Clinical trial NCT05951595: A Study to Find Out if a Combination of 3 Medicines for the Treatment of Malaria Works as Well and is as Safe and Tolerable as Combinations of 2 Medicines
Official title: An Open-label, Randomised, Controlled, Non-inferiority Trial to Compare the Efficacy, Safety and Tolerability of a Fixed Dose Triple Artemisinin-based Combination Therapy (TACT) Artemether-lumefantrine-amodiaquine Versus First-line Artemisinin-based Combination Therapies (ACTs) for the Treatment of Uncomplicated Plasmodium Falciparum Malaria
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Uncomplicated Plasmodium Falciparum Malaria
Keywords: Artemether
Lumefantrine
Amodiaquine
Artesunate
Triple Artemisinin-based Combination Therapy (TACT)
Lead sponsor: University of Oxford
Sponsor class: OTHER
First posted: 2023-07-19
Enrollment: 1440
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The goal of this open-label randomised, controlled, non-inferiority trial is to assess and compare the efficacy, tolerability and safety of a fixed dose TACT artemether-lumefantrine-amodiaquine (ALAQ) to the ACTs artemether-lumefantrine (AL), artesunate-amodiaquine (ASAQ) (with single low-dose primaquine in some sites) for the treatment of uncomplicated Plasmodium falciparum malaria in patient. The main question it aims to answer is whether ALAQ, a fixed dose TACT, is as efficacious, safe and tolerable in comparison with AL and ASAQ.

Participants will be enrolled, admitted and randomised to receive the study drug (ALAQ, AL or ASAQ). Patients will receive directly observed treatments and will be followed up at least once daily for the first 3 days after enrolment followed by weekly visits from D7 up to D42. Patients will be asked to report to the clinics between scheduled visits in case of any illness or other symptoms or complaints.

Detailed description: Study participants with an uncomplicated P. falciparum monoinfection complying with all the inclusion criteria and without any of the exclusion criteria will be enrolled and randomised to up to three arms TACT (ALAQ), ACT1 (AL), ACT2 (ASAQ) in a 2:1:1 ratio. 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 World Health Organization (WHO) for patients ≥10 kg.

Participants will be admitted for three days to an in-patient unit for directly observed treatment and to perform all the required study procedures from D0H0 (time of first dose intake) to D3 (H72). They will be followed up weekly starting D7 up to D42.

Microscopy to detect and quantify malaria parasitaemia will be performed daily (more frequently in participants with parasite density of \>5000/µL at screening) during hospitalization and at all weekly and unscheduled visits. In participants with parasite densities \>5000/µL at screening, parasite clearance rates will be assessed by repeated assessments of the parasite counts after the start of the antimalarial treatments. A capillary blood sample will be taken at each of the time-points for these parasite counts.

A physical examination and measurements of vital signs along with a symptom questionnaire 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.

Safety assessments will be performed by measuring markers of renal and hepatic toxicity, haemoglobin, platelet counts, absolute and differential white blood cell counts and electrocardiographs (ECGs). ECGs will be performed during hospitalization (H0, H4, and 4 hours after the last dose) and day 42 of follow up to assess and compare the effect of the TACT and ACTs on QT or corrected QT (QTc) intervals.

Pharmacokinetic measurements will be linked to measures of efficacy and toxicity. To reduce the burden of blood draws, especially in children, a population pharmacokinetic approach requiring sparse blood sampling will be followed in a subset of participants.

Blood samples for parasite genotyping as well as genomic and transcriptomic studies will be collected at baseline and also on the day of a recurrent infection. In selected study sites, P. falciparum parasites will be cryopreserved for in vitro antimalarial drug sensitivity testing. Where possible, ex vivo or in vitro assessments of parasite susceptibility to artemisinins and partner drugs will be assessed. The in vivo and ex vivo data on artemisinin and partner drug sensitivity will potentially be used to identify new genetic or transcriptomic markers/patterns of artemisinin or partner drug resistance.

Eligibility criteria: Inclusion Criteria:

* Male or female, aged ≥6 months (no upper limit unless one is required by local regulations)
* Ability to take oral medication
* Fever defined as ≥38°C tympanic temperature or a history of fever within the last 24 hours
* Acute uncomplicated P. falciparum monoinfection
* Asexual P. falciparum parasitaemia: 1,000/µL to 250,000/µL determined on a peripheral blood film
* Written informed consent by the participant, or by the parent/guardian in case of children lower than the age of consent, and assent if required (per local regulations)
* Willingness and ability of the participants 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 other indication(s) for parenteral antimalarial treatment at the discretion of the treating physician
* Haemoglobin \<7 g/dL at screening
* Participants who have received artemisinin or a derivative within the previous 7 days OR lumefantrine or amodiaquine within the previous 14 days
* In applicable countries: use of seasonal malaria chemoprophylaxis (SMC) within the last 30 days
* Acute illness other than malaria requiring systemic treatment
* Severe acute malnutrition
* Known HIV, tuberculosis, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or other severe infection
* For women of child-bearing age: 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
* Participation in the previous 3 months and/or ongoing follow-up for another interventional study

Primary outcomes:
measure: 28-day efficacy
timeFrame: 28 days
Secondary outcomes:
measure: 28-day PCR uncorrected efficacy
timeFrame: 28 days
measure: 42-day efficacy
timeFrame: 42 days
measure: 42-day PCR-uncorrected efficacy
timeFrame: 42 days
measure: Parasite clearance half-life
timeFrame: 3 days
measure: Proportion of participants with microscopically detectable P. falciparum parasitaemia at Day 3
timeFrame: 3 days
measure: Fever clearance time
timeFrame: 42 days
measure: Proportion of participants with gametocytaemia
timeFrame: 42 days
measure: Incidence of adverse events (AEs)
timeFrame: 42 days
measure: Incidence of serious adverse events (SAEs)
timeFrame: 42 days
measure: Number of cardiotoxicity events
timeFrame: 42 days
measure: Proportion of participants requiring retreatment due to vomiting
timeFrame: 1 hour after administration of each dose of the treatment
measure: Proportion of participants who report completing a full course of observed TACT
timeFrame: 3 days
measure: Proportion of participants who report completing a full course of observed ACT
timeFrame: 2 or 3 days depending on the treatment
measure: Peak plasma concentration
timeFrame: 42 days
measure: Area under curve
timeFrame: 42 days
measure: Pharmacokinetic interactions - peak plasma concentration
timeFrame: 42 days
measure: Pharmacokinetic interactions - area under curve
timeFrame: 42 days
measure: Plasma levels of partner drugs
timeFrame: 7 days
Other outcomes:
measure: Comparison of 28-day PCR-corrected efficacy of ALAQ vs AL
timeFrame: 28 days
measure: Comparison of 28-day PCR-uncorrected efficacy of ALAQ vs AL
timeFrame: 28 days
measure: Comparison of 42-day PCR-corrected efficacy of ALAQ vs AL
timeFrame: 42 days
measure: Comparison of 42-day PCR-uncorrected efficacy of ALAQ vs AL
timeFrame: 42 days
measure: Comparison of 28-day PCR-corrected efficacy of ALAQ vs ASAQ
timeFrame: 28 days
measure: Comparison of 28-day PCR-uncorrected efficacy of ALAQ vs ASAQ
timeFrame: 28 days
measure: Comparison of 42-day PCR-corrected efficacy of ALAQ vs ASAQ
timeFrame: 42 days
measure: Comparison of 42-day PCR-uncorrected efficacy of ALAQ vs ASAQ
timeFrame: 42 days
measure: Proportions of recurrent infections with mutations
timeFrame: 42 days
measure: Proportions of specimens collected at baseline with parasites carrying mutations
timeFrame: Baseline
measure: Change in haemoglobin concentration stratified for Glucose-6-Phosphate Dehydrogenase (G6PD) status/genotype
timeFrame: 28 days
measure: Comparison of transcriptomic patterns of drug sensitive and resistant parasites
timeFrame: 24 hours
measure: Levels of RNA transcription coding for male or female specific gametocytes
timeFrame: 14 days
measure: In vitro susceptibility of P. falciparum to artemisinins and partner drugs
timeFrame: 42 days
measure: Ex vivo susceptibility of P. falciparum to artemisinins and partner drugs
timeFrame: 42 days
Locations:
Study officials:
affiliation: Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
name: Mehul Dhorda, Ph.D
role: PRINCIPAL_INVESTIGATOR
affiliation: Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
name: Arjen Dondorp, Prof.
role: PRINCIPAL_INVESTIGATOR
References: