The injectable agent 17-α-hydroxyprogesterone (Makena), which is FDA approved for certain pregnant women with a prior preterm birth to prevent subsequent preterm birth, actually had no effect on preterm birth or neonatal morbidity compared with placebo in this population, researchers found.
The findings call the product's continued market presence into question, as the study was required by the FDA as a condition of its initial approval.
There was no significant difference in preterm birth at less than 35 weeks gestation between the intervention and control groups (11.0% vs 11.5%, respectively, RR 0.95, 95% CI 0.71-1.26), nor was there a difference in neonatal morbidity index (5.6% vs 5.0%, RR 1.12, 95% CI 0.68-1.61), reported Sean Blackwell, MD, of McGovern Medical School at UTHealth in Houston, and colleagues.
Moreover, there was no difference in secondary outcomes between the two groups, such as frequency of fetal/infant death or maternal outcomes, the authors wrote in the American Journal of Perinatology. The FDA will address these findings on Oct 29 as part of an advisory committee meeting about Makena.
In 2011, 17-α-hydroxyprogesterone, or 17-OHPC, received conditional approval from the FDA under an accelerated approval pathway, for use in women with a prior preterm birth to prevent a subsequent preterm birth. But this trial by Blackwell and colleagues, which showed no difference in preterm birth or neonatal morbidity, was the confirmatory trial that was required as part of the approval.
Previously, a 2003 trial found that 17-OHPC was effective compared with placebo in this population -- so effective that the trial was stopped early. Blackwell and colleagues noted that "although not planned or conducted as a drug approval trial, [this trial] was a key aspect to provide evidence of 17-OHPC effectiveness" and played a role in the approval of Makena.
Major obstetric care organizations weighed in with their opinions on the new findings ahead of the planned FDA advisory committee review. The Society for Maternal-Fetal Medicine (SMFM) released updated clinical guidance recommending that obstetric care providers continue to use "an individualized approach" in counseling patients about the use of 17-OHPC, and the organization called for additional research to identify populations where the agent is likely to be effective.
However, SMFM also noted differences in the populations of the 2003 trial and this current trial, stating that the 2003 trial had a larger proportion of patients with additional risk factors for preterm birth, and there were differences between the two trials in regard to race/ethnicity, number of previous preterm births, marital status, and substance use.
The American College of Obstetricians and Gynecologists (ACOG) released a statement indicating that its current clinical guidance about preterm birth will remain in effect.
In the PROLONG trial, Blackwell and colleagues examined data from women at 93 clinical centers -- 41 in the U.S. and 52 outside the U.S. Participants were women with a previous preterm birth, who were from 16 to 20 weeks gestation. Participants were randomized 2:1 to receive either weekly intramuscular injections of 17-OHPC or inert oil placebo. The treatment was continued through 36 weeks or delivery.
Co-primary outcomes were preterm birth prior to 35 weeks gestation and a neonatal composite morbidity index, including neonatal death, grade 3 or 4 intraventricular hemorrhage, respiratory distress syndrome, bronchopulmonary dysplasia, and necrotizing enterocolitis.
Overall, 1,130 women received the intervention and 578 women received placebo. Baseline characteristics were similar, as over 85% of women were Caucasian, 12% had a prior preterm birth, and 7% were smokers.
There was no significant difference in the primary outcome, nor was there a difference in preterm birth in a subanalysis of women from the U.S. only (15.6% vs 17.6%, RR 0.88, 95% CI 0.55-1.40).
The study was supported by AMAG Pharmaceuticals.
Blackwell disclosed no conflicts of interest; other co-authors disclosed support from AMAG Pharmaceuticals.
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