The aim of the OPPTIMUM study is to determine whether, in women at high risk of preterm labour, prophylactic vaginal natural progesterone, 200 mg daily from 22 – 34 weeks gestation, compared to placebo:
Improves obstetric outcome by reducing the incidence of preterm delivery (before 34 weeks gestation).
Improves neonatal outcome by reducing a composite of death and major morbidity.
Leads to improved childhood cognitive and neurosensory outcomes at two years.
More than 60 hospitals, principally in the UK.
Double blind randomized placebo controlled trial. The study is in two phases, a screening phase and a treatment phase.
Inclusion and exclusion criteria
Screening phase inclusion criteria
High risk for preterm birth (as indicated by AT LEAST ONE of the criteria i-iv) and ALL of the criteria v-vii:
History of previous PTB/second trimester loss (≥16 weeks or ≤37 weeks gestation)
Previous preterm premature rupture of the fetal membranes (≤ 37 weeks gestation)
Short cervical length (≤ 25 mm) on ultrasound at 18–0 -24 + 0 weeks gestation
Any cervical procedure to treat abnormal smears i.e. large loop excision, laser conisation, cold knife conisation or radical diathermy
Gestation established by scan at ≤ 16 weeks to ensure that the estimated date of delivery is accurate or the consultant must be confident that the gestation dates are accurate.
Signed Consent form
16 years of age or older.
Treatment phase inclusion criteria
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.
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
Known significant congenital structural or chromosomal fetal anomaly
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)
Suspected or proven rupture of the fetal membranes at the time of recruitment
Prescription or ingestion of medications known to interact with progesterone (e.g. Bromocriptine, Rifamycin, Ketoconazole or Ciclosporin)
Intervention(s) Progesterone (Utrogestan) 200 mg soft capsules or placebo will to be inserted once daily vaginally at bedtime from 22+0 - 24+0 up to 34+0 weeks gestation.
Randomisation will be carried out online via the web portal or via telephone to the central randomisation facility based at the Robertson Centre for Biostatistics, at the Glasgow Clinical Trials Unit, University of Glasgow.
Concealment of allocation
Concealment of allocation will be achieved by randomising participants to active or placebo capsules. Placebo capsules will appear identical to active treatment. The outcomes will be measured blind to the allocation.
Primary and any secondary endpoint(s)
Obstetric: delivery <34 completed weeks of gestation (Yes/No), (<34 + 0 weeks: outcome of the treatment phase)
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.
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)
Gestation at delivery
Fetal or neonatal/infant death after trial entry up to 2 years of age .
Incidence of the individual components of the primary neonatal outcome
Incidence of other major neonatal complications:
Level of care days, which includes: days of respiratory support, (Either mechanical ventilation or CPAP) and days of oxygen therapy.
Necrotising enterocolitis, (medical or surgical treatment of confirmed cases)
Number of discrete episodes of bloodstream or CNS infection (positive blood  or CSF culture)
Daily level of care .
Composite outcome of death or moderate/severe neurodevelopmental impairment at two years of age, defined as per national recommendations .
Individual components of the disability definition and non-neurological disability as defined .
Strengths and difficulties questionnaire (http://www.sdqinfo.com/)
Score on the PARCA-r (parent assessment of child abilities revised).
Women’s perceptions of their treatment.
Maternal and child adverse events (e.g. operative delivery).
Side-effects reporting and quantification (e.g, WHO scale)
Participants are instructed to contact their Investigator at any time after consenting to join the trial if any symptoms or side effects develop. In the case of any events the Investigator should initiate the appropriate treatment according to their medical judgment. All adverse events (AEs) and Serious Adverse Events (SAE) that occur after being randomized to treatment must be recorded in detail in the patient notes. SAEs occurring in mother or baby from the time a participant is randomised until 30 days after stopping taking study treatment/placebo or until 28 days after delivery (whichever is the later) should be reported to the co-sponsors using the trial documentation. The standard definition of a serious adverse event will be used . This is any event that: results in death; is life threatening (i.e. the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe); requires hospitalisation or prolongation of existing hospitalisation; results in persistent or significant disability or incapacity; is a congenital anomaly or birth defect. Hospitalisations for treatment planned prior to randomisation and hospitalisation for elective treatment of a pre-existing condition will not be considered as an SAE, nor, for the purposes of this study, will the following events: miscarriage, preterm labour / suspected preterm labour, premature rupture of membranes (PROM) / suspected PROM, preterm delivery, preterm delivery in maternal interest, preterm delivery in fetal interest, hospitalisation for pregnancy induced hypertension, hospitalisation for “maternal discomfort”, hospitalisation for “rest”, hospitalisation for “observation” or “monitoring” for which the women are admitted for a period of less than 12 hours; normal” childhood illnesses (including infectious diseases and minor injuries) and complications arising from prematurity.
Statistical analysis plan, including sample size and power calculations
At the commencement of the study in 2008, we planned to recruit 750 women in the “fFN positive” group. We estimated that such a sample size would provide 80 – 95% power at the 5% level of significance for the primary obstetric outcome, 80% power for the neonatal outcome and 93% power for the childhood outcome (although further dilution of the latter was anticipated after incorporation of the deaths in a two stage statistical model – see below).
In 2010, the study was expanded to allow randomisation of women in the “fFN negative” group after analysis of preliminary (blinded) data in July 2010, together with the result of an HTA funded systematic review on screening for preterm birth  showed that our initial selection strategy erroneously missed women at medium to high risk of preterm birth. This change was endorsed by the Trial Steering committee, the MHRA, the ethics committee, and by the funder. The inclusion of women at a lower risk of the primary outcomes necessitated an increase in the sample size. The minimum new sample size is anticipated to be in the order of 1125 (375 fFN positive and 750 fFN negative women), but the proportions of each will dictate the exact sample size, as it is anticipated that at least 2 fFN negative women are required to achieve the event rate predicted in 1 fFN positive woman. Workings for the sample size calculation for the fFN positive group alone, and for the revised combined group of fFN positive and fFN negative women are shown in the Appendix.
Type of analysis (e.g. intention to treat) and statistical tests
All primary efficacy analyses are carried out on the intention to treat population (ITT). Safety analyses are carried out on the safety population (those who initiated on what study medication they received). Primary analyses are repeated in an exploratory manner on the per protocol population (including [i] compliance within an acceptable range and [ii] fulfilment of inclusion and exclusion criteria).
The primary obstetric outcome is delivery or fetal death before 34 completed weeks of gestation based on ultrasound (based on the projected date of delivery estimated from scan in the first trimester). The following null hypothesis will be tested: ‘There is no difference in the incidence of delivery or fetal death before 34 completed weeks of gestation between the group treated with 200 mg / day progesterone and the group treated with placebo from week 22–24 to week 34 of gestation or earlier delivery’.
The outcome is compared between the treatment groups using a logistic regression model including treatment and previous pregnancy of at least 14 weeks. The hypothesis will be tested with a likelihood ratio test.
The primary neonatal outcome is a binary outcome indicating whether one of the following has occurred:
Brain injury (defined as any intraventricular haemorrhage (IVH) (excludes subependymal haemorrhages), parenchymal cystic or haemorrhagic lesion or persistent ventriculomegaly (VI >97th percentile)
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).
The following null hypothesis will be tested: ‘There is no difference in the combined incidence of neonatal death, brain injury or severe chronic lung disease between the group treated with 200 mg / day progesterone and the group treated with placebo from week 22–24 to week 34 or earlier delivery’ This outcome is also compared between the treatment groups using a logistic regression model including treatment and previous pregnancy of at least 14 weeks. The hypothesis will be tested with a likelihood ratio test.
The primary childhood outcome is the Bayley III score, a continuous measure. This outcome will, by definition, not be available on babies who have died. Thus deaths need to be incorporated into the analysis, since the number of deaths may be sufficiently large as not to be negligible, and/or there may be a difference in the number of deaths between the two randomised groups. We will therefore use a two-stage statistical model that jointly models the treatment effect in both deaths and survivors , with deaths modelled using a binomial test and survivors modelled using a generalised linear model. The two parts are then combined to form the appropriate test statistic. Secondary analyses that adjust the estimated treatment effect for covariates felt to be of importance will be used as appropriate. Note that we will not be adjusting for gestational age in our analysis of childhood outcomes. The hypothesised mechanism of action of progesterone is to increase gestational age by reducing the proportion of women giving birth prematurely. To adjust for a post randomisation covariate (gestational age) which is a direct measure of the treatment effect, in a model that is estimating the consequence of that treatment effect (in terms of developmental outcome) is not statistically sound.
A fully detailed Statistical Analysis Plan will be prepared prior to unblinding.
Planned subgroup analyses
In order to determine whether a reduced or improved response to progesterone can be predicted, subgroups of the ITT population will be formed according to the following factors:
reason for risk of preterm delivery (spontaneous preterm birth yes / no and any preterm birth yes / no)
previous pregnancy of at least 14 weeks (yes / no)
cervical length at 18–24 weeks gestation (≤25 mm / >25 mm and ≤15 mm / >15 mm)
chorioamnionitis diagnosed on pathology (yes / no)
Ethical issues, including: Ethics committee approval
The study has been approved by the Scotland (A) Research Ethics Committee, reference number 08/MRE00/6.
Interim analyses and stopping rules
Interim unblinded analyses will be performed on safety, efficacy and possibly futility criteria for the purposes of review by the independent Data Monitoring Committee (iDMC) only. Masking will be maintained and analysis of obstetric and neonatal outcomes will be deferred until conclusion of the two-year childhood assessments. Thus no interim analyses will be revealed to investigators, participants, or anyone other than the DMC members (and statistical advisors) until completion of the two-year childhood assessments.
There is an independent Trial Steering Committee and independent Data Monitoring Committee.
The sponsor has clinical trial insurance which covers this study. This insurance includes indemnification for the TSC and DMC. There is no “no fault” indemnity.
The results of the trial will be published in peer reviewed journals. The results of the obstetric and neonatal outcomes will not be published until data collection for the childhood follow up part of the study is complete.
The study is funded by the MRC/EME -funder reference G0700452, grant No: 84982
Recruitment began in January 2009, as of May 2012, over 800 women had been randomized
End of data collection
Estimated October 2015
Estimated mid 2016