Clinical trial NCT03863613: Pessary Versus Cerclage With or Without Progesterone in Twins
Official title: The Effectiveness of Cervical Pessary Compared to Cervical Cerclage With or Without Vaginal Progesterone for the Prevention of Preterm Birth in Women With a Twin Pregnancy and a Short Cervix: a Two-by-two Factorial Randomised Clinical Trial
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Preterm Birth
Twin Pregnancy
Short Cervix
Keywords: Pessary, Cerclage, Progesterone, Twins, Preterm birth
Lead sponsor: Mỹ Đức Hospital
Sponsor class: OTHER
First posted: 2019-03-05
Enrollment: 219
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention model description: Participants will be randomised to either cerclage, pessary, cerclage plus progesterone or pessary plus progesterone in a 1:1:1:1 ratio with a variable block size of 4 or 8.
Primary purpose: PREVENTION

Brief summary: This study compares the effectiveness of cervical pessary and cervical cerclage with or without vaginal progesterone for prevention of preterm birth in women with a twin pregnancy and a cervix ≤28 mm.

Participants will be randomly assigned in a 1:1:1:1 ratio to receive cerclage, pessary, cerclage plus progesterone or pessary plus progesterone.

Detailed description: This open label, multi-center, two-by-two factorial, randomised controlled trial aims to compare the effectiveness of cervical pessary to cervical cerclage and also to determine the effectiveness of vaginal progesterone for the prevention of PTB in women with a twin pregnancy and a cervix ≤28 mm.

All women with a twin pregnancy will undergo cervical length measurement and digital examination at screening. Prior to CL measurement, women will be given a short brochure outlining risk factors and available PTB prevention methods. Only women with a CL ≤28 mm will be eligible for the study. Eligible participants will be screened by midwives or gynaecologists, then participants will be provided a full participant Information Sheet, Consent Form and will be invited to a full discussion with investigators about the study. Eligible women will further undergo a speculum examination to assess the feasibility of treatment with either cerclage or cervical pessary with or without progesterone and to exclude premature rupture of the membranes (PROM), acute vaginitis and cervicitis. All eligible women will be invited to participate in the study.

After written informed consent, women will be randomly assigned in a 1:1:1:1 ratio to receive a cerclage, pessary, cerclage plus progesterone or pessary plus progesterone. Assignment to treatment allocation will be done via a web portal hosted by HOPE Research Center, Vietnam. The randomisation schedule will be computer-generated at HOPE Research Center, with a permuted random block size of 4 or 8. Blinding will not be possible due to the nature of interventions. However, neonatologists assessing the children will be unaware of treatment allocation. Apart from randomisation, patients will be followed up and treated according to local protocol.

Women allocated to a cervical cerclage will be receiving the intervention according to local protocol, within a week after randomisation. Briefly, 2 to 3 senior clinicians, who had experienced with cerclage, will perform cervical cerclage, using Mc Donald technique, under spinal anaesthesia with a single dose of prophylactic antibiotics.

For those who randomised to pessary group, a soft, flexible, silicone pessary, purchased from the manufacturer (Arabin®, Dr Arabin GmbH \& Co KG, Germany), will be inserted through the vagina, upward around the cervix by 4 senior clinicians, who had experienced with pessary used, within one week of randomisation. The size of the pessary will be determined at the time of speculum inspection (Arabin and Alfirevic, 2013).

In the cerclage plus progesterone group, 400 mg vaginal progesterone, purchased from the manufacturer (Cyclogest® 400mg, Actavis, United Kingdom), will be applied once daily at bedtime, within two days after cerclage insertion. Participants will be asked to record their drug application in a patient diary sheet for up to 140 days.

In the pessary plus progesterone group, 400 mg vaginal progesterone, purchased from the manufacturer (Cyclogest® 400mg, Actavis, United Kingdom), will be applied once daily at bedtime, within two days after pessary insertion, in addition to the pessary that has been placed. Participants will be asked to record their drug application in a patient diary sheet for up to 147 days.

In all groups, participants will be re-assessed at 14 days post-randomisation for any possible adverse event. After that, participants will be seen monthly or weekly per local protocol. CL measurement will not be performed routinely after randomisation, unless for patients' preference. In case the CL was shortened, further intervention, if any, will be based on the clinician's decision after a discussion with the patient.

In case of premature rupture of the membranes, active vaginal bleeding, other signs of preterm labor or severe patient discomfort, the vaginal progesterone and pessary or cerclage, will be removed. If participants develop (threatened) preterm labor, participants will receive treatment per local protocol. Intervention will be stopped at 37 0/7 weeks of gestation or at delivery.

Compliance rate to progesterone will be calculated by dividing the number of progesterone doses used since the last visit by the number of progesterone doses that should have been used since the last visit. Women will be defined as compliant when the compliance rate are over 80%.

Statistical analysis will be conducted according to the intention-to-treat principle, in which all randomised women will be considered in the primary comparison between treatment groups. The per-protocol analysis may be conducted, but these results would be considered exploratory only. All tests will be two-tailed, and differences with p-value \<0.05 will be considered statistically significant.

In view of the two-by-two factorial design, the analysis will be done separately for cerclage versus pessary and for progesterone versus no progesterone. The investigators will test for interaction between CL and treatment effect on PTB \<34 weeks and the composite of poor perinatal outcomes.

A pre-specified subgroup analysis in women with a CL \<25th percentile, and at the 25-50th percentile, 50-75th percentile and \>75th percentile is planned. The percentile will be determined based on the CL from all women after randomisation.

The investigators plan one interim analysis. The interim analysis will be performed by an independent statistician who will not directly involve in the study, after completion of data collection of the first 150 randomised patients. At interim analyses, data will be assessed for safety, efficacy, and futility. Safety will be assessed in terms of serious adverse events (perinatal death, maternal mortality or severe maternal morbidity). 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% with stopping criteria of p \<0.001 (Z alpha = 3.29). Based on this report, the DSMB will provide guidance on whether to stop or continue the study.

A separated detailed statistical analysis plan will be developed and completed prior to data lock.

Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices) and study protocol will be available, upon request from investigators whose proposed use of the data has been approved by an independent review committee ("learned intermediary") identified for this purpose to achieve aims in the approved proposal. Data will be available at the beginning 9 months and ending 36 months following article publication. Proposals should be directed to bsvinh.dq@myduchospital.vn. To gain access, data requestors will need to sign a data access agreement. Data are available for 5 years at https://www.project-redcap.org/.

Eligibility criteria: Inclusion Criteria:

* Women with a twin pregnancy (mono- and di-chorionic)
* 16 0/7 to 22 0/7 weeks of gestation
* Maternal age ≥18 yrs
* Cervical length ≤28 mm
* Informed consent
* Not participating in another preterm birth study at the same time

Exclusion Criteria:

* Uterine anomalies
* Cervical dilation with visible amniotic membranes or amniotic membranes prolapsed into the vagina
* Twin-to-twin transfusion syndrome
* Stillbirth or major congenital abnormalities in any of the fetus
* Severe vaginal discharge
* Acute vaginitis or cervicitis
* Vaginal bleeding
* Placental preavia
* Vasa preavia
* Premature rupture of membranes
* Premature labor with/without ruptured membrane
* Suspicion of chorioamnionitis
* Cerclage or pessary in place or unable to undergo cervical cerclage or pessary

Primary outcomes:
measure: Preterm birth <34 weeks
timeFrame: From date of randomisation until 33 6/7 weeks
Secondary outcomes:
measure: Gestational age at delivery
timeFrame: At birth
measure: Time from randomisation to delivery
timeFrame: From date of randomisation until the date of delivery, assessed up to 22 weeks
measure: Preterm birth <28 weeks
timeFrame: From date of randomisation until 27 6/7 weeks
measure: Preterm birth <37 weeks
timeFrame: From date of randomisation until 36 6/7 weeks
measure: Spontaneous preterm birth <28 weeks
timeFrame: From date of randomisation until 27 6/7 weeks
measure: Spontaneous preterm birth <34 weeks
timeFrame: From date of randomisation until 33 6/7 weeks
measure: Spontaneous preterm birth <37 weeks
timeFrame: From date of randomisation until 36 6/7 weeks
measure: Iatrogenic preterm birth <28 weeks
timeFrame: From date of randomisation until 27 6/7 weeks
measure: Iatrogenic preterm birth <34 weeks
timeFrame: From date of randomisation until 33 6/7 weeks
measure: Iatrogenic preterm birth <37 weeks
timeFrame: From date of randomisation until 36 6/7 weeks
measure: Onset of labor
timeFrame: At birth
measure: Mode of delivery
timeFrame: At birth
measure: Livebirth
timeFrame: At birth
measure: Use of tocolytic drugs
timeFrame: From 24 0/7 to 33 6/7 weeks' gestation
measure: Use of antenatal corticosteroids
timeFrame: From 24 0/7 to 33 6/7 weeks' gestation
measure: Use of MgSO4 for neuroprotection
timeFrame: From 28 0/7 to 31 6/7 weeks' gestation
measure: Preterm prelabour rupture of membranes
timeFrame: From randomization to less than 37 weeks, up to 21 weeks
measure: Length of maternal admission for preterm labour
timeFrame: From 24 weeks to 37 week
measure: Chorioamnionitis
timeFrame: From randomization to delivery, up to 22 weeks
measure: Maternal mortality
timeFrame: From randomization to delivery, up to 22 weeks
measure: Birthweight
timeFrame: At birth
measure: Birthweight <1500 g
timeFrame: At birth
measure: Birthweight <2500 g
timeFrame: At birth
measure: Congenital anomalies after randomisation
timeFrame: At birth
measure: 5-min Apgar score
timeFrame: At birth
measure: 5-min Apgar score <7
timeFrame: At birth
measure: Admission to neonatal intensive care unit (NICU)
timeFrame: Within 7 days after birth
measure: Length of NICU admission
timeFrame: Up to 28 days after birth
measure: Respiratory distress syndrome
timeFrame: Up to 28 days after birth
measure: Periventricular haemorrhage II B or worse
timeFrame: Up to 28 days after birth
measure: Necrotizing enterocolitis
timeFrame: Up to 28 days after birth
measure: Proven sepsis
timeFrame: Up to 28 days after birth
measure: Stillbirth
timeFrame: At birth
measure: Death before discharge
timeFrame: Up to 28 days after birth
measure: Composite of poor perinatal outcomes
timeFrame: Up to 28 days after birth
measure: Maternal side effects
timeFrame: From date of randomisation until delivery, which is up to 22 weeks
measure: Fetal death <24 weeks
timeFrame: From randomization to 23 6/7 weeks
Other outcomes:
Locations:
city: Ho Chi Minh City
country: Vietnam
facility: My Duc Phu Nhuan Hospital
Study officials:
affiliation: My Duc Phu Nhuan Hospital
name: Yen TN He, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Dang VQ, He YT, Pham HN, Trieu TT, Bui TQ, Vuong NT, Nguyen LM, Nguyen DT, Le TV, Li W, Le CH, Mol BW, Vuong LN. Effectiveness of cervical pessary compared to cervical cerclage with or without vaginal progesterone for the prevention of preterm birth in women with twin pregnancies and a short cervix: study protocol for a two-by-two factorial randomised clinical trial. BMJ Open. 2020 Jun 16;10(6):e036587. doi: 10.1136/bmjopen-2019-036587.