Study to Compare the Triple ACT AL+AQ With the ACT AL in Cambodia and Vietnam

Study Overview
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Brief Summary
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This study is a multi-centre, open-label randomised trial to assess the efficacy, safety and tolerability of the Triple ACT artemether-lumefantrine+amodiaquine (AL+AQ) compared to the ACT artemether-lumefantrine (AL) in uncomplicated falciparum malaria in Cambodia and Vietnam. The estimated total sample size is 600 patients from 2 sites in Cambodia and 2 sites in Vietnam. There are 2 treatment arms Arm 1: Artemether-lumefantrine for 3 days Arm 2: Artemether-lumefantrine for 3 days plus Amodiaquine for 3 days. According to the World Health Organization guideline, all patients except children under 10 kilograms will also be treated with a single dose of primaquine as a gametocytocidal treatment. Funder :Bill & Melinda Gates Foundation (BMGF) Grant reference number: OPP1132628

Detailed Description
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The study of artemether-lumefantrine or artemether-lumefantrine combined with amodiaquine will be a two-arm randomized open label comparative study. The main activity proposed is a series of detailed in vivo clinical, parasitological and pharmacological assessments in 600 subjects across 2 sites in Cambodian (400 subjects) and 2 sites in Vietnam (200 subjects). The subjects will be randomized between the ACT artemether-lumefantrine and the TACT artemether-lumefantrine+amodiaquine. Parasite clearance rates will be assessed by repeated assessments of the parasite counts after the start of the antimalarial treatments. Efficacy, safety and tolerability of ACTs and TACTs will be assessed through weekly follow up visits where vital signs, symptom questionnaires, physical examinations, blood smears, biochemistry assays and full blood counts will be performed. Ex vivo assessments of parasite susceptibility to artemisinins and partner drugs will be measured and compared to historical data, clinical phenotype and other sites in an effort to identify artemisinin and partner drug resistance. This study will obtain data on the effect of antimalarials on the corrected QT intervals. In addition, the effects of antimalarials on factors such as post-treatment haematocrit and haemoglobin levels will be assessed. Extensive pharmacokinetic analysis will allow for an assessment of drug-drug interactions. Plasma histidine-rich protein 2 (HRP2) levels (a marker of parasite biomass) that could potentially serve for the estimation of parasitaemia dynamics before and after treatment will be measured and subsequently modelled.

Official Title
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A Multi-centre, Open-label Randomised Trial to Assess the Efficacy, Safety and Tolerability of the Triple ACT Artemether-lumefantrine+Amodiaquine (AL+AQ) Compared to the ACT Artemether-lumefantrine (AL) in Uncomplicated Falciparum Malaria in Cambodia and Vietnam

Conditions
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Malaria, Falciparum

Intervention / Treatment
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* Drug: ACT
* Drug: TACT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, aged from 2 years 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: 16 to 200,000/microlitre, determined on a thin or thick blood film 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 < 8 g/dL at screening 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 History of allergy or known contraindication to artemisinins, lumefantrine or amodiaquine Previous splenectomy corrected QT interval > 450 milliseconds at moment of presentation Documented or claimed history of cardiac conduction problems Previous participation in the current study or another study in the previous 3 months

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: open-label randomised trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ACT<br>Artemether-lumefantrine for 3 days plus primaquine at hour 24 | Drug: ACT<br>* Artemether-lumefantrine (20/120 mg) as a fixed dose combination twice daily for 3 days according to weight plus low dose primaquine at hour 24<br>|
| Experimental: TACT<br>Artemether-lumefantrine for 3 days plus Amodiaquine for 3 days plus primaquine at hour 24 | Drug: TACT<br>* Artemether-lumefantrine (20/120 mg) as a fixed dose combination twice daily for 3 days according to weight plus Amodiaquine (150mg) twice daily for 3 days according to weight plus low dose primaquine at hour 24<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Polymerase Chain Reaction Corrected Efficacy Defined as Adequate Clinical and Parasitological Response (ACPR) by Study Arm | Efficacy is defined as participants, following initial parasite and fever clearance, not having a recrudescence of the original plasmodium infection and fever, up to 42 days of follow up. | 42 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 42-day Polymerase Chain Reaction Corrected Efficacy According to Site/Geographic Region | 42-day polymerase chain reaction corrected efficacy defined as adequate clinical and parasitological response (ACPR) according to site/geographic region. | 42 day | 
| Parasite Clearance Half-life | Parasite clearance half-life assessed by microscopy as primary parameter to determine parasite clearance | 42 day | 
| Fever Clearance Time | The time taken for the tympanic temperature to fall below 37.5˚C and remain there for at least 24 hours | 42 day | 
| Number of Severe Adverse Events by Study Arm | All numerators in AE tables mean that the AE was reported as present according to the definitions defined in the US government DAIDS 2017 grading tables for reporting of adverse events. The AEs are reported without grading in this table, but are graded in the paper reporting this clinical trial. All Primary analyses are reported (also in the accepted manuscript) along with the secondary outcomes needed to support the primary analysis. Secondary outcomes not involving the randomised comparison will be updated when the analyses are available. Please note that analyses of these Secondary outcomes will take time. | 42 days | 
| Incidence of Adverse Events Concerning Markers of Hepatic or Renal Toxicity | Total bilirubin, Alanine transaminase, Aspartate transaminase, Alkaline phosphatase and creatinine will be measured | 42 day | 
| Incidence of Prolongation of the Corrected QT Interval | We record the number of events where the QT interval exceeds 500ms or increases by 60ms or greater. | 28 day | 
| Prolongation of the Corrected QT Interval | We record the number of events where the QT interval exceeds 500ms or increases by 60ms or greater. There were zero events of this at any time point in either study arm. So no further analyses are possible. | Hour 4, Hour 24, Hour 28, Hour 48, Hour 52, Hour 60, Hour 64, Day 7 and Day 28 and between these time points | 
| Parasite Reduction Rates | Parasite reduction rates and ratios at 24 and 48 hours assessed by microscopy The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. | 24 and 48 hours | 
| Parasite Count to Fall 50% | Time for parasite count to fall 50% of initial parasite density The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. | 42 days | 
| Parasite Count to Fall 90% | Time for parasite count to fall 90% of initial parasite density The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. | 42 days | 
| Parasite Count to Fall 99% | Time for parasite count to fall 99% of initial parasite density The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. | 42 days | 
| Change in Haematocrit | Change in haematocrit at specified time points according to geographical location and study arm, stratified for G6PD status The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. | Day 1 to 7, 14, 21, 28, 35, 42 | 
| Correlation Between the Host Genotype and the Pharmacokinetics and Pharmacodynamics of Antimalarials | Correlation between the host genotype and the pharmacokinetics and pharmacodynamics of antimalarials The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. | 42 day | 
| Proportion of Patients That Reports Completing a Full Course of Observed TACT or ACT | Proportion of patients that reports completing a full course of observed TACT or ACT without withdrawal of consent or exclusion from study because of drug related serious adverse event The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. | 42 day | 
| Prevalence of Kelch13 Mutations of Known Significance | Prevalence of Kelch13 mutations of known significance The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. | 42 day | 
| Prevalence/Incidence of Other Genetic Markers of Antimalarial Drug Resistance Such as Multidrug Resistance Gene 1 Copy Number and Multidrug Resistance Gene 1 Mutations | Prevalence/incidence of other genetic markers of antimalarial drug resistance such as multidrug resistance gene 1 copy number and multidrug resistance gene 1 mutations The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. | 48 hours | 
| Genome Wide Association With in Vivo/in Vitro Sensitivity Parasite Phenotype | Genome wide association with in vivo/in vitro sensitivity parasite phenotype The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. | 42 day | 
| Correlation Between Single Nucleotide Polymorphisms and Whole Genome Sequencing | Correlation between single nucleotide polymorphisms measured in dry blood spots and whole genome sequencing in leukocyte depleted blood samples The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. | 42 day | 
| A Comparison of Transcriptomic Patterns Between Sensitive and Resistant Parasites | Transcriptomic patterns measure at baseline and at specified time points after the start of treatment comparing sensitive and resistant parasites. The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. | baseline and t = 6 hours | 
| Correlation Between Quantitative Polymerase Chain Reaction Based Versus Microscopy Based Assessments of Parasite Clearance Dynamics | Correlation between qPCR based versus microscopy based assessments of parasite clearance dynamics The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. | 14 days | 
| Proportion of Patients With Gametocytaemia Before, During and After Treatment With TACT or ACT | Proportion of patients with gametocytaemia before, during and after treatment with TACT or ACT stratified by the presence of gametocytes at enrolment The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. | At admission and up to day 14 | 
| Levels of RNA Transcription Coding for Male or Female Specific Gametocytes | Levels of RNA transcription coding for male or female specific gametocytes at admission up to day 14, stratified by the presence of gametocytes at enrolment The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. | 14 days | 
| In Vitro Sensitivity of P. Falciparum to Artemisinins and Partner Drugs | In vitro sensitivity of P. falciparum to artemisinins and partner drugs according to study sites and genotype The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. | At admission & subjects with recurrent parasitaemia, up to 42 days | 
| Pharmacokinetic Profiles and Interactions (Cmax) of Artemisinin-derivatives and Partner Drugs | Pharmacokinetic profiles and interactions (Cmax) of artemisinin-derivatives and partner drugs in 20 ACT treated and 20 TACT treated patients of both study arms in Vietnam The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. | 42 days | 
| Pharmacokinetic Profiles and Interactions (AUC) of Artemisinin-derivatives and Partner Drugs | Pharmacokinetic profiles and interactions (AUC) of artemisinin-derivatives and partner drugs in 20 ACT treated and 20 TACT treated patients of both study arms in Vietnam The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. | 42 days | 
| Day 7 Drug Levels of Partner Drugs in Association With Treatment Efficacy and Treatment Arm | Day 7 drug levels of partner drugs in association with treatment efficacy and treatment arm The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. | 7 days | 
| Correlation Between Histidine-rich Protein 2 (HRP2) Based Versus Microscopy Based Assessments of Parasite Clearance Dynamics | Correlation between histidine-rich protein 2 (HRP2) based versus microscopy based assessments of parasite clearance dynamics The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. | 42 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Malaria, Falciparum, Malaria, Protozoan Infections, Lumefantrine, Artemether, Amodiaquine, Piperaquine, Artemether-lumefantrine combination, Artemisinins, Dihydroartemisinin, Mefloquine, Artemisinin, Antimalarials, Antiparasitic Agents, Anti-Infective Agents, ACT, TACT, Triple ACT(s), Resistance, Antimalarial resistance, Cardiotoxicity, Safety, Tolerability, Efficacy