The Impact of Artemether-Lumefantrine on Genes Associated With Antimalarial Resistance

Sponsor

Tropical Medicine Research Institute (Other)

Overall Status

Completed

CT.gov ID

NCT00440752

Collaborator

London School of Hygiene and Tropical Medicine (Other), World Health Organization (Other), International Atomic Energy Agency (Other)

100

Enrollment

Location

Duration (Months)

49.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The newly introduced antimalarial drug artemether-lumefantrine is currently recommended as second line antimalarial in Sudan. Recurrent infection after treatment with this drug has been associated with selection of certain genes in the malaria parasite. However there is no information on this association in Sudan.This study is going to look into the genetics of resistance to artemether-lumefantrine.

Condition or Disease	Intervention/Treatment	Phase
Falciparum Malaria Antimalarials

Detailed Description

In Sudan the current treatment protocol includes two artemisinin combinations (ACT); artesunate + sulphadoxine/pyrimethamine (AS/SP) as first line and artemether-lumefantrine (AL) as second line. This protocol has been implemented in 2004, since then various studies have reported the high efficacy of both combinations (e.g. Adam et al., 2005; Elamin et al., 2005; Mohamed et al., 2006).

However, there has been no report of the impact of these combinations on drug resistance markers in Sudan. Data from other African countries has shown that AL selects for certain alleles in the pfmdr-1 gene (Sisowath et al., 2005, Dokomajilar et al., 2006; Humphreys et al., 2007), but the impact on the prevalence of different pfcrt and pfmdr-1alleles remains unclear. It is essential to monitor ACT efficacy in addition to identify molecular markers that are associated with response to different drugs to facilitate epidemiological surveys for evidence based decision making. Recent work in The Gambia suggests that transmission-related endpoints, such as emergence of gametocytes after treatment, may be better indicators of emerging drug resistance (Hallett et al., 2006).

The aim of the proposed study is to examine the impact of treatment with artemether-lumefantrine (AL) on alleles of pfcrt and pfmdr-1 in P. falciparum isolates in an area of marked seasonal transmission in eastern Sudan. Most studies of resistance markers measure marker prevalence by DNA amplification, but we will also investigate gene expression using quantitative amplification of mRNA encoding pfcrt and pfmdr-1. The impact of genotype and gene expression levels on treatment outcome, and on the emergence and density of peripheral gametocytes will be examined.

Study Design

Study Type:

Observational

Actual Enrollment :

100 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

The Impact of Artemether-Lumefantrine on Genes Associated With Antimalarial Resistance in an Area of Seasonal Transmission

Study Start Date :

Oct 1, 2006

Actual Study Completion Date :

Dec 1, 2006

Arms and Interventions

Arm	Intervention/Treatment
AL Cohort of study participants receiving treatment with artemether-lumefantrine

Outcome Measures

Primary Outcome Measures

Levels of expression of pfcrt and pfmdr-1 alleles on day 0, 3, 7, 14, 21, 28 detected by real-time PCR. [2007 to 2009]

Secondary Outcome Measures

Parasitological failure occurring at day 3, 7, 14, 21, 28 or any other day during this period. [within 28 days of subject recruitment]
Gametocyte development detected by reverse transcriptase PCR on day 0, 3, 14 and 28 [2008 to 2009]

Eligibility Criteria

Criteria

Ages Eligible for Study:

2 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Mono-infection with P. falciparum by microscopy.
Initial parasite density of 1000 to 100,000 asexual parasites/µl.
Absence of general danger signs or other signs of severe and complicated falciparum malaria according to WHO definitions.
Informed consent provided by patient or parent/guardian.

Exclusion Criteria:

Pregnancy
Infection with mixed Plasmodium sp.
Signs of severe malaria or any danger signs
Refusal to provide consent

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Tropical Medicine Research Institute	Khartoum		Sudan	11111

Sponsors and Collaborators

Tropical Medicine Research Institute
London School of Hygiene and Tropical Medicine
World Health Organization
International Atomic Energy Agency

Investigators

Principal Investigator: Colin Sutherland, PhD., London School of Hygiene and Tropical Medicine
Study Chair: Badria B El-Sayed, PhD, Tropical Medicine Research Institute