akim North District

Sponsors (4)

Lead Sponsor	Collaborator
Bernhard Nocht Institute for Tropical Medicine	Kumasi Centre for Collaborative Research (KCCR), Presbyterian Health Service (PHS), School of Medical Sciences Kumasi (SMS/KNUST)

Country where clinical trial is conducted

Ghana, 

References & Publications (6)

Bukirwa H, Yeka A, Kamya MR, Talisuna A, Banek K, Bakyaita N, Rwakimari JB, Rosenthal PJ, Wabwire-Mangen F, Dorsey G, Staedke SG. Artemisinin combination therapies for treatment of uncomplicated malaria in Uganda. PLoS Clin Trials. 2006 May;1(1):e7. Epub 2006 May 19. — View Citation

Makanga M, Premji Z, Falade C, Karbwang J, Mueller EA, Andriano K, Hunt P, De Palacios PI. Efficacy and safety of the six-dose regimen of artemether-lumefantrine in pediatrics with uncomplicated Plasmodium falciparum malaria: a pooled analysis of individual patient data. Am J Trop Med Hyg. 2006 Jun;74(6):991-8. — View Citation

Mårtensson A, Strömberg J, Sisowath C, Msellem MI, Gil JP, Montgomery SM, Olliaro P, Ali AS, Björkman 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. Epub 2005 Sep 13. — View 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. — View Citation

Price RN, Uhlemann AC, van Vugt M, Brockman A, Hutagalung R, Nair S, Nash D, Singhasivanon P, Anderson TJ, Krishna S, White NJ, Nosten F. Molecular and pharmacological determinants of the therapeutic response to artemether-lumefantrine in multidrug-resistant Plasmodium falciparum malaria. Clin Infect Dis. 2006 Jun 1;42(11):1570-7. Epub 2006 Apr 26. — View 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. Epub 2006 Jul 11. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Clinical and PCR-controlled parasitological cure rate at day 28		28 days
Secondary	Clinical and PCR-controlled parasitological cure rate at day 14		14 days
Secondary	Effect on anaemia		28 days
Secondary	Molecular Drug Resistance Markers		28 days
Secondary	Recrudescence and Reinfection		28 days
Secondary	Effects on Gametocytemia		28 days
Secondary	Acceptance of Therapies		7 days
Secondary	Incidences of malaria episodes over a follow-up period of 1 year		12 months

External Links

•   Homepage of the Research Group Infection Epidemiology (co-ordination)