Clinical trial NCT00440752: The Impact of Artemether-Lumefantrine on Genes Associated With Antimalarial Resistance
Official title: The Impact of Artemether-Lumefantrine on Genes Associated With Antimalarial Resistance in an Area of Seasonal Transmission
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Falciparum Malaria
Antimalarials
Keywords: Artemether-lumefantrine
Plasmodium falciparum
drug resistance genes
Lead sponsor: Tropical Medicine Research Institute
Sponsor class: OTHER
Collaborators: name: London School of Hygiene and Tropical Medicine
name: World Health Organization
name: International Atomic Energy Agency
First posted: 2007-02-27
Enrollment: 100
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Levels of expression of pfcrt and pfmdr-1 alleles on day 0, 3, 7, 14, 21, 28 detected by real-time PCR.
timeFrame: 2007 to 2009
Secondary outcomes:
measure: Parasitological failure occurring at day 3, 7, 14, 21, 28 or any other day during this period.
timeFrame: within 28 days of subject recruitment
measure: Gametocyte development detected by reverse transcriptase PCR on day 0, 3, 14 and 28
timeFrame: 2008 to 2009
Other outcomes:
Locations:
city: Khartoum
country: Sudan
facility: Tropical Medicine Research Institute
Study officials:
affiliation: London School of Hygiene and Tropical Medicine
name: Colin Sutherland, PhD.
role: PRINCIPAL_INVESTIGATOR
affiliation: Tropical Medicine Research Institute
name: Badria B El-Sayed, PhD
role: STUDY_CHAIR
References:
citation: Dokomajilar C, Nsobya SL, Greenhouse B, Rosenthal PJ, Dorsey G. Selection of Plasmodium falciparum pfmdr1 alleles following therapy with artemether-lumefantrine in an area of Uganda where malaria is highly endemic. Antimicrob Agents Chemother. 2006 May;50(5):1893-5. doi: 10.1128/AAC.50.5.1893-1895.2006.
citation: Humphreys GS, Merinopoulos I, Ahmed J, Whitty CJ, Mutabingwa TK, Sutherland CJ, Hallett RL. Amodiaquine and artemether-lumefantrine select distinct alleles of the Plasmodium falciparum mdr1 gene in Tanzanian children treated for uncomplicated malaria. Antimicrob Agents Chemother. 2007 Mar;51(3):991-7. doi: 10.1128/AAC.00875-06. Epub 2006 Dec 28.
citation: Sisowath C, Stromberg J, Martensson A, Msellem M, Obondo C, Bjorkman A, Gil JP. In vivo selection of Plasmodium falciparum pfmdr1 86N coding alleles by artemether-lumefantrine (Coartem). J Infect Dis. 2005 Mar 15;191(6):1014-7. doi: 10.1086/427997. Epub 2005 Feb 8.