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A Trial to Compare the Efficacy, Safety and Tolerability of Combinations of 3 Anti-malarial Drugs Against Combinations of 2 Anti-malarial Drugs (Asia)

  • Clinicaltrials.gov identifier

    NCT03939104

  • Recruitment Status

    Not yet recruiting

  • First Posted

    May 6, 2019

  • Last update posted

    September 3, 2020

Study Description

Brief summary:

A partially blinded randomised controlled non-inferiority trial of the Triple ACTs artemether-lumefantrine + amodiaquine (AL+AQ) and artesunate- mefloquine+piperaquine (ASMQ+PPQ) with the ACTs artemether-lumefantrine + placebo (AL+PBO) and artesunate- mefloquine + placebo (ASMQ+PBO) for the treatment of uncomplicated Plasmodium falciparum malaria to assess and compare their efficacy, safety, tolerability.

  • Condition or Disease:Plasmodium Falciparum Malaria (Uncomplicated)
  • Intervention/Treatment: Drug: Artemether-lumefantrine+amodiaquine
    Drug: Artemether-lumefantrine+placebo
    Drug: Artesunate-mefloquine+piperaquine
    Drug: Artesunate-mefloquine+placebo
  • Phase: Phase 3

Detailed Description

Subjects will be randomized to up to four arms: artemether-lumefantrine + amodiaquine, artemether-lumefantrine + placebo, artesunate-mefloquine + piperaquine and artesunate-mefloquine + placebo. As a contingency measure in case of significant differences in the efficacy or safety of one of the combinations being tested and/or study drug expiry or unavailability, subjects may be randomised to 2 arms with a matching ACT-TACT pair, i.e., with artemether-lumefantrine + placebo or artemether-lumefantrine + amodiaquine OR artesunate-mefloquine + placebo or artesunate-mefloquine + piperaquine. Some sites may randomize between 2 arms only with matching ACT-TACT pairs, i.e., artemether-lumefantrine + placebo or artemether-lumefantrine + amodiaquine OR artesunate-mefloquine + placebo or artesunate-mefloquine + piperaquine. In the control arms, the ACT will be co-packed with a matched (appearance) placebo. In lower transmission settings (Annual Parasite Incidence <50 per 1000 population per year) the treatment will include a single 0.25 mg/kg gametocytocidal dose of primaquine as recommended by the WHO for children ≥10 kg. All drug administrations will be observed. Subjects will be treated in an in-patient unit for 3 days and followed up weekly up to D63. Microscopy to detect and quantify malaria parasitaemia will be performed daily (more frequently in patients with parasite density of >5000/µL at inclusion) during hospitalization, at all weekly and unscheduled visits. A physical examination and measurements of vital signs along with a symptom questionnaire for tolerability will be performed and recorded through a standardized method at baseline, daily during admission and weekly during follow up through D42 and at all unscheduled visits. Physical exam, vital sign measurements and assessments of symptoms will be performed on D49, D56, and D63 only for patients who are parasitaemic or those who report fever or other symptoms. Electrocardiographs will be performed during admission (H0, H4, H52, or H64) and day 42 of follow up to assess and compare the effect of ACTs and TACTs antimalarials on QT or QTc-intervals.

Study Design

  • Study Type: Interventional
  • Estimated Enrollment: 1368 participants
  • Allocation: Randomized
  • Intervention Model: Parallel Assignment
  • Intervention Model Description: A partially blinded randomised controlled non-inferiority trial comparing the efficacy, tolerability and safety of Triple ACTs artemether-lumefantrine+amodiaquine (AL+AQ) and artesunate- mefloquine+piperaquine (ASMQ+PPQ) and the ACTs artemether-lumefantrine+placebo (AL+PBO), artesunate-mefloquine+placebo (ASMQ+PBO) (with single-low dose primaquine in some sites) for the treatment of uncomplicated Plasmodium falciparum malaria to assess and compare their efficacy, safety, tolerability.
  • Masking: Single (Participant)
  • Primary Purpose: Treatment
  • Official Title: A Multi-centre Randomised Controlled Non-inferiority Trial to Compare the Efficacy, Safety and Tolerability of Triple Artemisinin-based Combination Therapies Versus First-line ACTs + Placebo for the Treatment of Uncomplicated Plasmodium Falciparum Malaria in Asia
  • Estimated Study Start Date: October 2020
  • Estimated Primary Completion Date: July 2022
  • Estimated Study Completion Date: July 2022

Arms and interventions

Arm Intervention/treatment
Active Comparator: Artemether-lumefantrine+amodiaquine (AL+AQ)
Triple ACTs
Drug: Artemether-lumefantrine+amodiaquine
AL: Currently available as dispersible tablets containing 20 mg of artemether and 120 mg of lumefantrine, in a fixed-dose combination formulation. The flavoured dispersible tablet paediatric formulation facilitates use in young children. The dose of artemether-lumefantrine is administered approaching the WHO-recommended target ranges of artemether 5-24 mg/kg and lumefantrine 29-144 mg/kg over 3 days. AQ: Amodiaquine is available as dispersible tablets of 40 mg. The weight-based treatment schedule aims for a dosage of approximately 10mg (4.5-15mg)/kg/day amodiaquine for three days.
Active Comparator: artemether-lumefantrine+placebo (AL+PBO)
ACTs
Drug: Artemether-lumefantrine+placebo
AL: Currently available as dispersible tablets containing 20 mg of artemether and 120 mg of lumefantrine, in a fixed-dose combination formulation. The flavoured dispersible tablet paediatric formulation facilitates use in young children. The dose of artemether-lumefantrine is administered approaching the WHO-recommended target ranges of artemether 5-24 mg/kg and lumefantrine 29-144 mg/kg over 3 days.
Active Comparator: Artesunate-mefloquine+piperaquine (AS-MQ+PPQ)
Triple ACTs
Drug: Artesunate-mefloquine+piperaquine
AS-MQ: Artesunate-mefloquine will be administered according to an optimised dosing schedule using tablets of 25 or 100 mg artesunate and 50 or 200 mg mefloquine with a dosing target of 4 mg/kg/day and 8.3 mg/kg/day, respectively PPQ:One tablet contains 250 mg of piperaquine. The weight-based treatment aims for a dosage of approximately 24 mg/kg/day in patients <25 kg (range 16.7 - 31.3 mg/kg) piperaquine for three days, thereby approaching the WHO-recommended target range of 20 - 32 mg/kg per day. 18 mg/kg/day in patients ≥25 kg (range 15.2 - 29.4 mg/kg) piperaquine for three days, thereby approaching the WHO-recommended target range of 16 - 27 mg/kg per day.
Active Comparator: Artesunate-mefloquine+placebo (AS-MQ+PBO)
ACTs.
Drug: Artesunate-mefloquine+placebo
AS-MQ: Artesunate-mefloquine will be administered according to an optimised dosing schedule using tablets of 25 or 100 mg artesunate and 50 or 200 mg mefloquine with a dosing target of 4 mg/kg/day and 8.3 mg/kg/day, respectively

Outcome Measures

  • Primary Outcome Measures: 1. Efficacy defined as PCR corrected adequate clinical and parasitological response (ACPR). [ Time Frame: 42 days ]
  • Secondary Outcome Measures: 1. Efficacy defined as PCR corrected adequate clinical and parasitological response (ACPR) [ Time Frame: 63-day ]
  • 2. Efficacy defined as adequate clinical and parasitological response (PCR) [ Time Frame: 63-day ]
  • 3. Efficacy defined as adequate clinical and parasitological response (ACPR) [ Time Frame: 42-day ]
  • 4. Parasite clearance half-life [ Time Frame: 7 days ]
  • 5. proportion of subjects with microscopically detectable P. falciparum parasitaemia [ Time Frame: 3 days ]
  • 6. Fever clearance time [ Time Frame: 7 days ]
    Time taken for the tympanic temperature to fall below 37.5 ºC in patients who were febrile at inclusion
  • 7. Proportion of subjects with gametocytemia during and after treatment stratified by presence of gametocytes at enrolment [ Time Frame: 63 days ]
  • 8. Number of adverse events [ Time Frame: 42 days ]
  • 9. Number of serious adverse events [ Time Frame: 42 days ]
    Including markers of hepatic, renal or bone marrow toxicity
  • 10. Number of cardiotoxicity events [ Time Frame: 52 or 64 hours depends on treatment arm ]
    In particular QTc-interval above 500 ms or an increase > 60 ms above baseline values at timepoint H4 and H52/H64 and between these time points
  • 11. Change in haemoglobin stratified for G6PD status/genotype [ Time Frame: 28 days ]
  • 12. Proportion of subjects requiring retreatment due to vomiting within 1 hour after administration of the study drugs [ Time Frame: 1 hour ]
  • 13. Proportion of subjects that reports completing a full course of observed TACT [ Time Frame: 3 days ]
  • 14. Proportion of subjects that reports completing a full course of observed ACT [ Time Frame: 3 days ]
  • 15. Pharmacokinetic profiles and interactions (including Cmax) of artemisinin-derivatives and partner drugs in ACT and TACT treated subjects in correlation with pharmacodynamics measures of drug efficacy [ Time Frame: 42 days ]
  • 16. Pharmacokinetic profiles and interactions (AUC) of artemisinin-derivatives and partner drugs in ACT and TACT treated subjects in correlation with pharmacodynamics measures of drug efficacy [ Time Frame: 42 days ]
  • 17. Plasma levels of partner drugs in correlation with treatment efficacy and treatment arm [ Time Frame: 7 days ]
  • Other Outcome Measures: 1. Comparison of efficacy, defined as PCR corrected adequate clinical and parasitological response (ACPR) at day 42 versus day 63 [ Time Frame: 63 days ]
  • 2. Comparison of efficacy, defined as adequate clinical and parasitological response (ACPR) at day 42 versus day 63 [ Time Frame: 63 days ]
  • 3. Proportions of recurrent infections with parasites carrying mutations of known functional significance [ Time Frame: 63 days ]
  • 4. Proportions of specimens collected at baseline with parasites carrying mutations of known functional or operational significance [ Time Frame: baseline ]
    Mutations include pfkelch13, pfcrt, pfmdr1, pfdhfr, pfdhps, pfplasmepsin2 , partial or complete deletions of pfhrp2 and other current parasite genetic markers associated with resistance or identified over the course of the study
  • 5. Number of samples from drug sensitive and resistant parasites that have common genomic patterns that associate with in vivo or in vitro parasite drug sensitivity phenotypes. [ Time Frame: 63 days ]
  • 6. Survival rate or IC50 in in vitro drug susceptibility assay of P. falciparum to artemisinins and partner drugs according to study sites and genotype [ Time Frame: 63 days ]
  • 7. Percent agreement and/or KAPPA score of SNPs assessed from dry blood spots versus from whole genome sequencing in leukocyte depleted blood samples [ Time Frame: 63 days ]
  • 8. Correlation between qPCR based versus microscopy based assessments of parasite clearance dynamics [ Time Frame: 14 days ]
  • 9. Correlation of parasite clearance metrics as assessed by microscopy versus digital microscopy [ Time Frame: 3 days ]
  • 10. Number of samples from drug sensitive and resistant parasites obtained before treatment and 6, 12, and 24 hours after start of treatment that can be assigned to a common transcriptomic pattern. [ Time Frame: 63 days ]
  • 11. 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 [ Time Frame: 14 days ]
  • 12. Correlation between the host genotype and the pharmacokinetics and pharmacodynamics of antimalarials [ Time Frame: 42 days ]
    Host genotype (e.g., CYP2D6, CYP3A4, KCNQ1/LQT1, KCNH2/LQT2, SCN5A/LQT3)
  • 13. Correlations between the place of residence, work, recent travel history assessed by interview and mobile phone records to identify behaviours and risk factors associated with malaria infection. [ Time Frame: 63 days ]
  • 14. Correlation between titres of antibodies against malaria parasite antigen and efficacy defined as PCR corrected adequate clinical and parasitological response (ACPR) [ Time Frame: 63 days ]
  • 15. Correlation between titres of antibodies against malaria parasite antigen and efficacy defined as adequate clinical and parasitological response (ACPR) [ Time Frame: 63 days ]

Eligibility Criteria

  • Ages Eligible for Study: 6 Months and older (Child, Adult, Older Adult)
  • Sexes Eligible for Study: All
  • Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

- Male or female, aged 6 months and above

- Ability to take oral medication

- Acute uncomplicated P. falciparum monoinfection

- Asexual P. falciparum parasitaemia: 96 to 200,000/µL, determined on a thin or thick
peripheral blood film

- Fever defined as >/= 37.5°C tympanic temperature or a history of fever within the last
24 hours

- Written informed consent by the subject or parent/guardian in case of children lower
than the age of consent and assent if required (per local regulations)

- Willingness and ability of the subjects or parents/guardians to comply with the study
protocol for the duration of the study

Exclusion Criteria:

- Signs of severe malaria

- Patients not fulfilling criteria for severe malaria but with another indication for
parenteral antimalarial treatment at the discretion of the treating physician

- Haematocrit 10%)

Contacts and Locations

Contacts

Contact: Chanaki Amaratunga, Ph.D +66 2 203-6333 Chanaki@tropmedres.ac

Locations

Sponsors and Collaborators

University of Oxford

More Information

  • Responsible Party: University of Oxford
  • ClinicalTrials.gov Identifier: NCT03939104 History of Changes
  • Other Study ID Numbers: MAL18005
  • First Posted: May 6, 2019 Key Record Dates
  • Last Update Posted: September 3, 2020
  • Last Verified: September 2020
  • Individual Participant
    Data (IPD) Sharing
    Statement:

  • Plan to Share IPD: Yes
  • Plan Description: With participant's consent, participant's data and results from blood analyses stored in the database may be shared according to the terms defined in the MORU data sharing policy with data repositories such as the WorldWide Antimalarial Resistance Network (WWARN, terms of submission here: http://www.wwarn.org/tools-resources/terms-submission) or other researchers to use in the future. All personal information will be anonymised so that no individual can be identified from their treatment records, through interviews, or from mapping data.
  • Time Frame: After completion of trial activities and reporting
  • Access Criteria: MORU Data Sharing Policy: http://www.tropmedres.ac/data-sharing WWARN terms of Data Access: http://www.wwarn.org/tools-resources/terms-reshouces/terms-data-access
  • URL: https://www.tropmedres.ac/units/moru-bangkok/bioethics-engagement/data-sharing
  • Studies a U.S. FDA-regulated Drug Product: No
  • Studies a U.S. FDA-regulated Device Product: No
  • Keywords provided by University of Oxford: Artesunate
    Mefloquine
    Lumefantrine
    Artemether
    Amodiaquine
    Piperaquine
  • Additional relevant MeSH terms: Malaria Malaria, Falciparum