Pessary Versus Progesterone in Singletons

Preterm Birth Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04300322
• Other study ID #: CS/BVMD/20/04
• Status: Recruiting
• Phase: N/A
• Start date: May 1, 2020
• Est. completion date: December 1, 2022

Study information

• Verified date: October 2020
• Source: M? Ð?c Hospital
• Contact: Vinh Q Dang, MD
• Phone: +84908225481
• Email: bsvinh.dq[@]myduchospital.vn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 804
• Est. completion date: December 1, 2022
• Est. primary completion date: March 1, 2022
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Premature Birth
• Preterm Birth
• Short Cervix

Intervention

Device:
• Cervical pessary
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

Drug:
• Vaginal Progesterone
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.

Locations

Country	Name	City	State
Vietnam	M? Ð?c Hospital	Ho Chi Minh City	Tan Binh
Vietnam	My Duc Phu Nhuan Hospital	Ho Chi Minh City	Phu Nhuan
Vietnam	Quang Ninh Obstetrics and Pediatrics Hospital	Quang Ninh

Sponsors (3)

Lead Sponsor	Collaborator
M? Ð?c Hospital	My Duc Phu Nhuan Hospital HCMC, Vietnam, Quang Ninh Obstetrics and Pediatrics Hospital, Quang Ninh, Vietnam

Country where clinical trial is conducted

Vietnam, 

References & Publications (16)

Arabin B, Halbesma JR, Vork F, Hübener M, van Eyck J. Is treatment with vaginal pessaries an option in patients with a sonographically detected short cervix? J Perinat Med. 2003;31(2):122-33. — View Citation

Blencowe H, Cousens S, Oestergaard MZ, Chou D, Moller AB, Narwal R, Adler A, Vera Garcia C, Rohde S, Say L, Lawn JE. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet. 2012 Jun 9;379(9832):2162-72. doi: 10.1016/S0140-6736(12)60820-4. — View Citation

Dang VQ, Nguyen LK, Pham TD, He YTN, Vu KN, Phan MTN, Le TQ, Le CH, Vuong LN, Mol BW. Pessary Compared With Vaginal Progesterone for the Prevention of Preterm Birth in Women With Twin Pregnancies and Cervical Length Less Than 38 mm: A Randomized Controlled Trial. Obstet Gynecol. 2019 Mar;133(3):459-467. doi: 10.1097/AOG.0000000000003136. — View Citation

Goya M, de la Calle M, Pratcorona L, Merced C, Rodó C, Muñoz B, Juan M, Serrano A, Llurba E, Higueras T, Carreras E, Cabero L; PECEP-Twins Trial Group. Cervical pessary to prevent preterm birth in women with twin gestation and sonographic short cervix: a multicenter randomized controlled trial (PECEP-Twins). Am J Obstet Gynecol. 2016 Feb;214(2):145-152. doi: 10.1016/j.ajog.2015.11.012. Epub 2015 Nov 25. — View Citation

Hassan SS, Romero R, Vidyadhari D, Fusey S, Baxter JK, Khandelwal M, Vijayaraghavan J, Trivedi Y, Soma-Pillay P, Sambarey P, Dayal A, Potapov V, O'Brien J, Astakhov V, Yuzko O, Kinzler W, Dattel B, Sehdev H, Mazheika L, Manchulenko D, Gervasi MT, Sullivan L, Conde-Agudelo A, Phillips JA, Creasy GW; PREGNANT Trial. Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol. 2011 Jul;38(1):18-31. doi: 10.1002/uog.9017. Epub 2011 Jun 15. — View Citation

Jin Z, Chen L, Qiao D, Tiwari A, Jaunky CD, Sun B, Wang L, Yu H. Cervical pessary for preventing preterm birth: a meta-analysis. J Matern Fetal Neonatal Med. 2019 Apr;32(7):1148-1154. doi: 10.1080/14767058.2017.1401998. Epub 2017 Nov 20. — View Citation

Lawn JE, Kinney MV, Belizan JM, Mason EM, McDougall L, Larson J, Lackritz E, Friberg IK, Howson CP; Born Too Soon Preterm Birth Action Group. Born too soon: accelerating actions for prevention and care of 15 million newborns born too soon. Reprod Health. 2013;10 Suppl 1:S6. doi: 10.1186/1742-4755-10-S1-S6. Epub 2013 Nov 15. Review. — View Citation

Leung TN, Pang MW, Leung TY, Poon CF, Wong SM, Lau TK. Cervical length at 18-22 weeks of gestation for prediction of spontaneous preterm delivery in Hong Kong Chinese women. Ultrasound Obstet Gynecol. 2005 Dec;26(7):713-7. — View Citation

Liem S, Schuit E, Hegeman M, Bais J, de Boer K, Bloemenkamp K, Brons J, Duvekot H, Bijvank BN, Franssen M, Gaugler I, de Graaf I, Oudijk M, Papatsonis D, Pernet P, Porath M, Scheepers L, Sikkema M, Sporken J, Visser H, van Wijngaarden W, Woiski M, van Pampus M, Mol BW, Bekedam D. Cervical pessaries for prevention of preterm birth in women with a multiple pregnancy (ProTWIN): a multicentre, open-label randomised controlled trial. Lancet. 2013 Oct 19;382(9901):1341-9. doi: 10.1016/S0140-6736(13)61408-7. Epub 2013 Aug 5. — View Citation

Norman JE, Marlow N, Messow CM, Shennan A, Bennett PR, Thornton S, Robson SC, McConnachie A, Petrou S, Sebire NJ, Lavender T, Whyte S, Norrie J; OPPTIMUM study group. Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial. Lancet. 2016 May 21;387(10033):2106-2116. doi: 10.1016/S0140-6736(16)00350-0. Epub 2016 Feb 24. Erratum in: Lancet. 2019 Jan 19;393(10168):228. Lancet. 2019 Apr 20;393(10181):1596. — View Citation

Platt MJ. Outcomes in preterm infants. Public Health. 2014 May;128(5):399-403. doi: 10.1016/j.puhe.2014.03.010. Epub 2014 May 1. Review. — View Citation

Romero R, Conde-Agudelo A, Da Fonseca E, O'Brien JM, Cetingoz E, Creasy GW, Hassan SS, Nicolaides KH. Vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in singleton gestations with a short cervix: a meta-analysis of individual patient data. Am J Obstet Gynecol. 2018 Feb;218(2):161-180. doi: 10.1016/j.ajog.2017.11.576. Epub 2017 Nov 17. Review. — View Citation

Romero R, Nicolaides K, Conde-Agudelo A, Tabor A, O'Brien JM, Cetingoz E, Da Fonseca E, Creasy GW, Klein K, Rode L, Soma-Pillay P, Fusey S, Cam C, Alfirevic Z, Hassan SS. Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data. Am J Obstet Gynecol. 2012 Feb;206(2):124.e1-19. doi: 10.1016/j.ajog.2011.12.003. Epub 2011 Dec 11. Review. — View Citation

Saccone G, Ciardulli A, Xodo S, Dugoff L, Ludmir J, Pagani G, Visentin S, Gizzo S, Volpe N, Maruotti GM, Rizzo G, Martinelli P, Berghella V. Cervical Pessary for Preventing Preterm Birth in Singleton Pregnancies With Short Cervical Length: A Systematic Review and Meta-analysis. J Ultrasound Med. 2017 Aug;36(8):1535-1543. doi: 10.7863/ultra.16.08054. Epub 2017 Apr 11. Review. — View Citation

Society for Maternal-Fetal Medicine (SMFM). Electronic address: pubs@smfm.org, McIntosh J, Feltovich H, Berghella V, Manuck T. The role of routine cervical length screening in selected high- and low-risk women for preterm birth prevention. Am J Obstet Gynecol. 2016 Sep;215(3):B2-7. doi: 10.1016/j.ajog.2016.04.027. Epub 2016 Apr 28. Review. — View Citation

Vogel JP, Chawanpaiboon S, Moller AB, Watananirun K, Bonet M, Lumbiganon P. The global epidemiology of preterm birth. Best Pract Res Clin Obstet Gynaecol. 2018 Oct;52:3-12. doi: 10.1016/j.bpobgyn.2018.04.003. Epub 2018 Apr 26. Review. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Gestational age at delivery	Gestational age at delivery	At birth
Secondary	Time from randomization to delivery	Time interval between randomisation and delivery	From date of randomisation until the date of delivery.
Secondary	Rate of preterm birth before 28 weeks of gestation	Birth before 28 weeks	From date of randomisation until 27 6/7 weeks
Secondary	Rate of preterm birth before 34 weeks of gestation	Birth before 34 weeks	From date of randomisation until 33 6/7 weeks
Secondary	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
Secondary	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
Secondary	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
Secondary	Rate of iatrogenic preterm birth <28 weeks	Birth non-spontaneously before 28 weeks' gestation	From date of randomisation until 27 6/7 weeks
Secondary	Rate of iatrogenic preterm birth <34 weeks	Birth non-spontaneously before 34 weeks' gestation	From date of randomisation until 33 6/7 weeks
Secondary	Rate of iatrogenic preterm birth <37 weeks	Birth non-spontaneously before 37 weeks' gestation	From date of randomisation until 36 6/7 weeks
Secondary	Rate of onset of labor	Spontaneous, labor induction, elective C-section	At birth
Secondary	Rate of modes of delivery	Vaginal delivery, C-section (elective, suspected fetal distress, non-progressive labor)	At birth
Secondary	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
Secondary	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
Secondary	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
Secondary	Rate of use of MgSO4 for neuroprotection	Use of MgSO4 for neuroprotection	From 28 0/7 to 31 6/7 weeks' gestation
Secondary	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
Secondary	Length of maternal admission for preterm labor (days)	Number of admission days for treatment of preterm labour	From randomization to 37 week
Secondary	Rate of chorioamnionitis	Intraamniotic infection	From randomization to delivery, up to 28 weeks
Secondary	Rate of maternal mortality	Death of the mother	From randomization to delivery, up to 28 weeks
Secondary	Birthweight (mean)	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	Rate of congenital anomalies	Any congenital anomalies detected in baby born	At birth
Secondary	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
Secondary	5-min Apgar score <7	Apgar score at 5 minute after birth <7. An increased relative risk of cerebral palsy.	At birth
Secondary	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
Secondary	Length of NICU admission	Number of admission days to NICU	Up to 28 days of life after the due day
Secondary	Rate of death before discharge	Death of newborn before discharge from nursery	Up to 28 days of life after the due day
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Rate of necrotizing enterocolitis	Diagnosed according to Bell	Up to 28 days of life after the due day
Secondary	Rate of proven sepsis	The combination of clinical signs and positive blood cultures	Up to 28 days of life after the due day
Secondary	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
Secondary	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
Secondary	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
Secondary	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