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

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

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.

Study Overview

• Status: Completed
• Conditions: Plasmodium Falciparum
• Intervention / Treatment: Drug: Arterolane-piperaquine; Drug: Arterolane-piperaquine+mefloquine; Drug: Artemether-lumefantrine

• Study Type: Interventional
• Enrollment (Actual): 219
• Phase: Phase 3

Contacts and Locations

Study Locations

• Kenya
  • Kilifi, Kenya, P.O Box P.O. Box 9
    • Kilifi County Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 12 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: University of Oxford
• Collaborators: Mahidol Oxford Tropical Medicine Research Unit

Publications and helpful links

General Publications

• 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, Gonçalves 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 7, 2018
• Primary Completion (Actual): June 3, 2019
• Study Completion (Actual): June 3, 2019

Study Registration Dates

• First Submitted: February 1, 2018
• First Submitted That Met QC Criteria: March 1, 2018
• First Posted (Actual): March 2, 2018

Study Record Updates

• Last Update Posted (Actual): September 29, 2021
• Last Update Submitted That Met QC Criteria: September 28, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Anti-Infective Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Lumefantrine; Artemether; Artemether, Lumefantrine Drug Combination; Piperaquine; Mefloquine
• Other Study ID Numbers: MAL17009

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD Plan Description: Anonymized data will be entered to a database maintained by Mahidol-Oxford-Research-Unit. Individual-level anonymized data will be shared with medical regulators where appropriate. For wider stake-holder engagement and the medical community summary-level statistical analyses will be shared. Information collected or generated during this study may be anonymised for use to support new research and policies for antimalarial drug resistance. Any future research using information from this study must first be approved by a local or national expert committee to make sure that the interests of participants and their communities are protected.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No