A Randomized Trial of Pessary in Singleton Pregnancies With a Short Cervix

NCT02901626 | Terminated Phase 3 Results DMC FDA Device

• 14 other identifiers: HD36801 - TOPSUG1HD087230UG1HD027915UG1HD034208UG1HD040500UG1HD040485UG1HD053097UG1HD040544UG1HD040545UG1HD040560UG1HD040512UG1HD087192U24HD036801UG1HD027869
• Study Type: interventional
• Target: 544
• Locations: 1 country
• Sites: 12

Brief Summary

The purpose of the study is to determine whether the Arabin pessary is a useful intervention of preterm birth at less than 37 weeks in women with a singleton gestation and a short cervix.

Conditions

Short Cervix; Preterm Delivery

Keywords

Short cervix; Preterm delivery; Singletons; Pregnancy; Pessary

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Preterm Delivery or Fetal Death at Less Than 37 Weeks.

  Participants who either delivered or experienced a fetal death prior to 37 weeks gestation.

  Before 37 weeks 0 days gestation, a period of up to 21 weeks from enrollment.

Secondary Outcomes (33)

• Interval From Randomization to Delivery or Fetal Death

  from randomization to delivery or fetal death (up to a length of 189 days)

• Gestational Age at Delivery

  From randomization to delivery (up to a length of 189 days)

• Number of Participants With Preterm Delivery or Fetal Death at Less Than 28 Weeks Gestation

  from randomization to less than 28 weeks gestation (a period of less than 91 days)

• Number of Participants With Preterm Delivery or Fetal Death at Less Than 32 Weeks Gestation

  from randomization to less than 32 weeks gestation (a period of less than 119 days)

• Number of Participants With Preterm Delivery or Fetal Death at Less Than 35 Weeks Gestation

  from randomization to less than 35 weeks gestation (a period of less than 140 days)

Study Arms (2)

Arabin Cervical Pessary

EXPERIMENTAL

Arabin pessary. Participants will also receive vaginal progesterone to be administered daily, if it is the local standard of care.

Device: Arabin Cervical Pessary

No Pessary

NO INTERVENTION

Participants will also receive vaginal progesterone to be administered daily, if it is the local standard of care.

Interventions

Arabin Cervical Pessary DEVICE

The Arabin cervical pessary is a soft, flexible silicone pessary and fits high around the cervix with no rigid metal framework or inflexible edges that put increase pressure on the vaginal wall. It is available in a variety of sizes however three sizes will be used in this study: Pessary Size upper diameter, lower diameter 1. Nulliparous 65 mm, 32 mm 2. Multiparous 70 mm, 32 mm 3. Alternative 70 mm, 35 mm

Also known as: Arabin pessary

Arabin Cervical Pessary

Eligibility Criteria

• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Singleton gestation. Twin gestation reduced to singleton either spontaneously or therapeutically, is not eligible unless the reduction occurred before 13 weeks 6 days project gestational age. Higher order multifetal gestations reduced to singletons are not eligible.
• Gestational age at randomization between 16 weeks 0 days and 23 weeks 6 days based on clinical information and evaluation of the earliest ultrasound.
• Cervical length on transvaginal examination of less than or equal to 20 mm by a study certified sonographer. There is no lower cervical length threshold.

You may not qualify if:

• Cervical dilation (internal os) 3 cm or greater on digital examination or evidence of prolapsed membranes beyond the external cervical os either at the time of the qualifying cervical ultrasound examination or at a cervical exam immediately before randomization.
• Fetal anomaly or imminent fetal demise. This includes lethal anomalies, or anomalies that may lead to early delivery or increased risk of neonatal death e.g., gastroschisis, spina bifida, serious karyotypic abnormalities. An ultrasound examination from 14 weeks 0 days to 23 weeks 6 days by project Estimated Date of Confinement (EDC) must be performed prior to randomization to evaluate the fetus for anomalies.
• Previous spontaneous preterm birth between 16 weeks 0 days and 36 weeks 6 days. This includes induction for pPROM in a prior pregnancy.
• Planned treatment with intramuscular 17-α hydroxy-progesterone caproate.
• Placenta previa, because of risk of bleeding and high potential for indicated preterm birth. A low lying placenta is acceptable.
• Active vaginal bleeding greater than spotting at the time of randomization, because of potential exacerbation due to pessary placement.
• Symptomatic, untreated vaginal or cervical infection because of potential exacerbation due to pessary placement. Patients may be treated and if subsequently asymptomatic, randomized. However, if it is more than 10 days since the cervical length measurement, a new cervical length measurement must be obtained.
• Rupture of membranes due to likelihood of pregnancy loss and preterm delivery as well as the risk of ascending infection which could be increased with pessary placement.
• More than six contractions per hour reported or documented prior to randomization. It is not necessary to place the patient on a tocodynamometer.
• Known major Mullerian anomaly of the uterus (specifically bicornuate, unicornuate, or uterine septum not resected) due to increased risk of preterm delivery which is unlikely to be affected by progesterone.
• Any fetal/maternal condition which would require invasive in-utero assessment or treatment, for example significant red cell antigen sensitization or neonatal alloimmune thrombocytopenia.
• Planned cerclage or cerclage already in place since it would preclude placement of a pessary.
• Planned indicated delivery prior to 37 weeks.
• Allergy to silicone.
• Participation in another interventional study that influences gestational age at delivery or neonatal morbidity or mortality.

Sponsors & Collaborators

• The George Washington University Biostatistics Center: lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (12)

University of Alabama - Birmingham

Birmingham, Alabama, 35233, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

Columbia University

New York, New York, 10032, United States

Location

University of North Carolina - Chapel Hill

Chapel Hill, North Carolina, 27599, United States

Location

Case Western Reserve University

Cleveland, Ohio, 44109, United States

Location

Ohio State University

Columbus, Ohio, 43210, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Magee Womens

Pittsburgh, Pennsylvania, 15213, United States

Location

Brown University

Providence, Rhode Island, 02905, United States

Location

University of Texas Medical Branch

Galveston, Texas, 77555, United States

Location

University of Texas - Houston

Houston, Texas, 77030, United States

Location

University of Utah

Salt Lake City, Utah, 84132, United States

Location

Related Publications (33)

• Hamilton BE, Martin JA, Osterman MJ, Curtin SC, Matthews TJ. Births: Final Data for 2014. Natl Vital Stat Rep. 2015 Dec;64(12):1-64.

  PMID: 26727629 BACKGROUND

• Lawn JE, Kerber K, Enweronu-Laryea C, Cousens S. 3.6 million neonatal deaths--what is progressing and what is not? Semin Perinatol. 2010 Dec;34(6):371-86. doi: 10.1053/j.semperi.2010.09.011.

  PMID: 21094412 BACKGROUND

• American College of Obstetricians and Gynecologists; Committee on Practice Bulletins-Obstetrics. ACOG practice bulletin no. 127: Management of preterm labor. Obstet Gynecol. 2012 Jun;119(6):1308-17. doi: 10.1097/AOG.0b013e31825af2f0.

  PMID: 22617615 BACKGROUND

• Meis PJ, Klebanoff M, Thom E, Dombrowski MP, Sibai B, Moawad AH, Spong CY, Hauth JC, Miodovnik M, Varner MW, Leveno KJ, Caritis SN, Iams JD, Wapner RJ, Conway D, O'Sullivan MJ, Carpenter M, Mercer B, Ramin SM, Thorp JM, Peaceman AM, Gabbe S; National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med. 2003 Jun 12;348(24):2379-85. doi: 10.1056/NEJMoa035140.

  PMID: 12802023 BACKGROUND

• da Fonseca EB, Bittar RE, Carvalho MH, Zugaib M. Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study. Am J Obstet Gynecol. 2003 Feb;188(2):419-24. doi: 10.1067/mob.2003.41.

  PMID: 12592250 BACKGROUND

• Petrini JR, Callaghan WM, Klebanoff M, Green NS, Lackritz EM, Howse JL, Schwarz RH, Damus K. Estimated effect of 17 alpha-hydroxyprogesterone caproate on preterm birth in the United States. Obstet Gynecol. 2005 Feb;105(2):267-72. doi: 10.1097/01.AOG.0000150560.24297.4f.

  PMID: 15684150 BACKGROUND

• Andersen HF, Nugent CE, Wanty SD, Hayashi RH. Prediction of risk for preterm delivery by ultrasonographic measurement of cervical length. Am J Obstet Gynecol. 1990 Sep;163(3):859-67. doi: 10.1016/0002-9378(90)91084-p.

  PMID: 2206073 BACKGROUND

• Iams JD, Goldenberg RL, Meis PJ, Mercer BM, Moawad A, Das A, Thom E, McNellis D, Copper RL, Johnson F, Roberts JM. The length of the cervix and the risk of spontaneous premature delivery. National Institute of Child Health and Human Development Maternal Fetal Medicine Unit Network. N Engl J Med. 1996 Feb 29;334(9):567-72. doi: 10.1056/NEJM199602293340904.

  PMID: 8569824 BACKGROUND

• Heath VC, Southall TR, Souka AP, Elisseou A, Nicolaides KH. Cervical length at 23 weeks of gestation: prediction of spontaneous preterm delivery. Ultrasound Obstet Gynecol. 1998 Nov;12(5):312-7. doi: 10.1046/j.1469-0705.1998.12050312.x.

  PMID: 9819868 BACKGROUND

• Fonseca EB, Celik E, Parra M, Singh M, Nicolaides KH; Fetal Medicine Foundation Second Trimester Screening Group. Progesterone and the risk of preterm birth among women with a short cervix. N Engl J Med. 2007 Aug 2;357(5):462-9. doi: 10.1056/NEJMoa067815.

  PMID: 17671254 BACKGROUND

• O'Brien JM, Adair CD, Lewis DF, Hall DR, Defranco EA, Fusey S, Soma-Pillay P, Porter K, How H, Schackis R, Eller D, Trivedi Y, Vanburen G, Khandelwal M, Trofatter K, Vidyadhari D, Vijayaraghavan J, Weeks J, Dattel B, Newton E, Chazotte C, Valenzuela G, Calda P, Bsharat M, Creasy GW. Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol. 2007 Oct;30(5):687-96. doi: 10.1002/uog.5158.

  PMID: 17899572 BACKGROUND

• 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.

  PMID: 21472815 BACKGROUND

• 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.

  PMID: 22284156 BACKGROUND

• Grobman WA, Thom EA, Spong CY, Iams JD, Saade GR, Mercer BM, Tita AT, Rouse DJ, Sorokin Y, Wapner RJ, Leveno KJ, Blackwell S, Esplin MS, Tolosa JE, Thorp JM Jr, Caritis SN, Van Dorsten JP; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units (MFMU) Network. 17 alpha-hydroxyprogesterone caproate to prevent prematurity in nulliparas with cervical length less than 30 mm. Am J Obstet Gynecol. 2012 Nov;207(5):390.e1-8. doi: 10.1016/j.ajog.2012.09.013. Epub 2012 Sep 17.

  PMID: 23010094 BACKGROUND

• 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.

  PMID: 26921136 BACKGROUND

• Committee on Practice Bulletins-Obstetrics, The American College of Obstetricians and Gynecologists. Practice bulletin no. 130: prediction and prevention of preterm birth. Obstet Gynecol. 2012 Oct;120(4):964-73. doi: 10.1097/AOG.0b013e3182723b1b. No abstract available.

  PMID: 22996126 BACKGROUND

• Society for Maternal-Fetal Medicine Publications Committee, with assistance of Vincenzo Berghella. Progesterone and preterm birth prevention: translating clinical trials data into clinical practice. Am J Obstet Gynecol. 2012 May;206(5):376-86. doi: 10.1016/j.ajog.2012.03.010.

  PMID: 22542113 BACKGROUND

• Cahill AG, Odibo AO, Caughey AB, Stamilio DM, Hassan SS, Macones GA, Romero R. Universal cervical length screening and treatment with vaginal progesterone to prevent preterm birth: a decision and economic analysis. Am J Obstet Gynecol. 2010 Jun;202(6):548.e1-8. doi: 10.1016/j.ajog.2009.12.005. Epub 2010 Jan 15.

  PMID: 20079888 BACKGROUND

• Werner EF, Han CS, Pettker CM, Buhimschi CS, Copel JA, Funai EF, Thung SF. Universal cervical-length screening to prevent preterm birth: a cost-effectiveness analysis. Ultrasound Obstet Gynecol. 2011 Jul;38(1):32-7. doi: 10.1002/uog.8911. Epub 2011 May 24.

  PMID: 21157771 BACKGROUND

• Berghella V, Odibo AO, To MS, Rust OA, Althuisius SM. Cerclage for short cervix on ultrasonography: meta-analysis of trials using individual patient-level data. Obstet Gynecol. 2005 Jul;106(1):181-9. doi: 10.1097/01.AOG.0000168435.17200.53.

  PMID: 15994635 BACKGROUND

• Owen J, Hankins G, Iams JD, Berghella V, Sheffield JS, Perez-Delboy A, Egerman RS, Wing DA, Tomlinson M, Silver R, Ramin SM, Guzman ER, Gordon M, How HY, Knudtson EJ, Szychowski JM, Cliver S, Hauth JC. Multicenter randomized trial of cerclage for preterm birth prevention in high-risk women with shortened midtrimester cervical length. Am J Obstet Gynecol. 2009 Oct;201(4):375.e1-8. doi: 10.1016/j.ajog.2009.08.015.

  PMID: 19788970 BACKGROUND

• 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.

  PMID: 12747228 BACKGROUND

• Goya M, Pratcorona L, Merced C, Rodo C, Valle L, Romero A, Juan M, Rodriguez A, Munoz B, Santacruz B, Bello-Munoz JC, Llurba E, Higueras T, Cabero L, Carreras E; Pesario Cervical para Evitar Prematuridad (PECEP) Trial Group. Cervical pessary in pregnant women with a short cervix (PECEP): an open-label randomised controlled trial. Lancet. 2012 May 12;379(9828):1800-6. doi: 10.1016/S0140-6736(12)60030-0. Epub 2012 Apr 3.

  PMID: 22475493 BACKGROUND

• Nicolaides KH, Syngelaki A, Poon LC, Picciarelli G, Tul N, Zamprakou A, Skyfta E, Parra-Cordero M, Palma-Dias R, Rodriguez Calvo J. A Randomized Trial of a Cervical Pessary to Prevent Preterm Singleton Birth. N Engl J Med. 2016 Mar 17;374(11):1044-52. doi: 10.1056/NEJMoa1511014.

  PMID: 26981934 BACKGROUND

• Hui SY, Chor CM, Lau TK, Lao TT, Leung TY. Cerclage pessary for preventing preterm birth in women with a singleton pregnancy and a short cervix at 20 to 24 weeks: a randomized controlled trial. Am J Perinatol. 2013 Apr;30(4):283-8. doi: 10.1055/s-0032-1322550. Epub 2012 Aug 8.

  PMID: 22875662 BACKGROUND

• Gyamfi-Bannerman C, Ananth CV. Trends in spontaneous and indicated preterm delivery among singleton gestations in the United States, 2005-2012. Obstet Gynecol. 2014 Dec;124(6):1069-1074. doi: 10.1097/AOG.0000000000000546.

  PMID: 25415156 BACKGROUND

• Committee opinion no 611: method for estimating due date. Obstet Gynecol. 2014 Oct;124(4):863-866. doi: 10.1097/01.AOG.0000454932.15177.be.

  PMID: 25244460 BACKGROUND

• Conde-Agudelo A, Romero R, Nicolaides K, Chaiworapongsa T, O'Brien JM, Cetingoz E, da Fonseca E, Creasy G, Soma-Pillay P, Fusey S, Cam C, Alfirevic Z, Hassan SS. Vaginal progesterone vs. cervical cerclage for the prevention of preterm birth in women with a sonographic short cervix, previous preterm birth, and singleton gestation: a systematic review and indirect comparison metaanalysis. Am J Obstet Gynecol. 2013 Jan;208(1):42.e1-42.e18. doi: 10.1016/j.ajog.2012.10.877. Epub 2012 Nov 15.

  PMID: 23157855 BACKGROUND

• Lan KK, Wittes J. The B-value: a tool for monitoring data. Biometrics. 1988 Jun;44(2):579-85.

  PMID: 3390511 BACKGROUND

• Stallones RA. The use and abuse of subgroup analysis in epidemiological research. Prev Med. 1987 Mar;16(2):183-94. doi: 10.1016/0091-7435(87)90082-x.

  PMID: 3295858 BACKGROUND

• Yusuf S, Wittes J, Probstfield J, Tyroler HA. Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials. JAMA. 1991 Jul 3;266(1):93-8.

  PMID: 2046134 BACKGROUND

• Facco FL, Simhan HN. Short ultrasonographic cervical length in women with low-risk obstetric history. Obstet Gynecol. 2013 Oct;122(4):858-862. doi: 10.1097/AOG.0b013e3182a2dccd.

  PMID: 24084545 BACKGROUND

• Hoffman MK, Clifton RG, Biggio JR, Saade GR, Ugwu LG, Longo M, Bousleiman SZ, Clark K, Grobman WA, Frey HA, Chauhan SP, Dugoff L, Manuck TA, Chien EK, Rouse DJ, Simhan HN, Esplin MS, Macones GA; National Institute of Child Health and Human Development Maternal-Fetal Medicine Units (MFMU) Network. Cervical Pessary for Prevention of Preterm Birth in Individuals With a Short Cervix: The TOPS Randomized Clinical Trial. JAMA. 2023 Jul 25;330(4):340-348. doi: 10.1001/jama.2023.10812.

  PMID: 37490086 DERIVED

MeSH Terms

Conditions

Premature Birth

Condition Hierarchy (Ancestors)

Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases

Results Point of Contact

• Title: Matthew Hoffman, MD, MPH
• Organization: Christiana Care Health System, Department of Obstetrics & Gynecology

mhoffman@christianacare.org

(302) 301-3350

Study Officials

• Rebecca Clifton, Ph.D.

  George Washington University Biostatistics Center

  PRINCIPAL INVESTIGATOR

• Monica Longo, MD

  Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

  STUDY DIRECTOR

• Matthew Hoffman, MD

  Christiana Care Health Services

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The study is an unblinded randomized controlled trial. Participants will receive usual care (vaginal progesterone if they meet criteria per local standard of care) or an Arabin cervical pessary (plus progesterone if the local usual care is to receive vaginal progesterone for a short cervix).

Study Record Dates

• First Submitted: September 12, 2016
• First Posted: September 15, 2016
• Study Start: February 14, 2017
• Primary Completion: April 2, 2022
• Study Completion: May 10, 2022
• Last Updated: June 22, 2023
• Results First Posted: June 22, 2023

Record last verified: 2023-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF

Locations

US (12)