Falciparum MalariaNCT00440752
The Impact of Artemether-Lumefantrine on Genes Associated With Antimalarial Resistance
An observational study of Falciparum Malaria and Antimalarials, run by Tropical Medicine Research Institute at 1 site in Sudan.
Trial 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. Read more about this study
- Who is it for?
- Ages 2 years and olderHealthy volunteers can take part
- Conditions the study is for
- Falciparum Malaria, Antimalarials
- How many people
- 100 participants
- Where
- 1 siteSudan
- Study dates
- Oct 2006to Dec 2006
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 2 years and older
- All sexes
- Healthy volunteers accepted
- Child, Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- Pregnancy
- Infection with mixed Plasmodium sp.
- Signs of severe malaria or any danger signs
- Refusal to provide consent
Trial locations and contacts
1 site in 1 country.
Sudan1 site
Tropical Medicine Research Institute
Khartoum, Khartoum State, 11111
About this study
Official title: The Impact of Artemether-Lumefantrine on Genes Associated With Antimalarial Resistance in an Area of Seasonal Transmission
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.
Read the 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.
- Conditions
- Falciparum Malaria, Antimalarials
- Keywords
- Artemether-lumefantrine, Plasmodium falciparum, drug resistance genes
- Medical subject headings
- Malaria, Falciparum
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| AL | Cohort of study participants receiving treatment with artemether-lumefantrine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Levels of expression of pfcrt and pfmdr-1 alleles on day 0, 3, 7, 14, 21, 28 detected by real-time PCR.
Measured: 2007 to 2009
Secondary outcomes (2)
Parasitological failure occurring at day 3, 7, 14, 21, 28 or any other day during this period.
Measured: within 28 days of subject recruitment
Gametocyte development detected by reverse transcriptase PCR on day 0, 3, 14 and 28
Measured: 2008 to 2009
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Feb 2007 (estimated)
- Study startOct 2006
- Study completionDec 2006
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Falciparum MalariaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 100 participants (actual)
Sponsor and investigators
- Lead sponsor
- Tropical Medicine Research Institute
- Sponsor type
- University, hospital or other
- Collaborators
- London School of Hygiene and Tropical Medicine, World Health Organization, International Atomic Energy Agency
- Investigators
- Colin Sutherland, PhD., Principal investigator, London School of Hygiene and Tropical MedicineBadria B El-Sayed, PhD, Study chair, Tropical Medicine Research Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00440752
- Sponsor's protocol ID
- AL Oct-Dec/06-07
- Status last verified
- Oct 2007
- First submitted
- 26 Feb 2007
- Last updated
- 26 Mar 2008
- Results posted
- No
- Data monitoring committee
- No
Publications
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.
PubMed 16641472Humphreys 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.
PubMed 17194834Sisowath 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.
PubMed 15717281
Study at a glance
From the registry record, last updated by the sponsor on 26 Mar 2008. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Impact of Artemether-Lumefantrine on Genes Associated With Antimalarial Resistance in an Area of Seasonal Transmission
- ClinicalTrials.gov ID
- NCT00440752
- Acronym / sponsor ID
- AL Oct-Dec/06-07
- Conditions
- Falciparum Malaria, Antimalarials
- Keywords
- Artemether-lumefantrine, Plasmodium falciparum, drug resistance genes
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 100 participants (actual)
- Lead sponsor
- Tropical Medicine Research InstituteUniversity, hospital or other
- Collaborators
- London School of Hygiene and Tropical Medicine, World Health Organization, International Atomic Energy Agency
- Study start
- Oct 2006
- Study completion
- Dec 2006 (actual)
- First posted
- 27 Feb 2007 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| AL | – | –Cohort of study participants receiving treatment with artemether-lumefantrine |
Who may qualify
- Ages
- 2 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (4 listed)
- 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.
Key exclusion criteria (4 listed)
- Pregnancy
- Infection with mixed Plasmodium sp.
- Signs of severe malaria or any danger signs
- Refusal to provide consent
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
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
2 secondary outcomes
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
Gametocyte development detected by reverse transcriptase PCR on day 0, 3, 14 and 28
Time frame: 2008 to 2009
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Mar 2008.
- Background: PubMed 16641472Dokomajilar 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.
- Background: PubMed 17194834Humphreys 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.
- Background: PubMed 15717281Sisowath 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Colin Sutherland, PhD. principal investigator
London School of Hygiene and Tropical Medicine
Badria B El-Sayed, PhD study chair
Tropical Medicine Research Institute
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Falciparum Malaria and Antimalarials, run by Tropical Medicine Research Institute at 1 site in Sudan.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 26 Mar 2008. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Sudan. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00440752, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Mar 2008.