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

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.

Safety review of hydroxyprogesterone caproate in women with a history of spontaneous preterm birth

“…There was relatively low (23%) enrollment in the US because 17P was considered standard of care in the US; as such, investigators were reluctant to randomize patients to a placebo-controlled trial. Thus, the PROLONG trial population was predominantly (77%) outside of the US, in countries with markedly lower background rates of PTB [10]. In contrast to the Meis trial, the PROLONG trial did not demonstrate a significant reduction in PTB with 17P; the incidence of PTB at <35 weeks was 11.0% in the 17P group vs 11.5% in the placebo groups.…”

“…PROLONG was an international, multi-center, randomized, double-blind, placebo-controlled trial conducted by a pharmaceutical sponsor, with enrollment between 2009 and 2018 [10]. PROLONG was designed in conjunction with the FDA as a required confirmatory trial.…”

“…There was a low percentage of AEs leading to study drug withdrawal; 11 subjects (1.0%) in the 17P vs 5 (0.9%) in the placebo group. Four of the eleven 17P subjects withdrew due to injection site events; two of the five placebo subjects group withdrew due to cholestasis [16]. Table 1 lists the relevant obstetrical outcomes and common adverse events (≥2% of subjects in the 17P group or at a higher rate in the 17P group).…”

“…As requested by the FDA, PROLONG had a primary safety outcome of excluding a doubling in the risk of fetal/early infant death as a composite endpoint. In both treatment groups, the rate of fetal/early infant death was low; 1.7% in the 17P and 1.9% in placebo groups (RR = 0.87, 95% CI 0.42-1.81) [10]. Given that the upper bound of the 95% CI was <2.0, a doubling in the risk of fetal/early infant death was excluded.…”

The use of progesterone during pregnancy to prevent preterm birth

“…30,38 A double-blind, placebo-controlled, international (PROLONG) trial published in 2019 found no benefit of weekly IM injection of 250 mg of 17-OHPC (from 16 to 36 weeks of gestation) compared to placebo in decreasing recurrent PTB risk and neonatal morbidity when given to women with singleton gestation and a history of SPTB. 39…”