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Am J Perinatol. 2019 Oct 25. doi: 10.1055/s-0039-3400227. [Epub ahead of print]

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

Author information

1
Department of Obstetrics, Gynecology, and Reproductive Sciences, McGovern Medical School-UTHealth, Houston, Texas.
2
Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, New York.
3
Section of Maternal Fetal Medicine, Women's Services, Ochsner Health Systems, New Orleans, Louisiana.
4
Department of Obstetrics and Gynecology, Duke University, Durham, North Carolina.
5
Department of Obstetrics and Gynecology, University of South Florida, Tampa, Florida.
6
Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, North Carolina.
7
Valley Perinatal Services, Watching Over Mothers and Babies Foundation, Tucson, Arizona.
8
Das Consulting, Guerneville, California.
9
Department of Obstetrics and Gynecology, University of Texas Medical Branch, University of Texas, Galveston, Texas.
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.
11
Clinical Research Prime, Idaho Falls, Idaho.
12
Department of Obstetrics and Gynecology, Bukovinian State Medical University, Chernivtsi, Ukraine.
13
Department of Obstetrics and Gynecology, Clinical Maternity Hospital # 4, Zaporizhzhya, Ukraine.
14
Department of Obstetrics and Gynecology, State Government-financed Healthcare Institution of Novosibirsk Region, Novosibirsk, Russia.
15
Department of Obstetrics and Gynecology, Saint-Petersburg Government-financed Healthcare Institution "Maternity Hospital #17," Saint-Petersburg, Russia.
16
AMAG Pharmaceuticals, Inc, Medical Development, Waltham, Massachusetts.
17
Formerly at AMAG Pharmaceuticals, Inc, Medical Development, Waltham, Massachusetts.
18
Jozwiakowski Pharma Consulting LLC, Santa Fe, New Mexico.

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: NCT01004029). 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.

PMID:
31652479
DOI:
10.1055/s-0039-3400227
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Conflict of interest statement

P.N., J.B., O.M.Y., G.I.R., N.Y.R., O.P., N.T. are PROLONG clinical site investigators.C.G.-B. and J.R.B. have received grant funding for other project(s) from the sponsor (AMAG Pharmaceuticals, Inc.).G.R.S. and H.S.M. have received consulting fees from AMAG Pharmaceuticals, Inc.A.F.D. has received consulting/personal fees related to her work on the project from the sponsor (AMAG Pharmaceuticals, Inc.).J.G., R.B., M.J.J., M.D., L.W., J.K. are current or former employees of AMAG Pharmaceuticals, Inc.

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