Comparison of Arterolane-piperaquine Versus Arterolane-piperaquine+Mefloquine Versus Artemether-lumefantrine in Kenyan Children

Study Overview
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Brief Summary
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This open-label randomised controlled clinical trial will compare the safety, tolerability, therapeutic efficacy and pharmacokinetics and pharmacodynamics of arterolane-piperaquine, arterolane-piperaquine plus mefloquine versus artemether-lumefantrine.in children with uncomplicated falciparum malaria in Kilifi, Kenya. This study will also provide an up to date insight on the current presence of antimalarial resistance in this site. In addition, all children will be treated with a single low dose of primaquine, dosing is age based. The investigators will recruit 219 patients aged 2 years to 12 years with acute uncomplicated falciparum malaria in Kilifi County Hospital.

Official Title
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An Open-label Randomised Trial to Assess the Therapeutic Efficacy and Tolerability of Arterolane-piperaquine Plus Single Low Dose Primaquine Versus Arterolane-piperaquine Plus Mefloquine and Single Low Dose Primaquine Versus Artemether-lumefantrine Plus Single Low Dose Primaquine in the Treatment of Uncomplicated Falciparum Malaria in Children in Kenya

Conditions
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Plasmodium Falciparum

Intervention / Treatment
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* Drug: Arterolane-piperaquine
* Drug: Arterolane-piperaquine+mefloquine
* Drug: Artemether-lumefantrine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female aged 2 years to <13-year-old Uncomplicated falciparum malaria as defined as: Positive blood smear with asexual forms of P. falciparum (may be mixed with non-falciparum species) Parasitaemia between 5,000-250,000 parasites/µL Fever defined as tympanic temperature >37.5°C or history of fever within last 48 hours Ability to take oral medication Willingness and ability to comply with study protocol for study duration Written informed consent given to participate in the trial Exclusion Criteria: Signs of severe/complicated malaria* Any clinical reason suggesting that the child's treatment should be given immediately and not delayed during the transfer to Kilifi County Hospital in the opinion of the treating physician. Acute illness other than malaria requiring urgent systemic treatment as assessed by the treating physician Previous splenectomy Treatment with artemisinin or ACT within the previous 7 days Treatment with mefloquine in the 2 months prior to presentation Known hypersensitivity or contraindication to arterolane-piperaquine, DHA-piperaquine, artemisinin, mefloquine (epilepsy, major psychiatric illness) or primaquine QTc interval >450 milliseconds at point of presentation Known personal or family history of cardiac conduction problems Participation within another clinical trial in the previous 3 months

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: randomised 1:1:1 to one of the three treatment arms
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arterolane-piperaquine<br>Arterolane-piperaquine for 3 days | Drug: Arterolane-piperaquine<br>* Arterolane maleate-piperaquine phosphate tablets (37.5 mg/187.5 mg)<br>|
| Active Comparator: Arterolane-piperaquine+mefloquine<br>Arterolane-piperaquine + mefloquine for 3 days | Drug: Arterolane-piperaquine+mefloquine<br>* Arterolane maleate-piperaquine phosphate tablets (37.5 mg/187.5 mg) Mefloquine tablets (250 mg)<br>|
| Active Comparator: Artemether-lumefantrine<br>Artemether-lumefantrine for 3 days | Drug: Artemether-lumefantrine<br>* Artemether-lumefantrine tablets (20 mg/120 mg)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 42-day PCR corrected adequate clinical and parasitological response (ACPR) by day 42 by study arm |  | 42 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parasite clearance half-life | Parasite clearance half-life is assessed by entering the parasite counts (assessed by microscopy) in the WWARN PCE calculator | 42 days | 
| Parasite reduction rates | Parasite reduction rates and ratios at 24 and 48 hours assessed by microscopy | 24 and 48 hours | 
| Parasite count to fall 50% | Time for parasite count to fall 50% of initial parasite density | 42 days | 
| Parasite count to fall 90% | Time for parasite count to fall 90% of initial parasite density | 42 days | 
| Fever clearance time | The time taken for the tympanic temperature to fall below 37.5˚C and remain there for at least 24 hours | 42 days | 
| Incidence of clinical adverse events and serious adverse events |  | 42 days | 
| Incidence of adverse events concerning markers of hepatic or renal toxicity | Total bilirubin, Alanine transaminase, Aspartate transaminase, Alkaline phosphatase and creatinine will be measured | 42 days | 
| Incidence of prolongation of the corrected QT interval | Incidence of the prolongation of the corrected QT interval above 500 ms or > 60 ms above baseline values | 42 days | 
| Prolongation of the corrected QT interval | Prolongation of the corrected QT interval compared at hour 4, hour 24, hour 28, hour 48 and hour 52 compared to baseline | Baseline, hour 4, hour 24, hour 28, hour 48 and hour 52 | 
| Change in haematocrit | Change in haematocrit at hour 24, hour 48, hour 72, day 7, day 14, day 21, day 28, day 35 and day 42 according to geographical location and study arm, stratified for G6PD status | Baseline, hour 24, hour 48, hour 72, day 7, day 14, day 21, day 28, day 35 and day 42 | 
| Proportion of patients that reports completing a full course of observed TACT or ACT | Proportion of patients 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 | 42 days | 
| Prevalence of Kelch13 mutations of known significance | Prevalence of Kelch13 mutations of known significance | Baseline | 
| Prevalence/incidence of other genetic markers of antimalarial drug resistance such as multidrug resistance gene 1 copy number and multidrug resistance gene 1 mutations | Prevalence/incidence of other genetic markers of antimalarial drug resistance such as multidrug resistance gene 1 copy number and multidrug resistance gene 1 mutations | Baseline | 
| Genome wide association with in vivo/in vitro sensitivity parasite phenotype | Genome wide association with in vivo/in vitro sensitivity parasite phenotype | Baseline | 
| A comparison of transcriptomic patterns between sensitive and resistant parasites | Transcriptomic patterns measure at baseline and at specified time points after the start of treatment comparing sensitive and resistant parasites | Baseline and 6 hours | 
| Proportion of patients with gametocytaemia before, during and after treatment | Proportion of patients with gametocytaemia before, during and after treatment | 42 days | 
| Levels of RNA transcription coding for male or female gametocytes | Levels of RNA transcription coding for male or female gametocytes at admission | Baseline | 
| In vitro sensitivity of P. falciparum to artemisinins and partner drugs |  | Baseline and day recurrent infection | 
| Pharmacokinetic profiles and interactions (Cmax) of arterolane and partner drugs | Pharmacokinetic profiles and interactions (Cmax) of arterolane and partner drugs | 42 days | 
| Day 7 drug levels of partner drugs in association with treatment efficacy and treatment arm | Day 7 drug levels of partner drugs in association with treatment efficacy and treatment arm | 7 days | 
| Data on recent travel and current location of living |  | Baseline |