Postpartum Endometritis, Postpartum Fever, Postpartum Sepsis
Conditions
Brief summary
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
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.
Interventions
DRUGAzithromycin
Azithromycin tablet
DRUGAzithromycin and amoxicillin
azithromycin and amoxicillin
DRUGPlacebo
Placebo tablet
Sponsors
Merck Sharp & Dohme LLC
University of Alabama at Birmingham
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Randomized Controlled Trial
Eligibility
Sex/Gender
FEMALE
Healthy volunteers
Yes
Inclusion criteria
* Women ≥ 37 weeks' viable singleton or twin gestation in labor planning a vaginal delivery with 1. Prolonged membrane rupture (≥8 hours) or 2. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced Composite Peripartum Infection or Death | Up to 6 weeks after delivery | Maternal peripartum infection including chorioamnionitis, endometritis, wound infection/abscess, sepsis, and death |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced Breast Infection | Up to 6 weeks after delivery | Other infections |
| Number of Participants Who Experienced Other Infection | up to 6 weeks after delivery | Includes Hepatitis B, thyroid infection, vaginal infection, viral infection, leg cellulitis, unknown abdominal infection,malaria |
| Number of Participants Who Experienced Fever | up to 6 weeks after delivery | Any fever higher than 38C |
| Number of Participants Who Experienced Hypothermia | up to 6 weeks after delivery | Any hypothermia less than 36C |
| Number of Participants Who Needed PP Antibiotic | up to 6 weeks after delivery | Any postpartum antibiotic |
| Number of Participants Who Experienced Pyelonephritis | Up to hospital discharge | Other Infections |
| Number of Participants Who Experienced Stillbirth | delivery | Any stillbirth |
| Length of Stay | up to 6 weeks postpartum | Length of stay in days |
| Number of Participants Who Experienced a Clinic Visit | up to 6 weeks after delivery | Clinic visit after discharge |
| Number of Participants Who Experienced a Maternal Readmission | up to 6 weeks after delivery | Maternal readmission |
| Number of Participants Who Experienced Transfusion | up to 6 weeks after delivery | Blood transfusion |
Countries
Cameroon
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Azithromycin and Amoxicillin Placebo Patients in this arm will receive 1 gram oral azithromycin as a single dose and amoxicillin placebo.
Azithromycin: Azithromycin tablet
Placebo: Placebo tablet | 253 |
| Azithromycin + Amoxicillin Patients in this arm will receive 1 gram oral azithromycin and 2 grams oral amoxicillin in a single dose.
Azithromycin and amoxicillin: azithromycin and amoxicillin | 253 |
| Usual Care 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)
Placebo: Placebo tablet | 250 |
| Total | 756 |
Baseline characteristics
| Characteristic | Azithromycin and Amoxicillin Placebo | Azithromycin + Amoxicillin | Usual Care | Total |
|---|---|---|---|---|
| Age, Customized | 27.2 years STANDARD_DEVIATION 5.3 | 26.4 years STANDARD_DEVIATION 5.6 | 26.0 years STANDARD_DEVIATION 5.3 | 26.5 years STANDARD_DEVIATION 5.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 253 Participants | 253 Participants | 250 Participants | 756 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Gestational age at Randomization | 39.4 Weeks STANDARD_DEVIATION 1.5 | 39.2 Weeks STANDARD_DEVIATION 1.4 | 39.2 Weeks STANDARD_DEVIATION 1.4 | 39.3 Weeks STANDARD_DEVIATION 1.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 253 Participants | 253 Participants | 250 Participants | 756 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 253 Participants | 253 Participants | 250 Participants | 756 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 253 | 0 / 253 | 0 / 250 |
| other Total, other adverse events | 0 / 253 | 0 / 253 | 0 / 250 |
| serious Total, serious adverse events | 0 / 253 | 0 / 253 | 0 / 250 |
Outcome results
Primary
Number of Participants Who Experienced Composite Peripartum Infection or Death
Maternal peripartum infection including chorioamnionitis, endometritis, wound infection/abscess, sepsis, and death
Time frame: Up to 6 weeks after delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azithromycin and Amoxicillin Placebo | Number of Participants Who Experienced Composite Peripartum Infection or Death | 15 Participants |
| Azithromycin + Amoxicillin | Number of Participants Who Experienced Composite Peripartum Infection or Death | 17 Participants |
| Usual Care | Number of Participants Who Experienced Composite Peripartum Infection or Death | 24 Participants |
Secondary
Length of Stay
Length of stay in days
Time frame: up to 6 weeks postpartum
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Azithromycin and Amoxicillin Placebo | Length of Stay | 3.7 days | Standard Deviation 2 |
| Azithromycin + Amoxicillin | Length of Stay | 3.7 days | Standard Deviation 2.2 |
| Usual Care | Length of Stay | 3.8 days | Standard Deviation 3.1 |
Secondary
Number of Participants Who Experienced a Clinic Visit
Clinic visit after discharge
Time frame: up to 6 weeks after delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azithromycin and Amoxicillin Placebo | Number of Participants Who Experienced a Clinic Visit | 13 Participants |
| Azithromycin + Amoxicillin | Number of Participants Who Experienced a Clinic Visit | 7 Participants |
| Usual Care | Number of Participants Who Experienced a Clinic Visit | 10 Participants |
Secondary
Number of Participants Who Experienced a Maternal Readmission
Maternal readmission
Time frame: up to 6 weeks after delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azithromycin and Amoxicillin Placebo | Number of Participants Who Experienced a Maternal Readmission | 11 Participants |
| Azithromycin + Amoxicillin | Number of Participants Who Experienced a Maternal Readmission | 4 Participants |
| Usual Care | Number of Participants Who Experienced a Maternal Readmission | 5 Participants |
Secondary
Number of Participants Who Experienced Breast Infection
Other infections
Time frame: Up to 6 weeks after delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azithromycin and Amoxicillin Placebo | Number of Participants Who Experienced Breast Infection | 2 Participants |
| Azithromycin + Amoxicillin | Number of Participants Who Experienced Breast Infection | 0 Participants |
| Usual Care | Number of Participants Who Experienced Breast Infection | 0 Participants |
Secondary
Number of Participants Who Experienced Fever
Any fever higher than 38C
Time frame: up to 6 weeks after delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azithromycin and Amoxicillin Placebo | Number of Participants Who Experienced Fever | 22 Participants |
| Azithromycin + Amoxicillin | Number of Participants Who Experienced Fever | 21 Participants |
| Usual Care | Number of Participants Who Experienced Fever | 28 Participants |
Secondary
Number of Participants Who Experienced Hypothermia
Any hypothermia less than 36C
Time frame: up to 6 weeks after delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azithromycin and Amoxicillin Placebo | Number of Participants Who Experienced Hypothermia | 9 Participants |
| Azithromycin + Amoxicillin | Number of Participants Who Experienced Hypothermia | 11 Participants |
| Usual Care | Number of Participants Who Experienced Hypothermia | 15 Participants |
Secondary
Number of Participants Who Experienced Other Infection
Includes Hepatitis B, thyroid infection, vaginal infection, viral infection, leg cellulitis, unknown abdominal infection,malaria
Time frame: up to 6 weeks after delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azithromycin and Amoxicillin Placebo | Number of Participants Who Experienced Other Infection | 4 Participants |
| Azithromycin + Amoxicillin | Number of Participants Who Experienced Other Infection | 3 Participants |
| Usual Care | Number of Participants Who Experienced Other Infection | 1 Participants |
Secondary
Number of Participants Who Experienced Pyelonephritis
Other Infections
Time frame: Up to hospital discharge
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azithromycin and Amoxicillin Placebo | Number of Participants Who Experienced Pyelonephritis | 2 Participants |
| Azithromycin + Amoxicillin | Number of Participants Who Experienced Pyelonephritis | 2 Participants |
| Usual Care | Number of Participants Who Experienced Pyelonephritis | 3 Participants |
Secondary
Number of Participants Who Experienced Stillbirth
Any stillbirth
Time frame: delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azithromycin and Amoxicillin Placebo | Number of Participants Who Experienced Stillbirth | 1 Participants |
| Azithromycin + Amoxicillin | Number of Participants Who Experienced Stillbirth | 0 Participants |
| Usual Care | Number of Participants Who Experienced Stillbirth | 1 Participants |
Secondary
Number of Participants Who Experienced Transfusion
Blood transfusion
Time frame: up to 6 weeks after delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azithromycin and Amoxicillin Placebo | Number of Participants Who Experienced Transfusion | 8 Participants |
| Azithromycin + Amoxicillin | Number of Participants Who Experienced Transfusion | 3 Participants |
| Usual Care | Number of Participants Who Experienced Transfusion | 4 Participants |
Secondary
Number of Participants Who Needed PP Antibiotic
Any postpartum antibiotic
Time frame: up to 6 weeks after delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azithromycin and Amoxicillin Placebo | Number of Participants Who Needed PP Antibiotic | 18 Participants |
| Azithromycin + Amoxicillin | Number of Participants Who Needed PP Antibiotic | 18 Participants |
| Usual Care | Number of Participants Who Needed PP Antibiotic | 26 Participants |