A Study by the Tracking Resistance to Artemisinin Collaboration (TRAC) (TRACII)

• Parasite clearance half-life [ Time Frame: 42 days ]
  Parasite clearance half-life assessed by microscopy as primary parameter to de-termine parasite clearance
• Parasite reduction rates and ratios at 24 and 48 hours assessed by microscopy [ Time Frame: at 24 and 48 hours ]
• Time for parasite count to fall to 50% of initial parasite density [ Time Frame: 42 days ]
• Time for parasite count to fall to 90% of initial parasite density [ Time Frame: 42 days ]
• Time for parasite count to fall to 99% of initial parasite density [ Time Frame: 42 days ]
• Fever clearance time [ Time Frame: 42 days ]
• Incidence of adverse events and serious adverse events [ Time Frame: 42 days ]
• Incidence of adverse events concerning markers of hepatic toxicity [ Time Frame: 42 days ]
  Total billirubin, ALT, AST and Alkaline Phosphatase will be measured
• Incidence of adverse events concerning markersof renal toxicity [ Time Frame: 42 days ]
  Creatinine will be measured
• Incidence of prolongation of the QTc-interval [ Time Frame: 3 days ]
  Incidence of prolongation of the Qtc-interval above 500 ms or > 60ms above baseline values
• Change in hemoglobin/hematocrit [ Time Frame: 42 days ]
  Change in hemoglobin/hematocrit on day 1 to 7, 14, 21, 28, 35 and 42 according to geographical location and study arm, stratified for G6PD status
• Proportion of patients that reports completing a full course of observed TACT or ACT without withdrawal of consent or exclusion from study [ Time Frame: 42 days ]
• Prevalence of Kelch13 mutations of known functional significance [ Time Frame: 42 days ]
• Prevalence/incidence of other genetic markers of antimalarial drug resistance [ Time Frame: 42 days ]
• Genome wide association with in vivo/in vitro sensitivity parasite phenotype [ Time Frame: 42 days ]
• Correlation between SNPs measured in dry blood spots and whole genome sequencing in leukocyte depleted blood samples [ Time Frame: 42 days ]
• Transcriptomic patterns at t=0 and t=6h comparing sensitive and resistant parasites [ Time Frame: 6hrs after start of treatment ]
• Correlation between qPCR based versus microscopy based assessments of parasite clearance dynamics [ Time Frame: 14 days ]
• Proportion of patients with gametocytemia before,after treatment with Primaquine [ Time Frame: assessed at admission, up to day 14 ]
• Levels of RNA transcription coding for male or female specific gametocytes [ Time Frame: at admission up to day 14 ]
• In vitro sensitivity (expressed in IC50 values among others) of P. falciparum to artemisinins and partner drugs [ Time Frame: 42 days ]
• • Pharmacokinetic profiles and interactions of artemisinin-derivatives and partner drugs (half-life, Cmax, AUC, Tmax) in 20 ACT treated and 20 TACT treated patients of both study arms [ Time Frame: 42 days ]
• Day 7 drug levels of partner drugs in association with treatment efficacy and treatment arm [ Time Frame: Day 7 ]

• Parasite clearance half-life [ Time Frame: 42 days ]
  Parasite clearance half-life assessed by microscopy as primary parameter to de-termine parasite clearance
• Parasite reduction rates and ratios at 24 and 48 hours assessed by microscopy [ Time Frame: at 24 and 48 hours ]
• Time for parasite count to fall to 50% of initial parasite density [ Time Frame: 42 days ]
• Time for parasite count to fall to 90% of initial parasite density [ Time Frame: 42 days ]
• Time for parasite count to fall to 99% of initial parasite density [ Time Frame: 42 days ]
• Fever clearance time [ Time Frame: 42 days ]
• Incidence of adverse events and serious adverse events [ Time Frame: 42 days ]
• Incidence of adverse events of hepatic toxicity [ Time Frame: 42 days ]
  Billirubin, ALT, AST and CPK will be measured
• Incidence of adverse events of renal toxicity [ Time Frame: 42 days ]
  Creatinine will be measured
• Incidence of prolongation of the QTc-interval [ Time Frame: 3 days ]
  Incidence of prolongation of the Qtc-interval above 500 ms or >30ms above baseline values
• hemoglobin/hematocrit [ Time Frame: 42 days ]
• Proportion of patients that reports completing a full course of observed TACT or ACT without withdrawal of consent or exclusion from study [ Time Frame: 42 days ]
• Prevalence of Kelch13 mutations of known functional significance [ Time Frame: 42 days ]
• Prevalence/incidence of other genetic markers of antimalarial drug resistance [ Time Frame: 42 days ]
• Genome wide association with in vivo/in vitro sensitivity parasite phenotype [ Time Frame: 42 days ]
• Correlation between SNPs measured in dry blood spots and whole genome sequencing in leukocyte depleted blood samples [ Time Frame: 42 days ]
• Transcriptomic patterns comparing sensitive and resistant parasites [ Time Frame: 6hrs after start of treatment ]
• Correlation between qPCR based versus microscopy based assessments of parasite clearance dynamics [ Time Frame: 14 days ]
• Proportion of patients with gametocytemia before, during and after treatment with TACTs or ACTs [ Time Frame: assessed at admission, up to day 14 ]
  Proportion of patients with gametocytemia before, during and after treatment with TACTs or ACTs, stratified by presence of gametocytes at enrolment
• Levels of RNA transcription coding for male or female specific gametocytes [ Time Frame: at admission up to day 14 ]
  Levels of RNA transcription coding for male or female specific gametocytes, stratified by the presence of gametocytes at enrolment
• In vitro sensitivity (expressed in IC50 values among others) of P. falciparum to artemisinins and partner drugs [ Time Frame: 42 days ]
• half-life, Cmax, AUC, Tmax [ Time Frame: 42 days ]
  Pharmacokinetic profiles and interactions of artemisinin-derivatives and partner drugs (half-life, Cmax, AUC, Tmax) in 20 ACT treated and 20 TACT treated pa-tients of both study arms
• Day 7 drug levels of partner drugs in association with treatment efficacy and treatment arm [ Time Frame: Day 7 ]

This study is an open-label randomised trial comparing standard ACT treatment with matching triple artemisinin-based combination therapies (TACTs), evaluating efficacy in safety and tolerability. The estimated total sample size is 2040 patients from 16 sites in Asia and 1 site in Africa. There are 2 arm study groups that have 2 treatment arms each.

Study group A:

A.1: Artemether-lumefantrine for 3 days. versus: A.2: Artemether-lumefantrine for 3 days. plus: Amodiaquine for 3 days.

Study group B:

B.1: Dihydroartemisinin-piperaquine for 3 days. versus: B.2: Dihydroartemisinin-piperaquine for 3 days. plus: Mefloquine hydrochloride for 3 days.

According to the WHO guideline, all patients except for children under the age of 1 year or a weight below 10 kilograms will also be treated with a single dose of low dose primaquine.

In Laos, Myanmar, Bangladesh, India and DRC, the following two combinations will be used:

1. Artemether-lumefantrine combined with amodiaquine (TACT arm) or
2. Artemether-lumefantrine (ACT arm)

In Cambodia, Myanmar, Vietnam and Thailand, the following two combinations will be used:

1. Dihydroartemisinin-piperaquine combined with mefloquine (TACT arm) or
2. Dihydroartemisinin-piperaquine (ACT arm)

• Drug: ACT
  1. Artemether-lumefantrine for 3 days
  2. Dihydroartemisinin-piperaquine for 3 days.
• Drug: TACT
  1. Artemether-lumefantrine for 3 days plus Amodiaquine for 3 days.
  2. Dihydroartemisinin-piperaquine for 3 days plus Mefloquine hydrochloride for 3 days.

• Active Comparator: ACT-arms

  1.1 Artemether-lumefantrine for 3 days.

  1.2 Dihydroartemisinin-piperaquine for 3 days

  Intervention: Drug: ACT
• Active Comparator: TACT-arms

  2.1: Artemether-lumefantrine for 3 days.plus: Amodiaquine for 3 days.

  2.2: Dihydroartemisinin-piperaquine for 3 days. plus: Mefloquine hydrochloride for 3 days.

  Intervention: Drug: TACT

Inclusion Criteria:

• Male or female, aged from 6 months to 65 years old
• Acute uncomplicated P. falciparum malaria, confirmed by positive blood smear with asexual forms of P. falciparum (or mixed with non-falciparum species)
• Asexual P. falciparum parasitaemia: 5,000 to 200,000/uL, de-termined on a thin or thick blood film (In Cambodia patients with a parasitaemia of 16 to 200,000/uL are eligible. In DRC patients with a parasitaemia of 10,000 to 250,000/ul are eligi-ble)
• Fever defined as >/= 37.5°C tympanic temperature or a history of fever within the last 24 hours
• Written informed consent (by parent/guardian in case of children)
• Willingness and ability of the patients or parents/guardians to comply with the study protocol for the duration of the study

Exclusion Criteria:

• Signs of severe/complicated malaria
• Haematocrit < 25% or Hb < 5 g/dL at enrollment (DRC: Hct<15% and Hb <5 g/dL due to high prevalence of anemia).
• Acute illness other than malaria requiring treatment
• For females: pregnancy, breast feeding
• Patients who have received artemisinin or a derivative or an artemisinin containing combination therapy (ACT) within the previous 7 days
• Treatment with mefloquine in the 2 months prior to presentation will be an exclusion criteria in the DHA-P+MQ sites
• History of allergy or known contraindication to artemisinins, or to the ACT or TACT to be used at the site e.g. neuropsychiatric disorders will be a contraindication for the use of mefloquine.
• Previous splenectomy
• QTc-interval > 450 milliseconds at moment of presentation
• Documented or claimed history of cardiac conduction problems
• Earlier participation within the TRACII trial or another trial in the previous 3 months.