Antimalarial Drug Resistance in Mali - Full Text View

Purpose

Resistance of Plasmodium falciparum (malaria) to current antimalarial drugs and the continuing development of resistance to new antimalarial formulations is one of the major obstacles to effective malaria control and case management. Efficient, comprehensive and validated methods for monitoring drug resistance in advance of the development of resistance to the antimalarial drugs that are in use are urgently needed. Molecular markers of genetic polymorphisms that give rise to resistant P. falciparum parasites and methods in population genetics for evaluating the data can be valuable tools for monitoring drug resistance in the field. This study aims to:

Prospectively measure the in vivo response of P. falciparum malaria in Mali to several different antimalarial drugs and drug combinations: chloroquine (CQ), sulfadoxine-pyrimethamine (SP), amodiaquine (AQ), sulfadoxine-pyrimethamine in combination with amodiaquine (SP/AQ), amodiaquine in combination with artesunate (AQ/AS), sulfadoxine-pyrimethamine in combination with artesunate (SP/AS), and artemether-lumefantrine (Co-artem). In one site with preliminary data showing a high rate of P. falciparum resistance to mefloquine (MQ), this drug will also be tested.
Measure the frequencies of molecular markers for antimalarial drug resistance, and examine how those results relate to the efficacy of these drugs in treating clinical malaria
Measure drug levels at 3 days and correlate with efficacy results.
Examine early clinical, parasitologic, and clinical predictors of late treatment failure.
Use the knowledge gained in Aims 1-3 to develop a molecular tool for a countrywide resistance surveillance system for antimalarial drugs.

Condition	Intervention
Malaria	Drug: chloroquine Drug: sulfadoxine-pyrimethamine Drug: amodiaquine Drug: amodiaquine+artesunate Drug: amodiaquine+sulfadoxine-pyrimethamine Drug: sulfadoxine-pyrimethamine+artesunate Drug: artemether-lumefantrine Drug: mefloquine


Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Characterization of Novel Molecular Tools for the Epidemiological Surveillance of Antimalarial Drug Resistance in Mali

Resource links provided by NLM:

MedlinePlus related topics: Malaria

Drug Information available for: Pyrimethamine

Genetic and Rare Diseases Information Center resources: Malaria

U.S. FDA Resources

Further study details as provided by Centers for Disease Control and Prevention:

Primary Outcome Measures:

Early Treatment Failure (ETF, defined as: Development of danger signs or severe malaria on Day 1, 2, or 3, in the presence of parasitemia
Parasitemia on Day 2 higher than Day 0 count irrespective of axillary temperature
Parasitemia on Day 3 with axillary temperature ≥37.5°C
Parasitemia on Day 3 ≥ 25% of count on Day 0
Late Clinical Failure (LCF), defined as: Development of danger signs or severe malaria from Day 4 to Day 28 in the presence of parasitemia, without previously meeting any of the criteria of ETF
Presence of parasitemia and axillary temperature ≥37.5° C on any day from Day 4 to Day 28, without previously meeting any of the criteria of ETF
Late parasitological failure (LPF), defined as: Presence of parasitemia on Day 14 to Day 28 and axillary temperature <37.5°C without previously meeting any of the criteria of ETF or LCF
Adequate Clinical and Parasitological Response (ACPR), defined as: Absence of parasitemia on Day 28 irrespective of axillary temperature, without previously meeting any of the criteria of ETF, LCF or LPF

Secondary Outcome Measures:

Frequencies of dhfr, dhps, pfcrt and pfmdr1 P. falciparum genotypes and relationship with in vivo resistance to SP (dhfr and dhps), CQ, AQ, SP/AQ, AQ/AS, SP/AS, and MQ
Drug levels at 3 days and correlation with in vivo efficacy results


Estimated Enrollment:	1011
Study Start Date:	July 2005

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Eligibility


Ages Eligible for Study:	6 Months to 59 Months
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Aged 6-59 months
Absence of severe malnutrition (defined as a child whose weight-for-height is below 3 standard deviations of less than 70% of the median of World Health Organization (WHO) reference values, or who has symmetrical edema involving at least the feet)
A slide-confirmed infection with P. falciparum only (i.e. no mixed infections)
Initial parasite density between 2,000 and 200,000 asexual parasites per microliter.
Absence of general danger signs among children < 5 years (inability to drink or breastfeed; vomiting everything; recent history of convulsions; lethargy or unconsciousness; inability to sit or stand up) or other signs of severe and complicated falciparum malaria according to WHO definitions
Measured axillary temperature ≥ 37.5 °C
Ability to attend stipulated follow-up visits
Informed consent provided by parent/guardian
Absence of history of hypersensitivity reactions to any of the drugs being evaluated

Exclusion Criteria:

Aged < 6 or >59 months
Severe malnutrition (defined as a child whose weight-for-height is below 3 standard deviations of less than 70% of the median of WHO reference values, or who has symmetrical edema involving at least the feet)
No slide confirmed infection with P. falciparum or a mixed infection that includes a non P. falciparum species
Initial parasite density < 2,000 or > 200,000 asexual parasites per microliter.
Presence of general danger signs among children < 5 years (inability to drink or breastfeed; vomiting everything; recent history of convulsions; lethargy or unconsciousness; inability to sit or stand up) or other signs of severe and complicated falciparum malaria according to WHO definitions
Measured axillary temperature <37.5 °C
Inability to attend stipulated follow-up visits
Unwilling to provide informed consent provided by parent/guardian
History of hypersensitivity reactions to any of the drugs being evaluated

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00127998

Locations


Mali
Faladje Missionary Dispensary
Faladje, Mali
Koro Health Center
Koro, Mali
Pongono Community Health Center
Pongono, Mali

Sponsors and Collaborators

Centers for Disease Control and Prevention

Malaria Research and Training Center, Bamako, Mali

Investigators


Principal Investigator:	Robert D. Newman, MD, MPH	Centers for Disease Control and Prevention
Principal Investigator:	Kassoum Kayentao, MD, MSPH	Malaria Research and Training Center, Bamako, Mali
Principal Investigator:	John Barnwell, PhD, MPH	Centers for Disease Control and Prevention
Principal Investigator:	Ogobara Doumbo, MD, PhD	Malaria Research and Training Center, Bamako, Mali

More Information

Publications:

WHO. Assessment and Monitoring of Antimalarial Drug Efficacy for the Treatment of Uncomplicated Falciparum Malaria. Geneva: World Health Organization, 2003

Plowe CV. Monitoring antimalarial drug resistance: making the most of the tools at hand. J Exp Biol. 2003 Nov;206(Pt 21):3745-52. Review.

Wernsdorfer WH, Noedl H. Molecular markers for drug resistance in malaria: use in treatment, diagnosis and epidemiology. Curr Opin Infect Dis. 2003 Dec;16(6):553-8. Review.

Djimdé A, Doumbo OK, Steketee RW, Plowe CV. Application of a molecular marker for surveillance of chloroquine-resistant falciparum malaria. Lancet. 2001 Sep 15;358(9285):890-1.

Djimdé A, Doumbo OK, Cortese JF, Kayentao K, Doumbo S, Diourté Y, Coulibaly D, Dicko A, Su XZ, Nomura T, Fidock DA, Wellems TE, Plowe CV. A molecular marker for chloroquine-resistant falciparum malaria. N Engl J Med. 2001 Jan 25;344(4):257-63.


ClinicalTrials.gov Identifier:	NCT00127998 History of Changes
Other Study ID Numbers:	CDC-NCID-4314
Study First Received:	July 7, 2005
Last Updated:	August 15, 2006
Health Authority:	United States: Federal Government Mali: Ministry of Health

Keywords provided by Centers for Disease Control and Prevention:


malaria Plasmodium falciparum drug resistance	antimalarials genotype treatment outcome

Additional relevant MeSH terms:


Amodiaquine Antimalarials Artesunate Fanasil, pyrimethamine drug combination Pyrimethamine Sulfadoxine Amebicides Anti-Infective Agents Anti-Infective Agents, Urinary	Antiparasitic Agents Antiprotozoal Agents Enzyme Inhibitors Folic Acid Antagonists Molecular Mechanisms of Pharmacological Action Pharmacologic Actions Renal Agents Therapeutic Uses

ClinicalTrials.gov processed this record on March 03, 2015