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Completed

NCT Number: NCT03355664

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

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

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Key information

Conditions

Malaria, Falciparum Cardiotoxicity Cardiovascular Diseases Chemically-Induced Disorders Drug-Related Side Effects and Adverse Reactions Heart Diseases Infections Malaria Mosquito-Borne Diseases Parasitic Diseases Pathologic Processes Pathological Conditions, Signs and Symptoms Protozoan Infections Radiation Injuries Vector Borne Diseases Wounds and Injuries

Age range

2 year–65 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

Siem Pang Health Center, Siem Pang, Stung Treng, Cambodia

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About this study

"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."

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

ACT

Drug

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

TACT

Drug

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

Primary outcomes

  1. Polymerase Chain Reaction Corrected Efficacy Defined as Adequate Clinical and Parasitological Response (ACPR) by Study Arm

    Time frame: 42 days

    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.

Secondary outcomes

  1. 42-day Polymerase Chain Reaction Corrected Efficacy According to Site/Geographic Region

    Time frame: 42 day

    42-day polymerase chain reaction corrected efficacy defined as adequate clinical and parasitological response (ACPR) according to site/geographic region.

  2. Parasite Clearance Half-life

    Time frame: 42 day

    Parasite clearance half-life assessed by microscopy as primary parameter to determine parasite clearance

  3. Fever Clearance Time

    Time frame: 42 day

    The time taken for the tympanic temperature to fall below 37.5˚C and remain there for at least 24 hours

  4. Number of Severe Adverse Events by Study Arm

    Time frame: 42 days

    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.

  5. Incidence of Adverse Events Concerning Markers of Hepatic or Renal Toxicity

    Time frame: 42 day

    Total bilirubin, Alanine transaminase, Aspartate transaminase, Alkaline phosphatase and creatinine will be measured

  6. Incidence of Prolongation of the Corrected QT Interval

    Time frame: 28 day

    We record the number of events where the QT interval exceeds 500ms or increases by 60ms or greater.

  7. Prolongation of the Corrected QT Interval

    Time frame: Hour 4, Hour 24, Hour 28, Hour 48, Hour 52, Hour 60, Hour 64, Day 7 and Day 28 and between these time points

    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.

  8. Parasite Reduction Rates

    Time frame: 24 and 48 hours

    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.

  9. Parasite Count to Fall 50%

    Time frame: 42 days

    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.

  10. Parasite Count to Fall 90%

    Time frame: 42 days

    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.

  11. Parasite Count to Fall 99%

    Time frame: 42 days

    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.

  12. Change in Haematocrit

    Time frame: Day 1 to 7, 14, 21, 28, 35, 42

    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.

  13. Correlation Between the Host Genotype and the Pharmacokinetics and Pharmacodynamics of Antimalarials

    Time frame: 42 day

    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.

  14. Proportion of Patients That Reports Completing a Full Course of Observed TACT or ACT

    Time frame: 42 day

    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.

  15. Prevalence of Kelch13 Mutations of Known Significance

    Time frame: 42 day

    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.

  16. Prevalence/Incidence of Other Genetic Markers of Antimalarial Drug Resistance Such as Multidrug Resistance Gene 1 Copy Number and Multidrug Resistance Gene 1 Mutations

    Time frame: 48 hours

    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.

  17. Genome Wide Association With in Vivo/in Vitro Sensitivity Parasite Phenotype

    Time frame: 42 day

    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.

  18. Correlation Between Single Nucleotide Polymorphisms and Whole Genome Sequencing

    Time frame: 42 day

    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.

  19. A Comparison of Transcriptomic Patterns Between Sensitive and Resistant Parasites

    Time frame: baseline and t = 6 hours

    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.

  20. Correlation Between Quantitative Polymerase Chain Reaction Based Versus Microscopy Based Assessments of Parasite Clearance Dynamics

    Time frame: 14 days

    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.

  21. Proportion of Patients With Gametocytaemia Before, During and After Treatment With TACT or ACT

    Time frame: At admission and up to day 14

    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.

  22. Levels of RNA Transcription Coding for Male or Female Specific Gametocytes

    Time frame: 14 days

    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.

  23. In Vitro Sensitivity of P. Falciparum to Artemisinins and Partner Drugs

    Time frame: At admission & subjects with recurrent parasitaemia, up to 42 days

    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.

  24. Pharmacokinetic Profiles and Interactions (Cmax) of Artemisinin-derivatives and Partner Drugs

    Time frame: 42 days

    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.

  25. Pharmacokinetic Profiles and Interactions (AUC) of Artemisinin-derivatives and Partner Drugs

    Time frame: 42 days

    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.

  26. Day 7 Drug Levels of Partner Drugs in Association With Treatment Efficacy and Treatment Arm

    Time frame: 7 days

    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.

  27. Correlation Between Histidine-rich Protein 2 (HRP2) Based Versus Microscopy Based Assessments of Parasite Clearance Dynamics

    Time frame: 42 days

    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.

Sponsors and collaborators

Lead sponsor

University of Oxford

Other

Registry information

Official study title

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

Acronym: TACT-CV

Important dates

Study start
2018
Primary completion
2020
Study completion
2020
First posted
Nov 28, 2017
Registry last updated
Jul 15, 2022

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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