The PROLONG Trial (Progesterone for Preterm Birth, Part II)

Last week, we introduced our major progesterone trial series with a discussion of the Meis trial. We finish up this week talking about the follow up trial: the PROLONG study.

The PROLONG Trial 

Methods

• Location

  • 93 total centers across 9 countries  

• Eligibility criteria and exclusion criteria: pretty much the same as the earlier trial 

• Randomization and treatment 

  • Randomized 2:1 to receive 17OHP weekly, to start between 16-20w6d 

  • Placebo was benzyl benzoate, caster oil, benzyl alcohol 

• Outcomes 

  • Measured preterm birth <35 weeks 

  • Composite neonatal morbidity and mortality index 

  • Secondary outcomes: 

    • Neonatal death, PTB <32 weeks, PTB <37 weeks and also medical indicated preterm births 

  • Primary safety outcome: fetal/early infant death 

• Stats 

  • Unlike previous trial, wanted it to have adequate power to identify both the primary efficacy and the primary safety analyses 

  • Therefore, needed 1665 liveborn infants to detect a reduction of 35% in the rate of the composite index 

  • Needed 1707 patients to provide 98% power to detect a reduction of approximately 30% in the rate of PTB <35w0d

Results 

• Timeline: November 12, 2009 - October 8, 2018 

• Total of 1740 women were consented and agreed to study 

  • 1130 allocated to 17OHP, 578 allocated to placebo 

  • 390 were randomized in the US, 1317 randomized in non-US 

• Demographics were similar between groups 

  • 88.8% vs. 87.2% Caucasion in 17OHP vs. placebo groups 

  • Prepregnancy BMI 23 

  • Almost 90% were married, living with partner compared to just about 50% in the other study 

  • Only 7-8% smoked in pregnancy compared 20-22% in other study 

• So… similar for each arm of this study, but very different demographic compared to the Meis trial.

• Primary Outcome 

  • Preterm birth prior to 35 weeks: 11.0% in 17OHP vs. 11.5%

    • Spontaneous was 8.4 vs 8.9%, RR 0.93, 95% CI 0.67-1.30

  • Not a primary outcome, but PTB <37 weeks: 23.1% vs 21.9% RR 1.06, 95% CI 0.88-1.28! 

    • So different from 36 vs. 50% in Meis study 

  • Neonatal outcomes: 

    • Unsurprisingly, given no diff in preterm labor, no diff in composite neonatal morbidity and mortality 

• Secondary Outcome 

  • Preterm birth <32 weeks - also not different 

  • Other things: cerclage, preterm labor eval, tocolysis, corticosteroids, maternal GDM, preeclampsia, chorio, abruption, CS all not different 

  • Neonatal: no difference in anything, including neonatal death, RDS, NEC, IVH, NICU admission, birth weight, TTN, PDA, ROP

Conclusions

• Study was done in consultation with the FDA as part of approval for use of 17OHP 

• Unlike the findings in the MFMU trial, this study had much lower event rate of PTB and did not confirm treatment efficacy 

Discussion points

• While the Meis study was conducted in the USA, the PROLONG study was mostly not, and that was because the findings from the Meis study had changed practice 

• Most places in the US were already prescribed 17OHP and likey didn’t want to change their practice 

• Also, the Meis showed a large predominance of black women (60%), while there were very few in the PROLONG study 

• Finally, there was a huge discrepancy in baseline preterm labor rates between the two studies, with the rates in PROLONG about ½ has much as that of the Meis study 

• Why castor oil? 

  • Not that it has shown to cause preterm labor, but castor oil can cause contractions, usually due to GI distress when ingested 

• Consequences of the Studies 

  • After Meis, everyone started doing 17OHP 

  • After PROLONG, an FDA advisory committee proposed to take Makena (17OHP) off the market in 2019 (9 to 7 vote) 

    • https://www.nytimes.com/2022/03/25/health/fda-drug-approvals-makena.html ← NY times article about all this 

  • Plan: Oct 17-19 the FDA’s advisory committee will meet to discuss the medicine and hear arguments if it should stay on the market 

• Follow up to the study 

  • EPPPIC - Evaluating Progesterone for Preventing Preterm birth International Collaborative - meta-analysis of individual participant data from randomized controlled trials 

    • Published in the Lancet in 2021 

    • Basically: 31 trials were included with individual participant data

      • From these studies, it seems that vaginal progesterone and 17OHP both reduce birth before 34 weeks gestation in high risk singleton pregnancies 

      • Absolute risk reduction is greater for women with short cervices 

      • The data seems a little better for vaginal progesterone in consistently decreasing preterm birth <37 weeks and <34 weeks

      • For 17OHP the data just crosses the line of no effect at <34 weeks