Description

This open-label, multi-center, randomized controlled trial aims to compare the effectiveness of cervical cerclage with vaginal progesterone (the combined therapy group) to vaginal progesterone only (the progesterone-only group) for the prevention of preterm birth in women with a singleton pregnancy and a cervical length ≤ 25mm.

After written informed consent, women will be randomly assigned in a 1:1 ratio to receive a cervical cerclage with vaginal progesterone or vaginal progesterone only. Randomization will be carried out by entering participant details into HOPE Epi® (a web portal of HOPE Research Center, My Duc Hospital). Treatment allocation will be assigned according to a computer-generated randomization list stored in the online system, with a permuted random block size of 2, 4, or 6. Blinding will not be possible due to the nature of interventions. However, neonatologists assessing the neonates will be unaware of treatment allocation. Apart from randomization, participants will be monitored and treated according to local protocol.

All women at 16 0/7 to 24 0/7 weeks' gestation with a singleton pregnancy will undergo cervical length measurement and digital examination at screening routinely. Women with a cervical length ≤25 mm will be eligible for the study. Eligible women will further undergo a speculum examination to assess the feasibility of treatment with either cervical cerclage or vaginal progesterone and to exclude premature rupture of the membranes, acute vaginitis, and cervicitis. Only women in whom the clinician assesses both treatments as feasible will be randomized.

Women allocated to a combined therapy group will receive the intervention according to local protocol within a week after randomization. Briefly, cervical cerclage (McDonald technique) will be performed in the operation theatre. From the same day of undergoing cerclage, participants will be receiving 200 mg vaginal progesterone, purchased from the manufacturer (Cyclogest® 200mg, Actavis, United Kingdom), once daily at bedtime. Participants will be asked to record their drug application in a participant diary sheet.

Women allocated to the progesterone-only group will be receiving 200 mg vaginal progesterone, purchased from the manufacturer (Cyclogest® 200mg, Actavis, United Kingdom), once daily at bedtime. Participants will be asked to record their drug application in a participant diary sheet.

In both groups, interventions will be stopped at 37 0/7 weeks of gestation or at delivery.

Primary analysis will be performed on an intention-to-treat basis. The primary outcome, the time from randomization to delivery, will be summarised as median and IQR and compared between the two arms using the Mann-Whitney test. A mean ratio with a 95% confidence interval will be calculated to assess the effect of the treatment. Kaplan-Meier and Cox proportional hazard analysis will be performed in which the gestational week at delivery will be the time scale, continued pregnancy will be the event, and results will be compared with a log-rank test. Hazard ratio (HR) values will be estimated using a Cox proportional hazards model, with a formal test of the proportional hazard assumption.

The secondary outcome will be analysed by reporting continuous variables as mean and standard deviation for normally distributed variables or median and interquartile range (Q1; Q3) for non-normally distributed variables. Categorical variables will be presented as the number of events and proportions. Student T-test or Mann-Whitney U test will be used for continuous outcomes to compare the differences between groups. For categorical outcomes, the Chi-squared or Fisher exact test will be used. In the case of dichotomous endpoints, the relative risk (RR) and 95% confidence interval (CI) values will be calculated using the Wald or Adjusted Wald methods for a small proportion. Per-protocol analysis will also be conducted if needed.

A prespecified subgroup analysis will be performed by quartiles of cervical length, which tested for interaction between cervical length and the treatment effect on the primary outcome, the major secondary outcome and PTB <28, <34, <37 weeks.

The p-values <0.05 will be considered to indicate statistical significance. Statistical analyses will be performed using the R statistical software.

Details of the analysis will be described in a separate statistical analysis plan developed during the study and finalized before the data lock. Cost data will be collected and will be reported on a separated paper.

Interim analysis will be done after completion of data recruitment of the first 162 participants, by an independent Data Safety Monitoring Committee. The Data Safety Monitoring Committee will be asked to assess the primary endpoint for effectiveness. Also, the Data Safety Monitoring Committee will be provided insight into the serious adverse events (SAEs) that have occurred. The interim analysis will be conducted using a two-sided significant test with the Haybittle-Peto spending function and a type I error rate of 5 percent with p <0.001 (Z alpha = 3.29) being a reason to stop the trial. The continuation of the study will depend on the advice of Data Safety Monitoring Committee.