Preterm Rupture of Membranes Optimising Antibiotics Trial

Not Applicable

Not yet recruiting

• Conditions: PPROM; Preterm
• Interventions: Drug: Erythromycin 250mg + placebo; Drug: Azithromycin 500mg + placebo; Drug: Erythromycin 250mg and Amoxicillin 500mg

• Registration Number: NCT06906757
• Lead Sponsor: University of Melbourne

Brief Summary

The goal of this clinical trial is to learn which antibiotic regimen works best to prevent infection in pregnant women whose waters break early (preterm, pre-labour rupture of membranes, or PPROM) and assess the health outcomes of babies born to pregnant women who have received these antibiotics.

PROMOAT aims to answer the question: Which antibiotic or combined antibiotic regimen most effectively prevents infection in pregnant women with PPROM \< 37+0 weeks' gestation.

Researchers will compare three antibiotic regimens already used in clinical practice to prevent infection in pregnant women with PPROM.

Participants will be randomly allocated to the antibiotic regimen they will follow for seven days, or until birth (whichever is earlier). All antibiotics will be taken orally.

Neonatal health outcomes will be collected at 42 weeks postmenstrual age and maternal birth and postpartum care outcomes assessed at 42 days postpartum.

Questionnaires will capture maternal mood at time of consent and at 42 days postpartum. Antibiotic tolerance will be assessed at the time antibiotic treatment is ceased.

This trial will be undertaken as part of the PLATIPUS trial (NCT06461429).

Detailed Description

PROMOAT aims to determine which of the most common antibiotic regimens are most effective in preventing infection in pregnant people with PPROM to improve health outcomes for their infants. PROMOAT is a pregnancy domain within the PLATIPUS adaptive platform trial (NCT06461429).

Preterm prelabour rupture of membranes (PPROM) precedes 30-40% of spontaneous preterm births and is an important cause of maternal and neonatal infection. Membrane rupture provides an entry point for microbes from the vagina to ascend into the uterine cavity, exposing the mother and the fetus to infectious pathogens leading to poor maternal and neonatal outcomes. Mothers with PPROM are at increased risk of haemorrhage, hysterectomy, sepsis, intensive care admission and death. Preterm infants exposed to in-utero infection are at higher risk of poor short- and long-term outcomes, including neonatal sepsis, neurodevelopmental delay, cerebral palsy, chronic lung disease and death.

Neonatal sepsis is the third most common cause of newborn deaths (\~340,000 per year) and prevention is a major research priority, Neonatal sepsis due to pathogens acquired after PPROM may present in the first days of life and result in bacteraemia, pneumonia and meningitis. The most common pathogens associated with early-onset neonatal sepsis are Streptococcus agalactiae (aka Group B Streptococcus: GBS), Escherichia coli and Ureaplasma sp. Mortality is highest in the most immature infants, with a 54% case fatality rate in infants born before 24 weeks' gestation.

The goal in managing pregnancies complicated by PPROM is to prolong the pregnancy to enable fetal maturity without an increased risk of infection (acquired while the fetus remains in utero). Antibiotic prophylaxis has been shown to increase latency to birth but there is limited evidence to guide antibiotic choice to prevent infection in PPROM.

In PROMOAT, pregnant women with PPROM will be randomly assigned to receive one of the three intervention arms:

* Erythromycin

* Azithromycin, or

* Erythromycin and Amoxicillin.

Health outcomes will be assessed using the PLATIPUS Ordinal Outcome Scale, at 42 weeks' postmenstrual age or discharge home, whichever is earliest.

A short questionnaire at Day 7 (or birth, whichever is earlier) will measure compliance and antibiotic tolerance. A maternal and family health questionnaire will be collected at Day 42 postpartum.

Study Timeline

• Status Verified: 2025-02
• Study First Submitted: 2025-02-18
• Study First Submitted QC: 2025-03-31
• Last Update Submitted: 2025-03-31
• Study First Posted: 2025-04-02
• Last Update Posted: 2025-04-02
• Study Start: 2025-09
• Primary Completion: 2029-12
• Study Completion: 2050-12

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: Female
• Target Recruitment: 3900

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Erythromycin 250mg + placebo	Erythromycin 250mg + placebo	Erythromycin 250mg, four times a day, for 7 days. Oral preparation only. Placebo tablets instead of penicillin for blinding purposes.
Azithromycin 500mg + placebo	Azithromycin 500mg + placebo	Azithromycin 500mg daily for 7 days. Oral preparation only. Placebo tablets instead of penicillin for blinding purposes.
Erythromycin 250mg and Amoxicillin 500mg	Erythromycin 250mg and Amoxicillin 500mg	Erythromycin 250mg, four times a day AND Amoxicillin 500mg three times a day, for 7 days. Oral preparations only.

Primary Outcome Measures

Name	Time	Method
Number of participants who progress by at least one level higher on the PLATIPUS Ordinal Outcome Scale [PLATIPUS Core Primary Outcome]	At any time prior to 42 weeks' postmenstrual age or first discharge home from hospital (whichever is earlier).]	The PLATIPUS-Ordinal Outcome Scale ranks the most severe core short-term infant health outcome in the specified time frame.; Levels 1-15: 1= Well, liveborn infant; 2= Neonatal unit admission for \<48 hours; 3= Neonatal unit admission for \>/= 48 hours; 4= Non-invasive respiratory support or oxygen therapy for ≥ 4 hours \& \< 5 days; 5= Non-invasive respiratory support or oxygen therapy \>/= 5 days; 6= Mechanical ventilation via endotracheal tube for ≥ 4 hours \& \<7 days; 7= Mechanical ventilation via endotracheal tube for \>/=7 days; 8= Moderate respiratory morbidity; 9=Necrotising enterocolitis AND/OR Sepsis; 10= Severe Respiratory Morbidity; 11= Major Surgery; 12= Brain Injury; 13= TWO of severe respiratory morbidity OR major surgery OR brain injury; 14= Severe respiratory morbidity \& major surgery \& brain injury; 15 = Death.

Secondary Outcome Measures

Name	Time	Method
Time (randomisation) to birth	From randomisation to birth	Number of days from randomisation to birth.
Estimated antepartum/intrapartum/postpartum (< 24 hours) blood loss	Less than 24 hours of birth.	Estimated antepartum/intrapartum/postpartum (\<24 hours of birth) blood loss.
Rate of histological chorioamnionitis/funisitis	To birth	Histological chorioamnionitis/funisitis; • Presence of inflammation in the placenta, chorion, umbilical cord and/or amnion with or without fetal inflammatory response defined according to staging of maternal (MIR) or fetal inflammatory response (FIR).
Rate of clinical chorioamnionitis	To birth.	Clinical chorioamnionitis Clinical suspicion of intra-amniotic infection such as: maternal fever (\>/= 38C AND 2 of maternal tachycardia (\> 100 beats/min), fetal tachycardia 26,27(\> 160 beats/min), uterine tenderness, purulent/malodorous amniotic fluid, maternal leukocytosis (white blood cell count \>/= 15,000/mm3) AND Antibiotics commenced for treatment for clinically suspected chorioamnionitis.
Rate of puerperal infection	From birth to day 42 postpartum	Puerperal infection Infection of the maternal genital tract, urinary tract and wound infection from birth to day 42 postpartum AND Antibiotic treatment commenced
Rate of early onset neonatal sepsis	Within 48 hours of birth.	Isolation of a bacterial or fungal organism from at least one of blood or CSF culture or by PCR sampled within 48 hours of birth AND after consideration of clinical and laboratory evidence, a decision is made to give the infant antibiotics with therapeutic intent against this organism for \>5 days
Duration of neonatal antibiotic use commenced within 48 hours of birth.	Within 48 hours of birth.	Duration of neonatal antibiotic treatment commenced within 48 hours of birth.
Number of days of maternal antibiotic prescription after birth to day 42 postpartum	From birth to Day 42 postpartum	Estimated cumulative days of maternal antibiotic use from birth to day 42 postpartum