Clinical trial NCT04300322: Pessary Versus Progesterone in Singletons
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Preterm Birth
Short Cervix
Keywords: Preterm Birth
Singleton Pregnancies
Short Cervix
Pessary
Progesterone
Lead sponsor: Mỹ Đức Hospital
Sponsor class: OTHER
Collaborators: name: My Duc Phu Nhuan Hospital HCMC, Vietnam
name: Quang Ninh Obstetrics and Pediatrics Hospital, Quang Ninh, Vietnam
First posted: 2020-03-09
Enrollment: 804
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: PREVENTION

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Rate of preterm birth <37 weeks of gestation by any cause
timeFrame: From date of randomisation until 36 6/7 weeks
Secondary outcomes:
measure: Gestational age at delivery
timeFrame: At birth
measure: Time from randomization to delivery
timeFrame: From date of randomisation until the date of delivery.
measure: Rate of preterm birth before 28 weeks of gestation
timeFrame: From date of randomisation until 27 6/7 weeks
measure: Rate of preterm birth before 34 weeks of gestation
timeFrame: From date of randomisation until 33 6/7 weeks
measure: Rate of spontaneous preterm birth <28 weeks
timeFrame: From date of randomisation until 27 6/7 weeks
measure: Rate of spontaneous preterm birth <34 weeks
timeFrame: From date of randomisation until 33 6/7 weeks
measure: Rate of spontaneous preterm birth <37 weeks
timeFrame: From date of randomisation until 36 6/7 weeks
measure: Rate of iatrogenic preterm birth <28 weeks
timeFrame: From date of randomisation until 27 6/7 weeks
measure: Rate of iatrogenic preterm birth <34 weeks
timeFrame: From date of randomisation until 33 6/7 weeks
measure: Rate of iatrogenic preterm birth <37 weeks
timeFrame: From date of randomisation until 36 6/7 weeks
measure: Rate of onset of labor
timeFrame: At birth
measure: Rate of modes of delivery
timeFrame: At birth
measure: Rate of all live births at any gestational age
timeFrame: At birth
measure: Rate of use of tocolytic drugs
timeFrame: From 24 0/7 to 36 6/7 weeks' gestation
measure: Rate of use of antenatal corticosteroids
timeFrame: From 24 0/7 to 36 6/7 weeks' gestation
measure: Rate of use of MgSO4 for neuroprotection
timeFrame: From 28 0/7 to 31 6/7 weeks' gestation
measure: Rate of preterm premature rupture of membranes
timeFrame: From randomization to less than 37 weeks, up to 21 weeks
measure: Length of maternal admission for preterm labor (days)
timeFrame: From randomization to 37 week
measure: Rate of chorioamnionitis
timeFrame: From randomization to delivery, up to 28 weeks
measure: Rate of maternal mortality
timeFrame: From randomization to delivery, up to 28 weeks
measure: Birthweight (mean)
timeFrame: At birth
measure: Birthweight <1500 g
timeFrame: At birth
measure: Birthweight <2500 g
timeFrame: At birth
measure: Rate of congenital anomalies
timeFrame: At birth
measure: 5-min Apgar score
timeFrame: At birth
measure: 5-min Apgar score <7
timeFrame: At birth
measure: Rate of admission to neonatal intensive care unit (NICU)
timeFrame: Up to 28 days of life after the due day
measure: Length of NICU admission
timeFrame: Up to 28 days of life after the due day
measure: Rate of death before discharge
timeFrame: Up to 28 days of life after the due day
measure: Rate of neonatal death
timeFrame: Up to 28 days of life after the due day
measure: Rate of perinatal death
timeFrame: After 20 weeks of gestation to 28 days of life after the due day
measure: Rate of stillbirth
timeFrame: After 20 weeks of gestation until the date of delivery
measure: Rate of composite of poor perinatal outcomes
timeFrame: Up to 28 days of life after the due day
measure: Rate of respiratory distress syndrome
timeFrame: Up to 28 days of life after the due day
measure: Rate of periventricular haemorrhage II B or worse
timeFrame: Up to 28 days of life after the due day
measure: Rate of necrotizing enterocolitis
timeFrame: Up to 28 days of life after the due day
measure: Rate of proven sepsis
timeFrame: Up to 28 days of life after the due day
measure: Rate of maternal vaginal side effects
timeFrame: From date of randomisation until delivery, which is up to 24 weeks
measure: Vaginal pain Score
timeFrame: From date of randomisation until delivery, which is up to 24 weeks
measure: Rate of pessary repositioning
timeFrame: From date of randomisation until delivery, which is up to 24 weeks
measure: Rate of maternal cervical side effects
timeFrame: From date of randomisation until delivery, which is up to 24 weeks
Other outcomes:
Locations:
city: Ho Chi Minh City
country: Vietnam
facility: My Duc Phu Nhuan Hospital
state: Phu Nhuan
city: Ho Chi Minh City
country: Vietnam
facility: Mỹ Đức Hospital
state: Tan Binh
city: Quang Ninh
country: Vietnam
facility: Quang Ninh Obstetrics and Pediatrics Hospital
Study officials:
affiliation: Mỹ Đức Hospital
name: Vinh Q Dang, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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(Suppl 1):S6. doi: 10.1186/1742-4755-10-S1-S6. Epub 2013 Nov 15.
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.
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.
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. doi: 10.1002/uog.2617.
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.
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.
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.
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.
citation: Arabin B, Halbesma JR, Vork F, Hubener 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. doi: 10.1515/JPM.2003.017.
citation: Goya M, de la Calle M, Pratcorona L, Merced C, Rodo C, Munoz 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.
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.
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.
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.
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.