A Study by the Tracking Resistance to Artemisinin Collaboration (TRAC)
- Conditions
- Malaria, Falciparum
- Interventions
- Drug: ACTDrug: TACT
- Registration Number
- NCT02453308
- Lead Sponsor
- University of Oxford
- Brief Summary
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.
- Detailed Description
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)
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 1110
- 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
- Signs of severe/complicated malaria
- Haematocrit < 25% or Hb < 5 g/dL at screening (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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description ACT-arms ACT 1.1 Artemether-lumefantrine for 3 days. 1.2 Dihydroartemisinin-piperaquine for 3 days 1.3 Artesunate-Mefloquine for 3 days TACT-arms TACT 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. 2.3 Dihydroartemisinin-piperaquine for 3 days. plus: Mefloquine hydrochloride for 3 days.
- Primary Outcome Measures
Name Time Method PCR corrected efficacy defined as adequate clinical and parasitological response (ACPR) 42 days
- Secondary Outcome Measures
Name Time Method Parasite clearance half-life 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 at 24 and 48 hours Time for parasite count to fall to 50% of initial parasite density 42 days Time for parasite count to fall to 90% of initial parasite density 42 days Time for parasite count to fall to 99% of initial parasite density 42 days Fever clearance time 42 days Incidence of adverse events and serious adverse events 42 days Incidence of adverse events concerning markers of hepatic toxicity 42 days Total billirubin, ALT, AST and Alkaline Phosphatase will be measured
Incidence of adverse events concerning markersof renal toxicity 42 days Creatinine will be measured
Incidence of prolongation of the QTc-interval 3 days Incidence of prolongation of the Qtc-interval above 500 ms or \> 60ms above baseline values
Change in hemoglobin/hematocrit 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 42 days Prevalence of Kelch13 mutations of known functional significance 42 days Prevalence/incidence of other genetic markers of antimalarial drug resistance 42 days Genome wide association with in vivo/in vitro sensitivity parasite phenotype 42 days Correlation between SNPs measured in dry blood spots and whole genome sequencing in leukocyte depleted blood samples 42 days Transcriptomic patterns at t=0 and t=6h comparing sensitive and resistant parasites 6hrs after start of treatment Correlation between qPCR based versus microscopy based assessments of parasite clearance dynamics 14 days Proportion of patients with gametocytemia before,after treatment with Primaquine assessed at admission, up to day 14 Levels of RNA transcription coding for male or female specific gametocytes at admission up to day 14 In vitro sensitivity (expressed in IC50 values among others) of P. falciparum to artemisinins and partner drugs 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 42 days Day 7 drug levels of partner drugs in association with treatment efficacy and treatment arm Day 7
Trial Locations
- Locations (20)
College of Medicine Chittagong
🇧🇩Ramu, Bangladesh
Ispat General hospital
🇮🇳Rourkela, India
Pyin oo Lwin hospital
🇲🇲Pyin oo Lwin, Myanmar
Tha Song Yang hospital
🇹🇭Tha Song Yang, Tak, Thailand
Chumphon hospital
🇹🇭Chumphon, Thailand
Preah Vihear
🇰🇭Preah Vihear, Cambodia
Pursat
🇰🇭Pursat, Cambodia
Kinshasa
🇨🇩Kinshasa, Congo, The Democratic Republic of the
Pailin
🇰🇭Pailin, Cambodia
Mohanpur Community health center
🇮🇳Agartala, India
Thabeikkyin hospital
🇲🇲Thabeikkyin, Myanmar
Phusing hospital
🇹🇭Phusing, Srisaket, Thailand
Kunhan Hospital
🇹🇭Si Sa Ket, Thailand
Thanto Hospital
🇹🇭Yala, Thailand
Ratanakiri
🇰🇭Ratankiri, Cambodia
Midnapore
🇮🇳Midnapore, India
Sekong
🇱🇦Sekong, Lao People's Democratic Republic
Ann Hospital
🇲🇲Ann, Myanmar
Pyay hospital
🇲🇲Pyay, Myanmar
Binh Phuoc hospital
🇻🇳Binh Phuoc, Vietnam