Malaria in PregnancyPhase 3MACOMBANCT01746199
Efficacy of Antifolates Against Malaria in HIV-infected Pregnant Women and the Emergence of Induced Resistance in Plasmodium Falciparum
A Phase 3 study testing cotrimoxazole daily prophylaxis and sulphadoxine-pyrimethamine in people with Malaria in Pregnancy and HIV Infection, run by Institut Pasteur at 4 sites in Central African Republic.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Malaria in Pregnancy, HIV Infection
- What is being tested?
- cotrimoxazole daily prophylaxis and sulphadoxine-pyrimethamine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 193 participants
- Where
- 4 sitesCentral African Republic
- Study dates
- Dec 2013to Dec 2019
- Phase
- Phase 3
- 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 18 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
4 sites in 1 country.
Central African Republic4 sites
Maternité de l'Hôpital communautaire
Bangui
Maternité de l'Hôpital de l'Amitié
Bangui
Maternité de la Gendarmerie Nationale
Bangui
Maternité du centre de santé des Castors
Bangui
About this study
Official title: Comparative Study of Efficacy of Two Antifolates Prophylactic Strategies Against Malaria in HIV Positive Pregnant Women (MACOMBA Study)
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.
Read the 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.
- Conditions
- Malaria in Pregnancy, HIV Infection
- Being tested
- cotrimoxazole daily prophylaxis, sulphadoxine-pyrimethamine
- Medical subject headings
- HIV Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
cotrimoxazole daily prophylaxisDrug
Also called - CTM, - Sulfamethoxazole- trimethoprime, - Bactrim®
sulphadoxine-pyrimethamineDrug
Also called - SP, - sulfadoxine-pyrimethamine, - Fansidar®
Intermittent preventive sulphadoxine-pyrimethamine treatment
| Study group | Role | What they receive |
|---|---|---|
| cotrimoxazole daily prophylaxis | Experimental | cotrimoxazole daily prophylaxis Receives: Drug: cotrimoxazole daily prophylaxis |
| Intermittent Preventive sulphadoxine-pyrimethamine Treatment | Active comparator | Referent treatment given according WHO recommendations Receives: Drug: sulphadoxine-pyrimethamine |
What is being measured
The primary outcome is the main question the study is designed to answer.
placental parasitaemia
microscopic observation and confirmation by Polymerase Chain Reaction (PCR)
Measured: at parturition
Secondary outcomes (3)
observance CTM prophylaxis
Measured: until the end of pregnancy
occurrence of specific events related to the effectiveness of CTM prophylaxis and IPT-SP
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
Measured: until the end of pregnancy
occurence of adverse events
Measured: until the end of pregnancy
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Dec 2012 (estimated)
- Study startDec 2013
- Primary completionOct 2015
- Study completionDec 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Malaria in PregnancyStudies of the same condition, open and under way.
- More trials run by Institut PasteurThe sponsor's other registered studies.
- 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
- Interventional
- Phase
- Phase 3
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 193 participants (actual)
Sponsor and investigators
- Lead sponsor
- Institut Pasteur
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Institut Pasteur de Bangui
- Responsible party
- Sponsor
- Investigators
- Muriel Vray, Study director, Unité d'épidémiologie des maladies émergentes, Institut Pasteur Paris, FranceAlexandre Manirakiza, MD, Principal investigator, Unité d'Epidémiologie, Institut Pasteur de Bangui, Central African RepublicMirdad Kazanji, Study chair, Director of the Institut Pasteur de Bangui, Central African Republic
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01746199
- Sponsor's protocol ID
- 2012-03
- Acronym
- MACOMBA
- Status last verified
- Nov 2020
- First submitted
- 30 Nov 2012
- Last updated
- 30 Nov 2020
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Pons-Duran C, Wassenaar MJ, Yovo KE, Marin-Carballo C, Briand V, Gonzalez R. Intermittent preventive treatment regimens for malaria in HIV-positive pregnant women. Cochrane Database Syst Rev. 2024 Sep 26;9(9):CD006689. doi: 10.1002/14651858.CD006689.pub3.
PubMed 39324693Manirakiza 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.
PubMed 23945130
Study at a glance
From the registry record, last updated by the sponsor on 30 Nov 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Comparative Study of Efficacy of Two Antifolates Prophylactic Strategies Against Malaria in HIV Positive Pregnant Women (MACOMBA Study)
- ClinicalTrials.gov ID
- NCT01746199
- Acronym / sponsor ID
- MACOMBA / 2012-03
- Conditions
- Malaria in Pregnancy, HIV Infection
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 193 participants (actual)
- Lead sponsor
- Institut PasteurIndustry (pharma, biotech, devices)
- Collaborators
- Institut Pasteur de Bangui
- Study start
- Dec 2013 (actual)
- Primary completion
- Oct 2015 (actual)
- Study completion
- Dec 2019 (actual)
- First posted
- 10 Dec 2012 (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.
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 design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| cotrimoxazole daily prophylaxis | Experimental | Drug: cotrimoxazole daily prophylaxiscotrimoxazole daily prophylaxis |
| Intermittent Preventive sulphadoxine-pyrimethamine Treatment | Active comparator | Drug: sulphadoxine-pyrimethamineReferent treatment given according WHO recommendations |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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
Key exclusion criteria (4 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| cotrimoxazole daily prophylaxisAlso: - CTM, - Sulfamethoxazole- trimethoprime, - Bactrim® | Drug | cotrimoxazole daily prophylaxis |
| sulphadoxine-pyrimethamineAlso: - SP, - sulfadoxine-pyrimethamine, - Fansidar®Intermittent preventive sulphadoxine-pyrimethamine treatment | Drug | Intermittent Preventive sulphadoxine-pyrimethamine Treatment |
Primary outcome
placental parasitaemia
Time frame: at parturition
microscopic observation and confirmation by Polymerase Chain Reaction (PCR)
3 secondary outcomes
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
occurence of adverse events
Time frame: until the end of pregnancy
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 30 Nov 2020.
- Derived from this study: PubMed 39324693Pons-Duran C, Wassenaar MJ, Yovo KE, Marin-Carballo C, Briand V, Gonzalez R. Intermittent preventive treatment regimens for malaria in HIV-positive pregnant women. Cochrane Database Syst Rev. 2024 Sep 26;9(9):CD006689. doi: 10.1002/14651858.CD006689.pub3.
- Derived from this study: PubMed 23945130Manirakiza 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.
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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.
Muriel Vray study director
Unité d'épidémiologie des maladies émergentes, Institut Pasteur Paris, France
Alexandre Manirakiza, MD principal investigator
Unité d'Epidémiologie, Institut Pasteur de Bangui, Central African Republic
Mirdad Kazanji study chair
Director of the Institut Pasteur de Bangui, Central African Republic
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing cotrimoxazole daily prophylaxis and sulphadoxine-pyrimethamine in people with Malaria in Pregnancy and HIV Infection, run by Institut Pasteur at 4 sites in Central African Republic.
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 7 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 30 Nov 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in Central African Republic. 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.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
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?
placental parasitaemia (time frame: at parturition). 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 NCT01746199, which also lists 2 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 30 Nov 2020.