Clinical trial NCT01350856: Tracking Resistance to Artemisinin (TRAC)
Official title: A Multicentre, Randomised Trial to Detect in Vivo Resistance of Plasmodium Falciparum to Artesunate in Patients With Uncomplicated Malaria.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Falciparum Malaria
Keywords: Uncomplicated P. falciparum malaria
Lead sponsor: University of Oxford
Sponsor class: OTHER
Collaborators: name: Mahidol University
name: Worldwide Antimalarial Resistance Network
First posted: 2011-05-10
Enrollment: 1700
Sex: ALL
Minimum age (years): 6
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 Two different dose regimens of artesunate will be compared at all sites except those in western Cambodia, as unpublished observations from the Thai-Myanmar border suggest the standard lower daily dose of 2mg/kg may enable the earlier detection of low level resistance than a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

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 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

Primary outcomes:
measure: Parasite clearance rate
timeFrame: Day 42
Secondary outcomes:
measure: Parasite clearance time
timeFrame: Day 42
measure: Parasite reduction rates and ratios
timeFrame: Day 42
measure: Time for parasite count to fall
timeFrame: 50%, 90%, and 99%
measure: Fever clearance time
timeFrame: > 24 hours
measure: Gametocytemia in patients
timeFrame: days 0, 3, 7 and 14
measure: Gametocyte carriage rates
timeFrame: 14 days
measure: In vitro susceptibility of P.falciparum to artemisinins
timeFrame: Day 42
measure: Pharmacokinetics relationships for artesunate and Dihydroartemisinin (DHA)
timeFrame: Day 42
measure: Parasite molecular markers of drug resistance
timeFrame: Day 42
measure: Identification of host factors that correlate with slow parasite clearance
timeFrame: Day 42
measure: Efficacy at D42
timeFrame: Day 42
measure: Pharmacodynamics relationships for artesunate and Dihydroartemisinin (DHA)
timeFrame: Day 42
Other outcomes:
Locations:
city: Cox's Bazaar
country: Bangladesh
facility: Ramu Upazila Health Complex
city: Pailin
country: Cambodia
facility: Pailin General Hospital
city: Preah Vihear
country: Cambodia
facility: District Referral Hospital
city: Pursat
country: Cambodia
facility: Pursat Referral Hospital
city: Rattanakiri
country: Cambodia
facility: District Referral Hospital
city: Kinshasa
country: Congo, The Democratic Republic of the
facility: Kingasani Health Centre
city: West Bengal
country: India
facility: Sulkapara Block Primary Health Center
city: Kilifi
country: Kenya
facility: Pingilikani Dispensary
city: Phouvong
country: Lao People's Democratic Republic
facility: Phouvong District Hospital
state: Attapeu
city: Myitkyina
country: Myanmar
facility: Myitkyina
state: Kachin
city: Luthaw
country: Myanmar
facility: Day Bu Noh
state: Karen
city: Mandalay
country: Myanmar
facility: Pyin Oo Lwin
state: Mandalay Region
city: Thabeikkyin
country: Myanmar
facility: Thabeikkyin Hospital
state: Mandalay
city: Shwe Kyin
country: Myanmar
facility: Shwe Kyin Hospital
city: Ilorin
country: Nigeria
facility: University of Ilorin Teaching Hospital
city: Mae Sot
country: Thailand
facility: Shoklo Malaria Research Unit
state: Tak
city: Ranong
country: Thailand
facility: Kraburi Hospital
city: Srisaket
country: Thailand
facility: Phusing Hospital
city: Binh Phuoc
country: Vietnam
facility: Phuoc Long Hospital
Study officials:
affiliation: Mahidol Oxford Research Unit
name: Nicholas J White, DSc MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.