Participant entry
Pre-randomisation evaluations
Blood pressure and urinalysis to exclude proteinuric hypertension.
Estimated date of delivery based on a dating scan performed before 22 weeks gestation.
Inclusion criteria
Nulliparous women who will be over 35 years at the expected date of delivery, with:
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A singleton live fetus.
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A cephalic presentation.
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Gestational age between 360/7 and 396/7.
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No medical contra-indication to induction of labour.
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No medical contra-indication to pregnancy being. allowed to proceed to term plus 10 days.
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Willingness to participate in the trial.
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Written informed consent.
Exclusion criteria
Women with a known lethal fetal congenital abnormality.
Women with a contraindication to labour or vaginal delivery (e.g. evidence of fetal compromise such that labour would be contraindicated; fetal congenital anomaly or condition that might cause a mechanical problem at delivery such as hydrocephalus or cystic hygroma; placenta praevia).
Women with a contraindication to expectant management (e.g. gestational diabetes, proteinuric hypertension (24 hr urine collection protein >250 mg/l or BP > 140/90 on more than two occasions, two hrs apart).
Women with a previous myomectomy.
Women who book late for antenatal care and have no dating scan performed before 22 weeks to provide an accurate EDD.
Women who have undergone IVF using donor eggs in the current pregnancy.
Withdrawal criteria
There are no formal stopping rules. The Data Monitoring and Ethics Committee will review un-blinded results, adverse events and any other published data at least annually, and may advise stopping if there is clear evidence of benefit or harm in one or other group.
Adverse events
Definitions
Adverse Event (AE): any untoward medical occurrence in a patient or clinical study subject.
Serious Adverse Event (SAE): any untoward and unexpected medical occurrence or effect that:
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Results in death.
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Is life-threatening – refers to an event in which 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.
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Requires hospitalisation, or prolongation of existing inpatients’ hospitalisation.
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Results in persistent or significant disability or incapacity.
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Is a congenital anomaly or birth defect.
Medical judgement should be exercised in deciding whether an AE is serious in other situations. Important AEs that are not immediately life-threatening or do not result in death or hospitalisation but may jeopardise the subject or may require intervention to prevent one of the other outcomes listed in the definition above, should also be considered serious.
Reporting procedures
All adverse events should be reported. Depending on the nature of the event the reporting procedures below should be followed. Any questions concerning adverse event reporting should be directed to the Chief Investigator in the first instance.
Non-serious AEs
All such events, whether expected or not, should be recorded.
Serious AEs
An SAE form should be completed and faxed to the Chief Investigator within 24 hours. However, adverse events do not include admissions or day unit attendances for fetal monitoring, maternal hypertension, antepartum haemorrhage, preterm labour, preterm prelabour rupture of membranes, abdominal pain, transverse or oblique lie or placenta praevia. Likewise hospitalisation for labour, normal delivery, Caesarean or for induction of labour, and hospitalisations for elective treatment of a pre-existing condition do not need reporting as adverse events. Admissions for common postpartum complications such as maternal hypertension, perineal problems, mental health problems, urinary problems, or infections do not need reporting as adverse events.
All SAEs should be reported to the Derby 1 REC where in the opinion of the Chief Investigator, the event was:
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‘related’, i.e. resulted from the administration of any of the research procedures; and
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‘unexpected’, i.e. an event that is not listed in the protocol as an expected occurrence.
Reports of related and unexpected SAEs should be submitted within 15 days of the Chief Investigator becoming aware of the event, using the NRES SAE form for non-IMP studies.
Local investigators should report any SAEs as required by their Local Research Ethics Committee and/or Research & Development Office.
Sponsor Contact Details for SAEs:
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Email to rdsae@nhs.nuh.uk,
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Fax to: 0115 8493295 and phone Research & Innovations Dept on 0115 9709049.
Assessment and follow-up
Post-randomisation data will be collected at discharge.
Local centres will identify an individual within their unit to collect outcome data at hospital discharge from the hospital notes. Outcome data will be collected immediately following discharge by the same individual identified above.
Part of the outcome data will include a maternal expectation/experience questionnaire to be completed by mothers one month following delivery [
15].
Participating women who deliver at NUH will also be invited to join a focus group to explore in-depth their views. The information obtained from the focus groups will allow us to collect richer outcome data from the trial that will allow a more in-depth contextual appreciation of the participants experience than a prescriptive survey would allow. The focus groups will be conducted by Kate Walker supervised by Associate Professor in Midwifery Denis Walsh who has agreed to be a co-supervisor on her PhD and will take place within 8 to 12 weeks following birth. This allows for women to reflect upon their birth as well as recover from it.
The focus groups will be split into two subgroups: women who underwent induction of labour and women who were part of the non-intervention group who underwent expectant management.
We will aim for 6 women per group.
The focus groups aim to provide a comprehensive sense of the acceptability of this treatment option to women.
The trial will end once all data has been collected for the 630 participants or at 2 years whichever is the later time point.
Statistics and data analysis
Sample size and justification
CS rates from 2004–2008 for women with singleton pregnancies in labour at term, excluding breech presentation was approximately 22% among women 35–39 years of age and approximately 27% among women aged 40 years or older (Smith GCS, personal communication).
Therefore assuming a Caesarean section rate of 25% in controls. This sample size has 80% power with a two-sided significance level of 5% to test the hypothesis that induction of labour reduces the Caesarean section rate to 16%, a 36% relative reduction (or a 9% absolute reduction).
We will recruit 315 women per group, a total of 630 women.
Statistical analysis
Demographic, measures of compliance and any other baseline data will be summarised by descriptive statistics (N (%), mean and standard deviation [sd], median, upper and lower quartiles {iqr}, minimum and maximum) or frequency tables, stratified by the two arms.
Effectiveness will be assessed using a generalised linear model (GLM) with the rate of Caesarean section as response and terms for treatment arm and centre. We will use the GLM to calculate relative risk and 95% confidence intervals. The primary analysis will be adjusted for recruitment centre.
Further details of the statistical analysis will be supplied in the Statistical Analysis Plan, to be finalised in a separate document before the data lock.
The analysis will be conducted according to the intention to treat (ITT).
Data and all appropriate documentation will be stored for a minimum of 5 years after the completion of the study, including the follow-up period.
Regulatory issues
Ethics approval
The Chief Investigator has obtained approval from the Derby 1 Research Ethics Committee. Where applicable the study must be submitted for Site Specific Assessment (SSA) at each participating NHS Trust. The Chief Investigator will require a copy of the SSA approval letter before accepting participants into the study. The study will be conducted in accordance with the recommendations for physicians involved in research on human subjects adopted by the 18th World Medical Assembly, Helsinki 1964 and later revisions.
Consent
Consent to enter the study must be sought from each participant only after a full explanation has been given, an information leaflet offered and time allowed for consideration. Signed participant consent should be obtained. The right of the participant to refuse to participate without giving reasons must be respected. After the participant has entered the study the clinician remains free to give alternative treatment to that specified in the protocol at any stage if he/she feels it is in the participant’s best interest, but the reasons for doing so should be recorded. In these cases the participants remain within the study for the purposes of follow-up and data analysis. All participants are free to withdraw at any time from the protocol treatment without giving reasons and without prejudicing further treatment.
Confidentiality
The Chief Investigator will preserve the confidentiality of participants taking part in the study and is registered under the Data Protection Act.
Indemnity
Standard NHS Indemnity applies.
Nottingham University Hospitals NHS Trust will act as the main sponsor for this study. Delegated responsibilities will be assigned to the NHS trusts taking part in this study.
Funding
The National Institute for Health Research – Research for Patient Benefit Programme is funding this study.
Audits
The study may be subject to inspection and audit by Nottingham University Hospitals under their remit as sponsor and other regulatory bodies to ensure adherence to GCP and the NHS Research Governance Framework for Health and Social Care (2nd edition).
Study management
The day-to-day management of the study will be co-ordinated through the Trial Manager – Dr Kate Walker supported by the Trial Management Group (Professor Jim Thornton, Mr George Bugg, Miss Marion Macpherson, Professor Gordon Smith, Miss Carol McCormick, Mrs Nicky Grace and Mr Chris Wildsmith).
The Trial Steering Committee (TSC) will provide overall supervision of the trial including trial progress, adherence to the protocol, patient safety and consideration of new information arising during the period of recruitment to the trial.
The Data Monitoring and Ethics Committee (DMEC) will meet regularly to review un-blinded data.
Publication policy
All papers will be authored by the “35/39” trial study group. All contributors will be fully acknowledged.