Condition category
Infections and Infestations
Date applied
14/05/2008
Date assigned
16/05/2008
Last edited
19/06/2015
Prospective/Retrospective
Retrospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Not provided at time of registration

Trial website

Contact information

Type

Scientific

Primary contact

Dr Arjen Dondrop

ORCID ID

Contact details

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

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

BKMAL0801; 077166

Study information

Scientific title

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

Acronym

Study hypothesis

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

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

Study design

Multicentre randomised controlled trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

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

Phase

Not Applicable

Drug names

Artesunate, mefloquine

Primary outcome measures

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 trial start date

01/04/2008

Overall trial end date

01/12/2010

Reason abandoned

Eligibility

Participant 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

Participant type

Patient

Age group

Mixed

Gender

Both

Target number of participants

160

Participant exclusion criteria

1. Pregnancy
2. Microscopy indicates a mixed infection
3. History of allergy to artesunate or mefloquine

Recruitment start date

01/04/2008

Recruitment end date

31/10/2010

Locations

Countries of recruitment

Cambodia, Thailand

Trial participating centre

Mahidol-Oxford Research Unit
Bangkok
10400
Thailand

Sponsor information

Organisation

University of Oxford (UK)

Sponsor details

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

Sponsor type

University/education

Website

http://www.ox.ac.uk/

Funders

Funder type

Charity

Funder name

Wellcome Trust (UK) (grant ref: 077166)

Alternative name(s)

Funding Body Type

private sector organisation

Funding Body Subtype

international

Location

United Kingdom

Funder name

Bill and Melinda Gates Foundation (USA) (grant ref: 48821)

Alternative name(s)

Bill & Melinda Gates Foundation

Funding Body Type

private sector organisation

Funding Body Subtype

foundation

Location

United States of America

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

2010 results in http://www.ncbi.nlm.nih.gov/pubmed/20350192

Publication citations

  1. Results

    Anderson TJ, Nair S, Nkhoma S, Williams JT, Imwong M, Yi P, Socheat D, Das D, Chotivanich K, Day NP, White NJ, Dondorp AM, High heritability of malaria parasite clearance rate indicates a genetic basis for artemisinin resistance in western Cambodia., J. Infect. Dis., 2010, 201, 9, 1326-1330, doi: 10.1086/651562.

Additional files

Editorial Notes