Clinical trial NCT06463652: Cerclage with Progesterone Versus Progesterone Only in Singleton Pregnancies
Official title: Cervical Cerclage with Vaginal Progesterone Versus Vaginal Progesterone Only for Preterm Birth Prevention in Women with a Singleton Pregnancy and a Short Cervical Length: a Randomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Preterm Birth
Short Cervix
Keywords: Cerclage
Progesterone
Singleton
Preterm birth
Lead sponsor: Mỹ Đức Hospital
Sponsor class: OTHER
First posted: 2024-06-18
Enrollment: 328
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: This study compares the effectiveness of cervical cerclage with vaginal progesterone to vaginal progesterone only for the prevention of preterm birth in women with a singleton pregnancy and a short cervical length. Participants will be randomly assigned in a 1:1 ratio to receive cerclage plus progesterone or progesterone only.

Detailed 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.

Eligibility criteria: Inclusion Criteria:

* Maternal age ≥18 years
* Singleton pregnancy
* Cervical length ≤ 25 mm, measured by TVS at the second-trimester ultrasonography (16 0/7 - 24 0/7 weeks of gestation)
* Not participating in any other study which has intervention on maternity or fetus
* Provision of written informed consent as shown by a signature on the participant consent form.

Exclusion Criteria:

* Cervical dilation with visible amniotic membranes or amniotic membranes prolapsed into the vagina
* Major congenital abnormalities of the fetus
* Intrauterine fetal demise
* Presence of severe vaginal discharge\*
* Presence of vaginitis or cervicitis\*
* Presence of vaginal bleeding\*
* Placenta previa or vasa previa
* Preterm premature rupture of membranes
* Preterm labor without ruptured membrane at the time of screening
* Suspected chorioamnionitis
* Unable to undergo cerclage
* Cerclage in place
* Allergy to progesterone

(\*Women with acute cervicitis, vaginitis or severe vaginal discharge are eligible once they have been treated and if they have a CL ≤25 mm between 16 0/7 - 24 0/7 weeks of gestation.)

Primary outcomes:
measure: Time from randomization to delivery
timeFrame: From date of randomization until the date of delivery
Secondary outcomes:
measure: Composite poor neonatal outcomes (major sencondary endpoint)
timeFrame: From 20 weeks of gestation to 28 days after estimated due date
measure: Miscarriage <22 weeks (late miscarriage)
timeFrame: From date of randomization to 22 weeks of gestation
measure: Gestational age at delivery
timeFrame: At delivery
measure: Preterm birth <24 weeks, <28 weeks, <32 weeks, <34 weeks and <37 weeks of gestation
timeFrame: At delivery
measure: Spontaneous preterm birth <24 weeks, <28 weeks, <32 weeks, <34 weeks and <37 weeks of gestation
timeFrame: At delivery
measure: Iatrogenic preterm birth <24 weeks, <28 weeks, <32 weeks, <34 weeks and <37 weeks of gestation
timeFrame: At delivery
measure: Onset of labor
timeFrame: At birth
measure: Mode of delivery
timeFrame: At birth
measure: Live birth
timeFrame: At birth
measure: Use of tocolytic drugs
timeFrame: From 24 0/7 to 33 6/7 weeks' gestation
measure: Use of Post cerclage antibiotics
timeFrame: Within one week after the cerclage procedure
measure: Use of antenatal corticosteroids
timeFrame: From 24 0/7 to 33 6/7 weeks' gestation
measure: Use of MgSO4 for neuroprotection
timeFrame: From 24 0/7 to 31 6/7 weeks' gestation
measure: Fetal growth restriction
timeFrame: From randomization to delivery
measure: Preterm premature rupture of membranes
timeFrame: From randomization to before 37 weeks of gestation
measure: Length of maternal admission for labour
timeFrame: Up to 2 weeks after birth
measure: Total length of admission for threatened preterm labor
timeFrame: From 22 0/7 to 36 6/7 weeks of gestation
measure: Chorioamnionitis
timeFrame: From randomization to delivery
measure: Maternal mortality
timeFrame: From randomization to during pregnancy and childbirth or within 42 days of termination of pregnancy
measure: Maternal side effects
timeFrame: From date of randomization until delivery
measure: Birthweight
timeFrame: At birth
measure: Birthweight <1500 g
timeFrame: At birth
measure: Birthweight <2500 g
timeFrame: At birth
measure: Congenital anomalies
timeFrame: After randomization to at birth
measure: 1-min Apgar score
timeFrame: 1 min after birth
measure: 5-min Apgar score
timeFrame: 5 min after birth
measure: Admission to neonatal intensive care unit
timeFrame: At birth and up to 28 days after birth
measure: Length of stay in the neonatal intensive care unit
timeFrame: Up to 28 days after estimated due date
measure: Neonatal death
timeFrame: Within the first 28 days of life after delivery
measure: All stillbirth
timeFrame: After 20 weeks of gestation
measure: Early stillbirth
timeFrame: ≥ 20 weeks and < 28 weeks of gestation
measure: Late stillbirth
timeFrame: After 28 weeks of gestation
measure: Perinatal death
timeFrame: From 20 weeks of gestation to the first 28 days of life after delivery
measure: Respiratory distress syndrome
timeFrame: Up to 28 days after estimated due date
measure: Intraventricular haemorrhage II B or worse
timeFrame: Up to 28 days after estimated due date
measure: Necrotizing enterocolitis
timeFrame: Up to 28 days after estimated due date
measure: Neonatal sepsis
timeFrame: Up to 28 days after estimated due date
Other outcomes:
Locations:
city: Ho Chi Minh City
country: Vietnam
facility: My Duc Hospital
Study officials:
affiliation: University of Medicine and Pharmacy at Ho Chi Minh City
name: Lan N Vuong, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: