Tracking Resistance to Artemisinin (TRAC)

This study is currently recruiting participants. (see Contacts and Locations)
Verified December 2013 by University of Oxford
Sponsor:
Collaborators:
Mahidol University
Worldwide Antimalarial Resistance Network
Information provided by (Responsible Party):
University of Oxford
ClinicalTrials.gov Identifier:
NCT01350856
First received: April 19, 2011
Last updated: December 20, 2013
Last verified: December 2013

April 19, 2011
December 20, 2013
May 2011
April 2014   (final data collection date for primary outcome measure)
Parasite clearance rate [ Time Frame: Day 42 ] [ Designated as safety issue: No ]
Defined by the slope of the linear portion of the natural logarithm parasite clearance curve.
Same as current
Complete list of historical versions of study NCT01350856 on ClinicalTrials.gov Archive Site
  • Parasite clearance time [ Time Frame: Day 42 ] [ Designated as safety issue: No ]
    Assessed by microscopy
  • Parasite reduction rates and ratios [ Time Frame: Day 42 ] [ Designated as safety issue: No ]
    Assessed by microscopy and quantitative PCR.
  • Time for parasite count to fall [ Time Frame: 50%, 90%, and 99% ] [ Designated as safety issue: No ]
    Time for parasite count to fall to 50%, 90%, and 99% of initial parasite density
  • Fever clearance time [ Time Frame: > 24 hours ] [ Designated as safety issue: No ]
    The time taken for tympanic temperature to fall below 37˚C and remain there for at least 24 hours
  • Gametocytemia in patients [ Time Frame: days 0, 3, 7 and 14 ] [ Designated as safety issue: No ]
    Proportion of patients with gametocytemia before, during and after treatment with artesunate, assessed at admission, on days 3, 7 and 14, stratified by presence of gametocytes at enrolment
  • Gametocyte carriage rates [ Time Frame: 14 days ] [ Designated as safety issue: No ]
  • In vitro susceptibility of P.falciparum to artemisinins [ Time Frame: Day 42 ] [ Designated as safety issue: No ]
    Measure the inhibitory concentrations (IC) 50, IC90, IC99 of P. falciparum responses to artemisinins ex vivo
  • Pharmacokinetics relationships for artesunate and Dihydroartemisinin (DHA) [ Time Frame: Day 42 ] [ Designated as safety issue: No ]
    Measure half-life, Cmax, AUC, Tmax of artesunate and DHA.
  • Parasite molecular markers of drug resistance [ Time Frame: Day 42 ] [ Designated as safety issue: No ]
    To identify the parasite specific molecular marker which is correlated to artemisinin resistance
  • Identification of host factors that correlate with slow parasite clearance [ Time Frame: Day 42 ] [ Designated as safety issue: No ]
    To identify host factors influencing the clearance of P. falciparum, e.g. haemoglobinopathies and G6PD deficiency
  • Efficacy at D42 [ Time Frame: Day 42 ] [ Designated as safety issue: No ]
    The cure rate of artesunate plus ACT treatments at 42 day of follow up.
  • Pharmacodynamics relationships for artesunate and Dihydroartemisinin (DHA) [ Time Frame: Day 42 ] [ Designated as safety issue: No ]
  • Parasite clearance time [ Time Frame: Day 42 ] [ Designated as safety issue: No ]
    Assessed by microscopy
  • Parasite reduction rates and ratios [ Time Frame: Day 42 ] [ Designated as safety issue: No ]
    Assessed by microscopy and quantitative PCR.
  • Time for parasite count to fall [ Time Frame: 50%, 90%, and 99% ] [ Designated as safety issue: No ]
    Time for parasite count to fall to 50%, 90%, and 99% of initial parasite density
  • Fever clearance time [ Time Frame: > 24 hours ] [ Designated as safety issue: No ]
    The time taken for tympanic temperature to fall below 37˚C and remain there for at least 24 hours
  • Gametocytemia in patients [ Time Frame: days 0, 3, 7 and 14 ] [ Designated as safety issue: No ]
    Proportion of patients with gametocytemia before, during and after treatment with artesunate, assessed at admission, on days 3, 7 and 14, stratified by presence of gametocytes at enrolment
  • Gametocyte carriage rates [ Time Frame: 14 days ] [ Designated as safety issue: No ]
  • In vitro susceptibility of P.falciparum to artemisinins [ Time Frame: Day 42 ] [ Designated as safety issue: No ]
    Measure the inhibitory concentratios (IC) 50, IC90, IC99 of P. falciparum responses to artemisinins ex vivo
  • Pharmacokinetics and Pharmacodynamics relationships for artesunate and Dihydroartemisinin (DHA) [ Time Frame: Day 42 ] [ Designated as safety issue: No ]
    Measure half-life, Cmax, AUC, Tmax of artesunate and DHA.
  • Parasite molecular markers of drug resistance [ Time Frame: Day 42 ] [ Designated as safety issue: No ]
    To identify the parasite specific molecular marker which is correlatd to artemisinin resistance
  • Identification of host factors that correlate with slow parasite clearance [ Time Frame: Day 42 ] [ Designated as safety issue: No ]
    To identify host factors influencing the clearance of P. falciparum, e.g. haemoglobinopathies and G6PD deficiency
  • Efficacy at D42 [ Time Frame: Day 42 ] [ Designated as safety issue: No ]
    The cure rate of artesunate plus ACT treatments at 42 day of follow up.
Not Provided
Not Provided
 
Tracking Resistance to Artemisinin (TRAC)
A Multicentre, Randomised Trial to Detect in Vivo Resistance of Plasmodium Falciparum to Artesunate in Patients With Uncomplicated Malaria.

Because the artemisinins are the most potent antimalarial drugs, the reduction in parasite numbers is rapid. Therefore, early measures of reducing parasite counts are needed. This study will look at conventional markers of parasite reduction e.g. parasite clearance time, parasite reduction ratio, and the time to achieve a fall of 50%, 90% and 99% of the pre-treatment parasitaemia.

Defining artemisinin resistance requires the use of artesunate (AS) alone because it is now appreciated that the partner drug in a combination treatment has a significant impact on the rate of parasite clearance. This study will dose patients for 3 days with AS alone (or longer until parasites clear) and measure the parasite count frequently in order to be able to define an accurate regression line of a graph of the natural logarithm of the parasite count (Y axis) versus time (X axis). This will be followed by a full course of an artemisinin combination therapy (ACT). Two different dose regimens of artesunate will be compared at all sites except those in western Cambodia, as unpublished observations from the Thai-Myanmar border suggest the standard lower daily dose of 2mg/kg may enable the earlier detection of low level resistance than a 4mg/kg daily dose.

Background:

Artemisinins are the cornerstone of current antimalarial treatment. Evidence of reduced susceptibility to artemisinins in Western Cambodia was first presented in January 2007 and confirmed in a subsequent detailed pharmacokinetic-pharmacodynamic study conducted by our group. Artemisinin resistance was manifest by a marked slowing of parasite clearance. The spread of highly artemisinin resistant falciparum malaria would have devastating consequences for malaria control and elimination. The response to artemisinin resistance in P. falciparum depends critically upon answering one pivotal question: how far has it spread? This research proposal focuses on filling critical gaps in knowledge that are essential to planning an effective response.

Objectives/Hypothesis/Questions:

This is a multi-centre study with the primary objective of comparing the P. falciparum parasite clearance compared to a reference parasite clearance rate obtained from historical data in artemisinin sensitive falciparum malaria.

The aim of this large scale study is to determine if artemisinin resistance has spread and if so, how far it has spread.

Research design:

This is a multi-centre, open-label randomised trial to assess the clearance rates of peripheral blood P. falciparum parasitaemias in patients with acute uncomplicated falciparum malaria treated with two different doses of artesunate.

The study will recruit patients with acute uncomplicated P. falciparum malaria. The total number of patients for this study is expected to be 1800.

Patients will be randomised 1:1 to receive either:

  • AS2: Artesunate 2 mg/kg/day for 3 days OR
  • AS4: Artesunate 4 mg/kg/day for 3 days
  • followed by a full course of Artesunate- mefloquine (MAS3) Patients will be hospitalised for at least the 1st three days. During hospitalisation, patients will have malaria parasite count done at 0, 4, 6, 8, 12, then every 6 hours until parasite clearance. The weekly follow up is until day 14 (on Day 7 and Day 14).

Value and significance of the research The study aims to address a simple but crucial question regarding artemisinin resistance for which currently there is no answer: has artemisinin resistant Plasmodium falciparum spread from Western Cambodia? The results will determine how to approach the subsequent efforts; strengthening of strategies for eliminating the resistant parasites in Western Cambodia if the resistance is confined to this area, or for containment and malaria control if the resistant parasites have already spread.

Potential outcomes Within one year we expect to produce a map of the geographical extent, prevalence and severity of artemisinin resistance.

Interventional
Phase 4
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Falciparum Malaria
  • Drug: Artesunate 2
    Artesunate 2 mg/kg/day for 3 days followed by a full course of either artemether-lumefantrine or DHA-piperaquine or artesunate-mefloquine or artesunate-amodiaquine
  • Drug: Artesunate 4
    Artesunate 4 mg/kg/day for 3 days followed by a full course of either artemether-lumefantrine or DHA-piperaquine or artesunate-mefloquine or artesunate-amodiaquine
  • Active Comparator: Artesunate 2
    Artesunate 2 mg/kg/day for 3 days followed by a full course of either artemether-lumefantrine or DHA-piperaquine or artesunate-mefloquine or artesunate-amodiaquine
    Intervention: Drug: Artesunate 2
  • Experimental: Artesunate 4
    Artesunate 4 mg/kg/day for 3 days followed by a full course of either artemether-lumefantrine or DHA-piperaquine or artesunate-mefloquine or artesunate-amodiaquine
    Intervention: Drug: Artesunate 4
Ashley EA, Dhorda M, Fairhurst RM, Amaratunga C, Lim P, Suon S, Sreng S, Anderson JM, Mao S, Sam B, Sopha C, Chuor CM, Nguon C, Sovannaroth S, Pukrittayakamee S, Jittamala P, Chotivanich K, Chutasmit K, Suchatsoonthorn C, Runcharoen R, Hien TT, Thuy-Nhien NT, Thanh NV, Phu NH, Htut Y, Han KT, Aye KH, Mokuolu OA, Olaosebikan RR, Folaranmi OO, Mayxay M, Khanthavong M, Hongvanthong B, Newton PN, Onyamboko MA, Fanello CI, Tshefu AK, Mishra N, Valecha N, Phyo AP, Nosten F, Yi P, Tripura R, Borrmann S, Bashraheil M, Peshu J, Faiz MA, Ghose A, Hossain MA, Samad R, Rahman MR, Hasan MM, Islam A, Miotto O, Amato R, MacInnis B, Stalker J, Kwiatkowski DP, Bozdech Z, Jeeyapant A, Cheah PY, Sakulthaew T, Chalk J, Intharabut B, Silamut K, Lee SJ, Vihokhern B, Kunasol C, Imwong M, Tarning J, Taylor WJ, Yeung S, Woodrow CJ, Flegg JA, Das D, Smith J, Venkatesan M, Plowe CV, Stepniewska K, Guerin PJ, Dondorp AM, Day NP, White NJ; Tracking Resistance to Artemisinin Collaboration (TRAC). Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2014 Jul 31;371(5):411-23. doi: 10.1056/NEJMoa1314981.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
1800
April 2014
April 2014   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Male or female, aged from 6 months to 65 years old, inclusive
  • 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: 10,000 to 200,000/uL, determined on a thin or thick blood film
  • Fever defined as > 37.5°C tympanic temperature or a history of fever within the last 24 hours
  • Written informed consent (by legally acceptable representative in case of children)
  • Willingness and ability of the patients/guardians to comply with the study protocol for the duration of the study

Exclusion Criteria:

  • Signs of severe/complicated malaria (WHO, 2000)
  • Haematocrit < 25% or haemoglobin (Hb) < 8 g/dL at enrollment
  • 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
  • History of allergy or known contraindication to artemisinins, or to the ACT to be used at the site
  • Previous splenectomy
Both
6 Months to 65 Years
No
Contact: Nicholas J White, DSc MD +662-203-6301 nickw@tropmedres.ac
Contact: Elizabeth Ashley, MB BS PhD liz@tropmedres.ac
Myanmar,   Cambodia,   Congo, The Democratic Republic of the,   Thailand,   Lao People's Democratic Republic,   Vietnam,   Kenya,   Bangladesh,   India,   Nigeria
 
NCT01350856
BAKMAL1101
Yes
University of Oxford
University of Oxford
  • Mahidol University
  • Worldwide Antimalarial Resistance Network
Principal Investigator: Nicholas J White, DSc MD Mahidol Oxford Research Unit
University of Oxford
December 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP