Evaluation of Alternative Antimalarial Drugs for Malaria in Pregnancy

Study Overview
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Brief Summary
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The study aims at comparing the safety, tolerability and efficacy of Mefloquine (MQ) to Sulfadoxine-Pyrimethamine (SP) as Interment Preventive Treatment in pregnancy (IPTp) for the prevention of malaria effects on the mother and her infant.

Detailed Description
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The current recommendation by the World Health Organization (WHO) to prevent malaria infection in pregnancy in areas of stable malaria transmission relies on: Prompt and effective case management of malaria illness The use of intermittent preventive treatment (IPTp) with at least 2 treatment doses of sulfadoxine-pyrimethamine (SP) and The use of insecticide treated nets (ITNs) However, the spread of parasite resistance to SP, particularly in eastern Africa, and the significant overlap in some regions of malaria transmission and high prevalence of HIV infection, have raised concerns about the medium and long-term use of SP for IPTp. HIV infection increases susceptibility to malaria and may reduce the efficacy of interventions. The evaluation of alternative antimalarials for IPTp is thus urgently needed also involving HIV infected women. Of all the current available alternative antimalarial drugs, mefloquine (MQ) is the one that offers the most comparative advantages to SP. A randomized multicenter trial will be conducted in 4 sites in Africa (Benin, Gabon, Tanzania and Mozambique) in order to compare the safety and efficacy of SP versus MQ as IPTp in the context of ITNs. In addition, MQ tolerability will be also evaluated by comparing the administration of MQ as a single intake with its administration as split dose in two days. In total 4716 pregnant women will be enrolled at the antenatal clinic (ANC) and will be followed until the infant is one year old. Besides, in those countries where HIV prevalence in pregnant women is > 10%, MQ-IPTp will be compared to Placebo-IPTp in HIV infected pregnant women receiving cotrimoxazole (CTX) prophylaxis. This trial will be double blinded and will be carried out in Kenya, Tanzania and Mozambique. It will involve 1070 pregnant women that will be followed until the infant is 2 months old.

Official Title
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Evaluation of the Safety and Efficacy of Mefloquine as Intermittent Preventive Treatment of Malaria in Pregnancy

Conditions
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Pregnancy, Malaria, HIV Infections

Intervention / Treatment
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* Drug: Sulphadoxine-pyrimethamine
* Drug: Mefloquine (full dose)
* Drug: Mefloquine (split dose)
* Drug: placebo
* Drug: mefloquine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Trial 1: Permanent resident in the area Gestational age at the first antenatal visit ≤ 28 weeks Signed informed consent Agreement to deliver in the study site's maternity(ies) wards Trial 2: Permanent resident in the area. Gestational age at the first antenatal visit ≤ 28 weeks HIV seropositive (after voluntary counseling and testing) Indication to receive CTX prophylaxis (according to the national guidelines) Signed informed consent Agreement to deliver in the study site's maternity(ies) wards. Exclusion Criteria: Trial 1: Residence outside the study area or planning to move out in the following 18 months from enrollment Gestational age at the first antenatal visit > 28 weeks of pregnancy Known history of allergy to sulfa drugs or mefloquine Known history of severe renal, hepatic, psychiatric or neurological disease MQ or halofantrine treatment in the preceding 4 weeks HIV infection Participating in other studies Trial 2: Residence outside the study area or planning to move out in the following 10 months from enrollment Gestational age at the first antenatal visit > 28 weeks of pregnancy Known history of allergy to CTX or MQ Known history of severe renal, hepatic, psychiatric or neurological disease MQ or halofantrine treatment in the preceding 4 weeks
Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Trial 1: IPTp-SP+LLITNs<br>HIV-negative pregnant women receiving 2 doses of IPTp (500mg of sulfadoxine and 25 mg of pyrimethamine) in the context of long lasting Insecticide Treated Nets (LLITNs) | Drug: Sulphadoxine-pyrimethamine<br>* SP oral administration (500mg sulphadoxine and 25mg pyrimethamine) as IPTp at the 1st and 2nd Antenatal Clinic visit<br>|
| Experimental: Trial 1: IPTp-MQ (full dose) + LLITNs<br>HIV-negative pregnant women receiving 2 full doses of IPTp (15 mg/Kg) in the context of long lasting Insecticide Treated Nets (LLITNs) | Drug: Mefloquine (full dose)<br>* MQ oral administration (15 mg/Kg) on 1 day at the 1st and 2nd Antenatal Clinic visit as IPTp<br>|
| Experimental: Trial 1: IPTp-MQ (split dose)+LLITNs<br>HIV-negative pregnant women receiving 2 doses of MQ as IPTp split dose over 2 days (15mg/kg) in the context of long lasting Insecticide Treated Nets (LLITNs | Drug: Mefloquine (split dose)<br>* MQ oral administration (15 mg/kg) split dose over 2 days at the 1st and 2nd ANC visit as IPTp<br>|
| Experimental: Trial 2: CTX+IPTp-Placebo+LLITNs<br>HIV-positive pregnant women receiving 3 doses of IPTp (placebo) in the context of long lasting Insecticide Treated Nets (LLITNs) | Drug: placebo<br>* MQ-placebo oral administration at the 1st, 2nd and 3rd Antenatal Clinic visit as IPTp<br>|
| Experimental: Trial 2: CTX + IPTp-MQ+ LLITNs<br>HIV-positive pregnant women receiving 3 doses of IPTp (15 mg/Kg) in the context of long lasting Insecticide Treated Nets (LLITNs) | Drug: mefloquine<br>* MQ oral administration (15 mg/Kg) at the 1st and 2nd Antenatal Clinic visit as IPTp<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trial 1 (IPTp MQ vs IPTp SP): Low birth weight. |  | day 0, birth | 
| Trial 2 (CTX+IPTp MQ vs. CTX+IPTp placebo): Peripheral parasitaemia. |  | day 0, delivery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trial 1: Prevalence of placental P. falciparum infection. Prevalence of moderate maternal anaemia at delivery. |  | day 0, delivery | 
| Trial 2: Prevalence of placental P. falciparum infection. Prevalence of low birth weight babies (< 2500 g). |  | day 0, birth | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Malaria, Pregnancy, HIV, Prevention, Malaria prevention