Condition category
Infections and Infestations
Date applied
06/04/2005
Date assigned
22/07/2005
Last edited
19/10/2016
Prospective/Retrospective
Retrospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Background and study aims
Malaria is a serious tropical disease caused by a parasite that is spread by mosquitoes. Antimalarial medication is used to prevent and treat malaria. However, resistance to antimalarial drugs can develop when genetic mutations allow the parasite to survive in the presence of the drug. The development of resistance is of huge public health concern. In Malawi, sulphadoxine-pyrimethamine (SDX-PYM) replaced chloroquine (CQ) in 1993 as the first-line treatment for uncomplicated malaria because of high levels of CQ resistance. However, SDX-PYM resistance is increasing. Combination treatment with two or more drugs working by different mechanisms is proposed as a means to delay the development of resistance. Combination treatments containing artemisinin (ART) are proposed as ideal for this purpose because they kill malaria parasites very rapidly and no resistance had been reported at the time of this study. There is also evidence supporting the possible use of a non-ART combination treatment as a possible alternative. Since CQ was withdrawn in 1993 there has been evidence suggesting a possible return of CQ sensitivity. Amodiaquine (AQ) in combination with SDX-PYM has been shown to be effective and well tolerated in Uganda in an area of high-level CQ resistance. This issue is of huge public health importance as combinations of CQ or AQ plus SDX-PYM would be considerably more affordable compared to ART combination treatment. The aims of this study are:
1. To compare the effectiveness of different antimalarial combination treatments
2. To compare the development of resistance when using these different treatments
3. To investigate what happens to the drugs after they are taken – their absorption and how fast they are eliminated from the body

Who can participate?
Children aged between 1 and 5 with uncomplicated malaria

What does the study involve?
Participants are randomly allocated to receive one of four treatment combinations:
1. SDX-PYM (single oral dose) and placebo (dummy drug)
2. SDX-PYM (single oral dose) + CQ (once daily for 3 days)
3. SDX-PYM (single oral dose) + Artesunate (once daily for 3 days)
4. SDX-PYM (single oral dose) + AQ (once daily for 3 days)
Participants are followed up for 42 days to assess their response to treatment and the development of resistance or side effects.

What are the possible benefits and risks of participating?
The treatments offered all contain SDX-PYM, the standard treatment for malaria in Malawi, plus an additional medicine – placebo, CQ, AQ or ART. Apart from the placebo, all of these treatments are expected to improve the cure rates for the children. Participation in the study involves additional blood tests for all the children and additional visits to the clinic. These may be an inconvenience for the children and mothers, but do provide a higher level of care than is otherwise available.

Where is the study run from?
Chileka Health Centre (Malawi)

When is the study starting and how long is it expected to run for?
September 2003 to March 2006

Who is funding the study?
Wellcome Trust (UK)

Who is the main contact?
Dr David Bell
belldavidj@gmail.com

Trial website

Contact information

Type

Scientific

Primary contact

Dr David Bell

ORCID ID

Contact details

Wellcome Trust Tropical Centre
Block E
Royal Infirmary Complex
University of Liverpool
70 Pembroke Place
Liverpool
L69 3GF
United Kingdom
+44 (0)151 794 4221
belldavidj@gmail.com

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

066681

Study information

Scientific title

Evaluating strategies to delay the emergence of resistance to antimalarial drugs

Acronym

SP Combinations Study

Study hypothesis

Compared to sulfadoxine-pyrimethamine monotherapy, the addition of chloroquine or amodiaquine or artesunate results in:
1. Improved clinical and parasitological outcomes at 14, 28 and 42 days
2. Decreased selection of resistance mutations
3. Clinical failures that cannot be explained by the parasite genotype have a pharmacokinetic basis

Ethics approval

1. Liverpool School of Tropical Medicine, Research Ethics Commitee, 02/03/2002, ref: 01.72
2. University of Malawi, College of Medicine Research Ethics Committee, 05/08/2002, ref: P.01/02/140

Study design

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 contact details to request a participant information sheet

Condition

Uncomplicated malaria

Intervention

Four armed, blinded, randomised trial comparing:
1. SP (single oral dose) and placebo
2. SP (single oral dose) and chloroquine (once daily for 3 days)
3. SP (single oral dose) and amodiaquine (once daily for 3 days)
4. SP (single oral dose) and artesunate (once daily for 3 days)

Total duration of follow up in study was 42 days for all participants.

Intervention type

Drug

Phase

Not Applicable

Drug names

Sulfadoxine-pyrimethamine, chloroquine, amodiaquine, artesunate

Primary outcome measures

1. World Health Organization (WHO) treatment response endpoints on days 14, 28 and 42
2. Selection of Dihydrofolate Reductase (DHFR) and Dihydropteroate Synthetase (DHPS) resistance associated genotypes
3. Fever clearance time
4. Parasite clearance time
5. Change in haemoglobin between day zero to 14
6. Gametocyte prevalence on day seven or 14
7. Adverse events clinical and laboratory

Secondary outcome measures

No secondary outcome measures

Overall trial start date

01/09/2003

Overall trial end date

15/03/2006

Reason abandoned

Eligibility

Participant inclusion criteria

1. Age more than or equal to 12 and less than 60 months, either sex
2. Weight more than or equal to 6 kg
3. Pure (on microscopic grounds) P. falciparum parasitaemia of 2000 to 200,000 ul
4. Written consent has been obtained from the parent or legal guardian

Participant type

Patient

Age group

Child

Gender

Both

Target number of participants

450

Participant exclusion criteria

1. Severe malaria
2. Antimalarials in previous week
3. Other comcomitant infection at time of presentation
4. Allergy to sulphonamides
5. Involvement in the study in the previous 12 months

Recruitment start date

01/09/2003

Recruitment end date

01/02/2006

Locations

Countries of recruitment

Malawi

Trial participating centre

Wellcome Trust Tropical Centre
Liverpool
L69 3GF
United Kingdom

Sponsor information

Organisation

University of Liverpool (UK)

Sponsor details

Research Support
Senate House
Abercromby Square
Liverpool
L69 3BX
United Kingdom

Sponsor type

University/education

Website

http://www.liv.ac.uk/

Funders

Funder type

Charity

Funder name

Wellcome Trust

Alternative name(s)

Funding Body Type

private sector organisation

Funding Body Subtype

international

Location

United Kingdom

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

2008 results in: http://www.ncbi.nlm.nih.gov/pubmed/18270569

Publication citations

  1. Results

    Bell DJ, Nyirongo SK, Mukaka M, Zijlstra EE, Plowe CV, Molyneux ME, Ward SA, Winstanley PA, Sulfadoxine-pyrimethamine-based combinations for malaria: a randomised blinded trial to compare efficacy, safety and selection of resistance in Malawi., PLoS ONE, 2008, 3, 2, e1578, doi: 10.1371/journal.pone.0001578.

Additional files

Editorial Notes

19/10/2016: Plain English summary added.