Antibiotic Prophlaxis for High-risk Laboring Women in Low Income Countries

Study Overview
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Brief Summary
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This study, performed over a course of 3 years in 5 collaborating hospitals in Cameroon, Africa, will randomize 750 women in labor with prolonged rupture of membranes ≥ 8 hours or prolonged labor ≥ 18 hours to identical oral regimens of 1 gram of azithromycin, 1 gram of azithromycin+2 grams of amoxicillin or placebo. Women will be followed to ascertain maternal infectious outcomes and perinatal outcomes.

Detailed Description
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This 3-arm study is a large randomized clinical trial designed to evaluate the comparative effectiveness and safety of single dose oral azithromycin or combined azithromycin+amoxicillin compared to placebo for the prevention of peripartum infections and sepsis in laboring women. We have previously shown the effectiveness of azithromycin for extended spectrum antibiotic prophylaxis in addition to the standard cephalosporin alone for reduction of post-cesarean infections. In LICs, the fraction of maternal infection and sepsis from cesarean delivery is minimal. Therefore, it is necessary to evaluate strategies aimed at reducing these morbidities in women who have vaginal births. There is an increased risk of infection in women who have prolonged labor or prolonged rupture of membranes. Drawing from our findings with azithromycin-based extended antibiotic prophylaxis for cesarean delivery, we propose to adapt the intervention and evaluate a single oral dose of azithromycin (with or without oral amoxicillin) to prevent maternal peripartum infection and sepsis. This study, performed over a course of 3 years in 5 collaborating hospitals in Cameroon, Africa, will randomize 750 women in labor with prolonged rupture of membranes ≥ 8 hours or prolonged labor ≥18 hours to 1 gram of oral azithromycin, 1 gram of azithromycin+2 grams of amoxicillin, compared to usual care (placebo). Women will be followed to ascertain maternal infectious outcomes and perinatal outcomes.

Official Title
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Azithromycin With or Without Amoxicillin to Prevent Peripartum Infection and Sepsis in Laboring High-risk Women: 3-Arm RCT

Conditions
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Postpartum Sepsis, Postpartum Endometritis, Postpartum Fever

Intervention / Treatment
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* Drug: Azithromycin
* Drug: Azithromycin and amoxicillin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women ≥ 37 weeks' viable singleton or twin gestation in labor planning a vaginal delivery with Prolonged membrane rupture (≥8 hours) or Prolonged labor (≥18 hours). Exclusion Criteria: Clinical chorioamnionitis or any other active bacterial infection (e.g. pyelonephritis, pneumonia, abscess) at time of randomization: because standard antibiotic therapy for these conditions may confound trial intervention. Allergy to azithromycin or amoxicillin Plan for cesarean delivery prior to enrollment Fetal demise or major congenital anomaly: Major congenital anomalies may confound assessment of neonatal outcomes and every attempt will be made up front to exclude them from randomization. However, some unrecognized fetal anomalies may inevitably be randomized. These will not be excluded post-randomization from the primary (maternal outcome) analysis; they will be taken into consideration in the secondary analyses of neonatal outcomes.
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
Interventional Model Description: Randomized Controlled Trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Azithromycin and amoxicillin placebo<br>Patients in this arm will receive 1 gram oral azithromycin as a single dose and amoxicillin placebo. | Drug: Azithromycin<br>* Azithromycin tablet<br>Drug: Placebo<br>* Placebo tablet<br>|
| Experimental: Azithromycin + amoxicillin<br>Patients in this arm will receive 1 gram oral azithromycin and 2 grams oral amoxicillin in a single dose. | Drug: Azithromycin and amoxicillin<br>* azithromycin and amoxicillin<br>* Other names: azithromycin, amoxicillin;|
| Placebo Comparator: Usual Care<br>This arm will consist of routine care at the clinical sites (which is usually no antibiotic). They will receive placebo (for azithromycin) and placebo (for amoxicillin) | Drug: Placebo<br>* Placebo tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced Composite Peripartum Infection or Death | Maternal peripartum infection including chorioamnionitis, endometritis, wound infection/abscess, sepsis, and death | Up to 6 weeks after delivery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced Pyelonephritis | Other Infections | Up to hospital discharge | 
| Number of Participants Who Experienced Breast Infection | Other infections | Up to 6 weeks after delivery | 
| Number of Participants Who Experienced Other Infection | Includes Hepatitis B, thyroid infection, vaginal infection, viral infection, leg cellulitis, unknown abdominal infection,malaria | up to 6 weeks after delivery | 
| Number of Participants Who Experienced Fever | Any fever higher than 38C | up to 6 weeks after delivery | 
| Number of Participants Who Experienced Hypothermia | Any hypothermia less than 36C | up to 6 weeks after delivery | 
| Number of Participants Who Needed PP Antibiotic | Any postpartum antibiotic | up to 6 weeks after delivery | 
| Number of Participants Who Experienced Transfusion | Blood transfusion | up to 6 weeks after delivery | 
| Number of Participants Who Experienced Stillbirth | Any stillbirth | delivery | 
| Length of Stay | Length of stay in days | up to 6 weeks postpartum | 
| Number of Participants Who Experienced a Clinic Visit | Clinic visit after discharge | up to 6 weeks after delivery | 
| Number of Participants Who Experienced a Maternal Readmission | Maternal readmission | up to 6 weeks after delivery |