Pessary Versus Cerclage With or Without Progesterone in Twins

Preterm Birth Clinical Trial

— PCP-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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03863613
• Other study ID #: CS/MD/19/01
• Status: Terminated
• Phase: N/A
• Start date: March 23, 2019
• Est. completion date: July 29, 2023

Study information

• Verified date: December 2023
• Source: M? Ð?c Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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/.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 219
• Est. completion date: July 29, 2023
• Est. primary completion date: July 8, 2023
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Premature Birth
• Preterm Birth
• Short Cervix
• Twin Pregnancy

Intervention

Device:
• Pessary
A soft, flexible, silicone pessary (Arabin®, Dr Arabin GmbH & Co KG, Germany) will be inserted through the vagina, upward around the cervix.

Procedure:
• Cervical cerclage
Cervical cerclage using Mc Donald technique, under anaesthesia

Drug:
• Vaginal progesterone
Cyclogest® 400mg, Actavis, United Kingdom, applied once daily at bedtime

Locations

Country	Name	City	State
Vietnam	My Duc Phu Nhuan Hospital	Ho Chi Minh City

Sponsors (1)

Lead Sponsor	Collaborator
M? Ð?c Hospital

Country where clinical trial is conducted

Vietnam, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Preterm birth <34 weeks	Birth before 34 weeks' gestation	From date of randomisation until 33 6/7 weeks
Secondary	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
Secondary	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
Secondary	Preterm birth <28 weeks	Birth before 28 weeks' gestation	From date of randomisation until 27 6/7 weeks
Secondary	Preterm birth <37 weeks	Birth before 37 weeks' gestation	From date of randomisation until 36 6/7 weeks
Secondary	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
Secondary	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
Secondary	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
Secondary	Iatrogenic preterm birth <28 weeks	Birth non-spontaneously before 28 weeks' gestation	From date of randomisation until 27 6/7 weeks
Secondary	Iatrogenic preterm birth <34 weeks	Birth non-spontaneously before 34 weeks' gestation	From date of randomisation until 33 6/7 weeks
Secondary	Iatrogenic preterm birth <37 weeks	Birth non-spontaneously before 37 weeks' gestation	From date of randomisation until 36 6/7 weeks
Secondary	Onset of labor	Spontaneous, labor induction, elective C-section	At birth
Secondary	Mode of delivery	Vaginal delivery, C-section (elective, suspected fetal distress, non-progressive labor)	At birth
Secondary	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
Secondary	Use of tocolytic drugs	Use of any tocolytic drug to treat preterm labour	From 24 0/7 to 33 6/7 weeks' gestation
Secondary	Use of antenatal corticosteroids	Use of antenatal corticosteroids to prevent respiratory distressed syndrome	From 24 0/7 to 33 6/7 weeks' gestation
Secondary	Use of MgSO4 for neuroprotection	Use of MgSO4 for neuroprotection in	From 28 0/7 to 31 6/7 weeks' gestation
Secondary	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
Secondary	Length of maternal admission for preterm labour	Number of admission days for treatment of preterm labour	From 24 weeks to 37 week
Secondary	Chorioamnionitis	Intraamniotic infection	From randomization to delivery, up to 22 weeks
Secondary	Maternal mortality	Death of the mother	From randomization to delivery, up to 22 weeks
Secondary	Birthweight	Weight of baby born	At birth
Secondary	Birthweight <1500 g	Weight of baby born <1500g	At birth
Secondary	Birthweight <2500 g	Weight of baby born <2500g	At birth
Secondary	Congenital anomalies after randomisation	Any congenital anomalies detected in baby born	At birth
Secondary	5-min Apgar score	Apgar score at 5 minute after birth	At birth
Secondary	5-min Apgar score <7	Apgar score at 5 minute after birth <7	At birth
Secondary	Admission to neonatal intensive care unit (NICU)	Admission to neonatal intensive care unit of baby	Within 7 days after birth
Secondary	Length of NICU admission	Number of admission days to NICU	Up to 28 days after birth
Secondary	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
Secondary	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
Secondary	Necrotizing enterocolitis	Diagnosed according to Bell	Up to 28 days after birth
Secondary	Proven sepsis	The combination of clinical signs and positive blood cultures	Up to 28 days after birth
Secondary	Stillbirth	Baby born with no signs of life at or after 28 weeks' gestation	At birth
Secondary	Death before discharge	Death of newborn before discharge from nursery	Up to 28 days after birth
Secondary	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
Secondary	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
Secondary	Fetal death <24 weeks	Fetal death before 24 weeks' gestation	From randomization to 23 6/7 weeks