Background, including rationale and any previous systematic review(s)
Methods
Aim(s)
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Improves obstetric outcome by reducing the incidence of preterm delivery (before 34 weeks gestation).
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Improves neonatal outcome by reducing a composite of death and major morbidity.
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Leads to improved childhood cognitive and neurosensory outcomes at two years.
Centre(s)
Design
Inclusion and exclusion criteria
Screening phase inclusion criteria
Treatment phase inclusion criteria
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All women fulfilling the inclusion criteria for the screening phase and who also have a positive screening (fFN) test at 22 + 0 weeks, will be eligible for the main (treatment) phase of the study – these women are subsequently referred to as the “fFN positive” group.
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Additionally, in September 2010, those who have a previous spontaneous labour resulting in a preterm birth ≤ 34 weeks gestation (delivery by any mode) or a short cervix in index pregnancy, defined as cervical length ≤ 25 mm at 18–0 -24 + 0 weeks gestation also became eligible for randomisation even with a negative fFN test. These women are subsequently referred to as the “fFN negative” group
Exclusion criteria
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Known significant congenital structural or chromosomal fetal anomaly
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Known sensitivity or listed contraindication to progesterone (known allergy or hypersensitivity to progesterone, severe hepatic dysfunction, undiagnosed vaginal bleeding, mammary or genital tract carcinoma, thrombophlebitis, thromboembolic disorders, cerebral haemorrhage, porphyria) or intolerance to progesterone or excipient (including peanut allergy prior to February 2011 given that peanut oil was the excipient in doses issued to participants until November 2010)
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Suspected or proven rupture of the fetal membranes at the time of recruitment
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Multiple pregnancy
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Women currently prescribed progesterone or who have taken progesterone beyond 18 weeks gestation.
Randomisation
Concealment of allocation
Primary and any secondary endpoint(s)
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Obstetric: delivery <34 completed weeks of gestation (Yes/No), (<34 + 0 weeks: outcome of the treatment phase)
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Neonatal: a composite of death or two markers of neonatal morbidity – bronchopulmonary dysplasia in children born at <32 weeks of gestation and brain injury on cerebral ultrasound.
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Childhood: The Bayley III cognitive scale standardised score at two years of chronological age (with an aim to test between 22 months to 26 months - as this is age-standardised all assessments will be valid)
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Gestation at delivery
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Fetal or neonatal/infant death after trial entry up to 2 years of age [18].
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Incidence of the individual components of the primary neonatal outcome
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Incidence of other major neonatal complications:
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Level of care days, which includes: days of respiratory support, (Either mechanical ventilation or CPAP) and days of oxygen therapy.
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Surfactant administration
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Necrotising enterocolitis, (medical or surgical treatment of confirmed cases)
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Number of discrete episodes of bloodstream or CNS infection (positive blood [19] or CSF culture)
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Daily level of care [20].
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Composite outcome of death or moderate/severe neurodevelopmental impairment at two years of age, defined as per national recommendations [21].
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Individual components of the disability definition and non-neurological disability as defined [21].
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Strengths and difficulties questionnaire (http://www.sdqinfo.com/)
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Score on the PARCA-r (parent assessment of child abilities revised).
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Women’s perceptions of their treatment.
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Maternal and child adverse events (e.g. operative delivery).
Side-effects reporting and quantification (e.g, WHO scale)
Statistical analysis plan, including sample size and power calculations
Type of analysis (e.g. intention to treat) and statistical tests
Obstetric outcome
Neonatal outcome
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Death
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Brain injury (defined as any intraventricular haemorrhage (IVH) (excludes subependymal haemorrhages), parenchymal cystic or haemorrhagic lesion or persistent ventriculomegaly (VI >97th percentile)
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Severe chronic lung disease (defined as need for ≥30% oxygen and/or positive pressure (positive pressure ventilation or nasal continuous positive airway pressure) at 36 weeks post menstrual age or discharge, which ever comes first).
Childhood outcome
Planned subgroup analyses
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reason for risk of preterm delivery (spontaneous preterm birth yes / no and any preterm birth yes / no)
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previous pregnancy of at least 14 weeks (yes / no)
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cervical length at 18–24 weeks gestation (≤25 mm / >25 mm and ≤15 mm / >15 mm)
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chorioamnionitis diagnosed on pathology (yes / no)
Ethical issues, including: Ethics committee approval
Interim analyses and stopping rules
Committee oversights
Indemnities
Publication plan
Funding
Start date
End of data collection
Reporting date
Trial registration
Discussion
Appendix
Sample size calculations
Original sample size calculation based on data in the literature on the “fFN +” group
The revised sample size calculation below, based on blinded data (as of April 2011) and inclusion of the "fFN"- group is around 1250 participants
fFN+ | fFN- | Subjects (fFN+/fFN-) [Total] | Power |
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40% | 10% | 375/750 (1125) | 81% |
400/800 (1200) | 83% | ||
425/850 (1275) | 85% | ||
45% | 13% | 375/750 (1125) | 88% |
400/800 (1200) | 90% | ||
425/850 (1275) | 92% | ||
50% | 15% | 375/750 (1125) | 93% |
400/800 (1200) | 94% | ||
425/850 (1275) | 95% |
fFN+ | fFN- | Subjects (fFN+/ fFN-) [Total] | Power |
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25% | 8% | 375/750 (1125) | 81% |
400/800 (1200) | 83% | ||
425/850 (1275) | 86% |