Preterm Rupture of Membranes Optimising Antibiotics Trial

Official title

Preterm Rupture of Membranes Optimising Antibiotics Trial (PROMOAT). A Pregnancy Domain Within PLATIPUS.

Overview

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.

Interventions

• Drug Erythromycin 250mg + placebo
  Antibiotic.
• Drug Azithromycin 500mg + placebo
  Antibiotic.
• Drug Erythromycin 250mg and Amoxicillin 500mg
  Antibiotics.

Primary outcome measures

• Number of participants who progress by at least one level higher on the PLATIPUS Ordinal Outcome Scale [PLATIPUS Core Primary Outcome] [Time frame: At any time prior to 42 weeks' postmenstrual age or first discharge home from hospital (whichever is earlier).]]

Secondary outcome measures (8)

• Time (randomisation) to birth [Time frame: From randomisation to birth]
• Estimated antepartum/intrapartum/postpartum (< 24 hours) blood loss [Time frame: Less than 24 hours of birth.]
• Rate of clinical chorioamnionitis [Time frame: To birth.]
• Rate of histological chorioamnionitis/funisitis [Time frame: To birth]
• Rate of puerperal infection [Time frame: From birth to day 42 postpartum]
• Rate of early onset neonatal sepsis [Time frame: Within 48 hours of birth.]
• Duration of neonatal antibiotic use commenced within 48 hours of birth. [Time frame: Within 48 hours of birth.]
• Number of days of maternal antibiotic prescription after birth to day 42 postpartum [Time frame: From birth to Day 42 postpartum]

Eligibility criteria

PLATFORM ELIGIBILITY

Participants must meet all core PLATIPUS platform inclusion criteria:

• Considered to be at risk of birth before 37 weeks gestation (spontaneous and provider-initiated)
• Receiving pregnancy care at a participating site (hospital) at the time of eligibility assessment and
• Meet eligibility criteria for one or more platform domains.

Participants will be excluded from participation if they meet any core PLATIPUS platform exclusion criteria:

• Inability to consent for themselves
• Perinatal death is deemed to be imminent and inevitable during the next 24 hours (at time of screening).

Pregnant women and people who meet ALL of the core platform inclusion criteria and none of the exclusion criteria will be considered for PROMOAT-specific eligibility.

PROMOAT-SPECIFIC ELIGIBILITY

Platform-eligible participants must meet all PROMOAT-specific inclusion criteria:

• Women with singleton or multiple pregnancies complicated by preterm prelabour rupture of membranes (PPROM) < 37+0 weeks' gestation as determined by the treating clinician and standard criteria:

• Maternal history consistent with loss of fluid per vagina
• Evidence of a pool of fluid in the vagina on sterile speculum examination
• +/- positive testing for IGFBP-1 (Actim PROM) or PAMG-1 (Amnisure) AND
• Are eligible for at least two treatment arms within the domain
• The fetus/fetuses are alive at randomisation
• The pregnancy is continuing and active neonatal management is planned.

Participants will be excluded from participation if they meet core PLATIPUS platform exclusion criteria:

• Inability to consent for themselves OR
• Perinatal death is deemed to be imminent and inevitable during the next 24 hours (at time of screening).

Participants will be excluded from participation if they meet any PROMOAT-specific exclusion criteria:

• Antibiotic treatment for > 24 hours administered with the aim of preventing infection from PPROM
• Suspected maternal or fetal infection (chorioamnionitis)
• Maternal or fetal indication for immediate birth
• Established preterm labour (cervical dilatation ≥ 3cm AND regular contractions)
• No appropriate antibiotic available within domain intervention arms due to allergy, contraindications, drug interactions, drug availability, or previous history of antibiotic-resistant infection/s
• Women with a previous infant affected by GBS sepsis
• Major congenital fetal anomaly.

Platform-eligible participants who meet all PROMOAT-specific inclusion criteria and none of the PROMOAT-specific exclusion criteria will be eligible to participate in PROMOAT.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Prevention

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT06906757 · P-P01-PROMOAT

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗