A Multi-centre Randomised Controlled Non-inferiority Trial to Compare the Efficacy, Safety and Tolerability of Triple Artemisinin-based Combination Therapies Versus First-line ACTs + Placebo for the Treatment of Uncomplicated Plasmodium Falciparum Malaria in Africa
Trial Snapshot
- Phase
- Phase 3
- Status
- Completed
- Sponsor
- University of Oxford
- Enrollment
- 2,583
- Locations
- 8
- Primary Endpoint
- 42 days Efficacy defined as PCR corrected adequate clinical and parasitological response (ACPR).
Study Overview
Brief Summary
A partially blinded randomised controlled non-inferiority trial comparing the efficacy, tolerability and safety of Triple ACTs artemether-lumefantrine+amodiaquine (AL+AQ) and artesunate-mefloquine+piperaquine (ASMQ+PPQ) and the ACTs artemether-lumefantrine+placebo (AL+PBO), artesunate-mefloquine+placebo (ASMQ+PBO) (with single-low dose primaquine in some sites) for the treatment of uncomplicated Plasmodium falciparum malaria to assess and compare their efficacy, safety, tolerability.
Detailed Description
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 Rwanda, subjects will be randomized between 2 arms consisting of artemether-lumefantrine + placebo or artemether-lumefantrine + amodiaquine.
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Single (Participant)
Eligibility Criteria
- Ages
- 6 Months to 12 Years (Child)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Male or female, aged ≥6 months to <12 years (For Gambia, Rwanda sites 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, Rwanda sites 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, Rwanda sites 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, Rwanda sites only: females who are pregnant, trying to get pregnant or are 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
Arms & Interventions
Artemether-lumefantrine+amodiaquine (AL+AQ)
Triple ACTs
Intervention: Artemether-lumefantrine+ Amodiaquine (AL+AQ) (Drug)
artemether-lumefantrine+placebo (AL+PBO)
ACTs
Intervention: Artemether-lumefantrine + placebo (AL+PBO) (Drug)
Artesunate-mefloquine+Piperaquine (AS-MQ+PPQ)
Triple ACTs
Intervention: Artesunate-mefloquine+piperaquine (AS-MQ+PPQ) (Drug)
Artesunate-mefloquine+placebo (AS-MQ+PBO)
ACTs
Intervention: Artesunate-mefloquine+placebo (AS-MQ+PBO) (Drug)
Outcomes
Primary Outcomes
42 days Efficacy defined as PCR corrected adequate clinical and parasitological response (ACPR).
Time Frame: 42 days
42 days Efficacy defined as PCR corrected adequate clinical and parasitological response (ACPR).
Secondary Outcomes
- Fever clearance time(63 Days)
- Change in haemoglobin stratified for G6PD status/genotype(28 days)
- 42-day PCR uncorrected efficacy(42 days)
- Proportion of subjects with microscopically detectable P. falciparum parasitaemia(Day 3)
- Incidence of serious adverse events(42 days)
- Number of cardiotoxicity events(52 or 64 hours depends on treatment arm)
- Proportion of subjects requiring retreatment due to vomiting(1 hour)
- 63-day PCR corrected and uncorrected efficacy(63 days)
- Parasite clearance half-life(3 Days)
- Incidence of adverse events(42 days)
- Pharmacokinetic profiles(42 days)
- Proportion of subjects with gametocytaemia(63 Days)
- Proportion of subjects that reports completing a full course of observed TACT(3 days)
- Proportion of subjects that reports completing a full course of observed ACT(3 days)
- proportion of subjects that reports completing a full course of observed TACT or ACT without withdrawal of consent or exclusion from study because of drug related serious adverse event.(42 days)
- Pharmacokinetic interactions(42 days)
- Plasma levels of partner drugs(7 days)