Antimalarial Drug Resistance in Mali

NCT00127998 | Completed

• 1 other identifier: CDC-NCID-4314
• Study Type: interventional
• Target: 1,011
• Locations: 1 country
• Sites: 3

Brief Summary

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:

1. 1.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.
2. 2.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
3. 3.Measure drug levels at 3 days and correlate with efficacy results.
4. 4.Examine early clinical, parasitologic, and clinical predictors of late treatment failure.
5. 5.Use the knowledge gained in Aims 1-3 to develop a molecular tool for a countrywide resistance surveillance system for antimalarial drugs.

Conditions

Malaria

Keywords

malaria; Plasmodium falciparum; drug resistance; antimalarials; genotype; treatment outcome

Outcome Measures

Primary Outcomes (8)

• 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 Outcomes (2)

• 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

Interventions

chloroquine DRUG

sulfadoxine-pyrimethamine DRUG

amodiaquine DRUG

amodiaquine+artesunate DRUG

amodiaquine+sulfadoxine-pyrimethamine DRUG

sulfadoxine-pyrimethamine+artesunate DRUG

artemether-lumefantrine DRUG

mefloquine DRUG

Eligibility Criteria

• Age: 6 Months - 59 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Centers for Disease Control and Prevention: lead
• Malaria Research and Training Center, Bamako, Mali: collaborator

Study Sites (3)

Faladje Missionary Dispensary

Faladié, Mali

Location

Koro Health Center

Koro, Mali

Location

Pongono Community Health Center

Pongono, Mali

Location

Related Publications (5)

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

  BACKGROUND

• Plowe CV. Monitoring antimalarial drug resistance: making the most of the tools at hand. J Exp Biol. 2003 Nov;206(Pt 21):3745-52. doi: 10.1242/jeb.00658.

  PMID: 14506209 BACKGROUND

• 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. doi: 10.1097/00001432-200312000-00007.

  PMID: 14624105 BACKGROUND

• Djimde 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. doi: 10.1016/S0140-6736(01)06040-8. No abstract available.

  PMID: 11567708 BACKGROUND

• Djimde A, Doumbo OK, Cortese JF, Kayentao K, Doumbo S, Diourte 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. doi: 10.1056/NEJM200101253440403.

  PMID: 11172152 BACKGROUND

MeSH Terms

Conditions

Malaria; Malaria, Falciparum

Interventions

Chloroquine; fanasil, pyrimethamine drug combination; Amodiaquine; amodiaquine, artesunate drug combination; sulfadoxine-pyrimethamine-artesunate; Artemether, Lumefantrine Drug Combination; Mefloquine

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Intervention Hierarchy (Ancestors)

Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Artemether; Artemisinins; Reactive Oxygen Species; Free Radicals; Inorganic Chemicals; Organic Chemicals; Lumefantrine; Fluorenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sesquiterpenes; Terpenes; Polycyclic Compounds; Drug Combinations; Pharmaceutical Preparations

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: FED

Study Record Dates

• First Submitted: July 7, 2005
• First Posted: August 9, 2005
• Study Start: July 1, 2005
• Last Updated: August 16, 2006

Record last verified: 2006-08

Locations

MA (3)