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

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ClinicalTrials.gov Identifier: NCT02453308
Recruitment Status : Completed
First Posted : May 25, 2015
Last Update Posted : May 9, 2018
Sponsor:
Information provided by (Responsible Party):
University of Oxford

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
Malaria, Falciparum Drug: ACT Drug: TACT 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)

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Study Type : Interventional  (Clinical Trial)
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 : August 2015
Actual Primary Completion Date : March 2018
Actual Study Completion Date : March 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Malaria

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
  1. Artemether-lumefantrine for 3 days
  2. Dihydroartemisinin-piperaquine for 3 days.
  3. 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
  1. Artemether-lumefantrine for 3 days plus Amodiaquine for 3 days.
  2. Dihydroartemisinin-piperaquine for 3 days plus Mefloquine hydrochloride for 3 days.
  3. Dihydroartemisinin-piperaquine for 3 days plus Mefloquine hydrochloride for 3 days.




Primary Outcome Measures :
  1. PCR corrected efficacy defined as adequate clinical and parasitological response (ACPR) [ Time Frame: 42 days ]

Secondary Outcome Measures :
  1. Parasite clearance half-life [ Time Frame: 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 [ Time Frame: at 24 and 48 hours ]
  3. Time for parasite count to fall to 50% of initial parasite density [ Time Frame: 42 days ]
  4. Time for parasite count to fall to 90% of initial parasite density [ Time Frame: 42 days ]
  5. Time for parasite count to fall to 99% of initial parasite density [ Time Frame: 42 days ]
  6. Fever clearance time [ Time Frame: 42 days ]
  7. Incidence of adverse events and serious adverse events [ Time Frame: 42 days ]
  8. Incidence of adverse events concerning markers of hepatic toxicity [ Time Frame: 42 days ]
    Total billirubin, ALT, AST and Alkaline Phosphatase will be measured

  9. Incidence of adverse events concerning markersof renal toxicity [ Time Frame: 42 days ]
    Creatinine will be measured

  10. Incidence of prolongation of the QTc-interval [ Time Frame: 3 days ]
    Incidence of prolongation of the Qtc-interval above 500 ms or > 60ms above baseline values

  11. Change in hemoglobin/hematocrit [ Time Frame: 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 [ Time Frame: 42 days ]
  13. Prevalence of Kelch13 mutations of known functional significance [ Time Frame: 42 days ]
  14. Prevalence/incidence of other genetic markers of antimalarial drug resistance [ Time Frame: 42 days ]
  15. Genome wide association with in vivo/in vitro sensitivity parasite phenotype [ Time Frame: 42 days ]
  16. Correlation between SNPs measured in dry blood spots and whole genome sequencing in leukocyte depleted blood samples [ Time Frame: 42 days ]
  17. Transcriptomic patterns at t=0 and t=6h comparing sensitive and resistant parasites [ Time Frame: 6hrs after start of treatment ]
  18. Correlation between qPCR based versus microscopy based assessments of parasite clearance dynamics [ Time Frame: 14 days ]
  19. Proportion of patients with gametocytemia before,after treatment with Primaquine [ Time Frame: assessed at admission, up to day 14 ]
  20. Levels of RNA transcription coding for male or female specific gametocytes [ Time Frame: at admission up to day 14 ]
  21. In vitro sensitivity (expressed in IC50 values among others) of P. falciparum to artemisinins and partner drugs [ Time Frame: 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 [ Time Frame: 42 days ]
  23. Day 7 drug levels of partner drugs in association with treatment efficacy and treatment arm [ Time Frame: Day 7 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   6 Months to 65 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02453308


Locations
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Bangladesh
College of Medicine Chittagong
Ramu, Bangladesh
Cambodia
Pailin
Pailin, Cambodia
Preah Vihear
Preah Vihear, Cambodia
Pursat
Pursat, Cambodia
Ratanakiri
Ratankiri, Cambodia
Congo, The Democratic Republic of the
Kinshasa
Kinshasa, Congo, The Democratic Republic of the
India
Mohanpur Community health center
Agartala, India
Midnapore
Midnapore, India
Ispat General hospital
Rourkela, India
Lao People's Democratic Republic
Sekong
Sekong, Lao People's Democratic Republic
Myanmar
Ann Hospital
Ann, Myanmar
Pyay hospital
Pyay, Myanmar
Pyin oo Lwin hospital
Pyin oo Lwin, Myanmar
Thabeikkyin hospital
Thabeikkyin, Myanmar
Thailand
Phusing hospital
Phusing, Srisaket, Thailand
Tha Song Yang hospital
Tha Song Yang, Tak, Thailand
Chumphon hospital
Chumphon, Thailand
Kunhan Hospital
Si Sa Ket, Thailand
Thanto Hospital
Yala, Thailand
Vietnam
Binh Phuoc hospital
Binh Phuoc, Vietnam
Sponsors and Collaborators
University of Oxford
Investigators
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Principal Investigator: Arjen Dondorp, MD Mahidol Oxford Tropical Medicine Research Unit (MORU)

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: University of Oxford
ClinicalTrials.gov Identifier: NCT02453308     History of Changes
Other Study ID Numbers: BAKMAL1502
First Posted: May 25, 2015    Key Record Dates
Last Update Posted: May 9, 2018
Last Verified: May 2018
Keywords provided by University of Oxford:
Artemisinin combination Therapies
Additional relevant MeSH terms:
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Malaria
Malaria, Falciparum
Protozoan Infections
Parasitic Diseases
Lumefantrine
Artemether
Piperaquine
Artemether, Lumefantrine Drug Combination
Dihydroartemisinin
Artemisinins
Mefloquine
Artemisinine
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents