Pessary Versus Cerclage With or Without Progesterone in Twins

Study Overview
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Brief Summary
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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
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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 they 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, they 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. We 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. 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/.

Official Title
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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

Conditions
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Preterm Birth, Twin Pregnancy, Short Cervix

Intervention / Treatment
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* Device: Pessary
* Procedure: Cervical cerclage
* Drug: Vaginal progesterone


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Pessary group<br>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. Size of the pessary will be determined at the time of speculum inspection. | Device: Pessary<br>* A soft, flexible, silicone pessary (Arabin®, Dr Arabin GmbH & Co KG, Germany) will be inserted through the vagina, upward around the cervix.<br>* Other names: Arabin;|
| Active Comparator: Cerclage group<br>Women will be receiving the cervical cerclage according to local protocol, within a week after randomisation. 3 senior clinicians who had experienced with cerclage, will perform cerclage, using Mc Donald technique, under spinal anaesthesia. | Procedure: Cervical cerclage<br>* Cervical cerclage using Mc Donald technique, under anaesthesia<br>* Other names: Stitch;|
| Active Comparator: Pessary plus progesterone group<br>400 mg vaginal progesterone, purchased from the manufacturer (Cyclogest® 400mg, Actavis, United Kingdom), will be applied once daily at bedtime, starting from the day of randomisation, 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 140 days. | Device: Pessary<br>* A soft, flexible, silicone pessary (Arabin®, Dr Arabin GmbH & Co KG, Germany) will be inserted through the vagina, upward around the cervix.<br>* Other names: Arabin;Drug: Vaginal progesterone<br>* Cyclogest® 400mg, Actavis, United Kingdom, applied once daily at bedtime<br>* Other names: Cyclogest 200 mg;|
| Active Comparator: Cerclage plus progesterone group<br>400 mg vaginal progesterone, purchased from the manufacturer (Cyclogest® 400mg, Actavis, United Kingdom), will be applied once daily at bedtime, starting from the day of randomisation, in addition to the cerclage that has been placed. Participants will be asked to record their drug application in a patient diary sheet for up to 140 days. | Procedure: Cervical cerclage<br>* Cervical cerclage using Mc Donald technique, under anaesthesia<br>* Other names: Stitch;Drug: Vaginal progesterone<br>* Cyclogest® 400mg, Actavis, United Kingdom, applied once daily at bedtime<br>* Other names: Cyclogest 200 mg;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Preterm birth <34 weeks | Birth before 34 weeks' gestation | From date of randomisation until 33 6/7 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gestational age at delivery | Gestational age at delivery Time from randomisation to delivery Delivery < 24 weeks, < 28 weeks, < 32 weeks and < 37 weeks of gestation Spontaneous preterm birth < 24 weeks, < 28 weeks, < 32 weeks and < 37 weeks of gestation Onset of labor: spontaneous, labor induction, elective C-section Mode of delivery: vaginal delivery, C-section All livebirths at any gestational age Use of tocolytic drugs Use of antenatal corticosteroids Use of magnesium sulfat for fetal neuroprotection Preterm prelabour rupture of membranes Length of maternal admission for preterm labor (days) Chorioamnionitis Marternal mortality | At birth | 
| Time from randomisation to delivery | Time interval between randomisation and delivery | From date of randomisation until the date of delivery, assessed up to 22 weeks | 
| Preterm birth <28 weeks | Birth before 28 weeks' gestation | From date of randomisation until 27 6/7 weeks | 
| Preterm birth <37 weeks | Birth before 37 weeks' gestation | From date of randomisation until 36 6/7 weeks | 
| Spontaneous preterm birth <28 weeks | Birth spontaneously before 28 weeks' gestation, including preterm spontaneous rupture of membranes, preterm premature rupture of membranes (PPROM) | From date of randomisation until 27 6/7 weeks | 
| Spontaneous preterm birth <34 weeks | Birth spontaneously before 34 weeks' gestation, including preterm spontaneous rupture of membranes, preterm premature rupture of membranes (PPROM) | From date of randomisation until 33 6/7 weeks | 
| Spontaneous preterm birth <37 weeks | Birth spontaneously before 37 weeks' gestation, including preterm spontaneous rupture of membranes, preterm premature rupture of membranes (PPROM) | From date of randomisation until 36 6/7 weeks | 
| Iatrogenic preterm birth <28 weeks | Birth non-spontaneously before 28 weeks' gestation | From date of randomisation until 27 6/7 weeks | 
| Iatrogenic preterm birth <34 weeks | Birth non-spontaneously before 34 weeks' gestation | From date of randomisation until 33 6/7 weeks | 
| Iatrogenic preterm birth <37 weeks | Birth non-spontaneously before 37 weeks' gestation | From date of randomisation until 36 6/7 weeks | 
| Onset of labor | Spontaneous, labor induction, elective C-section | At birth | 
| Mode of delivery | Vaginal delivery, C-section (elective, suspected fetal distress, non-progressive labor) | At birth | 
| Livebirth | The birth of at least one newborn, regardless of gestational age, that exhibits any sign of life such as respiration, heartbeat, umbilical pulsation or movement of voluntary muscles | At birth | 
| Use of tocolytic drugs | Use of any tocolytic drug to treat preterm labour | From 24 0/7 to 33 6/7 weeks' gestation | 
| Use of antenatal corticosteroids | Use of antenatal corticosteroids to prevent respiratory distressed syndrome | From 24 0/7 to 33 6/7 weeks' gestation | 
| Use of MgSO4 for neuroprotection | Use of MgSO4 for neuroprotection in | From 28 0/7 to 31 6/7 weeks' gestation | 
| Preterm prelabour rupture of membranes | Prelabour rupture of membranes and gestational age less than 37 weeks | From randomization to less than 37 weeks, up to 21 weeks | 
| Length of maternal admission for preterm labour | Number of admission days for treatment of preterm labour | From 24 weeks to 37 week | 
| Chorioamnionitis | Intraamniotic infection | From randomization to delivery, up to 22 weeks | 
| Maternal mortality | Death of the mother | From randomization to delivery, up to 22 weeks | 
| Birthweight | Weight of baby born | At birth | 
| Birthweight <1500 g | Weight of baby born <1500g | At birth | 
| Birthweight <2500 g | Weight of baby born <2500g | At birth | 
| Congenital anomalies after randomisation | Any congenital anomalies detected in baby born | At birth | 
| 5-min Apgar score | Apgar score at 5 minute after birth | At birth | 
| 5-min Apgar score <7 | Apgar score at 5 minute after birth <7 | At birth | 
| Admission to neonatal intensive care unit (NICU) | Admission to neonatal intensive care unit of baby | Within 7 days after birth | 
| Length of NICU admission | Number of admission days to NICU | Up to 28 days after birth | 
| Respiratory distress syndrome | The presence of tachypnoea >60/minute, sternal recession and expiratory grunting, need for supplemental oxygen, and a radiological picture of diffuse reticulogranular shadowing with an air bronchogram | Up to 28 days after birth | 
| Periventricular haemorrhage II B or worse | Repeated neonatal cranial ultrasound by the neonatologist according to the guidelines on neuro-imaging described by de Vries et al | Up to 28 days after birth | 
| Necrotizing enterocolitis | Diagnosed according to Bell | Up to 28 days after birth | 
| Proven sepsis | The combination of clinical signs and positive blood cultures | Up to 28 days after birth | 
| Stillbirth | Baby born with no signs of life at or after 28 weeks' gestation | At birth | 
| Death before discharge | Death of newborn before discharge from nursery | Up to 28 days after birth | 
| Composite of poor perinatal outcomes | Foetal or neonatal death, intraventricular haemorrhage, respiratory distress syndrome, necrotizing enterocolitis or neonatal sepsis | Up to 28 days after birth | 
| Maternal side effects | Including vaginal discharge, fever, vaginal bleeding, vaginal infection (confirmed by vaginal discharge culture), vaginal pain, pessary repositioning and necrosis or rupture of the cervix | From date of randomisation until delivery, which is up to 22 weeks | 
| Fetal death <24 weeks | Fetal death before 24 weeks' gestation | From randomization to 23 6/7 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pessary, Cerclage, Progesterone, Twins, Preterm birth