Malaria, Falciparum
Conditions
Keywords
Artemisinin combination Therapies
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)
Interventions
DRUGACT
1. Artemether-lumefantrine for 3 days 2. Dihydroartemisinin-piperaquine for 3 days. 3. Artesunate-mefloquine for 3 days
DRUGTACT
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.
Sponsors
University of Oxford
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Months to 65 Years
Healthy volunteers
No
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 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| PCR corrected efficacy defined as adequate clinical and parasitological response (ACPR) | 42 days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| Parasite clearance half-life | 42 days | Parasite clearance half-life assessed by microscopy as primary parameter to de-termine parasite clearance |
| 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 | — |
| Prevalence of Kelch13 mutations of known functional significance | 42 days | — |
Countries
Bangladesh, Burma, Cambodia, Democratic Republic of the Congo, India, Laos, Thailand, Vietnam
Outcome results
None listed