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A Trial to Compare the Efficacy, Safety and Tolerability of Combinations of 3 Anti-malarial Drugs Against Combina-tions of 2 Anti-malarial Drugs.

  • Clinicaltrials.gov identifier

    NCT03923725

  • Recruitment Status

    Recruiting

  • First Posted

    April 23, 2019

  • Last update posted

    March 16, 2021

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 (AL+AQ)
    Drug: Artemether-lumefantrine + placebo (AL+PBO)
    Drug: Artesunate-mefloquine+piperaquine (AS-MQ+PPQ)
    Drug: Artesunate-mefloquine+placebo (AS-MQ+PBO)
  • 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: 3456 participants
  • Allocation: Randomized
  • Intervention Model: Parallel Assignment
  • 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 Africa
  • Actual Study Start Date: September 2020
  • Estimated Primary Completion Date: July 2022
  • Estimated Study Completion Date: July 2022

Arms and interventions

Arm Intervention/treatment
Experimental: Artemether-lumefantrine+amodiaquine (AL+AQ)
Triple ACTs
Drug: Artemether-lumefantrine+ Amodiaquine (AL+AQ)
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: 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+PBO)
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. PBO: Placebo tablets for amodiaquine are currently under development. They will be identical in size, shape and color. We aim for a similar taste of amodiaquine and the placebo.
Experimental: Artesunate-mefloquine+Piperaquine (AS-MQ+PPQ)
Triple ACTs
Drug: Artesunate-mefloquine+piperaquine (AS-MQ+PPQ)
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+PBO)
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. PBO: Placebo tablets for mefloquine are currently under development. They will be identical in size, shape and colour. We aim for a similar taste of mefloquine and the placebo.

Outcome Measures

  • Primary Outcome Measures: 1. 42 days Efficacy defined as PCR corrected adequate clinical and parasitological response (ACPR). [ Time Frame: 42 days ]
    42 days Efficacy defined as PCR corrected adequate clinical and parasitological response (ACPR).
  • Secondary Outcome Measures: 1. 63-day PCR corrected and uncorrected efficacy [ Time Frame: 63 days ]
  • 2. 42-day PCR uncorrected efficacy [ Time Frame: 42 days ]
  • 3. Parasite clearance half-life [ Time Frame: 3 Days ]
    Assessed by microscopy as primary parameter to determine parasite clearance
  • 4. Proportion of subjects with microscopically detectable P. falciparum parasitaemia [ Time Frame: Day 3 ]
  • 5. Fever clearance time [ Time Frame: 63 Days ]
    fever clearance time (i.e. the time taken for the tympanic temperature to fall below 37.5 ºC)
  • 6. Proportion of subjects with gametocytaemia [ Time Frame: 63 Days ]
    proportion of subjects with gametocytaemia during and after treatment stratified by presence of gametocytes at enrolment
  • 7. Incidence of adverse events [ Time Frame: 42 days ]
    including markers of hepatic, renal or bone marrow toxicity; cardiotoxicity
  • 8. Incidence of serious adverse events [ Time Frame: 42 days ]
    including markers of hepatic, renal or bone marrow toxicity; cardiotoxicity
  • 9. Number of cardiotoxicity events [ Time Frame: 52 or 64 hours depends on treatment arm ]
    In particular QT or QTc-interval above 500 ms at timepoint H4 and H52/H64 and between these time points
  • 10. Change in haemoglobin stratified for G6PD status/genotype [ Time Frame: 28 days ]
  • 11. Proportion of subjects requiring retreatment due to vomiting [ Time Frame: 1 hour ]
    Proportion of subjects requiring retreatment due to vomiting within 1 hour after administration of the study drugs
  • 12. Proportion of subjects that reports completing a full course of observed TACT [ Time Frame: 3 days ]
  • 13. Proportion of subjects that reports completing a full course of observed ACT [ Time Frame: 3 days ]
  • 14. proportion of subjects 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. [ Time Frame: 42 days ]
  • 15. Pharmacokinetic profiles [ Time Frame: 42 days ]
    including Cmax and AUC) of artemisinin-derivatives and partner drugs in ACT and TACT treated subjects in correlation with pharmacodynamics measures of drug efficacy
  • 16. Pharmacokinetic interactions [ Time Frame: 42 days ]
    including Cmax and AUC) of artemisinin-derivatives and partner drugs in ACT and TACT treated subjects in correlation with pharmacodynamics measures of drug efficacy
  • 17. Plasma levels of partner drugs [ Time Frame: 7 days ]
    Plasma levels of partner drugs in correlation with treatment efficacy and treatment arm
  • Other Outcome Measures: 1. Comparison of 63-day vs 42-day PCR corrected and uncorrected efficacy [ Time Frame: 63 days ]
    Comparison of 63-day vs 42-day PCR corrected and uncorrected efficacy of ACTs vs TACTs
  • 2. Proportions of recurrent infections [ Time Frame: 63 days ]
    Proportions of recurrent infections with parasites carrying mutations of known functional significance
  • 3. Proportions of specimens collected at baseline with parasites carrying mutations [ Time Frame: baseline ]
    Proportions of specimens collected at baseline with parasites carrying mutations of known functional or operational significance (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)
  • 4. Candidate markers of resistance [ Time Frame: 63 days ]
    Candidate markers of resistance identified through genome wide association studies with in vivo or in vitro parasite drug sensitivity phenotypes
  • 5. In vitro sensitivity of P. falciparum to artemisinins and partner drugs [ Time Frame: 63 days. ]
    In vitro sensitivity of P. falciparum to artemisinins and partner drugs according to study sites and genotype
  • 6. Accuracy of SNPs assessment [ Time Frame: 63 days. ]
    Accuracy of SNPs assessment from dry blood spots versus from whole genome sequencing in leukocyte depleted blood samples
  • 7. Correlation between qPCR based versus microscopy based assessments of parasite clearance dynamics [ Time Frame: 14 days ]
  • 8. Correlation of parasite clearance metrics as assessed by microscopy versus digital microscopy [ Time Frame: 3 days ]
  • 9. Comparison of transcriptomic patterns of drug sensitive and resistant parasites [ Time Frame: 63 days ]
    Comparison of transcriptomic patterns of drug sensitive and resistant parasites before treatment and 6, 12 and 24 hours after start of treatment
  • 10. 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
  • 11. 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)
  • 12. Correlations between the place of residence, work, recent travel history [ Time Frame: 63 days ]
    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.
  • 13. Correlation between titres of antibodies against malaria parasite antigens and - efficacy defined as PCR corrected adequate clinical and parasitological response (ACPR) - efficacy defined as adequate clinical and parasitological response (ACPR) [ Time Frame: 63 days ]

Eligibility Criteria

  • Ages Eligible for Study: 6 to 12 Months (Child)
  • Sexes Eligible for Study: All
  • Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

- Male or female, aged ≥6 months to <12 years (For Gambia site only: ≥6 months) - Ability to take oral medication - Acute uncomplicated P. falciparum monoinfection - Asexual P. falciparum parasitaemia: 1,000/µL to ≤10% parasitaemia, determined on a peripheral blood film (At Gambia site only: For subjects ≥12 years - 1000/µL to 200,000/µL) - 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 by 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 (adapted from WHO criteria) - Patients not fulfilling criteria for severe malaria but with another indication for parenteral antimalarial treatment at the discretion of the treating physician - Haematocrit <15% at screening (For Gambia site only: For subjects ≥12 years - Haematocrit <20% at screening) - Subjects who have received artemisinin or a derivative within the previous 7 days OR lumefantrine or amodiaquine within the previous 14 days OR mefloquine or piperaquine within the previous 30 days - In applicable countries: use of seasonal malaria chemoprophylaxis (SMC) within the last 14 days. - Acute illness other than malaria requiring systemic treatment - Severe acute malnutrition (in Niger only - only those patients with Severe Acute Malnutrition and complications requiring inpatient nutritional treatment will be excluded) - Known HIV infection - Known tuberculosis infection - For females: post-menarche (For Gambia site only: Female who are pregnant, trying to get pregnant or lactating ) - History of allergy or known contraindication to any of the study drugs, including neuropsychiatric disorders and epilepsy - Previous splenectomy - Enrolment in DeTACT in the previous 3 months - Participation in another interventional study in the previous 3 months

Contacts and Locations

Contacts

Contact: Mehul Dhorda, Ph.D +66 2 203-6333 Mehul@tropmedres.ac

Contact: Arjen Mattheus Dondorp, Prof. +662-203-6333 ext 6303 arjen@tropmedres.ac

Locations

Niger
Epicentre Niger
Niamey

Burkina Faso
Institut des Sciences et Techniques (INSTech)
Bobo-Dioulasso 01

Congo, The Democratic Republic of the
Kinshasa School of Public Health
Kinshasa

Guinea
Centre National de Formation et de Recherche en Santé Rurale de Mafèrinyah
Conakry

Sponsors and Collaborators

University of Oxford

Mahidol Oxford Tropical Medicine Research Unit

More Information

  • Responsible Party: University of Oxford
  • ClinicalTrials.gov Identifier: NCT03923725 History of Changes
  • Other Study ID Numbers: MAL18004
  • First Posted: April 23, 2019 Key Record Dates
  • Last Update Posted: March 16, 2021
  • 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 https://www.wwarn.org/tools-resources/terms-data-access
  • Studies a U.S. FDA-regulated Drug Product: No
  • Studies a U.S. FDA-regulated Device Product: No
  • Keywords provided by University of Oxford: Artemether
    Artesunate
    Amodiaquine
    Mefloquine
    Lumefantrine
    Piperaquine
    Triple Artemisinin-based Combination Therapy (TACT)
  • Additional relevant MeSH terms: Malaria, Falciparum Malaria