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

Study Overview
=================
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: Artemether-lumefantrine combined with amodiaquine (TACT arm) or Artemether-lumefantrine (ACT arm) In Myanmar and Vietnam the following two combinations will be used: Dihydroartemisinin-piperaquine combined with mefloquine (TACT arm) or Dihydroartemisinin-piperaquine (ACT arm) In Cambodia and Thailand the following two combinations will be used: Dihydroartemisinin-piperaquine plus Mefloquine hydrochloride (TACT arm) or Artesunate-mefloquine (ACT arm)

Official Title
-----------------
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

Conditions
-----------------
Malaria, Falciparum

Intervention / Treatment
-----------------
* Drug: ACT
* Drug: TACT


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 6 Months
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ACT-arms<br>1.1 Artemether-lumefantrine for 3 days. 1.2 Dihydroartemisinin-piperaquine for 3 days 1.3 Artesunate-Mefloquine for 3 days | Drug: ACT<br>* Artemether-lumefantrine for 3 days Dihydroartemisinin-piperaquine for 3 days. Artesunate-mefloquine for 3 days<br>|
| Active Comparator: TACT-arms<br>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. | Drug: TACT<br>* 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.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PCR corrected efficacy defined as adequate clinical and parasitological response (ACPR) |  | 42 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parasite clearance half-life | Parasite clearance half-life assessed by microscopy as primary parameter to de-termine parasite clearance | 42 days | 
| 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 | Total billirubin, ALT, AST and Alkaline Phosphatase will be measured | 42 days | 
| Incidence of adverse events concerning markersof renal toxicity | Creatinine will be measured | 42 days | 
| Incidence of prolongation of the QTc-interval | Incidence of prolongation of the Qtc-interval above 500 ms or > 60ms above baseline values | 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 | 42 days | 
| 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Artemisinin combination Therapies