A Trial to Compare the Efficacy, Safety and Tolerability of Combinations of 3 Anti-malarial Drugs Against Combinations of 2 Anti-malarial Drugs (Asia)

NCT ID: NCT03939104

Last Updated: 2024-03-20

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

103 participants

Study Classification

INTERVENTIONAL

Study Start Date

2021-06-30

Study Completion Date

2023-01-28

Brief Summary

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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

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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.

Conditions

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Plasmodium Falciparum Malaria (Uncomplicated)

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

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 Study Purpose

TREATMENT

Blinding Strategy

SINGLE

Participants

Study Groups

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Artemether-lumefantrine+amodiaquine (AL+AQ)

Triple ACTs

Group Type ACTIVE_COMPARATOR

Artemether-lumefantrine+amodiaquine

Intervention Type DRUG

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: Amodiaquine 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.

Artesunate-mefloquine+piperaquine (AS-MQ+PPQ)

Triple ACTs

Group Type ACTIVE_COMPARATOR

Artesunate-mefloquine+piperaquine

Intervention Type DRUG

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

* 24 mg/kg/day in patients \<25 kg (range 16.0 - 32.0 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 15.0 - 29.4 mg/kg) piperaquine for three days, thereby approaching the WHO-recommended target range of 16 - 27 mg/kg per day.

artemether-lumefantrine+placebo (AL+PBO)

ACTs

Group Type ACTIVE_COMPARATOR

Artemether-lumefantrine+placebo

Intervention Type DRUG

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.

Artesunate-mefloquine+placebo (AS-MQ+PBO)

ACTs.

Group Type ACTIVE_COMPARATOR

Artesunate-mefloquine+placebo

Intervention Type DRUG

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.

Interventions

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Artemether-lumefantrine+amodiaquine

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: Amodiaquine 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.

Intervention Type DRUG

Artemether-lumefantrine+placebo

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.

Intervention Type DRUG

Artesunate-mefloquine+piperaquine

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

* 24 mg/kg/day in patients \<25 kg (range 16.0 - 32.0 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 15.0 - 29.4 mg/kg) piperaquine for three days, thereby approaching the WHO-recommended target range of 16 - 27 mg/kg per day.

Intervention Type DRUG

Artesunate-mefloquine+placebo

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.

Intervention Type DRUG

Eligibility Criteria

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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%)
Minimum Eligible Age

6 Months

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Mahidol Oxford Tropical Medicine Research Unit

OTHER

Sponsor Role collaborator

University of Oxford

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Locations

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Ramu Upazilla Health Complex

Cox’s Bāzār, Chittagong, Bangladesh

Site Status

Kravanh Referral Hospital

Phnum Kravanh, Pursat, Cambodia

Site Status

Siem Pang Health Center

Siem Pang, Stung Treng, Cambodia

Site Status

Countries

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Bangladesh Cambodia

Provided Documents

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Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

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MAL18005

Identifier Type: -

Identifier Source: org_study_id

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