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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00440752
Recruitment Status : Completed
First Posted : February 27, 2007
Last Update Posted : March 26, 2008
London School of Hygiene and Tropical Medicine
World Health Organization
International Atomic Energy Agency
Information provided by:
Tropical Medicine Research Institute

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
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 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 : October 2006
Actual Study Completion Date : December 2006

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Cohort of study participants receiving treatment with artemether-lumefantrine

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

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

Biospecimen Retention:   Samples With DNA
Blood spots on glass fibre membranes. 0.5ml of whole blood preserved in TRI reagent.

Information from the National Library of Medicine

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Ages Eligible for Study:   2 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00440752

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

Publications: Identifier: NCT00440752     History of Changes
Other Study ID Numbers: AL Oct-Dec/06-07
First Posted: February 27, 2007    Key Record Dates
Last Update Posted: March 26, 2008
Last Verified: October 2007

Keywords provided by Tropical Medicine Research Institute:
Plasmodium falciparum
drug resistance genes

Additional relevant MeSH terms:
Malaria, Falciparum
Protozoan Infections
Parasitic Diseases
Artemether-lumefantrine combination
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Antifungal Agents
Antiplatyhelmintic Agents