PROLONG trial fails to meet co-primary endpoints

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The much-anticipated top-line results of a clinical trial of injectable progestin for prevention for preterm birth (PTB) in women with a history of the complication showed that treatment was no better than placebo. The findings, which have not yet been published, were announced by AMAG Pharmaceuticals, Inc., manufacturers of Makena, the drug that was tested.

The US Food and Drug Administration (FDA) granted approval for 17 alpha-hydroxyprogesterone caproate (17P) in February 2011 and the drug had orphan drug exclusivity through February 3, 2018. The PROLONG (Progestin’s Role in Optimizing Neonatal Gestation) trial was part of an approval commitment under the FDA’s “Supbpart H” accelerated approval process.

The randomized, double-blinded, placebo-controlled trial was designed to assess the safety and efficacy of 17P injection, 250 mg/mL, in reducing risk of PTB and neonatal morbidity/mortality in women pregnant with a singleton gestation who had a previous singleton spontaneous PTB. For the multicenter, multinational research, the investigators chose a sample size of 1707 with the goal of achieving 95% power and a 35% reduction in neonatal reduction in neonatal morbidity and mortality. 

The trial had two coprimary outcomes: PTB < 35 weeks and a compositive neonatal morbidity and mortality index. Secondary outcomes included 2-year follow-up of infants.

According to press release from the drug’s manufacturer, PROLONG top-line results showed a 11.0% incidence of PTB at < 35 weeks in the treatment group vs. 11.5% for the placebo group (P= .72) and 5.4% vs. 5.2%, respectively (P= .84) for the neonatal morbidity and mortality composite index.  Adverse events of special interest, including miscarriage and stillbirth, were described as “infrequent” and “similar” between the two arms. 

Commenting in the release, principal investigator and chair of the PROLONG Publications Committee Sean Blackwell, MD, of UTHealth at Houston said, “Our committee will be reviewing the trial data in detail and we will be actively involved in the analysis and interpretation of the findings. It is clear that the overall study population of PROLONG is significantly different than those who participated in the NICHD MFMU trial with respect to race, socioeconomic status, and severity of disease. Thus, we need sufficient time to thoughtfully interpret these findings in the context of the prior clinical trials.”

Results of the previous trial, conducted by investigators from the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network, showed that weekly injections of 17P, 250 mg/mL, resulted in a substantial reduction in the rate of recurrent PTB in women at particularly high risk for the condition and reduced likelihood of several complications in their infants. The participants were all enrolled in US centers whereas more than 75% of the women in the PROLONG trial were from outside the United States.