Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

A Study by the Development of Triple Artemisinin Combination Therapies (DeTACT) Collaboration (Africa) (DeTACT-Africa)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03923725
Recruitment Status : Not yet recruiting
First Posted : April 23, 2019
Last Update Posted : November 5, 2019
Sponsor:
Information provided by (Responsible Party):
University of Oxford

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

Condition or disease Intervention/treatment Phase
Plasmodium Falciparum Malaria (Uncomplicated) 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 3

  Show Detailed Description

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 3456 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
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
Estimated Study Start Date : December 1, 2019
Estimated Primary Completion Date : July 15, 2022
Estimated Study Completion Date : July 15, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Malaria

Arm Intervention/treatment
Active Comparator: 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.


Active Comparator: 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 schedule in appendix 2 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.





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 days ]
  2. Efficacy defined as adequate clinical and parasitological response (ACPR). [ Time Frame: 63 days ]
  3. Efficacy defined as adequate clinical and parasitological response (ACPR). [ Time Frame: 42 days ]
  4. Parasite clearance half-life [ Time Frame: 7 days ]
    Assessed by microscopy as primary parameter to determine parasite clearance

  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 ]
    Including markers of hepatic, renal or bone marrow toxicity

  9. Number of serious adverse events [ Time Frame: 42 day ]
    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 QT or QTc-interval above 500 ms 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. Identify candidate markers of resistance identified through genome wide association studies 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. Comparison of transcriptomic patterns of drug sensitive and resistant parasites before treatment and 6, 12 and 24 hours after start of treatment [ 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 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 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
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 to <12 years (For Gambia site only: ≥6 months)
  • Ability to take oral medication
  • Acute uncomplicated P. falciparum (or mixed with other plasmodium species)
  • 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
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03923725


Contacts
Layout table for location contacts
Contact: Mehul Dhorda, Ph.D +66 2 203-6333 Mehul@tropmedres.ac

Sponsors and Collaborators
University of Oxford

Layout table for additonal 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: November 5, 2019
Last Verified: March 2019
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

Layout table for additional information
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
Lumefantrine
Amodiaquine
Artesunate
Piperaquine
Mefloquine
Additional relevant MeSH terms:
Layout table for MeSH terms
Malaria
Malaria, Falciparum
Protozoan Infections
Parasitic Diseases
Artesunate
Lumefantrine
Artemether
Piperaquine
Artemether, Lumefantrine Drug Combination
Amodiaquine
Mefloquine
Artemisinins
Artemisinine
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Antineoplastic Agents
Antiviral Agents
Schistosomicides
Antiplatyhelmintic Agents
Anthelmintics