A Trial to Compare the Efficacy, Safety and Tolerability of Combinations of 3 Anti-malarial Drugs Against Combina-tions of 2 Anti-malarial Drugs.

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. The DeTACT-Africa Trial is funded by UK Aid from the UK government's Foreign, Commonwealth and Development Office.

Official Title
-----------------
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

Conditions
-----------------
Plasmodium Falciparum Malaria (Uncomplicated)

Intervention / Treatment
-----------------
* Drug: Artemether-lumefantrine+ Amodiaquine (AL+AQ)
* Drug: Artemether-lumefantrine + placebo (AL+PBO)
* Drug: Artesunate-mefloquine+piperaquine (AS-MQ+PPQ)
* Drug: Artesunate-mefloquine+placebo (AS-MQ+PBO)


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 6 Months
Maximum Age: 12 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Artemether-lumefantrine+amodiaquine (AL+AQ)<br>Triple ACTs | Drug: Artemether-lumefantrine+ Amodiaquine (AL+AQ)<br>* 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.<br>|
| Active Comparator: artemether-lumefantrine+placebo (AL+PBO)<br>ACTs | Drug: Artemether-lumefantrine + placebo (AL+PBO)<br>* 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 identical in size, shape and color to the amodiaquine tablets.<br>|
| Experimental: Artesunate-mefloquine+Piperaquine (AS-MQ+PPQ)<br>Triple ACTs | Drug: Artesunate-mefloquine+piperaquine (AS-MQ+PPQ)<br>* AS: Artesunate will be administered according to an optimised dosing schedule using tablets of 32 or 100 mg artesunate with a dosing target of 4 mg/kg/day. MQ: Mefloquine will be administered according to an optimised dosing schedule using tablets of 70 or 220 mg mefloquine hydrochloride with a dosing target of 8.3 mg/kg/day. PPQ: Piperaquine will be administered according to an optimised dosing schedule using tablets of 160 or 500 mg of piperaquine tetraphosphate. The weight-based treatment aims for a dosage of approximately. 24 mg/kg/day in patients <25 kg (range 16.0 - 32.0 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 15.0 - 29.4 mg/kg) piperaquine for three days, thereby approaching the WHO-recommended target range of 16 - 27 mg/kg per day.<br>|
| Active Comparator: Artesunate-mefloquine+placebo (AS-MQ+PBO)<br>ACTs | Drug: Artesunate-mefloquine+placebo (AS-MQ+PBO)<br>* AS: Artesunate will be administered according to an optimised dosing schedule using tablets of 32 or 100 mg artesunate with a dosing target of 4 mg/kg/day. MQ: Mefloquine will be administered according to an optimised dosing schedule using tablets of 70 or 220 mg mefloquine hydrochloride with a dosing target of 8.3 mg/kg/day. PBO: Placebo tablets for piperaquine are identical in size, shape and colour to the piperaquine tablets.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 42 days Efficacy defined as PCR corrected adequate clinical and parasitological response (ACPR). | 42 days Efficacy defined as PCR corrected adequate clinical and parasitological response (ACPR). | 42 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 63-day PCR corrected and uncorrected efficacy |  | 63 days | 
| 42-day PCR uncorrected efficacy |  | 42 days | 
| Parasite clearance half-life | Assessed by microscopy as primary parameter to determine parasite clearance | 3 Days | 
| Proportion of subjects with microscopically detectable P. falciparum parasitaemia |  | Day 3 | 
| Fever clearance time | fever clearance time (i.e. the time taken for the tympanic temperature to fall below 37.5 ºC) | 63 Days | 
| Proportion of subjects with gametocytaemia | proportion of subjects with gametocytaemia during and after treatment stratified by presence of gametocytes at enrolment | 63 Days | 
| Incidence of adverse events | including markers of hepatic, renal or bone marrow toxicity; cardiotoxicity | 42 days | 
| Incidence of serious adverse events | including markers of hepatic, renal or bone marrow toxicity; cardiotoxicity | 42 days | 
| Number of cardiotoxicity events | In particular QT or QTc-interval above 500 ms at timepoint H4 and H52/H64 and between these time points | 52 or 64 hours depends on treatment arm | 
| Change in haemoglobin stratified for G6PD status/genotype |  | 28 days | 
| Proportion of subjects requiring retreatment due to vomiting | Proportion of subjects requiring retreatment due to vomiting within 1 hour after administration of the study drugs | 1 hour | 
| 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 profiles | including Cmax and AUC) of artemisinin-derivatives and partner drugs in ACT and TACT treated subjects in correlation with pharmacodynamics measures of drug efficacy | 42 days | 
| Pharmacokinetic interactions | including Cmax and AUC) of artemisinin-derivatives and partner drugs in ACT and TACT treated subjects in correlation with pharmacodynamics measures of drug efficacy | 42 days | 
| Plasma levels of partner drugs | Plasma levels of partner drugs in correlation with treatment efficacy and treatment arm | 7 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Artemether, Lumefantrine, Amodiaquine, Artesunate, Piperaquine, Mefloquine, Triple Artemisinin-based Combination Therapy (TACT)