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
Summary
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compared at all sites except those in western Cambodia, as unpublished observations from the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 timeParasite 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.
Eligibility
Minimum age: 6 Months.
Maximum age: 65 Years.
Gender(s): Both.
Criteria:
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
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