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

Sponsor
University of Oxford (Other)
Overall Status
Completed
CT.gov ID
NCT02453308
Collaborator
(none)
1,110
Enrollment
20
Locations
2
Arms
31
Actual Duration (Months)
55.5
Patients Per Site
1.8
Patients Per Site Per Month

Study Details

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.

Condition or Disease Intervention/Treatment Phase
Phase 2/Phase 3

Detailed Description

In Laos, Myanmar, Bangladesh, India and DRC, the following two combinations will be used:

  1. Artemether-lumefantrine combined with amodiaquine (TACT arm) or

  2. Artemether-lumefantrine (ACT arm)

In Myanmar and Vietnam the following two combinations will be used:

  1. Dihydroartemisinin-piperaquine combined with mefloquine (TACT arm) or

  2. Dihydroartemisinin-piperaquine (ACT arm)

In Cambodia and Thailand the following two combinations will be used:

  1. Dihydroartemisinin-piperaquine plus Mefloquine hydrochloride (TACT arm) or

  2. Artesunate-mefloquine (ACT arm)

Study Design

Study Type:
Interventional
Actual Enrollment :
1110 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
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
Actual Study Start Date :
Aug 1, 2015
Actual Primary Completion Date :
Mar 1, 2018
Actual Study Completion Date :
Mar 1, 2018

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: ACT-arms

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

Drug: ACT
Artemether-lumefantrine for 3 days Dihydroartemisinin-piperaquine for 3 days. Artesunate-mefloquine for 3 days
Active Comparator: TACT-arms

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.

Drug: TACT
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.

Outcome Measures

Primary Outcome Measures

  1. PCR corrected efficacy defined as adequate clinical and parasitological response (ACPR) [42 days]

Secondary Outcome Measures

  1. Parasite clearance half-life [42 days]

    Parasite clearance half-life assessed by microscopy as primary parameter to de-termine parasite clearance

  2. Parasite reduction rates and ratios at 24 and 48 hours assessed by microscopy [at 24 and 48 hours]

  3. Time for parasite count to fall to 50% of initial parasite density [42 days]

  4. Time for parasite count to fall to 90% of initial parasite density [42 days]

  5. Time for parasite count to fall to 99% of initial parasite density [42 days]

  6. Fever clearance time [42 days]

  7. Incidence of adverse events and serious adverse events [42 days]

  8. Incidence of adverse events concerning markers of hepatic toxicity [42 days]

    Total billirubin, ALT, AST and Alkaline Phosphatase will be measured

  9. Incidence of adverse events concerning markersof renal toxicity [42 days]

    Creatinine will be measured

  10. Incidence of prolongation of the QTc-interval [3 days]

    Incidence of prolongation of the Qtc-interval above 500 ms or > 60ms above baseline values

  11. Change in hemoglobin/hematocrit [42 days]

    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

  12. Proportion of patients that reports completing a full course of observed TACT or ACT without withdrawal of consent or exclusion from study [42 days]

  13. Prevalence of Kelch13 mutations of known functional significance [42 days]

  14. Prevalence/incidence of other genetic markers of antimalarial drug resistance [42 days]

  15. Genome wide association with in vivo/in vitro sensitivity parasite phenotype [42 days]

  16. Correlation between SNPs measured in dry blood spots and whole genome sequencing in leukocyte depleted blood samples [42 days]

  17. Transcriptomic patterns at t=0 and t=6h comparing sensitive and resistant parasites [6hrs after start of treatment]

  18. Correlation between qPCR based versus microscopy based assessments of parasite clearance dynamics [14 days]

  19. Proportion of patients with gametocytemia before,after treatment with Primaquine [assessed at admission, up to day 14]

  20. Levels of RNA transcription coding for male or female specific gametocytes [at admission up to day 14]

  21. In vitro sensitivity (expressed in IC50 values among others) of P. falciparum to artemisinins and partner drugs [42 days]

  22. • 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 [42 days]

  23. Day 7 drug levels of partner drugs in association with treatment efficacy and treatment arm [Day 7]

Eligibility Criteria

Criteria

Ages Eligible for Study:
6 Months to 65 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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.

Contacts and Locations

Locations

Site City State Country Postal Code
1 College of Medicine Chittagong Ramu Bangladesh
2 Pailin Pailin Cambodia
3 Preah Vihear Preah Vihear Cambodia
4 Pursat Pursat Cambodia
5 Ratanakiri Ratankiri Cambodia
6 Kinshasa Kinshasa Congo, The Democratic Republic of the
7 Mohanpur Community health center Agartala India
8 Midnapore Midnapore India
9 Ispat General hospital Rourkela India
10 Sekong Sekong Lao People's Democratic Republic
11 Ann Hospital Ann Myanmar
12 Pyay hospital Pyay Myanmar
13 Pyin oo Lwin hospital Pyin oo Lwin Myanmar
14 Thabeikkyin hospital Thabeikkyin Myanmar
15 Phusing hospital Phusing Srisaket Thailand
16 Tha Song Yang hospital Tha Song Yang Tak Thailand
17 Chumphon hospital Chumphon Thailand
18 Kunhan Hospital Si Sa Ket Thailand
19 Thanto Hospital Yala Thailand
20 Binh Phuoc hospital Binh Phuoc Vietnam

Sponsors and Collaborators

  • University of Oxford

Investigators

  • Principal Investigator: Arjen Dondorp, MD, Mahidol Oxford Tropical Medicine Research Unit

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
University of Oxford
ClinicalTrials.gov Identifier:
NCT02453308
Other Study ID Numbers:
  • BAKMAL1502
First Posted:
May 25, 2015
Last Update Posted:
May 9, 2018
Last Verified:
May 1, 2018
Keywords provided by University of Oxford
Artemisinin combination Therapies
Additional relevant MeSH terms:
Malaria
Malaria, Falciparum

Study Results

No Results Posted as of May 9, 2018