- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03923725
A Trial to Compare the Efficacy, Safety and Tolerability of Combinations of 3 Anti-malarial Drugs Against Combina-tions of 2 Anti-malarial Drugs. (DeTACT-Africa)
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
Study Overview
Status
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 Rwanda, subjects will be randomized between 2 arms consisting of artemether-lumefantrine + placebo or artemether-lumefantrine + amodiaquine.
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.
The DeTACT-Africa Trial is funded by UK Aid from the UK government's Foreign, Commonwealth and Development Office.
Study Type
Enrollment (Estimated)
Phase
- Phase 3
Contacts and Locations
Study Contact
- Name: Mehul Dhorda, Ph.D
- Phone Number: +66 2 203-6333
- Email: Mehul@tropmedres.ac
Study Contact Backup
- Name: Arjen Mattheus Dondorp, Prof.
- Phone Number: 6303 +662-203-6333
- Email: arjen@tropmedres.ac
Study Locations
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Bobo-Dioulasso 01, Burkina Faso
- Recruiting
- Institut des Sciences et Techniques (INSTech)
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Contact:
- Serge Yerbanga, MD
- Phone Number: +226 71 48 48 66
- Email: yrserge@yahoo.fr
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Kinshasa, Congo, The Democratic Republic of the, BP 11850 Kin
- Recruiting
- Kinshasa School of Public Health
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Contact:
- Caterina Fanello
- Phone Number: +(243) 99 00 24 201
- Email: caterina.fanello@ndm.ox.ac.uk
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Banjul
-
Fajara, Banjul, Gambia, 273
- Recruiting
- MRC Unit The Gambia at LSHTM
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Contact:
- Edgard Dabira, MD
- Email: edabira@mrc.gm
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Conakry, Guinea, B.P. 2649
- Recruiting
- Centre National de Formation et de Recherche en Santé Rurale de Mafèrinyah
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Contact:
- Abdoul Habib Beavogui, MD
- Email: bea@maferinyah.org
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Niamey, Niger, BP: 13 330
- Recruiting
- Epicentre Niger
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Contact:
- Ousmane Guindo, MD
- Email: ousmane.guindo@epicentre.msf.org
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Kwara State
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Ilorin, Kwara State, Nigeria, 1459
- Recruiting
- Centre for Malaria and Other Tropical Diseases (CEMTROD)
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Contact:
- Olugbenga Mokuolu, MD
- Email: oamokuolu@yahoo.com
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Kigali, Rwanda
- Recruiting
- College of Medicine and Health Sciences, University of Rwanda
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Contact:
- Leon Mutesa, MD
- Email: lmutesa@gmail.com
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Tanga, Tanzania
- Recruiting
- National Institute For Medical Research (NIMR), Tanga Medical Research Centre
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Contact:
- Samwel Gesase, MD
- Email: sgesase@yahoo.com
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Male or female, aged ≥6 months to <12 years (For Gambia, Rwanda sites 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, Rwanda sites 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, Rwanda sites 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, Rwanda sites only: females who are pregnant, trying to get pregnant or are 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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Single
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: artemether-lumefantrine+placebo (AL+PBO)
ACTs
|
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 identical in size, shape and color to the amodiaquine tablets. |
Experimental: Artemether-lumefantrine+amodiaquine (AL+AQ)
Triple ACTs
|
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. |
Experimental: Artesunate-mefloquine+Piperaquine (AS-MQ+PPQ)
Triple ACTs
|
AS: Artesunate will be administered according to an optimised dosing schedule using tablets of 32 or 100 mg artesunate with a dosing target of 4 mg/kg/day. MQ: Mefloquine will be administered according to an optimised dosing schedule using tablets of 70 or 220 mg mefloquine hydrochloride with a dosing target of 8.3 mg/kg/day. PPQ: Piperaquine will be administered according to an optimised dosing schedule using tablets of 160 or 500 mg of piperaquine tetraphosphate. The weight-based treatment aims for a dosage of approximately.
|
Active Comparator: Artesunate-mefloquine+placebo (AS-MQ+PBO)
ACTs
|
AS: Artesunate will be administered according to an optimised dosing schedule using tablets of 32 or 100 mg artesunate with a dosing target of 4 mg/kg/day. MQ: Mefloquine will be administered according to an optimised dosing schedule using tablets of 70 or 220 mg mefloquine hydrochloride with a dosing target of 8.3 mg/kg/day. PBO: Placebo tablets for piperaquine are identical in size, shape and colour to the piperaquine tablets. |
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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).
|
42 days
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in haemoglobin stratified for G6PD status/genotype
Time Frame: 28 days
|
28 days
|
|
Proportion of subjects that reports completing a full course of observed TACT
Time Frame: 3 days
|
3 days
|
|
Proportion of subjects that reports completing a full course of observed ACT
Time Frame: 3 days
|
3 days
|
|
63-day PCR corrected and uncorrected efficacy
Time Frame: 63 days
|
63 days
|
|
42-day PCR uncorrected efficacy
Time Frame: 42 days
|
42 days
|
|
Parasite clearance half-life
Time Frame: 3 Days
|
Assessed by microscopy as primary parameter to determine parasite clearance
|
3 Days
|
Proportion of subjects with microscopically detectable P. falciparum parasitaemia
Time Frame: Day 3
|
Day 3
|
|
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)
|
63 Days
|
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
|
63 Days
|
Incidence of adverse events
Time Frame: 42 days
|
including markers of hepatic, renal or bone marrow toxicity; cardiotoxicity
|
42 days
|
Incidence of serious adverse events
Time Frame: 42 days
|
including markers of hepatic, renal or bone marrow toxicity; cardiotoxicity
|
42 days
|
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
|
52 or 64 hours depends on treatment arm
|
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
|
1 hour
|
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
|
42 days
|
|
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
|
42 days
|
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
|
42 days
|
Plasma levels of partner drugs
Time Frame: 7 days
|
Plasma levels of partner drugs in correlation with treatment efficacy and treatment arm
|
7 days
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Correlation between qPCR based versus microscopy based assessments of parasite clearance dynamics
Time Frame: 14 days
|
14 days
|
|
Correlation of parasite clearance metrics as assessed by microscopy versus digital microscopy
Time Frame: 3 days
|
3 days
|
|
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
|
63 days
|
Proportions of recurrent infections
Time Frame: 63 days
|
Proportions of recurrent infections with parasites carrying mutations of known functional significance
|
63 days
|
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)
|
baseline
|
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
|
63 days
|
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
|
63 days.
|
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
|
63 days.
|
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
|
63 days
|
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
|
14 days
|
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)
|
42 days
|
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.
|
63 days
|
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
|
63 days
|
Collaborators and Investigators
Sponsor
Collaborators
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Infections
- Vector Borne Diseases
- Parasitic Diseases
- Protozoan Infections
- Mosquito-Borne Diseases
- Malaria
- Malaria, Falciparum
- Anti-Infective Agents
- Antiviral Agents
- Antineoplastic Agents
- Antiprotozoal Agents
- Antiparasitic Agents
- Antimalarials
- Anthelmintics
- Schistosomicides
- Antiplatyhelmintic Agents
- Lumefantrine
- Artemether
- Artesunate
- Artemether, Lumefantrine Drug Combination
- Piperaquine
- Amodiaquine
- Mefloquine
Other Study ID Numbers
- MAL18004
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
IPD Sharing Time Frame
IPD Sharing Access Criteria
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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