Clinical trial NCT02901626: A Randomized Trial of Pessary in Singleton Pregnancies With a Short Cervix
Official title: A Randomized Trial of Pessary in Singleton Pregnancies With a Short Cervix
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Short Cervix
Preterm Delivery
Keywords: Short cervix
Preterm delivery
Singletons
Pregnancy
Pessary
Lead sponsor: The George Washington University Biostatistics Center
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2016-09-15
Enrollment: 544
Sex: FEMALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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).
Primary purpose: PREVENTION

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.

Detailed description: While cervical length is one of the most powerful predictors of subsequent preterm birth, the best treatment to reduce subsequent preterm birth remains unknown. This study is a randomized trial of women who have a singleton pregnancy and a short cervical length on transvaginal ultrasound as determined by a study-certified sonographer. It is being conducted at 12 clinical centers across the country and the recruitment target is enrollment of 850 pregnant women. Participants will be randomized to 1) Arabin pessary or 2) usual care as per by local hospital protocol. Pessary is a promising low-cost, non-surgical intervention that appears to be well-tolerated. The pessary will be placed by obstetric providers trained in appropriate placement of the Arabin pessary. The primary outcome of the study is delivery or fetal death prior to 37 weeks 0 days gestational age.

In the literature, there are two large trials that have produced conflicting results (M Goya et al, 2012, K Nicolaides et al, 2016). Thus, the results of an adequately powered and appropriately conducted trial from the United States will be important in determining whether pessary is a useful intervention for the prevention of subsequent preterm birth in women with singleton gestation.

Eligibility criteria: Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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.
* Active, unhealed herpetic lesion on labia minora, vagina, or cervix due to the potential for significant patient discomfort or increasing genital tract viral spread. Once lesion(s) heal and the patient is asymptomatic, she may be randomized. History of herpes is not an exclusion.
* 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.
* Major maternal medical illness associated with increased risk for adverse pregnancy outcome or indicated preterm birth (treated hypertension requiring more than one agent, treatment for diabetes prior to pregnancy, chronic renal insufficiency defined by creatinine \>1.4 mg/dL, carcinoma of the breast, conditions treated with chronic oral glucocorticoid therapy). Lupus, uncontrolled thyroid disease, and New York Heart Association(NYHA) stage II or greater cardiac disease are also excluded. Patients with seizure disorders, HIV, and other medical conditions not specifically associated with an increased risk of indicated preterm birth are not excluded. Prior cervical cone/LOOP/Loop Electrocautery Excision Procedure (LEEP) is not an exclusion criterion.
* 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.
* Participation in this trial in a previous pregnancy. Patients who were screened in a previous pregnancy, but not randomized, may be included.
* Prenatal care or delivery planned elsewhere unless the study visits can be made as scheduled and complete outcome information can be obtained.

Primary outcomes:
measure: Number of Participants With Preterm Delivery or Fetal Death at Less Than 37 Weeks.
timeFrame: Before 37 weeks 0 days gestation, a period of up to 21 weeks from enrollment.
Secondary outcomes:
measure: Interval From Randomization to Delivery or Fetal Death
timeFrame: from randomization to delivery or fetal death (up to a length of 189 days)
measure: Gestational Age at Delivery
timeFrame: From randomization to delivery (up to a length of 189 days)
measure: Number of Participants With Preterm Delivery or Fetal Death at Less Than 28 Weeks Gestation
timeFrame: from randomization to less than 28 weeks gestation (a period of less than 91 days)
measure: Number of Participants With Preterm Delivery or Fetal Death at Less Than 32 Weeks Gestation
timeFrame: from randomization to less than 32 weeks gestation (a period of less than 119 days)
measure: Number of Participants With Preterm Delivery or Fetal Death at Less Than 35 Weeks Gestation
timeFrame: from randomization to less than 35 weeks gestation (a period of less than 140 days)
measure: Number of Participants With Preterm Premature Rupture of Membranes
timeFrame: Before 37 weeks 0 days gestation, a period of up to 21 weeks from enrollment
measure: Number of Participants With Spontaneous Preterm Delivery.
timeFrame: From randomization to delivery (up to a length of 189 days)
measure: Number of Participants With Indicated Preterm Delivery
timeFrame: from randomization to delivery (up to a length of 189 days)
measure: Number of Participants With Cesarean Delivery
timeFrame: From randomization to delivery (up to a length of 189 days)
measure: Number of Participants With Chorioamnionitis
timeFrame: From randomization to delivery (up to a length of 189 days)
measure: Median Length of Maternal Antepartum Hospital Stay Before Delivery
timeFrame: from date of admission for delivery up to delivery date (up to 5 days)
measure: Number of Participants With Vaginal Infection
timeFrame: From randomization to delivery (up to a length of 189 days)
measure: The Number of Participants Who Had a Vaginal Infection and Received Antibiotic Treatment, Among All Persons Enrolled With at Least One Study Visit
timeFrame: From randomization to delivery (up to a length of 189 days)
measure: Number of Participants Treated for Preterm Labor Including Placement of Cerclage
timeFrame: From randomization to delivery (up to a length of 189 days)
measure: Median Duration of Neonatal Ventilator or Continuous Positive Airway Pressure Use
timeFrame: delivery through hospital discharge (up to a length of 435 days)
measure: Number of Neonates Requiring Ventilator or Continuous Positive Airway Pressure Use
timeFrame: delivery through hospital discharge (up to a length of 435 days)
measure: Median Duration (in Days) of Neonatal Supplemental Oxygen Use
timeFrame: delivery through hospital discharge (up to a length of 435 days)
measure: Number of Neonates With Seizures Requiring Treatment
timeFrame: delivery through hospital discharge (up to a length of 435 days)
measure: Number of Neonates Small for Gestational Age < 5th Percentile
timeFrame: delivery through hospital discharge (up to a length of 435 days)
measure: Number of Neonates With Intraventricular Hemorrhage (IVH) Grades III or IV
timeFrame: delivery through hospital discharge (up to a length of 435 days)
measure: Number of Neonates With Retinopathy of Prematurity (ROP)
timeFrame: delivery through hospital discharge (up to a length of 435 days)
measure: Number of Neonates Experiencing Respiratory Distress Syndrome (RDS)
timeFrame: delivery through hospital discharge (up to a length of 435 days)
measure: Number of Neonates With Bronchopulmonary Dysplasia (BPD)
timeFrame: Delivery through 28 days of life if delivered at or after 32 weeks. Delivery through 36 weeks gestation if delivered before 32 weeks.
measure: Number of Neonates With Necrotizing Enterocolitis (NEC) Stage 2 or 3
timeFrame: delivery through hospital discharge (up to a length of 435 days)
measure: Number of Neonates With Hyperbilirubinemia
timeFrame: delivery through hospital discharge (up to a length of 435 days)
measure: Neonatal Infectious Morbidity Including Sepsis, Suspected Sepsis and Pneumonia
timeFrame: delivery through hospital discharge (up to a length of 435 days)
measure: Number of Neonates With Early Onset Sepsis
timeFrame: within 72 hours of birth
measure: Number of Neonates With Late Onset Sepsis
timeFrame: 72 hours of birth or later (up to hospital discharge - a maximum of 435 days)
measure: Number of Neonates With Suspected Sepsis
timeFrame: delivery through hospital discharge (up to a length of 435 days)
measure: Number of Neonates With Pneumonia
timeFrame: delivery through hospital discharge (up to a length of 435 days)
measure: Number of Neonates With Composite Outcome
timeFrame: delivery through hospital discharge (up to a length of 435 days)
measure: Median Length of Neonatal Hospital Stay
timeFrame: delivery through hospital discharge (up to a length of 435 days)
measure: Median Number of Days in Neonatal Intensive Care Unit (NICU)
timeFrame: delivery through hospital discharge (up to a length of 435 days)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama - Birmingham
state: Alabama
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: New York
country: United States
facility: Columbia University
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina - Chapel Hill
state: North Carolina
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Magee Womens
state: Pennsylvania
city: Providence
country: United States
facility: Brown University
state: Rhode Island
city: Galveston
country: United States
facility: University of Texas Medical Branch
state: Texas
city: Houston
country: United States
facility: University of Texas - Houston
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
Study officials:
affiliation: George Washington University Biostatistics Center
name: Rebecca Clifton, Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: Monica Longo, MD
role: STUDY_DIRECTOR
affiliation: Christiana Care Health Services
name: Matthew Hoffman, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
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: 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: 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.
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: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
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, 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: Lan KK, Wittes J. The B-value: a tool for monitoring data. Biometrics. 1988 Jun;44(2):579-85.
citation: 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.
citation: 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.
citation: 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.