CC BY 4.0 · Am J Perinatol
DOI: 10.1055/s-0039-3400227
Original Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

17-OHPC to Prevent Recurrent Preterm Birth in Singleton Gestations (PROLONG Study): A Multicenter, International, Randomized Double-Blind Trial

Sean C. Blackwell
1  Department of Obstetrics, Gynecology, and Reproductive Sciences, McGovern Medical School-UTHealth, Houston, Texas
,
Cynthia Gyamfi-Bannerman
2  Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, New York
,
Joseph R. Biggio Jr.
3  Section of Maternal Fetal Medicine, Women's Services, Ochsner Health Systems, New Orleans, Louisiana
,
Suneet P. Chauhan
1  Department of Obstetrics, Gynecology, and Reproductive Sciences, McGovern Medical School-UTHealth, Houston, Texas
,
Brenna L. Hughes
4  Department of Obstetrics and Gynecology, Duke University, Durham, North Carolina
,
Judette M. Louis
5  Department of Obstetrics and Gynecology, University of South Florida, Tampa, Florida
,
Tracy A. Manuck
6  Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, North Carolina
,
Hugh S. Miller
7  Valley Perinatal Services, Watching Over Mothers and Babies Foundation, Tucson, Arizona
,
Anita F. Das
8  Das Consulting, Guerneville, California
,
George R. Saade
9  Department of Obstetrics and Gynecology, University of Texas Medical Branch, University of Texas, Galveston, Texas
,
Peter Nielsen
10  Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Baylor College of Medicine and The Children's Hospital of San Antonio, San Antonio, Texas
,
Jeff Baker
11  Clinical Research Prime, Idaho Falls, Idaho
,
Oleksandr M. Yuzko
12  Department of Obstetrics and Gynecology, Bukovinian State Medical University, Chernivtsi, Ukraine
,
Galyna I. Reznichenko
13  Department of Obstetrics and Gynecology, Clinical Maternity Hospital # 4, Zaporizhzhya, Ukraine
,
Nataliya Y. Reznichenko
13  Department of Obstetrics and Gynecology, Clinical Maternity Hospital # 4, Zaporizhzhya, Ukraine
,
Oleg Pekarev
14  Department of Obstetrics and Gynecology, State Government-financed Healthcare Institution of Novosibirsk Region, Novosibirsk, Russia
,
Nina Tatarova
15  Department of Obstetrics and Gynecology, Saint-Petersburg Government-financed Healthcare Institution “Maternity Hospital #17,” Saint-Petersburg, Russia
,
Jennifer Gudeman
16  AMAG Pharmaceuticals, Inc, Medical Development, Waltham, Massachusetts
,
Robert Birch
17  Formerly at AMAG Pharmaceuticals, Inc, Medical Development, Waltham, Massachusetts
,
Michael J. Jozwiakowski
18  Jozwiakowski Pharma Consulting LLC, Santa Fe, New Mexico
,
Monique Duncan
16  AMAG Pharmaceuticals, Inc, Medical Development, Waltham, Massachusetts
,
Laura Williams
16  AMAG Pharmaceuticals, Inc, Medical Development, Waltham, Massachusetts
,
Julie Krop
16  AMAG Pharmaceuticals, Inc, Medical Development, Waltham, Massachusetts
› Author Affiliations
Funding This study was funded by AMAG Pharmaceuticals 1100 Winter Street Waltham, MA 02451.
Further Information

Publication History

15 October 2019

21 October 2019

Publication Date:
25 October 2019 (online)

  

Abstract

Background Women with a history of spontaneous preterm birth (SPTB) are at a significantly increased risk for recurrent preterm birth (PTB). To date, only one large U.S. clinical trial comparing 17-OHPC (17-α-hydroxyprogesterone caproate or “17P”) to placebo has been published, and this trial was stopped early due to a large treatment benefit.

Objective This study aimed to assess whether 17-OHPC decreases recurrent PTB and neonatal morbidity in women with a prior SPTB in a singleton gestation.

Study Design This was a double-blind, placebo-controlled international trial involving women with a previous singleton SPTB (clinicaltrials.gov: NCT 01004029). Women were enrolled at 93 clinical centers (41 in the United States and 52 outside the United States) between 160/7 to 206/7 weeks in a 2:1 ratio, to receive either weekly intramuscular (IM) injections of 250 mg of 17-OHPC or an inert oil placebo; treatment was continued until delivery or 36 weeks. Co-primary outcomes were PTB < 35 weeks and a neonatal morbidity composite index. The composite included any of the following: neonatal death, grade 3 or 4 intraventricular hemorrhage, respiratory distress syndrome, bronchopulmonary dysplasia, necrotizing enterocolitis, or proven sepsis. A planned sample size of 1,707 patients was estimated to provide 98% power to detect a 30% reduction in PTB < 35 weeks (30% to 21%) and 90% power to detect a 35% reduction in neonatal composite index (17%–11%) using a two-sided type-I error of 5%. Finally, this sample size would also provide 82.8% power to rule out a doubling in the risk of fetal/early infant death assuming a 4% fetal/early infant death rate. Analysis was performed according to the intention-to-treat principle.

Results Baseline characteristics between the 1,130 women who received 17-OHPC and 578 women who received placebo were similar. Overall, 87% of enrolled women were Caucasian, 12% had >1 prior SPTB, 7% smoked cigarettes, and 89% were married/lived with partner. Prior to receiving study drug, 73% women had a transvaginal cervical length measurement performed and <2% had cervical shortening <25 mm. There were no significant differences in the frequency of PTB < 35 weeks (17-OHPC 11.0% vs. placebo 11.5%; relative risk = 0.95 [95% confidence interval (CI): 0.71–1.26]) or neonatal morbidity index (17-OHPC 5.6% vs. placebo 5.0%; relative risk = 1.12 [95% CI: 0.68–1.61]). There were also no differences in frequency of fetal/early infant death (17-OHPC 1.7% vs. placebo 1.9%; relative risk = 0.87 [95% CI: 0.4–1.81]. Maternal outcomes were also similar. In the subgroup of women enrolled in the United States (n = 391; 23% of all patients), although the rate of PTB < 35 weeks was higher than the overall study population, there were no statistically significant differences between groups (15.6% vs. 17.6%; relative risk = 0.88 [95% CI: 0.55, 1.40].

Conclusion In this study population, 17-OHPC did not decrease recurrent PTB and was not associated with increased fetal/early infant death.

Condensation

In women with a prior spontaneous preterm birth, weekly 17-OHPC compared with placebo did not reduce recurrent preterm birth or decrease neonatal morbidity.


Clinical Trial Registration

Date of registration: October 27, 2009.


Date of initial participant enrollment: November 12, 2009.


Clinical trials ID: NCT01004029.


URL: https://clinicaltrials.gov/ct2/show/NCT01004029?term=17P+AMAG&rank=2.


Supplementary Material