Confirmatory Study of 17P vs Vehicle for Prevention of Preterm Birth in Women w/ Previous Spontaneous Preterm Delivery (PROLONG)

A Phase 3B, Multi-Center, Randomized, Double-Blind Study of Hydroxyprogesterone Caproate (HPC) Injection, 250 mg/mL, Versus Vehicle for the Prevention of Preterm Birth in Women With a Previous Singleton Spontaneous Preterm Delivery

As part of the continuing effort to study the benefit and risks of 17P and preterm delivery, this study is designed as a multi-center, randomized, double-blind, vehicle-controlled clinical trial of 17P for the prevention of preterm birth prior to 35 weeks, 0 days of gestation in women with a singleton pregnancy, aged 18 years or older, with a previous singleton spontaneous preterm delivery. The study also includes a population pharmacokinetic (PK) substudy to assess the hydroxyprogesterone caproate (HPC) exposure-response relationship and the effect of body mass index (BMI) on the PK of 17P.

Study Overview

• Status: Completed
• Conditions: Preterm Birth
• Intervention / Treatment: Drug: Vehicle; Drug: Hydroxyprogesterone Caproate Injection (HPC), 250mg/mL

Detailed Description

One of the most significant risk factors for preterm birth is previous pregnancy history. Women who have had a prior preterm birth have a 2.5-fold greater risk than women with no prior history of preterm birth. Prophylactic methods for prevention of preterm birth, including tocolytic drugs, bed rest, and other interventions such as cerclage, have been shown in most studies to be ineffective. One of the preventive measures that has shown effectiveness in randomized trials is the use of progesterone agents.9,10 Progesterone has been shown to support gestation and to inhibit uterine activity.

• Study Type: Interventional
• Enrollment (Actual): 1740
• Phase: Phase 3

Contacts and Locations

Study Locations

• Bulgaria
  • Blagoevgrad, Bulgaria
    • MHAT "Blagoevgrad", Department of obstetrics and Gynecology
  • Russe, Bulgaria
    • Medical center "Teodora", LTD
  • Silistra, Bulgaria
    • MHAT "Silistra", Obstetrics and Gynecology Department
  • Sofia, Bulgaria
    • "Medical institute of Interior ministry", Sofia city PLC, Department of Gynecology
  • Sofia, Bulgaria
    • Medical Centre "Avicena" Ltd
  • Sofia, Bulgaria
    • SHAT " Sheinovo ",PLS, Maternity Clinic
• Canada
  • Alberta
    • Calgary, Alberta, Canada, AB T2N 2T9
      • University of Calgary - Foothills Hospital
  • British Columbia
    • North Vancouver, British Columbia, Canada, V7M 2H5
      • Lion's Gate Hospital (University of BC)
  • Ontario
    • Oshawa, Ontario, Canada, L1H2J9
      • Glazier Medical Centre
    • Ottawa, Ontario, Canada, K1H 8L6
      • The Ottawa Hospital, General Campus
    • Windsor, Ontario, Canada, N8W 5R7
      • Victory Reproductive Care
    • Windsor, Ontario, Canada, N8X 3V6
      • J. Leung Obstetrics and Gynaecology
• Czechia
  • Ceske Budejovice 7, Czechia, 37001
    • Nemocnice Ceske Budejovice, a.s. Gynekologicko-pordnicka klinika
  • Hradec Kralove, Czechia, 500 05
    • Fakultni nemocnice Hradec Kralove Porodnicka a gynekologicka klinika
  • Ostrava-Poruba, Czechia, 70852
    • Fakultni nemocnice Ostrava Porodnicko-gynekologicka klinika
  • Plzen-Lochotin, Czechia, 304 60
    • Fakultni nemocnice Pizen Gynekologicko-pordnicka klinika
  • Jihomoravsky KRAJ
    • Brno, Jihomoravsky KRAJ, Czechia, 62500
      • Fakultní Nemocnice Brno
  • Olomoucky KRAJ
    • Olomouc, Olomoucky KRAJ, Czechia, 77900
      • Fakultní Nemocnice Olomouc
• Hungary
  • Budapest, Hungary, 1097
    • Fovarosi Onkormanyzat Egyesitett Szent Istvan es Szent Laszlo Korhaz-Rendelointezet, Szuleszet - Nogyogyaszat
  • Gyor, Hungary, 9024
    • Petz Aladar Megyei Oktato Korhaz, Szuleszet-Nogyogyaszat
  • Kecskemet, Hungary, 6000
    • Bacs-Kiskun Megyei Onkormanyzat Korhaza, Svegedi Tudmanyegyetem Altalanos Orvostudomanyi kar Oktato Korhaza
  • Nyiregyhaza, Hungary, 4400
    • Josa Andras Oktato Korhaz Egeszsegugyi Szolgaltato Nonprofit Kft.
  • Szeged, Hungary, 6725
    • Szegedi Tudomanyegyetem, Szuleszeti es Nogyogyaszati Klinika
  • Hajdu-bihar
    • Debrecen, Hajdu-bihar, Hungary, 4032
      • Debreceni Egyetem Orvos és Egészségtudományi Centrum, Szülészeti és Nogyógyászati Klinika
• Italy
  • Bologna, Italy, 40100
    • Azienda Ospedaliero-Universitaria di Bologna Policlinico S. Orsola-Malpighi
  • Bolzano, Italy, 39100
    • Azienda Ospedaliera di Bolzano Ospedale Generale Regionale di Bolzano
  • Perugia, Italy, 06132
    • Azienda Ospedaliera di Perugia - Ospedale Santa Maria dell a Misericordia
• Russian Federation
  • Arkhangelsk, Russian Federation, 163000
    • Northern State Medical University
  • Arkhangelsk, Russian Federation
    • Northern State Medical University
  • Belgorod, Russian Federation
    • Belgorod Regional Clinical Hospital of St.Ioasaf
  • Kazan, Russian Federation, 420012
    • State Educational Institution of Higher Professional Education "Kazan State Medical University of RosZdrav"
  • Kemerovo, Russian Federation
    • Kemerovo State Medical Academy
  • Krasnoyarsk, Russian Federation, 660100
    • State Educational Institution of Higher Professional Education "Krasnoyarsk State University named After Prof. V.F. Voino-Yasenetsky of Ministry of Health Russia" Department of Perinatology, Obstetrics and Gynecology of Medical Faculty
  • Moscow, Russian Federation, 117333
    • State Educational Institution of Higher Professional Education "People's Friendship University of Russia" Department of Obstetrics and Gynecology with Course Perinatology
  • Moscow, Russian Federation
    • Russian National Research Medical University named after N.I. Pirogov
  • Novosibirsk, Russian Federation, 630089
    • Municipal Healthcare Institution "Novosibirsk Municipal Perinatal Centre"
  • Rostov-on-Don, Russian Federation, 344029
    • Rostov Medical State University
  • Saint Petersburg, Russian Federation
    • Almazov Federal Heart, Blood and Endocrinology Centre
  • St. Petersburg, Russian Federation, 195257
    • State Educational Institution of Higher Professional Education "St. Petersburg l.l Mechnikov State Medical Academy of RosZdrav" Department of Obstetrics, Gynecology and Perinatology
  • St. Petersburg, Russian Federation, 199034
    • State Institution "D.O. Otto Scientific Institute for Obstetrics and Gynecology"
  • Tomsk, Russian Federation
    • Regional perinatal center
  • Yaroslavl, Russian Federation, 150003
    • State Healthcare Institution "Regional Maternity Hospital"
  • Yekaterinburg, Russian Federation, 620028
    • Federal State Institution "Ural Research Institute of Maternity and Infancy Care of Rosmedtechnologies"
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
  • Cadiz, Spain, 11009
    • Hospital Universitario Puerta Del Mar
  • Las Palmas De Gran Canaria, Spain, 35016
    • Hospital Universitario Materno Infantil de Canarias
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Madrid, Spain
    • Hospital 12 de Octubre
  • Sevilla, Spain
    • Hospital Virgen del Rocío
  • Valencia, Spain, 46009
    • Hospital Universitario La Fe
  • Zaragoza, Spain, 50009
    • "Hospital Universitario Miguel Servet
• Ukraine
  • Chernivtsi, Ukraine
    • City Clinical Maternity Hospital #1
  • Donets'k, Ukraine, 83114
    • Donets'k Regional Centre of Mother and Child Care
  • Ivano-Frankivs'k, Ukraine
    • Ivano-Frankivs'k Regional Prenatal Center, department of pregnant pathology
  • Kyiv, Ukraine, 04050
    • <<Institute of Pediatrics, Obstetrics and Gynecology of AMS Ukraine>> Department of Rehabilitation and Reproduktive function of Women
  • Kyiv, Ukraine, 04220
    • Polyclinic #1, Obolon district of Kyiv, maternity welfare department
  • Kyiv, Ukraine
    • Kyiv City Centre of Reproduction and perinatal medicine, obstetric department
  • Kyiv, Ukraine
    • SI "Institute of pediatrics, obstetrics and gynecology of AMS of Ukraine". Department of extragenital pathology and postnatal rehabilitation
  • Odessa, Ukraine, 65039
    • Municipal Institution "Maternity Hospital #1"
  • Ternopil, Ukraine, 46001
    • Ternopil' Municipal Hospital # 2
  • Uzhgorod, Ukraine, 88017
    • Uzhgorod Municipal prenatal Centre, maternity welfare department #2
  • Zaporizhzhya, Ukraine, 69065
    • Clinical Maternity Hospital No 4
  • Zhaporizhzhya, Ukraine, 69071
    • Department of Obstetrics and Gynecology of Zhaporizhzhya Medical Academy of Postgraduate Education on the Base of Healthcare Institution Maternity Hospital No 3
• United States
  • Alabama
    • Montgomery, Alabama, United States, 36106
      • Drug Research & Analysis Corporation
  • Arizona
    • Tucson, Arizona, United States, 85712
      • Tucson Medical Center (Watching Over Mothers and Babies Foundation)
  • California
    • La Mesa, California, United States, 91942
      • Grossmont Center for Clinical Research
    • San Diego, California, United States, 92134-5000
      • Naval Medical Center San Diego - Department of Obstetrics and Gynecology
    • West Hills, California, United States, 91307
      • Womens Health Specialists
  • Colorado
    • Colorado Springs, Colorado, United States, 80903
      • Women's Associates, P.C.
    • Lakewood, Colorado, United States, 80228
      • Red Rocks OB/GYN - Physician's Research Options, LLC
  • Florida
    • Boynton Beach, Florida, United States, 33472
      • Visions Clinical Research
    • Lake Worth, Florida, United States, 33407
      • Palm Beach Obstetrics & Gynecology, PA (Altus Research)
    • Pembroke Pines, Florida, United States, 33024
      • Global Ob/Gyn Centers
  • Georgia
    • Riverdale, Georgia, United States, 30274
      • New Millennium Obstetrics & Gynecology, LLc
  • Hawaii
    • Honolulu, Hawaii, United States, 96859
      • Tripler Army Medical Center
  • Idaho
    • Boise, Idaho, United States, 83712
      • The Women's Clinic
    • Idaho Falls, Idaho, United States, 83404
      • Rosemark Women Care Specialists
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville
    • Louisville, Kentucky, United States, 40207
      • Women's Care Physicians/Obstetrical Specialists, PLLC
  • Maryland
    • Bel Air, Maryland, United States, 21014
      • Steven Z. Lenowitz, MD, LLC
  • Michigan
    • Grand Rapids, Michigan, United States, 49503
      • Female Pelvic Medicine and Urogynecology Institute of Michigan
    • Saginaw, Michigan, United States, 48604
      • Saginaw Valley Medical Research Group, LLC
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke University Medical Center
    • Fort Bragg, North Carolina, United States, 28310
      • Womack Army Medical Center
    • Winston-Salem, North Carolina, United States, 27103
      • Lyndhurst Clinical Research
    • Winston-Salem, North Carolina, United States, 27103
      • Triad Research Partners, LLC
  • North Dakota
    • Bismarck, North Dakota, United States, 58501
      • Mid Dakota clinicl, PC Center for Women
  • Ohio
    • Englewood, Ohio, United States, 45322
      • HWC Women's Research Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University Hospital
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University School of Medicine
  • South Carolina
    • Columbia, South Carolina, United States, 29201
      • SC Clinical Research Center, LLC
    • Greenville, South Carolina, United States, 29605
      • Greenville Hospital System University Medical Group
  • Tennessee
    • Memphis, Tennessee, United States, 38104
      • Women's Physician's Group, MPLLC
  • Texas
    • Dallas, Texas, United States, 75230
      • Practice Research Organization, Inc.
    • Fort Hood, Texas, United States, 76544
      • Carl R. Darnall Army Medical Center
    • Fort Sam Houston, Texas, United States, 78236
      • San Antonio Military Medical Center
    • McAllen, Texas, United States, 78503
      • Research Associates Rio Grande Valley
  • Utah
    • Layton, Utah, United States, 84041
      • Tanner Clinic
    • Pleasant Grove, Utah, United States, 84062
      • Mt. Timpanogos Women's Health Care
    • Sandy, Utah, United States, 84070
      • Salt Lake Women's Center, P.C.
  • Virginia
    • Portsmouth, Virginia, United States, 23708
      • Naval Medical Center - Portsmouth
  • Washington
    • Tacoma, Washington, United States, 98431
      • Madigan Army Medical Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53210
      • Wheaton Franciscan Healthcare - St. Joseph Campus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

Each subject must meet the following criteria to be enrolled in this study:

1. Age ≥ 18 years.
2. Singleton gestation.
3. Project gestational age 16 weeks 0 days of gestation or more and less than or equal to 20 weeks 6 days of gestation at the time of randomization, based on clinical information and evaluation of the first ultrasound.
4. Documented history of a previous singleton spontaneous preterm delivery. Spontaneous preterm birth is defined as delivery from 20 weeks 0 days to 36 weeks 6 days of gestation following spontaneous preterm labor or pPROM. Where possible, the gestational age of the previous preterm birth (referred to as the qualifying delivery) should be determined as described in "Gestational Age Determination". If the gestational age at delivery is obtained directly from the medical record and more than one gestational age appears, the latest will be used. As a validation of the gestational age of the previous delivery, if the infant weighed more than 3300 grams (the birth weight 90th percentile for 36 weeks gestational age), this will not qualify as preterm. The previous preterm delivery cannot be an antepartum stillbirth.

Exclusion Criteria:

1. Multifetal gestation.
2. Known major fetal anomaly or fetal demise. An ultrasound examination between 14 weeks 0 days through 20 weeks 3 days of gestation must be performed to rule out fetal anomalies.
3. Progesterone treatment in any form (i.e., vaginal, oral, intramuscular) during current pregnancy, other than micronized progesterone delivered orally or vaginally provided it is stopped at least 4 weeks prior to the first dose of study medication.
4. Heparin therapy during current pregnancy or history of thromboembolic disease.

5. Maternal medical/obstetrical complications including:

   • Current or planned cerclage
   • Hypertension requiring medication
   • Seizure disorder
6. Subjects with a uterine anomaly (uterine didelphys or bicornate uterus). However, subjects with uterine fibroids are eligible for the study.
7. Unwillingness to comply with and complete the study.
8. A 14 weeks 0 days through 20 weeks 3 days of gestation ultrasound cannot be arranged before randomization.
9. Participation in an antenatal study in which the clinical status or intervention may influence gestational age at delivery.
10. Participation in this trial in a previous pregnancy. Women who were screened in a previous pregnancy, but not randomized, do not have to be excluded.
11. Known hypersensitivity to hydroxyprogesterone caproate or its components.
12. Have any significant medical disorder that, in the opinion of the investigator, would be a contraindication to the use of the drug including those listed in section 5.3.2 of the investigational brochure. Other examples to consider include uncontrolled diabetes, known HIV infection or renal dysfunction.
13. Have any significant medical disorder that, in the opinion of the investigator, would preclude accurate evaluation of the subject's condition or outcome in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Vehicle; Castor Oil	Drug: Vehicle; Weekly intramuscular injections of 1 mL vehicle inert oil until 36 weeks, 6 days of gestation or delivery, whichever occurs first.; Other Names: Placebo
Active Comparator: Hydroxyprogesterone Caproate Injection (HPC), 250 mg/mL; HPC 250 mg/mL in oil	Drug: Hydroxyprogesterone Caproate Injection (HPC), 250mg/mL; 1 mL intramuscular injection every week until 36 weeks, 6 days of gestation or delivery, whichever occurs first.; Other Names: 17P; Makena

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Preterm Birth <35 Weeks Gestation	Determine if treatment with 17P reduces the rate of preterm birth < 35 weeks, 0 days of gestation in women with a previous singleton spontaneous preterm delivery.	Up to 35 weeks
Neonatal Composite Index (NCI)	The composite index is defined as a liveborn neonate with any of the following occurring at any time during the birth hospitalization up through discharge from the NICU: neonatal death, grade 3 or 4 intraventricular hemorrhage, respiratory distress syndrome, bronchopulmonary dysplasia, necrotizing enterocolitis or proven sepsis.	Until 28 days of life or discharge from the neonatal intensive care unit (NICU), whichever occurred later.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fetal/Early Infant Death	Defined as spontaneous abortion/miscarriage (delivery from 16 weeks 0 days through 19 weeks 6 days of gestation) or neonatal death occurring in liveborns born at less than 24 weeks gestation or stillbirth (antepartum or intrapartum death from 20 weeks gestation through term), in the 17P group compared to the vehicle group	Delivery from 16 weeks 0 days through 19 weeks 6 days of gestation; or neonatal death occurring in liveborns born at less than 24 weeks gestation; or stillbirth (antepartum or intrapartum death) from 20 weeks gestation through term).
Preterm Birth Prior to 32 Weeks Gestation		Up to 32 weeks
Preterm Birth Prior to 37 Weeks Gestation		Up to 37 weeks
Stillbirths	Defined as all stillbirths/fetal deaths/in utero fetal losses occurring from 20 weeks gestation until term.	20 weeks gestation until term
Neonatal Deaths With ≥24 Weeks Gestational Age	Neonatal death (from minutes after birth until 28 days of life) occurring in liveborns born at 24 weeks gestation or greater	Until 28 days of life or discharge from the NICU whichever occurred later.

Collaborators and Investigators

• Sponsor: AMAG Pharmaceuticals, Inc.
• Collaborators: ResearchPoint Global

Publications and helpful links

General Publications

• Blackwell SC, Gyamfi-Bannerman C, Biggio JR Jr, Chauhan SP, Hughes BL, Louis JM, Manuck TA, Miller HS, Das AF, Saade GR, Nielsen P, Baker J, Yuzko OM, Reznichenko GI, Reznichenko NY, Pekarev O, Tatarova N, Gudeman J, Birch R, Jozwiakowski MJ, Duncan M, Williams L, Krop J. 17-OHPC to Prevent Recurrent Preterm Birth in Singleton Gestations (PROLONG Study): A Multicenter, International, Randomized Double-Blind Trial. Am J Perinatol. 2020 Jan;37(2):127-136. doi: 10.1055/s-0039-3400227. Epub 2019 Oct 25.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2009
• Primary Completion (Actual): October 1, 2018
• Study Completion (Actual): October 1, 2018

Study Registration Dates

• First Submitted: October 27, 2009
• First Submitted That Met QC Criteria: October 28, 2009
• First Posted (Estimate): October 29, 2009

Study Record Updates

• Last Update Posted (Actual): June 1, 2022
• Last Update Submitted That Met QC Criteria: May 10, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: preterm birth; spontaneous preterm birth; 17-hydroxyprogesterone caproate; progestogens; 17P; 17-HPC; 17-OHPC; recurrent preterm birth
• Additional Relevant MeSH Terms: Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Premature Birth; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Estrogen Antagonists; Progestins; 17 alpha-Hydroxyprogesterone Caproate; 11-hydroxyprogesterone
• Other Study ID Numbers: 17P-ES-003