Plasmodium Falciparum
Conditions
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.
Interventions
DRUGArterolane-piperaquine
Arterolane maleate-piperaquine phosphate tablets (37.5 mg/187.5 mg)
DRUGArterolane-piperaquine+mefloquine
Arterolane maleate-piperaquine phosphate tablets (37.5 mg/187.5 mg) Mefloquine tablets (250 mg)
DRUGArtemether-lumefantrine
Artemether-lumefantrine tablets (20 mg/120 mg)
Sponsors
Mahidol Oxford Tropical Medicine Research Unit
University of Oxford
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
randomised 1:1:1 to one of the three treatment arms
Eligibility
Sex/Gender
ALL
Age
2 Years to 12 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 42-day PCR corrected adequate clinical and parasitological response (ACPR) by day 42 by study arm | 42 days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Parasite clearance half-life | 42 days | Parasite clearance half-life is assessed by entering the parasite counts (assessed by microscopy) in the WWARN PCE calculator |
| Parasite reduction rates | 24 and 48 hours | Parasite reduction rates and ratios at 24 and 48 hours assessed by microscopy |
| Parasite count to fall 50% | 42 days | Time for parasite count to fall 50% of initial parasite density |
| Parasite count to fall 90% | 42 days | Time for parasite count to fall 90% of initial parasite density |
| Fever clearance time | 42 days | The time taken for the tympanic temperature to fall below 37.5˚C and remain there for at least 24 hours |
| Incidence of clinical adverse events and serious adverse events | 42 days | — |
| Incidence of adverse events concerning markers of hepatic or renal toxicity | 42 days | Total bilirubin, Alanine transaminase, Aspartate transaminase, Alkaline phosphatase and creatinine will be measured |
| Prolongation of the corrected QT interval | Baseline, hour 4, hour 24, hour 28, hour 48 and hour 52 | Prolongation of the corrected QT interval compared at hour 4, hour 24, hour 28, hour 48 and hour 52 compared to baseline |
| Change in haematocrit | Baseline, hour 24, hour 48, hour 72, day 7, day 14, day 21, day 28, day 35 and day 42 | 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 |
| Proportion of patients that reports completing a full course of observed TACT or ACT | 42 days | 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 |
| Incidence of prolongation of the corrected QT interval | 42 days | Incidence of the prolongation of the corrected QT interval above 500 ms or \> 60 ms above baseline values |
| 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 | Prevalence/incidence of other genetic markers of antimalarial drug resistance such as multidrug resistance gene 1 copy number and multidrug resistance gene 1 mutations |
| Genome wide association with in vivo/in vitro sensitivity parasite phenotype | Baseline | Genome wide association with in vivo/in vitro sensitivity parasite phenotype |
| A comparison of transcriptomic patterns between sensitive and resistant parasites | Baseline and 6 hours | Transcriptomic patterns measure at baseline and at specified time points after the start of treatment comparing sensitive and resistant parasites |
| Proportion of patients with gametocytaemia before, during and after treatment | 42 days | Proportion of patients with gametocytaemia before, during and after treatment |
| Levels of RNA transcription coding for male or female gametocytes | Baseline | Levels of RNA transcription coding for male or female gametocytes at admission |
| 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 | 42 days | Pharmacokinetic profiles and interactions (Cmax) of arterolane and partner drugs |
| Day 7 drug levels of partner drugs in association with treatment efficacy and treatment arm | 7 days | Day 7 drug levels of partner drugs in association with treatment efficacy and treatment arm |
| Data on recent travel and current location of living | Baseline | — |
| Prevalence of Kelch13 mutations of known significance | Baseline | Prevalence of Kelch13 mutations of known significance |
Countries
Kenya
Outcome results
None listed