Clinical trial NCT03452475: Comparison of Arterolane-piperaquine Versus Arterolane-piperaquine+Mefloquine Versus Artemether-lumefantrine in Kenyan Children
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Plasmodium Falciparum
Lead sponsor: University of Oxford
Sponsor class: OTHER
Collaborators: name: Mahidol Oxford Tropical Medicine Research Unit
First posted: 2018-03-02
Enrollment: 219
Sex: ALL
Minimum age (years): 2
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: randomised 1:1:1 to one of the three treatment arms
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

1. Male or female aged 2 years to \<13-year-old
2. 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
3. Ability to take oral medication
4. Willingness and ability to comply with study protocol for study duration
5. Written informed consent given to participate in the trial

Exclusion Criteria:

1. Signs of severe/complicated malaria\*
2. 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.
3. Acute illness other than malaria requiring urgent systemic treatment as assessed by the treating physician
4. Previous splenectomy
5. Treatment with artemisinin or ACT within the previous 7 days
6. Treatment with mefloquine in the 2 months prior to presentation
7. Known hypersensitivity or contraindication to arterolane-piperaquine, DHA-piperaquine, artemisinin, mefloquine (epilepsy, major psychiatric illness) or primaquine
8. QTc interval \>450 milliseconds at point of presentation
9. Known personal or family history of cardiac conduction problems
10. Participation within another clinical trial in the previous 3 months

Primary outcomes:
measure: 42-day PCR corrected adequate clinical and parasitological response (ACPR) by day 42 by study arm
timeFrame: 42 days
Secondary outcomes:
measure: Parasite clearance half-life
timeFrame: 42 days
measure: Parasite reduction rates
timeFrame: 24 and 48 hours
measure: Parasite count to fall 50%
timeFrame: 42 days
measure: Parasite count to fall 90%
timeFrame: 42 days
measure: Fever clearance time
timeFrame: 42 days
measure: Incidence of clinical adverse events and serious adverse events
timeFrame: 42 days
measure: Incidence of adverse events concerning markers of hepatic or renal toxicity
timeFrame: 42 days
measure: Incidence of prolongation of the corrected QT interval
timeFrame: 42 days
measure: Prolongation of the corrected QT interval
timeFrame: Baseline, hour 4, hour 24, hour 28, hour 48 and hour 52
measure: Change in haematocrit
timeFrame: Baseline, hour 24, hour 48, hour 72, day 7, day 14, day 21, day 28, day 35 and day 42
measure: Proportion of patients that reports completing a full course of observed TACT or ACT
timeFrame: 42 days
measure: Prevalence of Kelch13 mutations of known significance
timeFrame: Baseline
measure: Prevalence/incidence of other genetic markers of antimalarial drug resistance such as multidrug resistance gene 1 copy number and multidrug resistance gene 1 mutations
timeFrame: Baseline
measure: Genome wide association with in vivo/in vitro sensitivity parasite phenotype
timeFrame: Baseline
measure: A comparison of transcriptomic patterns between sensitive and resistant parasites
timeFrame: Baseline and 6 hours
measure: Proportion of patients with gametocytaemia before, during and after treatment
timeFrame: 42 days
measure: Levels of RNA transcription coding for male or female gametocytes
timeFrame: Baseline
measure: In vitro sensitivity of P. falciparum to artemisinins and partner drugs
timeFrame: Baseline and day recurrent infection
measure: Pharmacokinetic profiles and interactions (Cmax) of arterolane and partner drugs
timeFrame: 42 days
measure: Day 7 drug levels of partner drugs in association with treatment efficacy and treatment arm
timeFrame: 7 days
measure: Data on recent travel and current location of living
timeFrame: Baseline
Other outcomes:
Locations:
city: Kilifi
country: Kenya
facility: Kilifi County Hospital
Study officials:
References:
citation: Hamaluba M, van der Pluijm RW, Weya J, Njuguna P, Ngama M, Kalume P, Mwambingu G, Ngetsa C, Wambua J, Boga M, Mturi N, Lal AA, Khuroo A, Taylor WRJ, Goncalves S, Miotto O, Dhorda M, Mutinda B, Mukaka M, Waithira N, Hoglund RM, Imwong M, Tarning J, Day NPJ, White NJ, Bejon P, Dondorp AM. Arterolane-piperaquine-mefloquine versus arterolane-piperaquine and artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in Kenyan children: a single-centre, open-label, randomised, non-inferiority trial. Lancet Infect Dis. 2021 Oct;21(10):1395-1406. doi: 10.1016/S1473-3099(20)30929-4. Epub 2021 Jun 7.