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A Study by the Tracking Resistance to Artemisinin Collaboration (TRAC) (TRACII)

Primary Purpose

Malaria, Falciparum

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
ACT
TACT
Sponsored by
University of Oxford
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Malaria, Falciparum focused on measuring Artemisinin combination Therapies

Eligibility Criteria

6 Months - 65 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Male or female, aged from 6 months to 65 years old
  • Acute uncomplicated P. falciparum malaria, confirmed by positive blood smear with asexual forms of P. falciparum (or mixed with non-falciparum species)
  • Asexual P. falciparum parasitaemia: 5,000 to 200,000/uL, de-termined on a thin or thick blood film (In Cambodia patients with a parasitaemia of 16 to 200,000/uL are eligible. In DRC patients with a parasitaemia of 10,000 to 250,000/ul are eligi-ble)
  • Fever defined as >/= 37.5°C tympanic temperature or a history of fever within the last 24 hours
  • Written informed consent (by parent/guardian in case of children)
  • Willingness and ability of the patients or parents/guardians to comply with the study protocol for the duration of the study

Exclusion Criteria:

  • Signs of severe/complicated malaria
  • Haematocrit < 25% or Hb < 5 g/dL at screening (DRC: Hct<15% and Hb <5 g/dL due to high prevalence of anemia).
  • Acute illness other than malaria requiring treatment
  • For females: pregnancy, breast feeding
  • Patients who have received artemisinin or a derivative or an artemisinin containing combination therapy (ACT) within the previous 7 days
  • Treatment with mefloquine in the 2 months prior to presentation will be an exclusion criteria in the DHA-P+MQ sites
  • History of allergy or known contraindication to artemisinins, or to the ACT or TACT to be used at the site e.g. neuropsychiatric disorders will be a contraindication for the use of mefloquine.
  • Previous splenectomy
  • QTc-interval > 450 milliseconds at moment of presentation
  • Documented or claimed history of cardiac conduction problems
  • Earlier participation within the TRACII trial or another trial in the previous 3 months.

Sites / Locations

  • College of Medicine Chittagong
  • Pailin
  • Preah Vihear
  • Pursat
  • Ratanakiri
  • Kinshasa
  • Mohanpur Community health center
  • Midnapore
  • Ispat General hospital
  • Sekong
  • Ann Hospital
  • Pyay hospital
  • Pyin oo Lwin hospital
  • Thabeikkyin hospital
  • Phusing hospital
  • Tha Song Yang hospital
  • Chumphon hospital
  • Kunhan Hospital
  • Thanto Hospital
  • Binh Phuoc hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

ACT-arms

TACT-arms

Arm Description

1.1 Artemether-lumefantrine for 3 days. 1.2 Dihydroartemisinin-piperaquine for 3 days 1.3 Artesunate-Mefloquine for 3 days

2.1: Artemether-lumefantrine for 3 days.plus: Amodiaquine for 3 days. 2.2: Dihydroartemisinin-piperaquine for 3 days. plus: Mefloquine hydrochloride for 3 days. 2.3 Dihydroartemisinin-piperaquine for 3 days. plus: Mefloquine hydrochloride for 3 days.

Outcomes

Primary Outcome Measures

PCR corrected efficacy defined as adequate clinical and parasitological response (ACPR)

Secondary Outcome Measures

Parasite clearance half-life
Parasite clearance half-life assessed by microscopy as primary parameter to de-termine parasite clearance
Parasite reduction rates and ratios at 24 and 48 hours assessed by microscopy
Time for parasite count to fall to 50% of initial parasite density
Time for parasite count to fall to 90% of initial parasite density
Time for parasite count to fall to 99% of initial parasite density
Fever clearance time
Incidence of adverse events and serious adverse events
Incidence of adverse events concerning markers of hepatic toxicity
Total billirubin, ALT, AST and Alkaline Phosphatase will be measured
Incidence of adverse events concerning markersof renal toxicity
Creatinine will be measured
Incidence of prolongation of the QTc-interval
Incidence of prolongation of the Qtc-interval above 500 ms or > 60ms above baseline values
Change in hemoglobin/hematocrit
Change in hemoglobin/hematocrit on day 1 to 7, 14, 21, 28, 35 and 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 without withdrawal of consent or exclusion from study
Prevalence of Kelch13 mutations of known functional significance
Prevalence/incidence of other genetic markers of antimalarial drug resistance
Genome wide association with in vivo/in vitro sensitivity parasite phenotype
Correlation between SNPs measured in dry blood spots and whole genome sequencing in leukocyte depleted blood samples
Transcriptomic patterns at t=0 and t=6h comparing sensitive and resistant parasites
Correlation between qPCR based versus microscopy based assessments of parasite clearance dynamics
Proportion of patients with gametocytemia before,after treatment with Primaquine
Levels of RNA transcription coding for male or female specific gametocytes
In vitro sensitivity (expressed in IC50 values among others) of P. falciparum to artemisinins and partner drugs
• Pharmacokinetic profiles and interactions of artemisinin-derivatives and partner drugs (half-life, Cmax, AUC, Tmax) in 20 ACT treated and 20 TACT treated patients of both study arms
Day 7 drug levels of partner drugs in association with treatment efficacy and treatment arm

Full Information

First Posted
April 20, 2015
Last Updated
May 3, 2018
Sponsor
University of Oxford
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1. Study Identification

Unique Protocol Identification Number
NCT02453308
Brief Title
A Study by the Tracking Resistance to Artemisinin Collaboration (TRAC)
Acronym
TRACII
Official Title
A Multi-centre, Open-label Randomised Trial to Assess the Efficacy, Safety and Tolerability of Triple Artemisinin-based Combination Therapies (TACTs) Com-pared to Artemisinin-based Combination Therapies (ACTs) in Uncomplicated Falciparum Malaria and to Map the Geographical Spread of Artemisinin and Partner Drug Resistance
Study Type
Interventional

2. Study Status

Record Verification Date
May 2018
Overall Recruitment Status
Completed
Study Start Date
August 2015 (Actual)
Primary Completion Date
March 2018 (Actual)
Study Completion Date
March 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Oxford

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This study is an open-label randomised trial comparing standard ACT treatment with matching triple artemisinin-based combination therapies (TACTs), evaluating efficacy in safety and tolerability. The estimated total sample size is 2040 patients from 16 sites in Asia and 1 site in Africa. There are 2 arm study groups that have 2 treatment arms each. Study group A: A.1: Artemether-lumefantrine for 3 days. versus: A.2: Artemether-lumefantrine for 3 days plus Amodiaquine for 3 days. Study group B: B.1: Dihydroartemisinin-piperaquine for 3 days. versus: B.2: Dihydroartemisinin-piperaquine for 3 days plus Mefloquine hydrochloride for 3 days. Study group C: C.1: Artesunate-mefloquine for 3 days versus: C.2: Dihydroartemisinin-piperaquine for 3 days plus Mefloquine hydrochloride for 3 days. According to the WHO guideline, all patients except for children under the age of 1 year or a weight below 10 kilograms will also be treated with a single dose of low dose primaquine.
Detailed Description
In Laos, Myanmar, Bangladesh, India and DRC, the following two combinations will be used: Artemether-lumefantrine combined with amodiaquine (TACT arm) or Artemether-lumefantrine (ACT arm) In Myanmar and Vietnam the following two combinations will be used: Dihydroartemisinin-piperaquine combined with mefloquine (TACT arm) or Dihydroartemisinin-piperaquine (ACT arm) In Cambodia and Thailand the following two combinations will be used: Dihydroartemisinin-piperaquine plus Mefloquine hydrochloride (TACT arm) or Artesunate-mefloquine (ACT arm)

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malaria, Falciparum
Keywords
Artemisinin combination Therapies

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
1110 (Actual)

8. Arms, Groups, and Interventions

Arm Title
ACT-arms
Arm Type
Active Comparator
Arm Description
1.1 Artemether-lumefantrine for 3 days. 1.2 Dihydroartemisinin-piperaquine for 3 days 1.3 Artesunate-Mefloquine for 3 days
Arm Title
TACT-arms
Arm Type
Active Comparator
Arm Description
2.1: Artemether-lumefantrine for 3 days.plus: Amodiaquine for 3 days. 2.2: Dihydroartemisinin-piperaquine for 3 days. plus: Mefloquine hydrochloride for 3 days. 2.3 Dihydroartemisinin-piperaquine for 3 days. plus: Mefloquine hydrochloride for 3 days.
Intervention Type
Drug
Intervention Name(s)
ACT
Intervention Description
Artemether-lumefantrine for 3 days Dihydroartemisinin-piperaquine for 3 days. Artesunate-mefloquine for 3 days
Intervention Type
Drug
Intervention Name(s)
TACT
Intervention Description
Artemether-lumefantrine for 3 days plus Amodiaquine for 3 days. Dihydroartemisinin-piperaquine for 3 days plus Mefloquine hydrochloride for 3 days. Dihydroartemisinin-piperaquine for 3 days plus Mefloquine hydrochloride for 3 days.
Primary Outcome Measure Information:
Title
PCR corrected efficacy defined as adequate clinical and parasitological response (ACPR)
Time Frame
42 days
Secondary Outcome Measure Information:
Title
Parasite clearance half-life
Description
Parasite clearance half-life assessed by microscopy as primary parameter to de-termine parasite clearance
Time Frame
42 days
Title
Parasite reduction rates and ratios at 24 and 48 hours assessed by microscopy
Time Frame
at 24 and 48 hours
Title
Time for parasite count to fall to 50% of initial parasite density
Time Frame
42 days
Title
Time for parasite count to fall to 90% of initial parasite density
Time Frame
42 days
Title
Time for parasite count to fall to 99% of initial parasite density
Time Frame
42 days
Title
Fever clearance time
Time Frame
42 days
Title
Incidence of adverse events and serious adverse events
Time Frame
42 days
Title
Incidence of adverse events concerning markers of hepatic toxicity
Description
Total billirubin, ALT, AST and Alkaline Phosphatase will be measured
Time Frame
42 days
Title
Incidence of adverse events concerning markersof renal toxicity
Description
Creatinine will be measured
Time Frame
42 days
Title
Incidence of prolongation of the QTc-interval
Description
Incidence of prolongation of the Qtc-interval above 500 ms or > 60ms above baseline values
Time Frame
3 days
Title
Change in hemoglobin/hematocrit
Description
Change in hemoglobin/hematocrit on day 1 to 7, 14, 21, 28, 35 and 42 according to geographical location and study arm, stratified for G6PD status
Time Frame
42 days
Title
Proportion of patients that reports completing a full course of observed TACT or ACT without withdrawal of consent or exclusion from study
Time Frame
42 days
Title
Prevalence of Kelch13 mutations of known functional significance
Time Frame
42 days
Title
Prevalence/incidence of other genetic markers of antimalarial drug resistance
Time Frame
42 days
Title
Genome wide association with in vivo/in vitro sensitivity parasite phenotype
Time Frame
42 days
Title
Correlation between SNPs measured in dry blood spots and whole genome sequencing in leukocyte depleted blood samples
Time Frame
42 days
Title
Transcriptomic patterns at t=0 and t=6h comparing sensitive and resistant parasites
Time Frame
6hrs after start of treatment
Title
Correlation between qPCR based versus microscopy based assessments of parasite clearance dynamics
Time Frame
14 days
Title
Proportion of patients with gametocytemia before,after treatment with Primaquine
Time Frame
assessed at admission, up to day 14
Title
Levels of RNA transcription coding for male or female specific gametocytes
Time Frame
at admission up to day 14
Title
In vitro sensitivity (expressed in IC50 values among others) of P. falciparum to artemisinins and partner drugs
Time Frame
42 days
Title
• Pharmacokinetic profiles and interactions of artemisinin-derivatives and partner drugs (half-life, Cmax, AUC, Tmax) in 20 ACT treated and 20 TACT treated patients of both study arms
Time Frame
42 days
Title
Day 7 drug levels of partner drugs in association with treatment efficacy and treatment arm
Time Frame
Day 7

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Months
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male or female, aged from 6 months to 65 years old Acute uncomplicated P. falciparum malaria, confirmed by positive blood smear with asexual forms of P. falciparum (or mixed with non-falciparum species) Asexual P. falciparum parasitaemia: 5,000 to 200,000/uL, de-termined on a thin or thick blood film (In Cambodia patients with a parasitaemia of 16 to 200,000/uL are eligible. In DRC patients with a parasitaemia of 10,000 to 250,000/ul are eligi-ble) Fever defined as >/= 37.5°C tympanic temperature or a history of fever within the last 24 hours Written informed consent (by parent/guardian in case of children) Willingness and ability of the patients or parents/guardians to comply with the study protocol for the duration of the study Exclusion Criteria: Signs of severe/complicated malaria Haematocrit < 25% or Hb < 5 g/dL at screening (DRC: Hct<15% and Hb <5 g/dL due to high prevalence of anemia). Acute illness other than malaria requiring treatment For females: pregnancy, breast feeding Patients who have received artemisinin or a derivative or an artemisinin containing combination therapy (ACT) within the previous 7 days Treatment with mefloquine in the 2 months prior to presentation will be an exclusion criteria in the DHA-P+MQ sites History of allergy or known contraindication to artemisinins, or to the ACT or TACT to be used at the site e.g. neuropsychiatric disorders will be a contraindication for the use of mefloquine. Previous splenectomy QTc-interval > 450 milliseconds at moment of presentation Documented or claimed history of cardiac conduction problems Earlier participation within the TRACII trial or another trial in the previous 3 months.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Arjen Dondorp, MD
Organizational Affiliation
Mahidol Oxford Tropical Medicine Research Unit
Official's Role
Principal Investigator
Facility Information:
Facility Name
College of Medicine Chittagong
City
Ramu
Country
Bangladesh
Facility Name
Pailin
City
Pailin
Country
Cambodia
Facility Name
Preah Vihear
City
Preah Vihear
Country
Cambodia
Facility Name
Pursat
City
Pursat
Country
Cambodia
Facility Name
Ratanakiri
City
Ratankiri
Country
Cambodia
Facility Name
Kinshasa
City
Kinshasa
Country
Congo, The Democratic Republic of the
Facility Name
Mohanpur Community health center
City
Agartala
Country
India
Facility Name
Midnapore
City
Midnapore
Country
India
Facility Name
Ispat General hospital
City
Rourkela
Country
India
Facility Name
Sekong
City
Sekong
Country
Lao People's Democratic Republic
Facility Name
Ann Hospital
City
Ann
Country
Myanmar
Facility Name
Pyay hospital
City
Pyay
Country
Myanmar
Facility Name
Pyin oo Lwin hospital
City
Pyin oo Lwin
Country
Myanmar
Facility Name
Thabeikkyin hospital
City
Thabeikkyin
Country
Myanmar
Facility Name
Phusing hospital
City
Phusing
State/Province
Srisaket
Country
Thailand
Facility Name
Tha Song Yang hospital
City
Tha Song Yang
State/Province
Tak
Country
Thailand
Facility Name
Chumphon hospital
City
Chumphon
Country
Thailand
Facility Name
Kunhan Hospital
City
Si Sa Ket
Country
Thailand
Facility Name
Thanto Hospital
City
Yala
Country
Thailand
Facility Name
Binh Phuoc hospital
City
Binh Phuoc
Country
Vietnam

12. IPD Sharing Statement

Citations:
PubMed Identifier
32171078
Citation
van der Pluijm RW, Tripura R, Hoglund RM, Pyae Phyo A, Lek D, Ul Islam A, Anvikar AR, Satpathi P, Satpathi S, Behera PK, Tripura A, Baidya S, Onyamboko M, Chau NH, Sovann Y, Suon S, Sreng S, Mao S, Oun S, Yen S, Amaratunga C, Chutasmit K, Saelow C, Runcharern R, Kaewmok W, Hoa NT, Thanh NV, Hanboonkunupakarn B, Callery JJ, Mohanty AK, Heaton J, Thant M, Gantait K, Ghosh T, Amato R, Pearson RD, Jacob CG, Goncalves S, Mukaka M, Waithira N, Woodrow CJ, Grobusch MP, van Vugt M, Fairhurst RM, Cheah PY, Peto TJ, von Seidlein L, Dhorda M, Maude RJ, Winterberg M, Thuy-Nhien NT, Kwiatkowski DP, Imwong M, Jittamala P, Lin K, Hlaing TM, Chotivanich K, Huy R, Fanello C, Ashley E, Mayxay M, Newton PN, Hien TT, Valecha N, Smithuis F, Pukrittayakamee S, Faiz A, Miotto O, Tarning J, Day NPJ, White NJ, Dondorp AM; Tracking Resistance to Artemisinin Collaboration. Triple artemisinin-based combination therapies versus artemisinin-based combination therapies for uncomplicated Plasmodium falciparum malaria: a multicentre, open-label, randomised clinical trial. Lancet. 2020 Apr 25;395(10233):1345-1360. doi: 10.1016/S0140-6736(20)30552-3. Epub 2020 Mar 11. Erratum In: Lancet. 2020 Apr 25;395(10233):1344.
Results Reference
derived
PubMed Identifier
31345710
Citation
van der Pluijm RW, Imwong M, Chau NH, Hoa NT, Thuy-Nhien NT, Thanh NV, Jittamala P, Hanboonkunupakarn B, Chutasmit K, Saelow C, Runjarern R, Kaewmok W, Tripura R, Peto TJ, Yok S, Suon S, Sreng S, Mao S, Oun S, Yen S, Amaratunga C, Lek D, Huy R, Dhorda M, Chotivanich K, Ashley EA, Mukaka M, Waithira N, Cheah PY, Maude RJ, Amato R, Pearson RD, Goncalves S, Jacob CG, Hamilton WL, Fairhurst RM, Tarning J, Winterberg M, Kwiatkowski DP, Pukrittayakamee S, Hien TT, Day NP, Miotto O, White NJ, Dondorp AM. Determinants of dihydroartemisinin-piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study. Lancet Infect Dis. 2019 Sep;19(9):952-961. doi: 10.1016/S1473-3099(19)30391-3. Epub 2019 Jul 22.
Results Reference
derived

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A Study by the Tracking Resistance to Artemisinin Collaboration (TRAC)

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