Pessary Versus Progesterone in Singletons

Study Overview
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Brief Summary
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This study compares the effectiveness of cervical pessary to vaginal progesterone for prevention of preterm birth in women with singleton pregnancies and a cervix ≤25 mm. Participants will be randomly assigned in a 1:1 ratio to receive cervical pessary or vaginal progesterone.

Detailed Description
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This open label, multi-center, randomized controlled trial aims to compare the effectiveness of cervical pessary to vaginal progesterone for prevention of PTB in women with singleton pregnancies and a cervix ≤25 mm. All women at 16 0/7 to 22 0/7 weeks with singleton pregnancies will undergo cervical length (CL) measurement and digital examination at screening routinely. Women with a CL ≤25 mm will be eligible for the study. Subjects meeting the study criteria will be randomized into two groups: (1) treated with cervical pessary (Arabin) or (2) treated with 200 mg vaginal progesterone, once daily. After written informed consent, women will be randomly assigned in a 1:1 ratio to receive a cervical pessary or progesterone. Assignment to treatment allocation will be done via a web portal hosted by HOPE Research Center, Vietnam. The randomization schedule will be computer-generated at HOPE Research Center, with a permuted random block size of 2, 4 or 6. Blinding will not be possible due to the nature of interventions. For those who randomised to pessary group, a pessary certified by European Conformity (Arabin®, Dr Arabin GmbH & Co KG, Germany) will be inserted through the vagina, upward around the cervix by 2-4 senior clinicians, who had experienced with pessary used at each site, within one week of randomization. Women allocated to progesterone group will be receiving 200 mg vaginal progesterone, purchased from the manufacturer (Cyclogest® 200 mg, Actavis, United Kingdom), once daily at bedtime. They will be given a monitoring sheet and instructed to note everyday the date of using. In case of premature rupture of membranes, active vaginal bleeding, other signs of preterm labor or severe patient discomfort, the pessary may be removed. If participants develop (threatened) preterm labor, they will receive treatment per local protocol. Intervention will be stopped at 370/7 weeks of gestation or at delivery. Along side with this trial, another study will be conducted to determine how changes in peripheral blood and cervical inflammatory markers are impacted by progesterone versus pessary. Because of that, participants will be asked to take 5 ml blood sample and cervical-vaginal discharge sampling at the time of randomization, 4-8 weeks after randomization and before giving birth. A cost-effectiveness analysis will also be conducted alongside this RCT. Data will be reported in a separated paper.

Official Title
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The Effectiveness of Cervical Pessary Versus Vaginal Progesterone for the Prevention of Preterm Birth in Women With Singleton Pregnancies and Short Cervix: a Multicenter Randomized Controlled Trial

Conditions
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Preterm Birth, Short Cervix

Intervention / Treatment
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* Device: Cervical pessary
* Drug: Vaginal Progesterone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Singleton pregnancies Cervical length ≤ 25 mm, measured by TVS at the second-trimester ultrasonography (16 0/7-22 0/7 weeks of gestation) Not participating in any other study which has intervention on maternity or fetus at the same time Provision of written informed consent to participate as shown by a signature on the patient consent form. Exclusion Criteria: Cervical dilation with visible amniotic membranes or amniotic membranes prolapsed into the vagina Major congenital abnormalities of the fetus Presence of severe vaginal discharge Presence of vaginitis or cervicitis Presence of vaginal bleeding Preterm premature rupture of membranes Premature labor without ruptured membrane at the time of screening Suspected chorioamnionitis Unable to have cervical pessary inserted Cerclage or pessary in place

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: Parallel Assignment
Interventional Model Description: Participants will be randomised to either pessary or progesterone in a 1:1 ratio with a variable block size of 2, 4 or 6.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cervical pessary<br>Cervical pessary (Arabin) will be inserted to participants at 16-22 weeks and removed at 37 weeks of pregnancy or in case of premature rupture of membranes, signs of preterm labour or patient severe discomfort. | Device: Cervical pessary<br>* Arabin (cervical pessary) will be inserted at 16-22 weeks and removed at 37 weeks of pregnancy or in case of premature rupture of membranes, signs of preterm labour or patient severe discomfort<br>* Other names: Arabin;|
| Active Comparator: Vaginal Progesterone<br>Vaginal progesterone (Cyclogest 200 mg) once a day will be used, from 16-22 to 37 weeks of pregnancy or in case of premature rupture of membranes, signs of preterm labour or patient severe discomfort. | Drug: Vaginal Progesterone<br>* Vaginal progesterone (Cyclogest 200 mg) once a day will be used, from 16-22 to 37 weeks of pregnancy or in case of premature rupture of membranes, signs of preterm labour or patient severe discomfort.<br>* Other names: Cyclogest 200 mg;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of preterm birth <37 weeks of gestation by any cause | Birth before 37 weeks | From date of randomisation until 36 6/7 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gestational age at delivery | Gestational age at delivery | At birth | 
| Time from randomization to delivery | Time interval between randomisation and delivery | From date of randomisation until the date of delivery. | 
| Rate of preterm birth before 28 weeks of gestation | Birth before 28 weeks | From date of randomisation until 27 6/7 weeks | 
| Rate of preterm birth before 34 weeks of gestation | Birth before 34 weeks | From date of randomisation until 33 6/7 weeks | 
| Rate of 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 | 
| Rate of 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 | 
| Rate of 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 | 
| Rate of iatrogenic preterm birth <28 weeks | Birth non-spontaneously before 28 weeks' gestation | From date of randomisation until 27 6/7 weeks | 
| Rate of iatrogenic preterm birth <34 weeks | Birth non-spontaneously before 34 weeks' gestation | From date of randomisation until 33 6/7 weeks | 
| Rate of iatrogenic preterm birth <37 weeks | Birth non-spontaneously before 37 weeks' gestation | From date of randomisation until 36 6/7 weeks | 
| Rate of onset of labor | Spontaneous, labor induction, elective C-section | At birth | 
| Rate of modes of delivery | Vaginal delivery, C-section (elective, suspected fetal distress, non-progressive labor) | At birth | 
| Rate of all live births at any gestational age | 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 | 
| Rate of use of tocolytic drugs | Use of any tocolytic drug to treat preterm labour | From 24 0/7 to 36 6/7 weeks' gestation | 
| Rate of use of antenatal corticosteroids | Use of antenatal corticosteroids to prevent respiratory distressed syndrome | From 24 0/7 to 36 6/7 weeks' gestation | 
| Rate of use of MgSO4 for neuroprotection | Use of MgSO4 for neuroprotection | From 28 0/7 to 31 6/7 weeks' gestation | 
| Rate of preterm premature 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 labor (days) | Number of admission days for treatment of preterm labour | From randomization to 37 week | 
| Rate of chorioamnionitis | Intraamniotic infection | From randomization to delivery, up to 28 weeks | 
| Rate of maternal mortality | Death of the mother | From randomization to delivery, up to 28 weeks | 
| Birthweight (mean) | 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 | 
| Rate of congenital anomalies | Any congenital anomalies detected in baby born | At birth | 
| 5-min Apgar score | Apgar score at 5 minute after birth. 5-minute Apgar score of 7-10 as reassuring, a score of 4-6 as moderately abnormal, and a score of 0-3 as low in the term infant and late-preterm infant. | At birth | 
| 5-min Apgar score <7 | Apgar score at 5 minute after birth <7. An increased relative risk of cerebral palsy. | At birth | 
| Rate of admission to neonatal intensive care unit (NICU) | Admission to neonatal intensive care unit of baby | Up to 28 days of life after the due day | 
| Length of NICU admission | Number of admission days to NICU | Up to 28 days of life after the due day | 
| Rate of death before discharge | Death of newborn before discharge from nursery | Up to 28 days of life after the due day | 
| Rate of neonatal death | Death of a live-born infant within the first 28 days of life after the due day | Up to 28 days of life after the due day | 
| Rate of perinatal death | Intrauterine fetal death after 20 weeks of gestation, or neonatal death | After 20 weeks of gestation to 28 days of life after the due day | 
| Rate of stillbirth | Baby born with no signs of life at or after 20 weeks' gestation | After 20 weeks of gestation until the date of delivery | 
| Rate of composite of poor perinatal outcomes | Foetal or neonatal death, intraventricular haemorrhage, respiratory distress syndrome, necrotizing enterocolitis or neonatal sepsis | Up to 28 days of life after the due day | 
| Rate of respiratory distress syndrome | 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 of life after the due day | 
| Rate of 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 of life after the due day | 
| Rate of necrotizing enterocolitis | Diagnosed according to Bell | Up to 28 days of life after the due day | 
| Rate of proven sepsis | The combination of clinical signs and positive blood cultures | Up to 28 days of life after the due day | 
| Rate of maternal vaginal side effects | Including vaginal discharge, vaginal bleeding, vaginal infection (confirmed by vaginal discharge culture) | From date of randomisation until delivery, which is up to 24 weeks | 
| Vaginal pain Score | Evaluated by VAS numerical rating scale. Assessments with units on a Scale. | From date of randomisation until delivery, which is up to 24 weeks | 
| Rate of pessary repositioning | After pessary initial placement, requiring to reposition the pessary by any reasons | From date of randomisation until delivery, which is up to 24 weeks | 
| Rate of maternal cervical side effects | Including necrosis or rupture of the cervix, cervical laceration | From date of randomisation until delivery, which is up to 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Preterm Birth, Singleton Pregnancies, Short Cervix, Pessary, Progesterone