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

Primary Purpose

Plasmodium Falciparum

Status
Completed
Phase
Phase 3
Locations
Kenya
Study Type
Interventional
Intervention
Arterolane-piperaquine
Arterolane-piperaquine+mefloquine
Artemether-lumefantrine
Sponsored by
University of Oxford
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Plasmodium Falciparum

Eligibility Criteria

2 Years - 12 Years (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Kilifi County Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Active Comparator

Active Comparator

Arm Label

Arterolane-piperaquine

Arterolane-piperaquine+mefloquine

Artemether-lumefantrine

Arm Description

Arterolane-piperaquine for 3 days

Arterolane-piperaquine + mefloquine for 3 days

Artemether-lumefantrine for 3 days

Outcomes

Primary Outcome Measures

42-day PCR corrected adequate clinical and parasitological response (ACPR) by day 42 by study arm

Secondary Outcome Measures

Parasite clearance half-life
Parasite clearance half-life is assessed by entering the parasite counts (assessed by microscopy) in the WWARN PCE calculator
Parasite reduction rates
Parasite reduction rates and ratios at 24 and 48 hours assessed by microscopy
Parasite count to fall 50%
Time for parasite count to fall 50% of initial parasite density
Parasite count to fall 90%
Time for parasite count to fall 90% of initial parasite density
Fever clearance time
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
Incidence of adverse events concerning markers of hepatic or renal toxicity
Total bilirubin, Alanine transaminase, Aspartate transaminase, Alkaline phosphatase and creatinine will be measured
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
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
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
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
Prevalence of Kelch13 mutations of known significance
Prevalence of Kelch13 mutations of known significance
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
Genome wide association with in vivo/in vitro sensitivity parasite phenotype
Genome wide association with in vivo/in vitro sensitivity parasite phenotype
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
Proportion of patients with gametocytaemia before, during and after treatment
Proportion of patients with gametocytaemia before, during and after treatment
Levels of RNA transcription coding for male or female gametocytes
Levels of RNA transcription coding for male or female gametocytes at admission
In vitro sensitivity of P. falciparum to artemisinins and partner drugs
Pharmacokinetic profiles and interactions (Cmax) of arterolane and partner drugs
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
Day 7 drug levels of partner drugs in association with treatment efficacy and treatment arm
Data on recent travel and current location of living

Full Information

First Posted
February 1, 2018
Last Updated
September 28, 2021
Sponsor
University of Oxford
Collaborators
Mahidol Oxford Tropical Medicine Research Unit
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1. Study Identification

Unique Protocol Identification Number
NCT03452475
Brief Title
Comparison of Arterolane-piperaquine Versus Arterolane-piperaquine+Mefloquine Versus Artemether-lumefantrine in Kenyan Children
Acronym
TACTKenya
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

2. Study Status

Record Verification Date
September 2021
Overall Recruitment Status
Completed
Study Start Date
March 7, 2018 (Actual)
Primary Completion Date
June 3, 2019 (Actual)
Study Completion Date
June 3, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Oxford
Collaborators
Mahidol Oxford Tropical Medicine Research Unit

4. Oversight

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
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Plasmodium Falciparum

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Model Description
randomised 1:1:1 to one of the three treatment arms
Masking
None (Open Label)
Allocation
Randomized
Enrollment
219 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arterolane-piperaquine
Arm Type
Active Comparator
Arm Description
Arterolane-piperaquine for 3 days
Arm Title
Arterolane-piperaquine+mefloquine
Arm Type
Active Comparator
Arm Description
Arterolane-piperaquine + mefloquine for 3 days
Arm Title
Artemether-lumefantrine
Arm Type
Active Comparator
Arm Description
Artemether-lumefantrine for 3 days
Intervention Type
Drug
Intervention Name(s)
Arterolane-piperaquine
Intervention Description
Arterolane maleate-piperaquine phosphate tablets (37.5 mg/187.5 mg)
Intervention Type
Drug
Intervention Name(s)
Arterolane-piperaquine+mefloquine
Intervention Description
Arterolane maleate-piperaquine phosphate tablets (37.5 mg/187.5 mg) Mefloquine tablets (250 mg)
Intervention Type
Drug
Intervention Name(s)
Artemether-lumefantrine
Intervention Description
Artemether-lumefantrine tablets (20 mg/120 mg)
Primary Outcome Measure Information:
Title
42-day PCR corrected adequate clinical and parasitological response (ACPR) by day 42 by study arm
Time Frame
42 days
Secondary Outcome Measure Information:
Title
Parasite clearance half-life
Description
Parasite clearance half-life is assessed by entering the parasite counts (assessed by microscopy) in the WWARN PCE calculator
Time Frame
42 days
Title
Parasite reduction rates
Description
Parasite reduction rates and ratios at 24 and 48 hours assessed by microscopy
Time Frame
24 and 48 hours
Title
Parasite count to fall 50%
Description
Time for parasite count to fall 50% of initial parasite density
Time Frame
42 days
Title
Parasite count to fall 90%
Description
Time for parasite count to fall 90% of initial parasite density
Time Frame
42 days
Title
Fever clearance time
Description
The time taken for the tympanic temperature to fall below 37.5˚C and remain there for at least 24 hours
Time Frame
42 days
Title
Incidence of clinical adverse events and serious adverse events
Time Frame
42 days
Title
Incidence of adverse events concerning markers of hepatic or renal toxicity
Description
Total bilirubin, Alanine transaminase, Aspartate transaminase, Alkaline phosphatase and creatinine will be measured
Time Frame
42 days
Title
Incidence of prolongation of the corrected QT interval
Description
Incidence of the prolongation of the corrected QT interval above 500 ms or > 60 ms above baseline values
Time Frame
42 days
Title
Prolongation of the corrected QT interval
Description
Prolongation of the corrected QT interval compared at hour 4, hour 24, hour 28, hour 48 and hour 52 compared to baseline
Time Frame
Baseline, hour 4, hour 24, hour 28, hour 48 and hour 52
Title
Change in haematocrit
Description
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
Time Frame
Baseline, hour 24, hour 48, hour 72, day 7, day 14, day 21, day 28, day 35 and day 42
Title
Proportion of patients that reports completing a full course of observed TACT or ACT
Description
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
Time Frame
42 days
Title
Prevalence of Kelch13 mutations of known significance
Description
Prevalence of Kelch13 mutations of known significance
Time Frame
Baseline
Title
Prevalence/incidence of other genetic markers of antimalarial drug resistance such as multidrug resistance gene 1 copy number and multidrug resistance gene 1 mutations
Description
Prevalence/incidence of other genetic markers of antimalarial drug resistance such as multidrug resistance gene 1 copy number and multidrug resistance gene 1 mutations
Time Frame
Baseline
Title
Genome wide association with in vivo/in vitro sensitivity parasite phenotype
Description
Genome wide association with in vivo/in vitro sensitivity parasite phenotype
Time Frame
Baseline
Title
A comparison of transcriptomic patterns between sensitive and resistant parasites
Description
Transcriptomic patterns measure at baseline and at specified time points after the start of treatment comparing sensitive and resistant parasites
Time Frame
Baseline and 6 hours
Title
Proportion of patients with gametocytaemia before, during and after treatment
Description
Proportion of patients with gametocytaemia before, during and after treatment
Time Frame
42 days
Title
Levels of RNA transcription coding for male or female gametocytes
Description
Levels of RNA transcription coding for male or female gametocytes at admission
Time Frame
Baseline
Title
In vitro sensitivity of P. falciparum to artemisinins and partner drugs
Time Frame
Baseline and day recurrent infection
Title
Pharmacokinetic profiles and interactions (Cmax) of arterolane and partner drugs
Description
Pharmacokinetic profiles and interactions (Cmax) of arterolane and partner drugs
Time Frame
42 days
Title
Day 7 drug levels of partner drugs in association with treatment efficacy and treatment arm
Description
Day 7 drug levels of partner drugs in association with treatment efficacy and treatment arm
Time Frame
7 days
Title
Data on recent travel and current location of living
Time Frame
Baseline

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Years
Maximum Age & Unit of Time
12 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Facility Information:
Facility Name
Kilifi County Hospital
City
Kilifi
ZIP/Postal Code
P.O Box P.O. Box 9
Country
Kenya

12. IPD Sharing Statement

Plan to Share IPD
Undecided
IPD Sharing 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.
Citations:
PubMed Identifier
34111412
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.
Results Reference
derived

Learn more about this trial

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

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