A Novel Regimen to Prevent Malaria and STI in Pregnant Women With HIV

Study Overview
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Brief Summary
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More than 3 billion people worldwide are at risk of acquiring malaria and pregnant women living with HIV in Africa are at particular risk. An effective prophylaxis regimen capable of preventing malaria and other common perinatal infections would have great potential to improve adverse birth outcomes. The purpose of this randomized controlled trial is to evaluate a new combination prophylaxis regimen in pregnant women with HIV in Cameroon to determine its efficacy and safety.

Detailed Description
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The World Health Organization (WHO) recommends malaria prophylaxis for all pregnant women living in endemic areas in order to reduce maternal anemia, low birth weight and perinatal mortality by 25-45%. The most commonly used regimen is intermittently dosed sulfadoxine-pyrimethamine (SP).Unfortunately, SP prophylaxis is contraindicated for HIV-infected pregnant women since co-administration with TMPS (trimethoprim-sulfamethoxazole) causes serious adverse events. TMPS (Bactrim or Cotrimoxazole) is an effective, well-tolerated, low-cost antibiotic that is used as prophylaxis in HIV-patients with low CD4 counts. It has anti-malarial activity with prophylactic efficacy that is comparable to SP (30-90%). Daily TMPS is recommended as malaria prophylaxis in pregnant women with HIV in many African countries (including Cameroon) but malaria infection rates are high even when medication compliance is excellent; thus, new and improved options are urgently needed. Azithromycin (AZ) is a macrolide antibiotic with activity against malaria, a good safety profile in pregnancy and proven utility as a part of combination malaria prevention regimens (such as SP-AZ). It also has activity against sexually transmitted infections (STI) and perinatal pathogens, including chlamydia (CT), gonorrhea (GC), syphilis and GBS (Streptococcus agalactiae or Group B Streptococcus), a potential but understudied contributor to high rates of newborn sepsis and death in Africa. SP-AZ prophylaxis in HIV-uninfected pregnant women has been reported to reduce prevalence of low birth weight (RR 0.74, 95% confidence interval (CI) 0.6-0.9) and preterm delivery (RR 0.66, 95% CI 0.48-0.91) compared to SP alone. Thus, the central hypothesis is that a TMPS-AZ combination will be more effective than standard TMPS malaria prophylaxis in pregnant women with HIV, and that it will also decrease STI coinfection. Investigators plan a test-of-concept of the central hypothesis by conducting a double blinded, Phase II randomized controlled trial (RCT).

Official Title
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The PREMISE Trial: A Novel Regimen to Prevent Malaria and Sexually Transmitted Infections in Pregnant Women With HIV

Conditions
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HIV, Pregnancy Malaria, Sexually Transmitted Infection

Intervention / Treatment
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* Drug: Azithromycin/TMPS
* Drug: Placebo/TMPS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed HIV-infection (documented in medical record) Age ≥16 years Confirmed pregnancy, <28 weeks estimated gestational age (by best obstetric estimate which may include ultrasound or fundal height and LMP) Live singleton pregnancy Receiving prenatal care at Mboppi Hospital or Mutengene Hospital Plan to receive follow up prenatal care and deliver at study facility Capable of providing written informed consent Able and agree to come to facility for febrile episodes or acute illness during pregnancy (with reimbursement of transportation costs). Agree to avoid antimalarial medications outside of study protocol. Exclusion Criteria: Severe anemia (last hemoglobin <6) History of severe adverse reaction to co-trimoxazole or azithromycin Active medical problem requiring inpatient evaluation at the time of screening Intention of moving far away from the facility during pregnancy or not likely to return for follow up care or delivery Signs or symptoms of early or active labor History of severe cardiac disease (including congestive heart failure, severe valvular disease or arrhythmias).

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Azithromycin/TMPS<br>Azithromycin 1 gm po daily x 3 days at enrollment and at each 4 week follow up visit. TMPS double strength 1 tablet po daily. | Drug: Azithromycin/TMPS<br>* 2 tabs po daily x 3 days at enrollment and at each monthly follow up visit<br>* Other names: Cotrimoxazole;|
| Placebo Comparator: Placebo/TMPS<br>Azithromycin placebo 1 gm po daily x 3 days at enrollment and at each 4 week follow up visit. TMPS double strength 1 tablet po daily. | Drug: Placebo/TMPS<br>* 2 tabs po daily x 3 days at enrollment and at each monthly follow up visit<br>* Other names: Co-Trimoxazole;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasmodium Falciparum Peripheral Parasitemia | P. falciparum detected by microscopy or polymerase chain reaction (PCR) | At end of pregnancy (>35 weeks) or at delivery | 
| Proportion With Composite STI Outcome | Including chlamydia (NAAT (nucleic acid amplification test) positive) , gonorrhea (NAAT positive), syphilis (non-treponemal and treponemal test positive) infections. | will be measured in both groups (>35 weeks) or at delivery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Low Birthweight (<2500 Grams) | Neonatal weight measured with digital scale | at birth | 
| Proportion With Adverse Birth Outcomes | Composite measure: low infant birthweight (<2500 grams), miscarriage (<28 weeks), preterm delivery (<37 weeks), small for gestational age (SGA), congenital anomaly detected on surface examination, early neonatal mortality (within 7 days of birth) | Birth outcomes will be measured at birth for all outcomes except early neonatal mortality defined as within 7 days of birth. Early neonatal mortality will be assessed at a six week follow up phone call. | 
| Maternal Adherence to the Prophylactic Regimen | Directly observed therapy (DOT) in clinic for the 1st dose of study medication. Self-report and pill count will be used to assess adherence and maternal tolerability for study medications taken at home from the time of enrollment until delivery. At each follow up visit and at delivery, participants will complete a medication adherence survey. They will self-report adherence to the 3 day study regimen (AZ or placebo). | Adherence of study medication taken at home will be documented from the date of randomization until the time of delivery, assessed up to 42 weeks. | 
| Proportion of Participants With Symptomatic Malaria | Fever and positive malaria test (rapid diagnostic test) at routine visits or sick call visits or maternal report of malaria diagnosis. | From the date of randomization until the time of delivery, assessed up to 42 weeks. | 
| Proportion With Placental Malaria | Placentas will be collected on a subset of women and impression smear will be used to assess for malaria infection | At delivery | 
| Proportion With Maternal Anemia and Severe Maternal Anemia | anemia defined as hemoglobin <11 g/dL, severe anemia defined as hemoglobin <7 g/dL. | At the end of pregnancy (>35 weeks) or at delivery | 
| Composite STI Measure (Including All STI Tests) | Proportion of women with GC/CT (by NAAT), syphilis (by serology), Mycoplasma genitalium (NAAT). | After 35 weeks GA or at delivery | 
| GBS Colonization | anogenital GBS colonization detected by NAAT (PCR) | at or near term or at delivery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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STI Prevention, Cameroon, sub-Saharan Africa, HIV pregnancy, Malaria in pregnancy