• Efficacy defined as PCR corrected adequate clinical and parasitological response (ACPR) [ Time Frame: 63-day ]
• Efficacy defined as adequate clinical and parasitological response (PCR) [ Time Frame: 63-day ]
• Efficacy defined as adequate clinical and parasitological response (ACPR) [ Time Frame: 42-day ]
• Parasite clearance half-life [ Time Frame: 7 days ]
• proportion of subjects with microscopically detectable P. falciparum parasitaemia [ Time Frame: 3 days ]
• Fever clearance time [ Time Frame: 7 days ]
  Time taken for the tympanic temperature to fall below 37.5 ºC in patients who were febrile at inclusion
• Proportion of subjects with gametocytemia during and after treatment stratified by presence of gametocytes at enrolment [ Time Frame: 63 days ]
• Number of adverse events [ Time Frame: 42 days ]
• Number of serious adverse events [ Time Frame: 42 days ]
  Including markers of hepatic, renal or bone marrow toxicity
• Number of cardiotoxicity events [ Time Frame: 52 or 64 hours depends on treatment arm ]
  In particular QTc-interval above 500 ms or an increase > 60 ms above baseline values at timepoint H4 and H52/H64 and between these time points
• Change in haemoglobin stratified for G6PD status/genotype [ Time Frame: 28 days ]
• Proportion of subjects requiring retreatment due to vomiting within 1 hour after administration of the study drugs [ Time Frame: 1 hour ]
• Proportion of subjects that reports completing a full course of observed TACT [ Time Frame: 3 days ]
• Proportion of subjects that reports completing a full course of observed ACT [ Time Frame: 3 days ]
• Pharmacokinetic profiles and interactions (including Cmax) of artemisinin-derivatives and partner drugs in ACT and TACT treated subjects in correlation with pharmacodynamics measures of drug efficacy [ Time Frame: 42 days ]
• Pharmacokinetic profiles and interactions (AUC) of artemisinin-derivatives and partner drugs in ACT and TACT treated subjects in correlation with pharmacodynamics measures of drug efficacy [ Time Frame: 42 days ]
• Plasma levels of partner drugs in correlation with treatment efficacy and treatment arm [ Time Frame: 7 days ]

• Comparison of efficacy, defined as PCR corrected adequate clinical and parasitological response (ACPR) at day 42 versus day 63 [ Time Frame: 63 days ]
• Comparison of efficacy, defined as adequate clinical and parasitological response (ACPR) at day 42 versus day 63 [ Time Frame: 63 days ]
• Proportions of recurrent infections with parasites carrying mutations of known functional significance [ Time Frame: 63 days ]
• Proportions of specimens collected at baseline with parasites carrying mutations of known functional or operational significance [ Time Frame: baseline ]
  Mutations include pfkelch13, pfcrt, pfmdr1, pfdhfr, pfdhps, pfplasmepsin2 , partial or complete deletions of pfhrp2 and other current parasite genetic markers associated with resistance or identified over the course of the study
• Number of samples from drug sensitive and resistant parasites that have common genomic patterns that associate with in vivo or in vitro parasite drug sensitivity phenotypes. [ Time Frame: 63 days ]
• Survival rate or IC50 in in vitro drug susceptibility assay of P. falciparum to artemisinins and partner drugs according to study sites and genotype [ Time Frame: 63 days ]
• Percent agreement and/or KAPPA score of SNPs assessed from dry blood spots versus from whole genome sequencing in leukocyte depleted blood samples [ Time Frame: 63 days ]
• Correlation between qPCR based versus microscopy based assessments of parasite clearance dynamics [ Time Frame: 14 days ]
• Correlation of parasite clearance metrics as assessed by microscopy versus digital microscopy [ Time Frame: 3 days ]
• Number of samples from drug sensitive and resistant parasites obtained before treatment and 6, 12, and 24 hours after start of treatment that can be assigned to a common transcriptomic pattern. [ Time Frame: 63 days ]
• Levels of RNA transcription coding for male or female specific gametocytes at admission up to day 14, stratified by the presence of gametocytes at enrolment [ Time Frame: 14 days ]
• Correlation between the host genotype and the pharmacokinetics and pharmacodynamics of antimalarials [ Time Frame: 42 days ]
  Host genotype (e.g., CYP2D6, CYP3A4, KCNQ1/LQT1, KCNH2/LQT2, SCN5A/LQT3)
• Correlations between the place of residence, work, recent travel history assessed by interview and mobile phone records to identify behaviours and risk factors associated with malaria infection. [ Time Frame: 63 days ]
• Correlation between titres of antibodies against malaria parasite antigen and efficacy defined as PCR corrected adequate clinical and parasitological response (ACPR) [ Time Frame: 63 days ]
• Correlation between titres of antibodies against malaria parasite antigen and efficacy defined as adequate clinical and parasitological response (ACPR) [ Time Frame: 63 days ]

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.

• Drug: Artemether-lumefantrine+amodiaquine

  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: Amodiaquine 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.

• Drug: Artemether-lumefantrine+placebo

  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.

• Drug: Artesunate-mefloquine+piperaquine

  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.
• Drug: Artesunate-mefloquine+placebo
  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

• Active Comparator: Artemether-lumefantrine+amodiaquine (AL+AQ)
  Triple ACTs
  Intervention: Drug: Artemether-lumefantrine+amodiaquine
• Active Comparator: Artesunate-mefloquine+piperaquine (AS-MQ+PPQ)
  Triple ACTs
  Intervention: Drug: Artesunate-mefloquine+piperaquine
• Active Comparator: artemether-lumefantrine+placebo (AL+PBO)
  ACTs
  Intervention: Drug: Artemether-lumefantrine+placebo
• Active Comparator: Artesunate-mefloquine+placebo (AS-MQ+PBO)
  ACTs.
  Intervention: Drug: Artesunate-mefloquine+placebo

Inclusion Criteria:

• Male or female, aged 6 months and above
• Ability to take oral medication
• Acute uncomplicated P. falciparum monoinfection
• Asexual P. falciparum parasitaemia: 96 to 200,000/µL, determined on a thin or thick peripheral blood film
• 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 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
• Patients not fulfilling criteria for severe malaria but with another indication for parenteral antimalarial treatment at the discretion of the treating physician
• 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
• Acute illness other than malaria requiring systemic treatment
• Severe acute malnutrition
• Known HIV infection
• Known tuberculosis infection
• For females: 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

Criteria for severe malaria

• Impaired consciousness (Glasgow Coma Scale, Blantyre Coma Scale)
• Prostration
• Respiratory distress (defined as maximal respiratory rate, by age)
• ≥2 convulsions in the past 24 hours
• Circulatory collapse
• Pulmonary edema
• Abnormal bleeding
• Visible jaundice
• Haemoglobinuria (blackwater)
• Hyperparasitaemia (>10%)