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. Study group C: C.1: Artesunate-mefloquine for 3 days versus: C.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 Myanmar and Vietnam the following two combinations will be used: 1. Dihydroartemisinin-piperaquine combined with mefloquine (TACT arm) or 2. Dihydroartemisinin-piperaquine (ACT arm) In Cambodia and Thailand the following two combinations will be used: 1. Dihydroartemisinin-piperaquine plus Mefloquine hydrochloride (TACT arm) or 2. Artesunate-mefloquine (ACT arm)
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
1,110
1. Artemether-lumefantrine for 3 days 2. Dihydroartemisinin-piperaquine for 3 days. 3. Artesunate-mefloquine for 3 days
1. Artemether-lumefantrine for 3 days plus Amodiaquine for 3 days. 2. Dihydroartemisinin-piperaquine for 3 days plus Mefloquine hydrochloride for 3 days. 3. Dihydroartemisinin-piperaquine for 3 days plus Mefloquine hydrochloride for 3 days.
College of Medicine Chittagong
Rāmu, Bangladesh
Ann Hospital
Ann Town, Burma
Pyay hospital
Prome, Burma
Pyin oo Lwin hospital
Pyin Oo Lwin, Burma
Thabeikkyin hospital
Thabeikkyin, Burma
Pailin
Pailin, Cambodia
Preah Vihear
Preah Vihear, Cambodia
Pursat
Pursat, Cambodia
Ratanakiri
Ratankiri, Cambodia
Kinshasa
Kinshasa, Democratic Republic of the Congo
...and 10 more locations
PCR corrected efficacy defined as adequate clinical and parasitological response (ACPR)
Time frame: 42 days
Parasite clearance half-life
Parasite clearance half-life assessed by microscopy as primary parameter to de-termine parasite clearance
Time frame: 42 days
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
Total billirubin, ALT, AST and Alkaline Phosphatase will be measured
Time frame: 42 days
Incidence of adverse events concerning markersof renal toxicity
Creatinine will be measured
Time frame: 42 days
Incidence of prolongation of the QTc-interval
Incidence of prolongation of the Qtc-interval above 500 ms or \> 60ms above baseline values
Time frame: 3 days
Change in hemoglobin/hematocrit
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
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 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
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