Clinical trial NCT03939104: A Trial to Compare the Efficacy, Safety and Tolerability of Combinations of 3 Anti-malarial Drugs Against Combinations of 2 Anti-malarial Drugs (Asia)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Plasmodium Falciparum Malaria (Uncomplicated)
Keywords: Artemether
Lumefantrine
Amodiaquine
Piperaquine
Artesunate
Mefloquine
Lead sponsor: University of Oxford
Sponsor class: OTHER
Collaborators: name: Mahidol Oxford Tropical Medicine Research Unit
First posted: 2019-05-06
Enrollment: 103
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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 (AS-MQ+PPQ) and the ACTs artemether-lumefantrine+placebo (AL+PBO), artesunate-mefloquine+placebo (AS-MQ+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.
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 (AS-MQ+PPQ) with the ACTs artemether-lumefantrine + placebo (AL+PBO) and artesunate- mefloquine + placebo (AS-MQ+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 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-ASIA Trial is funded by UK Aid from the UK government's Foreign, Commonwealth and Development Office (FCDO). The FCDO project number is 300341-114.

Eligibility criteria: Inclusion Criteria:

* Male or female, \>/= 6 months
* Ability to take oral medication
* Acute uncomplicated P. falciparum monoinfection
* Asexual P. falciparum parasitaemia: 96 to 200,000/µL, determined on a 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 (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 \< 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
* Acute illness other than malaria requiring systemic treatment
* Severe acute malnutrition
* Known HIV infection
* Known tuberculosis infection
* For females: 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

Criteria for severe malaria

* Impaired consciousness (Glasgow Coma Scale, Blantyre Coma Scale)
* Prostration
* Respiratory distress (defined as maximal respiratory rate, by age)
* ≥2 convulsions in the past 24 hours
* Circulatory collapse
* Pulmonary edema
* Abnormal bleeding
* Visible jaundice
* Haemoglobinuria (blackwater)
* Hyperparasitaemia (\>10%)

Primary outcomes:
measure: Efficacy defined as PCR corrected adequate clinical and parasitological response (ACPR).
timeFrame: 42 days
Secondary outcomes:
measure: Efficacy defined as PCR corrected adequate clinical and parasitological response (ACPR)
timeFrame: 63-day
measure: Efficacy defined as adequate clinical and parasitological response (PCR)
timeFrame: 63-day
measure: Efficacy defined as adequate clinical and parasitological response (ACPR)
timeFrame: 42-day
measure: Parasite clearance half-life
timeFrame: 7 days
measure: proportion of subjects with microscopically detectable P. falciparum parasitaemia
timeFrame: 3 days
measure: Fever clearance time
timeFrame: 7 days
measure: Proportion of subjects with gametocytemia during and after treatment stratified by presence of gametocytes at enrolment
timeFrame: 63 days
measure: Number of adverse events
timeFrame: 42 days
measure: Number 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 within 1 hour after administration of the study drugs
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: 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
timeFrame: 42 days
measure: 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
timeFrame: 42 days
measure: Plasma levels of partner drugs in correlation with treatment efficacy and treatment arm
timeFrame: 7 days
Other outcomes:
measure: Comparison of efficacy, defined as PCR corrected adequate clinical and parasitological response (ACPR) at day 42 versus day 63
timeFrame: 63 days
measure: Comparison of efficacy, defined as adequate clinical and parasitological response (ACPR) at day 42 versus day 63
timeFrame: 63 days
measure: Proportions of recurrent infections with parasites carrying mutations of known functional significance
timeFrame: 63 days
measure: Proportions of specimens collected at baseline with parasites carrying mutations of known functional or operational significance
timeFrame: baseline
measure: 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.
timeFrame: 63 days
measure: Survival rate or IC50 in in vitro drug susceptibility assay of P. falciparum to artemisinins and partner drugs according to study sites and genotype
timeFrame: 63 days
measure: Percent agreement and/or KAPPA score of SNPs assessed from dry blood spots versus from whole genome sequencing in leukocyte depleted blood samples
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: 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.
timeFrame: 63 days
measure: 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
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 assessed by interview and mobile phone records to identify behaviours and risk factors associated with malaria infection.
timeFrame: 63 days
measure: Correlation between titres of antibodies against malaria parasite antigen and efficacy defined as PCR corrected adequate clinical and parasitological response (ACPR)
timeFrame: 63 days
measure: Correlation between titres of antibodies against malaria parasite antigen and efficacy defined as adequate clinical and parasitological response (ACPR)
timeFrame: 63 days
Locations:
city: Cox's Bāzār
country: Bangladesh
facility: Ramu Upazilla Health Complex
state: Chittagong
city: Phnum Kravanh
country: Cambodia
facility: Kravanh Referral Hospital
state: Pursat
city: Siem Pang
country: Cambodia
facility: Siem Pang Health Center
state: Stung Treng
Study officials:
References: