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

Overview

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.

Full Title of Study: “A Multi-centre, Open-label Randomised Trial to Assess the Efficacy, Safety and Tolerability of Triple Artemisinin-based Combination Therapies (TACTs) Com-pared to Artemisinin-based Combination Therapies (ACTs) in Uncomplicated Falciparum Malaria and to Map the Geographical Spread of Artemisinin and Partner Drug Resistance”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: March 2018

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

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

Arms, Groups and Cohorts

  • Active Comparator: ACT-arms
    • 1.1 Artemether-lumefantrine for 3 days. 1.2 Dihydroartemisinin-piperaquine for 3 days 1.3 Artesunate-Mefloquine for 3 days
  • 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. 2.3 Dihydroartemisinin-piperaquine for 3 days. plus: Mefloquine hydrochloride for 3 days.

Clinical Trial Outcome Measures

Primary Measures

  • PCR corrected efficacy defined as adequate clinical and parasitological response (ACPR)
    • Time Frame: 42 days

Secondary Measures

  • 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

Participating in This Clinical Trial

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 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.

Gender Eligibility: All

Minimum Age: 6 Months

Maximum Age: 65 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • University of Oxford
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Arjen Dondorp, MD, Principal Investigator, Mahidol Oxford Tropical Medicine Research Unit

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