April 23, 2019
March 16, 2021
A partially blinded randomised controlled non-inferiority trial of the Triple ACTs artemether-lumefantrine + amodiaquine (AL+AQ) and artesunate-mefloquine + piperaquine (ASMQ+PPQ) with the ACTs artemether-lumefantrine + placebo (AL+PBO) and artesunate-mefloquine + placebo (ASMQ+PBO) for the treatment of uncomplicated Plasmodium falciparum malaria to assess and compare their efficacy, safety, tolerability.
Subjects will be randomized to up to four arms: artemether-lumefantrine + amodiaquine, artemether-lumefantrine + placebo, artesunate-mefloquine + piperaquine and artesunate-mefloquine + placebo. As a contingency measure in case of significant differences in the efficacy or safety of one of the combinations being tested and/or study drug expiry or unavailability, subjects may be randomised to 2 arms with a matching ACT-TACT pair, i.e., with artemether-lumefantrine + placebo or artemether-lumefantrine + amodiaquine OR artesunate-mefloquine + placebo or artesunate-mefloquine + piperaquine. Some sites may randomize between 2 arms only with matching ACT-TACT pairs, i.e., artemether-lumefantrine + placebo or artemether-lumefantrine + amodiaquine OR artesunate-mefloquine + placebo or artesunate-mefloquine + piperaquine. In the control arms, the ACT will be co-packed with a matched (appearance) placebo. In lower transmission settings (Annual Parasite Incidence <50 per 1000 population per year) the treatment will include a single 0.25 mg/kg gametocytocidal dose of primaquine as recommended by the WHO for children ≥10 kg. All drug administrations will be observed. Subjects will be treated in an in-patient unit for 3 days and followed up weekly up to D63. Microscopy to detect and quantify malaria parasitaemia will be performed daily (more frequently in patients with parasite density of >5000/µL at inclusion) during hospitalization, at all weekly and unscheduled visits. A physical examination and measurements of vital signs along with a symptom questionnaire for tolerability will be performed and recorded through a standardized method at baseline, daily during admission and weekly during follow up through D42 and at all unscheduled visits. Physical exam, vital sign measurements and assessments of symptoms will be performed on D49, D56, and D63 only for patients who are parasitaemic or those who report fever or other symptoms. Electrocardiographs will be performed during admission (H0, H4, H52 or H64) and day 42 of follow up to assess and compare the effect of ACTs and TACTs antimalarials on QT or QTc intervals.
|Experimental: Artemether-lumefantrine+amodiaquine (AL+AQ)
Drug: Artemether-lumefantrine+ Amodiaquine (AL+AQ)
AL: Currently available as dispersible tablets containing 20 mg of artemether and 120 mg of lumefantrine, in a fixed-dose combination formulation. The flavoured dispersible tablet paediatric formulation facilitates use in young children. The dose of artemether-lumefantrine is administered approaching the WHO-recommended target ranges of artemether 5-24 mg/kg and lumefantrine 29-144 mg/kg over 3 days. AQ: is available as dispersible tablets of 40 mg. The weight-based treatment schedule aims for a dosage of approximately 10mg (4.5-15mg)/kg/day amodiaquine for three days.
|Active Comparator: artemether-lumefantrine+placebo (AL+PBO)
Drug: Artemether-lumefantrine + placebo (AL+PBO)
AL: Currently available as dispersible tablets containing 20 mg of artemether and 120 mg of lumefantrine, in a fixed-dose combination formulation. The flavoured dispersible tablet paediatric formulation facilitates use in young children. The dose of artemether-lumefantrine is administered approaching the WHO-recommended target ranges of artemether 5-24 mg/kg and lumefantrine 29-144 mg/kg over 3 days. PBO: Placebo tablets for amodiaquine are currently under development. They will be identical in size, shape and color. We aim for a similar taste of amodiaquine and the placebo.
|Experimental: Artesunate-mefloquine+Piperaquine (AS-MQ+PPQ)
Drug: Artesunate-mefloquine+piperaquine (AS-MQ+PPQ)
AS-MQ: Artesunate-mefloquine will be administered according to an optimised dosing schedule using tablets of 25 or 100 mg artesunate and 50 or 200 mg mefloquine with a dosing target of 4 mg/kg/day and 8.3 mg/kg/day, respectively. PPQ: One tablet contains 250 mg of piperaquine. The weight-based treatment aims for a dosage of approximately. 24 mg/kg/day in patients <25 kg (range 16.7 - 31.3 mg/kg) piperaquine for three days, thereby approaching the WHO-recommended target range of 20 - 32 mg/kg per day. 18 mg/kg/day in patients ≥25 kg (range 15.2 - 29.4 mg/kg) piperaquine for three days, thereby approaching the WHO-recommended target range of 16 - 27 mg/kg per day.
|Active Comparator: Artesunate-mefloquine+placebo (AS-MQ+PBO)
Drug: Artesunate-mefloquine+placebo (AS-MQ+PBO)
AS-MQ: Artesunate-mefloquine will be administered according to an optimised dosing schedule using tablets of 25 or 100 mg artesunate and 50 or 200 mg mefloquine with a dosing target of 4 mg/kg/day and 8.3 mg/kg/day, respectively. PBO: Placebo tablets for mefloquine are currently under development. They will be identical in size, shape and colour. We aim for a similar taste of mefloquine and the placebo.
- Male or female, aged ≥6 months to <12 years (For Gambia site only: ≥6 months) - Ability to take oral medication - Acute uncomplicated P. falciparum monoinfection - Asexual P. falciparum parasitaemia: 1,000/µL to ≤10% parasitaemia, determined on a peripheral blood film (At Gambia site only: For subjects ≥12 years - 1000/µL to 200,000/µL) - Fever defined as ≥ 37.5°C tympanic temperature or a history of fever within the last 24 hours - Written informed consent by the subject or by parent/guardian in case of children lower than the age of consent and assent if required (per local regulations) - Willingness and ability of the subjects or parents/guardians to comply with the study protocol for the duration of the study Exclusion Criteria: - Signs of severe malaria (adapted from WHO criteria) - Patients not fulfilling criteria for severe malaria but with another indication for parenteral antimalarial treatment at the discretion of the treating physician - Haematocrit <15% at screening (For Gambia site only: For subjects ≥12 years - Haematocrit <20% at screening) - Subjects who have received artemisinin or a derivative within the previous 7 days OR lumefantrine or amodiaquine within the previous 14 days OR mefloquine or piperaquine within the previous 30 days - In applicable countries: use of seasonal malaria chemoprophylaxis (SMC) within the last 14 days. - Acute illness other than malaria requiring systemic treatment - Severe acute malnutrition (in Niger only - only those patients with Severe Acute Malnutrition and complications requiring inpatient nutritional treatment will be excluded) - Known HIV infection - Known tuberculosis infection - For females: post-menarche (For Gambia site only: Female who are pregnant, trying to get pregnant or lactating ) - History of allergy or known contraindication to any of the study drugs, including neuropsychiatric disorders and epilepsy - Previous splenectomy - Enrolment in DeTACT in the previous 3 months - Participation in another interventional study in the previous 3 months
Contact: Mehul Dhorda, Ph.D +66 2 203-6333 Mehul@tropmedres.ac
Contact: Arjen Mattheus Dondorp, Prof. +662-203-6333 ext 6303 firstname.lastname@example.org
Institut des Sciences et Techniques (INSTech)
Congo, The Democratic Republic of the
Kinshasa School of Public Health
Centre National de Formation et de Recherche en Santé Rurale de Mafèrinyah
University of Oxford
Mahidol Oxford Tropical Medicine Research Unit