Clinical investigation of in-vivo susceptibility of Plasmodium falciparum to artesunate in Western Cambodia (study 2)

ISRCTN	ISRCTN15351875
DOI	https://doi.org/10.1186/ISRCTN15351875
Secondary identifying numbers	BKMAL0801; 077166

Submission date: 14/05/2008
Registration date: 16/05/2008
Last edited: 19/06/2015

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Infections and Infestations

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Not provided at time of registration

Contact information

Dr Arjen Dondrop
Scientific

Mahidol-Oxford Research Unit
Faculty of Tropical Medicine, Mahidol University
3rd Floor, 60th Anniversary Chalermprakiat Building
420/6 Rajvithi Road
Khet Ratchathevi
Bangkok
10400
Thailand

Phone	+66 (0)2 203 6303
Email	arjen@tropmedres.ac

Study information

Study design	Multicentre randomised controlled trial
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please use the contact details below to request a patient information sheet
Scientific title	Clinical investigation of in-vivo susceptibility of Plasmodium falciparum to artesunate in Western Cambodia (study 2)
Study objectives	There are worrying signs from Western Cambodia that parasitological responses to artesunate and artemether containing treatment regimens for uncomplicated falciparum malaria are slower than elsewhere in the world. Both delayed parasite clearance and unusually high failure rates with artesunate-mefloquine and artemether-lumefantrine have been reported. Although occasional poor responses to artesunate have been described previously the current reports suggest a consistent problem. In pooled data from 12,553 patients receiving artemisinin derivatives, 17% had parasite clearance times (PCTs) over 48 hours and 5% had PCTs over 72 hours. As the rate of parasite clearance is a good pharmacodynamic measure of efficacy of the artemisinin related compounds, slow parasite clearance could indicate the emergence of significant resistance. These antimalarials are central to current treatment strategies, and so spread of significant resistance outside this area would be a disaster. Radical containment measures might be needed. In this context there is an urgent need to proceed quickly to investigate the level of resistance to artemisinin derivatives in Western Cambodia to provide a definitive assessment so that if necessary containment plans can be developed in 2007/2008. A group of malaria investigators from Cambodia and Thailand have joined together to address this urgent question as quickly and effectively as possible. The trial described here proposes to assess the current recommended doses given in the normal way, and if necessary a higher dose of artesunate. There is no known dose related toxicity with artesunate, and doses up to 10 mg/kg/day have been given (by us) without any adverse effects. The two features of this study which differ from normal studies in uncomplicated malaria are the repeated blood sampling and the seven-day in-patient stay. If responses to artesunate are poor it is essential to have characterised the blood concentration profile as well as the parasitological response to differentiate resistance from abnormal pharmacokinetics. As of 22/02/2010 this record has been updated to include an extended sample size due to the inclusion of a site in Thailand as well as the original site in Cambodia. The target number of participants has been updated to reflect this; the initial target number of participants was 40 (planned end of recruitment = 31/12/2008). The overall trial end date was also extended; the initial overall trial end date was 31/03/2009.
Ethics approval(s)	1. Oxford Tropical Medicine Research Ethics Committee (sponsor ethics approval), 13/12/2007, ref: OXTREC [015/07] 2. National Ethics Committee for Health Research (Cambodia), 07/12/2007, for the site: Pailin Hospital
Health condition(s) or problem(s) studied	Acute falciparum malaria
Intervention	Current interventions as of 22/02/2010: Arm 1 (N = 40): receive artesunate alone at a dose of 6 mg/kg/day for seven days Arm 2 (N = 40): receive artesunate alone at a dose of 6 mg/kg/day in two divided doses for seven days Arm 3 (N = 40): receive artesunate at a dose of 8 mg/kg/day for three days, plus mefloquine at a dose of 15 mg/kg on day three and 10 mg/kg on day four Arm 4 (N = 40): receive artesunate at a dose of 8 mg/kg/day in two divided doses for three days, plus mefloquine at a dose of 15 mg/kg on day three and 10 mg/kg on day four Follow up duration for all arms: 63 days Initial information at time of registration: Arm 1 (N = 10): receive artesunate alone at a dose of 6 mg/kg/day for seven days Arm 2 (N = 10): receive artesunate alone at a dose of 6 mg/kg/day in two divided doses for seven days Arm 3 (N = 10): receive artesunate at a dose of 8 mg/kg/day for three days, plus mefloquine at a dose of 15 mg/kg on day three and 10 mg/kg on day four Arm 4 (N = 10): receive artesunate at a dose of 8 mg/kg/day in two divided doses for three days, plus mefloquine at a dose of 15 mg/kg on day three and 10 mg/kg on day four Follow up duration for all arms: 63 days
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Not Applicable
Drug / device / biological / vaccine name(s)	Artesunate, mefloquine
Primary outcome measure	Parasite clearance times in relation to artesunate/dihydroartemisinin (DHA) plasma concentration (PK/PD) (time point: 63 days).
Secondary outcome measures	1. Cure rates (time point: 63 days) 2. In vitro sensitivity of P. falciparum to artesunate measured prior to treatment (time point not applicable) 3. Molecular markers of drug resistance measured prior to treatment (time point not applicable)
Overall study start date	01/04/2008
Completion date	01/12/2010

Eligibility

Participant type(s)	Patient
Age group	Mixed
Sex	Both
Target number of participants	160
Key inclusion criteria	Children greater than 6 years old and adults (either sex) presenting with acute falciparum malaria will be eligible for this study provided that: 1. They or their parents/guardians give fully informed consent 2. They have not received antimalarial drugs in the previous 48 hours 3. Plasmodium falciparum parasitaemia exceeds 10,000 /uL 4. They agree to seven days of hospitalisation
Key exclusion criteria	1. Pregnancy 2. Microscopy indicates a mixed infection 3. History of allergy to artesunate or mefloquine
Date of first enrolment	01/04/2008
Date of final enrolment	31/10/2010

Locations

Countries of recruitment

Cambodia
Thailand

Study participating centre

Mahidol-Oxford Research Unit

Bangkok
10400
Thailand

Sponsor information

University of Oxford (UK)
University/education

Manor House
John Radcliffe Hospital
Headington
Oxford
OX3 9DU
England
United Kingdom

Website	http://www.ox.ac.uk/
"ROR"	https://ror.org/052gg0110

Funders

Funder type

Charity

Wellcome Trust (UK) (grant ref: 077166)
Private sector organisation / International organizations

Location: United Kingdom

Bill and Melinda Gates Foundation (USA) (grant ref: 48821)
Government organisation / Trusts, charities, foundations (both public and private)

Alternative name(s): Bill & Melinda Gates Foundation, Gates Foundation, BMGF, B&MGF, GF
Location: United States of America

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
Publication and dissemination plan	Not provided at time of registration
IPD sharing plan

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	results	01/05/2010		Yes	No