Triple Artemisinin-based Combination Therapy for Delaying Drug Resistance Development - a Randomized Clinical Trial

Can Triple Artemisinin-based Combination Therapy for Treatment of Uncomplicated Plasmodium Falciparum Malaria, Delay Drug Resistance Development of Plasmodium Falciparum in Tanzania: a Randomized Three Arm Clinical Trial

Background: Artemisinin resistance has emerged in parts of Southeast Asia, and there are reports in Africa of reduced susceptibility of Plasmodium falciparum parasites against artemisinin-based combination therapy (ACT). No new drugs are available in the pipeline to replace ACTs in case they fail.

This study aims to assess whether a sequential administration of triple ACTs with different partner-drugs can improve the efficacy of ACT for treatment of uncomplicated malaria.

Methods: A health facility-based, three-arm partially blinded randomized clinical trial will be conducted to assess efficacy and safety of a sequential administration of artemether-lumefantrine followed immediately by artesunate-amodiaquine (AL+ASAQ) or artemether-lumefantrine with by amodiaquine (AL+AQ) compared to artemether-lumefantrine plus placebo (AL+PBO). Eligible children aged 6 - 120 months and with microscopy confirmed uncomplicated P. falciparum malaria will be enrolled, administered with trial medicines and followed-up at 0 (just prior to first drug intake) and 8 hours on day 0, 12 hourly on days 1, 2, 3, 4, 5, followed by once daily on days 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 28, 35, 42 and 56 for clinical and laboratory evaluations. Clinical evaluation will involve assessment of signs and symptoms related to the disease and or trial medicine during follow-up. Laboratory evaluation will include microscopic determination of presence of malaria parasites and species, hemoglobin level, molecular analysis for markers of drug resistance and to differentiate recrudescence from new infection. The primary outcome will be Polymerase Chain Reaction (PCR)-adjusted adequate clinical and parasitological cure rate on days 28 and 42.

Expected outcomes: The findings will give an insight on whether 3 ACTs are more efficacious than the use of first-line regimen alone, and are tolerable for treatment of uncomplicated falciparum malaria.

Patients presenting at the health facility with suspected acute uncomplicated malaria will be screened for eligibility.

Inclusion Criteria:

• Age from 6 - 120 months
• Weight ≥ 5 kg
• Body temperature ≥37.5°C or history of fever in the last 24 hours
• Microscopy confirmed P. falciparum mono-infection
• Parasitemia level of 1000-200000/μL
• Ability to swallow oral medication
• Ability and willingness to abide by the study protocol and the stipulated follow-up visits
• A written proxy informed consent from a parent/guardian

Exclusion Criteria:

• Children aged below 6 months will not be included in the study because ACTs are contraindicated in this group.
• Evidence of severe malaria or danger signs
• Known allergy to trial medicines
• Reported antimalarial intake ≤2 weeks
• Haemoglobin <5 g/dL
• Blood transfusion within last 90 days
• Febrile condition other than malaria
• Known underlying chronic or severe disease (including severe malnutrition).