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Efficacy of Antifolates Against Malaria in HIV-infected Pregnant Women and the Emergence of Induced Resistance in Plasmodium Falciparum (MACOMBA)

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ClinicalTrials.gov Identifier: NCT01746199
Recruitment Status : Unknown
Verified December 2012 by Institut Pasteur.
Recruitment status was:  Not yet recruiting
First Posted : December 10, 2012
Last Update Posted : November 15, 2013
Sponsor:
Collaborator:
Institut Pasteur de Bangui
Information provided by (Responsible Party):
Institut Pasteur

Tracking Information
First Submitted Date  ICMJE November 30, 2012
First Posted Date  ICMJE December 10, 2012
Last Update Posted Date November 15, 2013
Study Start Date  ICMJE December 2013
Estimated Primary Completion Date October 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 6, 2012)
placental parasitaemia [ Time Frame: at parturition ]
microscopic observation and confirmation by Polymerase Chain Reaction (PCR)
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 6, 2012)
  • observance CTM prophylaxis [ Time Frame: until the end of pregnancy ]
  • occurrence of specific events related to the effectiveness of CTM prophylaxis and IPT-SP [ Time Frame: until the end of pregnancy ]
    considered events :
    • maternal anemia (hemoglobinemia < 10g/dl)
    • incidence of malaria episodes during pregnancy
    • abortions, stillbirth, premature (birth <37 weeks of amenorrhea) and low birth weight (< 2500g)
    • placenta malaria and umbilical malaria transmission
  • occurence of adverse events [ Time Frame: until the end of pregnancy ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy of Antifolates Against Malaria in HIV-infected Pregnant Women and the Emergence of Induced Resistance in Plasmodium Falciparum
Official Title  ICMJE Comparative Study of Efficacy of Two Antifolates Prophylactic Strategies Against Malaria in HIV Positive Pregnant Women (MACOMBA Study)
Brief Summary

Given the resistance emergence of malaria in pregnant women receiving intermittent preventive treatment with sulfadoxine-pyrimethamine (IPT-SP) and the burden of this infection among pregnant women infected by HIV it is urgent to seek a more effective alternative treatment to optimize the prevention of malaria. Cotrimoxazole (CTM), actually administered daily as a prophylactic mean to opportunistic infections for HIV infected patients, showed encouraging results in preventing malaria in pregnant women. However, these results must be confirmed by randomized trials, particularly in pregnant women.

The main objective of this clinical trial is to compare the efficacy of cotrimoxazole (CTM), administered once daily with IPT-SP (3 curative doses spaced one month) on placental parasitaemia in pregnant women infected with HIV and cluster of differentiation 4 (CD4) > 350 cells/mm3.

The main hypothesis is based on the premise that cotrimoxazole is more effective than IPT-SP for placental parasitaemia. This might be due to the higher plasma concentration of cotrimoxazole attained with daily doses. If this hypothesis is proven, cotrimoxazole could be recommended as prophylaxis for HIV-positive pregnant women, whatever their CD4+ cell count. In this study, the investigators will also test the hypothesis that the strains of Plasmodium falciparum isolated from HIV-positive pregnant women express more dhfr and dhps resistance markers.

Detailed Description

Ascertainment of HIV serological status has become a prerequisite for better prevention of malaria. Studies reported that cotrimoxazole reduces malaria episodes in adults (other than pregnant women), and in children. Furthermore, several studies showed a good clinical and parasitological response to cotrimoxazole in treated children. Therefore, preventive treatment with SP for all HIV+ patients (including pregnant women) who are receiving treatment containing cotrimoxazole is superfluous and is even contraindicated because of the increase risk of severe adverse reactions. Few studies, however, have described the efficacy of cotrimoxazole in the prevention of malaria in pregnant women, particularly in an area where the frequency of therapeutic failures with SP in cases of Plasmodium falciparum malaria is increasing.

The emergence and augmentation of the frequency of resistance of Plasmodium falciparum to SP, which has already been observed in numerous countries of sub-Saharan Africa and in the Central African Republic, challenges the short-term usefulness of this drug combination in the prevention of malaria in pregnant women. The resistance is due to accumulation of point mutations at various sites on the genes coding for dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps). The number of mutations correlates with the extent of resistance of Plasmodium falciparum to SP in vitro. In studies carried out in Bangui, the prevalence of therapeutic failure was estimated to be 23.8% after 14 days of follow-up among children with uncomplicated malaria, while the resistance of Plasmodium falciparum to pyrimethamine in vitro was reported to be 38.3%. The frequency of mutations in dhfr and dhps alleles is correlated with in vitro response of Plasmodium falciparum strains to SP.

Pregnancy and HIV infection increase the risk for emergence of mutated strains that are resistant to SP, because a wide variety of types and clones are found in parasitaemia in pregnant women (genetic diversity). Furthermore, some studies raised concern about the possible development of cross-resistance of Plasmodium falciparum to both cotrimoxazole and SP because of the similarity of their mode of action, although this hypothesis has not been proven.

The national malaria programme in the Central African Republic recommends the use of IPT-SP since 2006.

The investigators' main hypothesis is based on the premise that cotrimoxazole is more effective than SP for placental parasitaemia. This might be due to the higher plasma concentration of cotrimoxazole attained with daily doses. If this hypothesis is proven, cotrimoxazole could be recommended as prophylaxis for HIV+ pregnant women, whatever their CD4+ cell count. In this study, the investigators will also test the hypothesis that the strains of Plasmodium falciparum isolated from HIV+ positive pregnant women express more dhfr and dhps resistance markers.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE
  • Malaria in Pregnancy
  • HIV Infection
Intervention  ICMJE
  • Drug: cotrimoxazole daily prophylaxis
    Other Names:
    • - CTM
    • - Sulfamethoxazole- trimethoprime
    • - Bactrim®
  • Drug: sulphadoxine-pyrimethamine
    Intermittent preventive sulphadoxine-pyrimethamine treatment
    Other Names:
    • - SP
    • - sulfadoxine-pyrimethamine
    • - Fansidar®
Study Arms  ICMJE
  • Experimental: cotrimoxazole daily prophylaxis
    cotrimoxazole daily prophylaxis
    Intervention: Drug: cotrimoxazole daily prophylaxis
  • Active Comparator: Intermittent Preventive sulphadoxine-pyrimethamine Treatment
    Referent treatment given according WHO recommendations
    Intervention: Drug: sulphadoxine-pyrimethamine
Publications * Manirakiza A, Sepou A, Serdouma E, Gondje S, Bata GG, Moussa S, Boulay A, Moyen JM, Sakanga O, Le-Fouler L, Kazanji M, Vray M. Effectiveness of two antifolate prophylactic strategies against malaria in HIV-positive pregnant women in Bangui, Central African Republic: study protocol for a randomized controlled trial (MACOMBA). Trials. 2013 Aug 14;14:255. doi: 10.1186/1745-6215-14-255.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Unknown status
Estimated Enrollment  ICMJE
 (submitted: December 6, 2012)
300
Original Estimated Enrollment  ICMJE Same as current
Study Completion Date  ICMJE Not Provided
Estimated Primary Completion Date October 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • age ≥ 18 years
  • HIV positivity
  • gestational age between 16 and 28 weeks
  • CD4+ count > 350 cells/mm3 and no sign of WHO stage 2, 3 or 4;
  • agreement to attend all the antenatal consultations for the study
  • willingness to adhere to all requirements of the study (including HIV-1 voluntary counseling and testing)
  • signed informed consent

Exclusion Criteria:

  • psychological instability that could interfere with compliance;
  • hypersensitivity to sulfamides or dermatological disease(eczema, pemphigoid exanthema) that would increase the risk for severe reactions to the drugs being tested
  • severe anaemia (Hb<7 g/dl)and any other severe disease
  • known hepatic cardiac or renal disease
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Central African Republic
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01746199
Other Study ID Numbers  ICMJE 2012-03
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Institut Pasteur
Study Sponsor  ICMJE Institut Pasteur
Collaborators  ICMJE Institut Pasteur de Bangui
Investigators  ICMJE
Study Director: Muriel Vray Unité d'épidémiologie des maladies émergentes, Institut Pasteur Paris, France
Principal Investigator: Alexandre Manirakiza, MD Unité d'Epidémiologie, Institut Pasteur de Bangui, Central African Republic
Study Chair: Mirdad Kazanji Director of the Institut Pasteur de Bangui, Central African Republic
PRS Account Institut Pasteur
Verification Date December 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP