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
- Conditions
- Uncomplicated Plasmodium Falciparum Malaria
- Interventions
- Drug: Artemether-Lumefantrine-Amodiaquine (ALAQ)Drug: Artemether-Lumefantrine (AL)Drug: Artesunate-Amodiaquine (ASAQ)
- Registration Number
- NCT05951595
- Lead Sponsor
- University of Oxford
- 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.
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 1440
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Artemether-Lumefantrine-Amodiaquine (ALAQ) Artemether-Lumefantrine-Amodiaquine (ALAQ) TACT group Artemether-Lumefantrine (AL) Artemether-Lumefantrine (AL) ACT 1 group Artesunate-Amodiaquine (ASAQ) Artesunate-Amodiaquine (ASAQ) ACT 2 group
- Primary Outcome Measures
Name Time Method 28-day efficacy 28 days 28-day efficacy defined as the proportion of patients with Polymerase Chain Reaction (PCR)-corrected adequate clinical and parasitological response (ACPR) at Day 28, i.e., absence up to Day 28 of P. falciparum parasitaemia (detected by microscopy) with parasites genetically identical to those detected at baseline (as determined by PCR product length polymorphisms)
- Secondary Outcome Measures
Name Time Method 42-day PCR-uncorrected efficacy 42 days 42-day PCR-uncorrected efficacy defined as the proportion of patients with absence up to Day 42 of P. falciparum parasitaemia
28-day PCR uncorrected efficacy 28 days 28-day PCR uncorrected efficacy defined as the proportion of patients with absence up to Day 28 of P. falciparum parasitaemia
42-day efficacy 42 days 42-day efficacy defined as the proportion of patients with PCR-corrected adequate clinical and parasitological response (ACPR) at Day 42, i.e., absence up to Day 42 of P. falciparum parasitaemia (detected by microscopy) with parasites genetically identical to those detected at baseline (as determined by PCR product length polymorphisms)
Incidence of adverse events (AEs) 42 days Incidence of AEs within the first 42 days including markers of hepatic, renal or bone marrow toxicity
Peak plasma concentration 42 days Peak plasma concentration (Cmax) of artemisinin-derivatives and partner drugs in ACT and TACT treated participants in correlation with pharmacodynamics measures of drug efficacy
Parasite clearance half-life 3 days Assessed by microscopy as primary parameter to determine parasite clearance half-life
Proportion of participants requiring retreatment due to vomiting 1 hour after administration of each dose of the treatment Proportion of participants requiring retreatment due to vomiting within 1 hour after administration of the study drugs
Proportion of participants who report completing a full course of observed TACT 3 days Proportion of participants who report completing a full course of observed TACT without withdrawal of consent or exclusion from study because of drug related serious adverse event
Proportion of participants who report completing a full course of observed ACT 2 or 3 days depending on the treatment Proportion of participants who report completing a full course of observed ACT without withdrawal of consent or exclusion from study because of drug related serious adverse event
Proportion of participants with microscopically detectable P. falciparum parasitaemia at Day 3 3 days Area under curve 42 days Area under the plasma concentration versus time curve (AUC) of artemisinin-derivatives and partner drugs in ACT and TACT treated participants in correlation with pharmacodynamic measures of drug efficacy
Pharmacokinetic interactions - peak plasma concentration 42 days Comparison of peak plasma concentration (Cmax) of artemisinin-derivatives and partner drugs in ACT and TACT treated participants in correlation with pharmacodynamics measures of drug efficacy
Pharmacokinetic interactions - area under curve 42 days Comparison of area under the plasma concentration versus time curve (AUC) of artemisinin-derivatives and partner drugs in ACT and TACT treated participants in correlation with pharmacodynamic measures of drug efficacy
Plasma levels of partner drugs 7 days Plasma levels of partner drugs in correlation with treatment efficacy and treatment arm on Day 7
Fever clearance time 42 days Fever clearance time (i.e., the time taken for the tympanic temperature to fall below 37.5°C in participants who were febrile at inclusion)
Proportion of participants with gametocytaemia 42 days Proportion of participants with gametocytaemia during and after treatment stratified by presence of gametocytes at enrolment
Incidence of serious adverse events (SAEs) 42 days Incidence of SAEs within the first 42 days including markers of hepatic, renal or bone marrow toxicity
Number of cardiotoxicity events 42 days Cardiotoxicity in particular QT or QTc-interval above 500 ms at timepoint H4, H52 or H64, D42