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.