Tracking Resistance to Artemisinin (TRAC)

Falciparum Malaria Clinical Trial

— TRAC  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01350856
• Other study ID #: BAKMAL1101
• Status: Completed
• Phase: Phase 4
• First received: April 19, 2011
• Last updated: May 29, 2015
• Start date: May 2011
• Est. completion date: December 2014

Study information

• Verified date: May 2015
• Source: University of Oxford
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdom: Research Ethics Committee
• Study type: Interventional

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 Two different dose regimens of artesunate will be compared at all sites except those in western Cambodia, as unpublished observations from the Thai-Myanmar border suggest the standard lower daily dose of 2mg/kg may enable the earlier detection of low level resistance than a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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1700
• Est. completion date: December 2014
• Est. primary completion date: April 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 6 Months to 65 Years

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

• Falciparum Malaria
• Malaria
• Malaria, Falciparum

Intervention

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
• 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

Locations

Country	Name	City	State
Bangladesh	Ramu Upazila Health Complex	Cox's Bazaar
Cambodia	Pailin General Hospital	Pailin
Cambodia	District Referral Hospital	Preah Vihear
Cambodia	Pursat Referral Hospital	Pursat
Cambodia	District Referral Hospital	Rattanakiri
Congo, The Democratic Republic o	Kingasani Health Centre	Kinshasa
India	Sulkapara Block Primary Health Center	West Bengal
Kenya	Pingilikani Dispensary	Kilifi
Lao People's Democratic Republic	Phouvong District Hospital	Phouvong	Attapeu
Myanmar	Day Bu Noh	Luthaw	Karen
Myanmar	Pyin Oo Lwin	Mandalay	Mandalay Region
Myanmar	Myitkyina	Myitkyina	Kachin
Myanmar	Shwe Kyin Hospital	Shwe Kyin
Myanmar	Thabeikkyin Hospital	Thabeikkyin	Mandalay
Nigeria	University of Ilorin Teaching Hospital	Ilorin
Thailand	Shoklo Malaria Research Unit	Mae Sot	Tak
Thailand	Kraburi Hospital	Ranong
Thailand	Phusing Hospital	Srisaket
Vietnam	Phuoc Long Hospital	Binh Phuoc

Sponsors (3)

Lead Sponsor	Collaborator
University of Oxford	Mahidol University, Worldwide Antimalarial Resistance Network

Countries where clinical trial is conducted

Bangladesh,  Cambodia,  Congo, The Democratic Republic of the,  India,  Kenya,  Lao People's Democratic Republic,  Myanmar,  Nigeria,  Thailand,  Vietnam, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Parasite clearance rate	Defined by the slope of the linear portion of the natural logarithm parasite clearance curve.	Day 42	No
Secondary	Parasite clearance time	Assessed by microscopy	Day 42	No
Secondary	Parasite reduction rates and ratios	Assessed by microscopy and quantitative PCR.	Day 42	No
Secondary	Time for parasite count to fall	Time for parasite count to fall to 50%, 90%, and 99% of initial parasite density	50%, 90%, and 99%	No
Secondary	Fever clearance time	The time taken for tympanic temperature to fall below 37°C and remain there for at least 24 hours	> 24 hours	No
Secondary	Gametocytemia in patients	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	days 0, 3, 7 and 14	No
Secondary	Gametocyte carriage rates		14 days	No
Secondary	In vitro susceptibility of P.falciparum to artemisinins	Measure the inhibitory concentrations (IC) 50, IC90, IC99 of P. falciparum responses to artemisinins ex vivo	Day 42	No
Secondary	Pharmacokinetics relationships for artesunate and Dihydroartemisinin (DHA)	Measure half-life, Cmax, AUC, Tmax of artesunate and DHA.	Day 42	No
Secondary	Parasite molecular markers of drug resistance	To identify the parasite specific molecular marker which is correlated to artemisinin resistance	Day 42	No
Secondary	Identification of host factors that correlate with slow parasite clearance	To identify host factors influencing the clearance of P. falciparum, e.g. haemoglobinopathies and G6PD deficiency	Day 42	No
Secondary	Efficacy at D42	The cure rate of artesunate plus ACT treatments at 42 day of follow up.	Day 42	No
Secondary	Pharmacodynamics relationships for artesunate and Dihydroartemisinin (DHA)		Day 42	No