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.
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Plasmodium Falciparum Malaria (Uncomplicated)
Keywords: Artemether
Lumefantrine
Amodiaquine
Artesunate
Piperaquine
Mefloquine
Triple Artemisinin-based Combination Therapy (TACT)
Lead sponsor: University of Oxford
Sponsor class: OTHER
Collaborators: name: Mahidol Oxford Tropical Medicine Research Unit
First posted: 2019-04-23
Enrollment: 3240
Sex: ALL
Minimum age (years): 6
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: 42 days Efficacy defined as PCR corrected adequate clinical and parasitological response (ACPR).
timeFrame: 42 days
Secondary outcomes:
measure: 63-day PCR corrected and uncorrected efficacy
timeFrame: 63 days
measure: 42-day PCR uncorrected efficacy
timeFrame: 42 days
measure: Parasite clearance half-life
timeFrame: 3 Days
measure: Proportion of subjects with microscopically detectable P. falciparum parasitaemia
timeFrame: Day 3
measure: Fever clearance time
timeFrame: 63 Days
measure: Proportion of subjects with gametocytaemia
timeFrame: 63 Days
measure: Incidence of adverse events
timeFrame: 42 days
measure: Incidence of serious adverse events
timeFrame: 42 days
measure: Number of cardiotoxicity events
timeFrame: 52 or 64 hours depends on treatment arm
measure: Change in haemoglobin stratified for G6PD status/genotype
timeFrame: 28 days
measure: Proportion of subjects requiring retreatment due to vomiting
timeFrame: 1 hour
measure: Proportion of subjects that reports completing a full course of observed TACT
timeFrame: 3 days
measure: Proportion of subjects that reports completing a full course of observed ACT
timeFrame: 3 days
measure: 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.
timeFrame: 42 days
measure: Pharmacokinetic profiles
timeFrame: 42 days
measure: Pharmacokinetic interactions
timeFrame: 42 days
measure: Plasma levels of partner drugs
timeFrame: 7 days
Other outcomes:
measure: Comparison of 63-day vs 42-day PCR corrected and uncorrected efficacy
timeFrame: 63 days
measure: Proportions of recurrent infections
timeFrame: 63 days
measure: Proportions of specimens collected at baseline with parasites carrying mutations
timeFrame: baseline
measure: Candidate markers of resistance
timeFrame: 63 days
measure: In vitro sensitivity of P. falciparum to artemisinins and partner drugs
timeFrame: 63 days.
measure: Accuracy of SNPs assessment
timeFrame: 63 days.
measure: Correlation between qPCR based versus microscopy based assessments of parasite clearance dynamics
timeFrame: 14 days
measure: Correlation of parasite clearance metrics as assessed by microscopy versus digital microscopy
timeFrame: 3 days
measure: Comparison of transcriptomic patterns of drug sensitive and resistant parasites
timeFrame: 63 days
measure: Levels of RNA transcription coding for male or female specific gametocytes
timeFrame: 14 days
measure: Correlation between the host genotype and the pharmacokinetics and pharmacodynamics of antimalarials.
timeFrame: 42 days
measure: Correlations between the place of residence, work, recent travel history
timeFrame: 63 days
measure: 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)
timeFrame: 63 days
Locations:
city: Bobo-Dioulasso 01
country: Burkina Faso
facility: Institut des Sciences et Techniques (INSTech)
city: Kinshasa
country: Congo, The Democratic Republic of the
facility: Kinshasa School of Public Health
city: Fajara
country: Gambia
facility: MRC Unit The Gambia at LSHTM
state: Banjul
city: Conakry
country: Guinea
facility: Centre National de Formation et de Recherche en Santé Rurale de Mafèrinyah
city: Ilorin
country: Nigeria
facility: Centre for Malaria and Other Tropical Diseases (CEMTROD)
state: Kwara State
city: Niamey
country: Niger
facility: Epicentre Niger
city: Kigali
country: Rwanda
facility: College of Medicine and Health Sciences, University of Rwanda
city: Tanga
country: Tanzania
facility: National Institute For Medical Research (NIMR), Tanga Medical Research Centre
Study officials:
References: