Study to Compare the Triple ACT AL+AQ With the ACT AL in Cambodia and Vietnam

A Multi-centre, Open-label Randomised Trial to Assess the Efficacy, Safety and Tolerability of the Triple ACT Artemether-lumefantrine+Amodiaquine (AL+AQ) Compared to the ACT Artemether-lumefantrine (AL) in Uncomplicated Falciparum Malaria in Cambodia and Vietnam

This study is a multi-centre, open-label randomised trial to assess the efficacy, safety and tolerability of the Triple ACT artemether-lumefantrine+amodiaquine (AL+AQ) compared to the ACT artemether-lumefantrine (AL) in uncomplicated falciparum malaria in Cambodia and Vietnam. The estimated total sample size is 600 patients from 2 sites in Cambodia and 2 sites in Vietnam. There are 2 treatment arms Arm 1: Artemether-lumefantrine for 3 days Arm 2: Artemether-lumefantrine for 3 days plus Amodiaquine for 3 days. According to the World Health Organization guideline, all patients except children under 10 kilograms will also be treated with a single dose of primaquine as a gametocytocidal treatment.

Funder :Bill & Melinda Gates Foundation (BMGF) Grant reference number: OPP1132628

"The study of artemether-lumefantrine or artemether-lumefantrine combined with amodiaquine will be a two-arm randomized open label comparative study.

The main activity proposed is a series of detailed in vivo clinical, parasitological and pharmacological assessments in 600 subjects across 2 sites in Cambodian (400 subjects) and 2 sites in Vietnam (200 subjects). The subjects will be randomized between the ACT artemether-lumefantrine and the TACT artemether-lumefantrine+amodiaquine.

Parasite clearance rates will be assessed by repeated assessments of the parasite counts after the start of the antimalarial treatments. Efficacy, safety and tolerability of ACTs and TACTs will be assessed through weekly follow up visits where vital signs, symptom questionnaires, physical examinations, blood smears, biochemistry assays and full blood counts will be performed.

Ex vivo assessments of parasite susceptibility to artemisinins and partner drugs will be measured and compared to historical data, clinical phenotype and other sites in an effort to identify artemisinin and partner drug resistance.

This study will obtain data on the effect of antimalarials on the corrected QT intervals. In addition, the effects of antimalarials on factors such as post-treatment haematocrit and haemoglobin levels will be assessed. Extensive pharmacokinetic analysis will allow for an assessment of drug-drug interactions.

Plasma histidine-rich protein 2 (HRP2) levels (a marker of parasite biomass) that could potentially serve for the estimation of parasitaemia dynamics before and after treatment will be measured and subsequently modelled."

Inclusion Criteria:

• Male or female, aged from 2 years to 65 years old
• Acute uncomplicated P. falciparum malaria, confirmed by positive blood smear with asexual forms of P. falciparum (or mixed with non-falciparum species)
• Asexual P. falciparum parasitaemia: 16 to 200,000/microlitre, determined on a thin or thick blood film
• Fever defined as > 37.5°C tympanic temperature or a history of fever within the last 24 hours
• Written informed consent (by parent/guardian in case of children)
• Willingness and ability of the patients or parents/guardians to comply with the study protocol for the duration of the study

Exclusion Criteria:

• Signs of severe/complicated malaria
• Haematocrit < 25% or Hb < 8 g/dL at screening
• Acute illness other than malaria requiring treatment
• For females: pregnancy, breast feeding
• Patients who have received artemisinin or a derivative or an artemisinin-containing combination therapy (ACT) within the previous 7 days
• History of allergy or known contraindication to artemisinins, lumefantrine or amodiaquine
• Previous splenectomy
• corrected QT interval > 450 milliseconds at moment of presentation
• Documented or claimed history of cardiac conduction problems
• Previous participation in the current study or another study in the previous 3 months