Aims of the trial
The aim of this trial is to test the hypothesis that IMN, 40 mg every 16 hours to a total of three doses improves the process of induction of labour. Specifically we aim to test the hypotheses that outpatient pre-induction cervical ripening with IMN:
i. Reduces the elapsed time from hospital admission to delivery
ii. Reduces the costs of induction of labour
iii. Improves women's experience of induction of labour
iv. Does not increase operative delivery rates
Women scheduled for induction of labour at term, and who require pre-induction cervical ripening will be invited to participate in the study. Participants will be randomised into an active (IMN) or a control (placebo) group and asked to self-administer either IMN 40 mg, or a placebo, each vaginally, at 48 hours, 32 hours and 16 hours before scheduled admission. After admission to hospital, treatment will revert to the usual induction of labour protocol whereby prostaglandins are given until cervical ripening is achieved, and fetal membrane rupture is performed thereafter, followed by syntocinon if contractions do not start spontaneously. Data on the outcome measures listed below will be collected and compared in the two groups.
IMOP is a double blind, randomised, placebo controlled trial in a single clinical setting. Active and placebo treatment will be allocated in a 1:1 ratio. The primary outcome measures are the effect of outpatient pre-induction cervical ripening with IMN on:
i. The elapsed time from hospital admission to delivery (defined as the time from admission to inpatient induction or admission in labour to delivery – either vaginally or by caeserean section)
ii. The costs of induction of labour
iii. Women's experience of induction of labour (maternal satisfaction)
iv. Operative delivery rates
The study will be carried out in a large UK NHS teaching hospital (Princess Royal Maternity, Glasgow).
Women scheduled for induction of labour will be invited to participate in the study. The rationale for induction of labour in the majority (but not all) of these women will be post-dates pregnancy. The hospital protocol is to offer induction of labour after 40 weeks and 10 days gestation, and in the PRIM study, "post dates" was the principal reason for induction of labour in over 70% of subjects. The other inclusion criteria will be as follows:
▪ Bishop Score ≤ 6
▪ Singleton pregnancy
▪ ≥37 completed weeks of gestation
▪ Willing to self administer vaginal tablets
▪ fetal compromise of sufficient severity that daily fetal monitoring is scheduled.
Recruitment and consent
Subjects will not be formally recruited to the study until the decision to induce labour is made. Potential subjects will be informed about the trial and given written information in the third trimester. Those women who wish to participate and who understand the nature of the trial will be asked to complete and sign two copies of the consent form. Those women who do not wish to participate, or who are ineligible will be asked (verbally) for permission to record some basic data so that the generalisability of the trial can be subsequently assessed.
Women scheduled for induction of labour at term will be recruited and randomised at an antenatal visit by the clinical research fellow, up to seven days prior to scheduled admission for induction of labour. A vaginal examination will not be repeated if one has been done and each of the components of the Bishop score documented within 7 days of anticipated start of outpatient treatment. Women willing to participate in the study will be given their randomised study medication (either IMN tablets or placebo) at this visit, with instructions to self-administer the tablets vaginally starting 48 hours prior to the scheduled time of admission for induction of labour.
Randomisation to IMN or placebo will be in the ratio 1:1, using randomised permuted blocks. The randomisation schedule will be generated by the Study Data Centre at the Centre for Healthcare Randomised Trials (CHaRT) at Aberdeen University. The randomisation schedule will be used by the Clinical Trials section of the pharmacy at the Western Infirmary, Glasgow, to make up treatment packs (either active or placebo) for each patient, each labelled with the relevant unique study number. Active and placebo treatments will otherwise appear identical, so that this will be a double blind study. A copy of the randomisation schedule will be held at the Clinical Trials Pharmacy at the Western Infirmary, and at CHaRT only. None of the investigators will have access to the schedule until completion of the study.
Within one hour after recruitment of each subject, the pack number for the subject will be allocated by phone call to the automated telephone randomisation service located at CHaRT in Aberdeen.
Cessation of randomised treatment
The following will be indications for early cessation of treatment
Admission in labour
Fetal membrane rupture
The general practitioner and referring obstetrician will be informed. The clinical research fellow will still collect outcome data from women who have stopped taking their study medication, unless the participant asks that her data are not collected. Women who are admitted in labour, women who experience spontaneous membrane rupture and those who experience antepartum haemorrhage will be asked not to take any more doses of study drug, but will still be followed up. Women in whom fetal membranes rupture after taking study medication will be asked to come into the hospital for assessment. They will normally be offered the option of immediate augmentation with syntocinon, or delaying augmentation with syntocinon until the next morning, depending on their preference.
In the event of a participant deciding to stop their medication themselves, or if cessation is recommended by the supervising obstetrician, the clinical research fellow will complete the withdrawal CRF. The clinical research fellow will also inform the hospital pharmacy, and return any unused medication. The general practitioner and referring obstetrician will be informed.
The intervention is one tablet inserted vaginally on three occasions every 16 hours. In the experimental (IMN) group, a 40 mg IMN tablet will be self-administered vaginally by the patient at home 48, 32 and 16 hours before scheduled admission for induction of labour. In the control group, a placebo tablet, with an identical appearance to that of IMN, will be self-administered vaginally by the patient at home 48, 32 and 16 hours before scheduled admission for induction of labour.
Rationale for dosage
IMN will be given in a dose of 40 mg. Previous studies have shown that this dose is effective in inducing cervical ripening both in the first trimester [8, 9] and at term  (PRIM) with no clinically significant effects on maternal haemodynamics  and without unacceptable side effects (PRIM) .
Rationale for dosage intervals
We have opted for a 16 hour dosage interval. Our previous studies suggest that systemic absorption of IMN from vaginally administered tablets is slow , thus a short dosage interval might lead to accumulating serum levels of drug. In the PRIM study, we gave a repeated dose of IMN after 16 hours. Haemodynamic and symptomatic side effects after the second dose of IMN were, if anything, less than after the first, suggesting that a 16 hour treatment interval is not associated with unacceptable systemic levels of drug.
Rationale for duration of treatment
We have opted to give IMN for 48 hours prior to admission. We anticipate that the ripening effects of IMN will continue after the first 24 hours, so that the cervix might be fully ripened by 48 hours after treatment.
With the exception of trial medication, subjects will normally be managed according to the induction of labour protocol. Thus, once a subject is admitted after trial medication, she will be managed according to the normal protocol, ignoring the use of the trial medication.
Data on the primary and secondary outcomes listed below will be recorded.
i. Elapsed time interval from hospital admission to delivery (defined as the time from admission for inpatient induction or admission in labour to delivery – either vaginally or by caesarean section)
ii. Costs to the health service of induction of labour
iii. Women's experience of induction of labour
iv. Primary clinical outcome (elapsed time from admission to delivery) for the subgroup of women who deliver vaginally
v. Operative delivery rates
vi. Incidence of unscheduled admission for reasons other than labour commencing
vii. Duration and frequency of neonatal admissions to special care
viii. Incidence of adverse maternal and fetal outcomes such as uterine hypercontractility, postpartum haemorrhage (maternal outcomes) and meconium stained liquor, five minute Apgar of less than seven (fetal outcomes)
ix. Length of labour
x. Oxytocin augmentation rates
xi. Epidural usage
xii. Proportion with unfavourable cervix at 24 hours after admission
xiii. Requirement for additional inpatient cervical ripening agent