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Premature Rupture Membranes and tPTL: a Personalised Approach (PROMPT) (PROMPT)

Primary Purpose

Preterm Rupture of Membranes, Threatened Preterm Labor

Status
Not yet recruiting
Phase
Not Applicable
Locations
Study Type
Interventional
Intervention
Amniocentesis
Routine care without amniocentesis
Sponsored by
Chelsea and Westminster NHS Foundation Trust
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Preterm Rupture of Membranes

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria:

  1. Pregnant women between 23+0 weeks and 34 weeks gestation.
  2. Admitted with signs and symptoms of threatened PTL with positive fetal fibronectin of 200ng/mL or clinical confirmation of preterm rupture of membranes
  3. Singleton pregnancy
  4. The ability to understand and sign a written informed consent form, prior to participation in any screening procedures and must be willing to comply with all study requirements.
  5. Women must be aged 18 years or older.

    -

Exclusion Criteria:

  1. Chorioamnionitis: Defined as maternal temperature was elevated to 37.8°C and two or more of the following criteria were present: uterine tenderness, malodorous vaginal discharge, maternal leucocytosis (>15 000 cells/mm3), maternal tachycardia (>100 beats/min) and fetal tachycardia (>160 beats/min).
  2. Multiple pregnancy
  3. Uterine contractions >2:10 and evidence on tocogram
  4. Maternal infections such as HIV and hepatitis
  5. Clinical suspicion of placental abruption
  6. Evidence of meconium stained liquor
  7. Fetal abnormality or growth restriction
  8. Abnormal fetal heart rate pattern
  9. Maternal pathologies in which preterm termination of pregnancy is required.

    -

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Active Comparator

    Experimental

    Arm Label

    Routine care

    Amniocentesis and biofire directed antibiotic use

    Arm Description

    Women who present with PPROM or threatened PTL and have routine care

    Women who present with PPROM or threatened PTL and randomised to amniocentesis and biofire directed antibiotic treatment

    Outcomes

    Primary Outcome Measures

    The length of latency of women receiving amniocentesis with BioFire filmArray POC test guided antibiotic selection compared to those receiving standard treatment.
    Days

    Secondary Outcome Measures

    Maternal outcome
    The number of women with (i) clinical diagnosis of infection including: chorioamnionitis (one or more of pyrexia, abdominal pain/tenderness, tachycardia, vaginal discharge) or (ii) postpartum endometritis with laboratory diagnosis (raised peripheral blood CRP and/or WCC, positive blood, vaginal or urine cultures)
    Neonatal outcome
    We will use a composite severe neonatal outcome of neonatal death, major adverse outcome ie, chronic lung disease (defined as the need for supplementary oxygen at 36 weeks post conception) major cerebral abnormality on ultrasonography identified prior to discharge or necrotising enterocolitis.
    Microbiota and inflammatory marker endpoints
    Maternal (vaginal, rectal, amniotic fluid) and neonatal (faecal) (measured using BioFire PCR, 16srRNA sequencing, multiplex ELISA, and associated clinical tests). Residual sample stored for future peptide/proteomics testing (e.g. MALDI-TOF multiplex). Incidence of antibiotic resistance (neonatal and maternal).
    Patient based endpoints
    Acceptability of having an amniocentesis; how risks communicated and understood; how test presented; how was the situation understood by the researchers/care givers and how did that impact on the subject's ability to understand what was being proposed? Partner perceptions and sense of inclusion/involvement. • Clinical data including previous obstetric history, demographic and socio-economic data and neonatal health data, the gestational age and cervical dilatation at randomisation, other drugs prescribed (corticosteroids, indomethacin, nifedipine, magnesium sulphate) will be collected.
    Timing of birth
    Number of women who deliver within 2 days
    Mode of delivery
    Vaginal, caesarean or assisted birth
    Length of hospitalisation
    Number of days of maternal hospitalisation
    Gestational age at delivery
    Weeks
    Outcomes for neonates admitted to NICU
    Number of neonates (i) admitted to NICU, (ii) ventilated, (iii) needing oxygen (iv) respiratory distress syndrome; (v) treatment with exogenous surfactant and (vi) with infection

    Full Information

    First Posted
    April 20, 2021
    Last Updated
    August 17, 2021
    Sponsor
    Chelsea and Westminster NHS Foundation Trust
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    1. Study Identification

    Unique Protocol Identification Number
    NCT04878978
    Brief Title
    Premature Rupture Membranes and tPTL: a Personalised Approach (PROMPT)
    Acronym
    PROMPT
    Official Title
    A Randomised Study of a Personalised Approach to the Management of Preterm Rupture of Membranes and Threatened Preterm Labour
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    April 2021
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    September 1, 2021 (Anticipated)
    Primary Completion Date
    June 1, 2024 (Anticipated)
    Study Completion Date
    June 1, 2025 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Chelsea and Westminster NHS Foundation Trust

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    No

    5. Study Description

    Brief Summary
    Preterm birth (less than 37 weeks) affect approximately 8% of babies in the UK and is the worldwide leading cause of death in children under the age of 5. Subclinical infection affects approximately 50% of women giving birth before 32 weeks. Infection contributes to significant neonatal morbidity and mortality. Antibiotics such as erythromycin is currently used to treat women who present with preterm rupture of membranes. While this has shown short-term improvement in neonatal morbidity, it has not had any impact in reducing the perinatal mortality and also little effect on the health of the children at age seven. Some antibiotics such as co-amoxiclav has not shown to be effective in delaying delivery and some studies have shown that antibiotics increases rather than reduces the risk of cerebral palsy. Many women do not display signs of infection and the underlying bacteria is multifactorial (bacterial vaginosis, trichomoniasis, gonorrhoea, Chlamydia, ureaplasma, Group B streptococcal and E. Coli) and remains a diagnostic challenge. The only available clinical approach is to test the sample of amniotic fluid for bacteria and small case series have shown prolongation of pregnancy when accurately targeted antibiotic treatment is used. This research aims to prove that targeted antibiotic therapy results in a greater prolongation of pregnancy than standard management for women with preterm prelabour rupture of membranes (PPROM) and/or threatened preterm labour (tPTL). Women will be randomised to standard care versus BioFire directed antibiotic treatment in addition to standard care. Investigators will use the BioFire point of care testing to identify the presence of infection and identify with anti-microbial resistance genes the bacteria possess to guide the antibiotic treatment. To be certain that the presence of infection is detected the investigators will use PCR to test the amniotic fluid for IL-6 and white cell count.
    Detailed Description
    Overall 10-15% of women delivering before 37 weeks have intraamniotic infection and of those delivering before 32 weeks have 50% chance. Consequently, since infection is one of the most important causes of spontaneous PTL it is possible that antibiotic treatment may delay delivery and reduce the risk of fetal damage and consequently long-term disability. However, most cases do not display typical symptoms or signs of infection, the only way to make the diagnosis reliably is through performing an amniocentesis. The risk of this procedure is low in the 3rd trimester and should be considered particularly in those in PTL at less than 32 weeks, when the risk of infection is high. Studies in non-human primate models of intra-amniotic infection support for this approach, showing that specific antibiotic therapy can prevent infection-induced PTL and prolong pregnancy with improved neonatal outcomes. Human studies have been less positive, with antibiotics failing to prolong pregnancy in PTL or eradicate infection in PPROM. The Oracle trial assessed the ability of two antibiotics, erythromycin and co-amoxiclav, to reduce the risk of PTD in women with PPROM using a composite primary outcome of neonatal death, chronic lung disease, or major cerebral abnormality on ultrasonography before discharge from hospital. Erythromycin, but not co-amoxiclav, reduced the risk of the primary outcome. Two recent papers have challenged this negative view of the use of antibiotics for intraamniotic infection. In the first, amniocentesis was performed to identify infection or inflammation and broad-spectrum antibiotics administered to women with a singleton pregnancy presenting with tPTL at between 20 and 34 weeks. Infection was thought to be present in at least 60% of cases as judged by the presence of a raised WCC, although only 20% had positive cultures using standard microbiological approaches. 100% had an elevated IL-6 level confirming inflammation. Repeat amniocentesis confirmed resolution of inflammation in all cases and overall average prolongation was 11.4 days. In a control group not given antibiotics average prolongation was 3 days. In 3 cases infection was shown to be cleared by antibiotic treatment. In the second report, women undergoing rescue cerclage had an amniocentesis and those found to have evidence of infection or inflammation treated with broad spectrum antibiotics. A repeat amniocentesis demonstrated resolution of infection/inflammation with antibiotic treatment. Investigators plan to recruit women to a multicenter randomised trial of standard management vs. amniocentesis with the use of BioFire filmArray point of care testing to identify the presence of bacteria and identify common anti-microbial resistance genes the bacteria possess to guide the selection of an additional antibiotic agent. The BioFire filmArray clinical application is currently being studied in patients with pneumonia in the INHALE study. Investigators plan to use the BioFire filmArray in a maternity setting and will use the information generated by the BioFire filmArray platform to give targeted antibiotics in the amniocentesis arm in addition to routine erythromycin with the aim of prolonging latency to delivery and of improving neonatal outcome.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Preterm Rupture of Membranes, Threatened Preterm Labor

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Not Applicable
    Interventional Study Model
    Parallel Assignment
    Model Description
    This is a single centre open labelled randomised study.
    Masking
    None (Open Label)
    Allocation
    Randomized
    Enrollment
    276 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Routine care
    Arm Type
    Active Comparator
    Arm Description
    Women who present with PPROM or threatened PTL and have routine care
    Arm Title
    Amniocentesis and biofire directed antibiotic use
    Arm Type
    Experimental
    Arm Description
    Women who present with PPROM or threatened PTL and randomised to amniocentesis and biofire directed antibiotic treatment
    Intervention Type
    Diagnostic Test
    Intervention Name(s)
    Amniocentesis
    Intervention Description
    Amniocentesis will be used to sample the amniotic fluid for Biofire detection of microorganism and to direct antibiotic treatment
    Intervention Type
    Other
    Intervention Name(s)
    Routine care without amniocentesis
    Intervention Description
    Routine clinical care
    Primary Outcome Measure Information:
    Title
    The length of latency of women receiving amniocentesis with BioFire filmArray POC test guided antibiotic selection compared to those receiving standard treatment.
    Description
    Days
    Time Frame
    4 years
    Secondary Outcome Measure Information:
    Title
    Maternal outcome
    Description
    The number of women with (i) clinical diagnosis of infection including: chorioamnionitis (one or more of pyrexia, abdominal pain/tenderness, tachycardia, vaginal discharge) or (ii) postpartum endometritis with laboratory diagnosis (raised peripheral blood CRP and/or WCC, positive blood, vaginal or urine cultures)
    Time Frame
    4 years
    Title
    Neonatal outcome
    Description
    We will use a composite severe neonatal outcome of neonatal death, major adverse outcome ie, chronic lung disease (defined as the need for supplementary oxygen at 36 weeks post conception) major cerebral abnormality on ultrasonography identified prior to discharge or necrotising enterocolitis.
    Time Frame
    4 years
    Title
    Microbiota and inflammatory marker endpoints
    Description
    Maternal (vaginal, rectal, amniotic fluid) and neonatal (faecal) (measured using BioFire PCR, 16srRNA sequencing, multiplex ELISA, and associated clinical tests). Residual sample stored for future peptide/proteomics testing (e.g. MALDI-TOF multiplex). Incidence of antibiotic resistance (neonatal and maternal).
    Time Frame
    4 years
    Title
    Patient based endpoints
    Description
    Acceptability of having an amniocentesis; how risks communicated and understood; how test presented; how was the situation understood by the researchers/care givers and how did that impact on the subject's ability to understand what was being proposed? Partner perceptions and sense of inclusion/involvement. • Clinical data including previous obstetric history, demographic and socio-economic data and neonatal health data, the gestational age and cervical dilatation at randomisation, other drugs prescribed (corticosteroids, indomethacin, nifedipine, magnesium sulphate) will be collected.
    Time Frame
    5 years
    Title
    Timing of birth
    Description
    Number of women who deliver within 2 days
    Time Frame
    4 years
    Title
    Mode of delivery
    Description
    Vaginal, caesarean or assisted birth
    Time Frame
    5 years
    Title
    Length of hospitalisation
    Description
    Number of days of maternal hospitalisation
    Time Frame
    4 years
    Title
    Gestational age at delivery
    Description
    Weeks
    Time Frame
    4 years
    Title
    Outcomes for neonates admitted to NICU
    Description
    Number of neonates (i) admitted to NICU, (ii) ventilated, (iii) needing oxygen (iv) respiratory distress syndrome; (v) treatment with exogenous surfactant and (vi) with infection
    Time Frame
    4 years

    10. Eligibility

    Sex
    Female
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Pregnant women between 23+0 weeks and 34 weeks gestation. Admitted with signs and symptoms of threatened PTL with positive fetal fibronectin of 200ng/mL or clinical confirmation of preterm rupture of membranes Singleton pregnancy The ability to understand and sign a written informed consent form, prior to participation in any screening procedures and must be willing to comply with all study requirements. Women must be aged 18 years or older. - Exclusion Criteria: Chorioamnionitis: Defined as maternal temperature was elevated to 37.8°C and two or more of the following criteria were present: uterine tenderness, malodorous vaginal discharge, maternal leucocytosis (>15 000 cells/mm3), maternal tachycardia (>100 beats/min) and fetal tachycardia (>160 beats/min). Multiple pregnancy Uterine contractions >2:10 and evidence on tocogram Maternal infections such as HIV and hepatitis Clinical suspicion of placental abruption Evidence of meconium stained liquor Fetal abnormality or growth restriction Abnormal fetal heart rate pattern Maternal pathologies in which preterm termination of pregnancy is required. -

    12. IPD Sharing Statement

    Learn more about this trial

    Premature Rupture Membranes and tPTL: a Personalised Approach (PROMPT)

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