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Tracking Resistance to Artemisinin (TRAC)

Information source: University of Oxford
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Falciparum Malaria

Intervention: Artesunate 2 (Drug); Artesunate 4 (Drug)

Phase: Phase 4

Status: Completed

Sponsored by: University of Oxford

Official(s) and/or principal investigator(s):
Nicholas J White, DSc MD, Principal Investigator, Affiliation: Mahidol Oxford Research Unit


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 Two different dose regimens of artesunate will be compared at all sites except those in western Cambodia, as unpublished observations from the Thai-Myanmar border suggest the standard lower daily dose of 2mg/kg may enable the earlier detection of low level resistance than a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.

Clinical Details

Official title: A Multicentre, Randomised Trial to Detect in Vivo Resistance of Plasmodium Falciparum to Artesunate in Patients With Uncomplicated Malaria.

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Parasite clearance rate

Secondary outcome:

Parasite clearance time

Parasite reduction rates and ratios

Time for parasite count to fall

Fever clearance time

Gametocytemia in patients

Gametocyte carriage rates

In vitro susceptibility of P.falciparum to artemisinins

Pharmacokinetics relationships for artesunate and Dihydroartemisinin (DHA)

Parasite molecular markers of drug resistance

Identification of host factors that correlate with slow parasite clearance

Efficacy at D42

Pharmacodynamics relationships for artesunate and Dihydroartemisinin (DHA)

Detailed description: 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.


Minimum age: 6 Months. Maximum age: 65 Years. Gender(s): Both.


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

Locations and Contacts

Ramu Upazila Health Complex, Cox's Bazaar, Bangladesh

Pailin General Hospital, Pailin, Cambodia

District Referral Hospital, Preah Vihear, Cambodia

Pursat Referral Hospital, Pursat, Cambodia

District Referral Hospital, Rattanakiri, Cambodia

Kingasani Health Centre, Kinshasa, Congo, The Democratic Republic of the

Sulkapara Block Primary Health Center, West Bengal, India

Pingilikani Dispensary, Kilifi, Kenya

Shwe Kyin Hospital, Shwe Kyin, Myanmar

University of Ilorin Teaching Hospital, Ilorin, Nigeria

Kraburi Hospital, Ranong, Thailand

Phusing Hospital, Srisaket, Thailand

Phuoc Long Hospital, Binh Phuoc, Vietnam

Phouvong District Hospital, Phouvong, Attapeu, Lao People's Democratic Republic

Myitkyina, Myitkyina, Kachin, Myanmar

Day Bu Noh, Luthaw, Karen, Myanmar

Thabeikkyin Hospital, Thabeikkyin, Mandalay, Myanmar

Pyin Oo Lwin, Mandalay, Mandalay Region, Myanmar

Shoklo Malaria Research Unit, Mae Sot, Tak, Thailand

Additional Information

Starting date: May 2011
Last updated: May 29, 2015

Page last updated: August 23, 2015

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