This entry has been updated with the latest FDA proposed decision and a summary of the review by Sibai et al. (Obstet Gynecol, 2020)

SUMMARY:

The authors of the PROLONG trial (Progestin’s Role in Optimizing Neonatal Gestation) reported on the use of 17α-hydroxyprogesterone caproate (17-OHPC) for the treatment of preterm birth (PTB)

In this study population, 250 mg 17-OHPC did not decrease recurrent PTB and was not associated with increased fetal/early infant death

On October 29, 2019, the FDA advisory committee recommended that the drug be withdrawn from the market (9 to 7 vote). On October 5, 2020, the Center for Drug Evaluation and Research (CDER) proposed that Makena be withdrawn from the market. The CDER proposal announcement further states

Makena and its approved generic equivalents will remain on the market until the manufacturers decide to remove the drugs or the FDA Commissioner mandates their removal

If AMAG Pharmaceuticals requests a hearing, the FDA Commissioner will determine whether to hold a public hearing and, following such hearing, decide whether to withdraw approval of Makena and its approved generic equivalents

In the interim, we recommend that health care professionals discuss Makena’s benefits, risks and uncertainties with their patients to decide whether to use Makena while a final decision is being made about the drug’s marketing status

We intend to hold a meeting with experts in obstetrics, neonatal care, and clinical trial design to discuss how to facilitate development of effective and safe therapies to treat preterm birth

Background to PROLONG Trial

• A previous study, on behalf of the NICHD, demonstrated success of IM 17-OHPC in preventing PTB (see ‘Learn More – Primary Sources)
  • Meis et al. (NEJM, 2003): 250 mg IM 17-OHPC reduced recurrent preterm birth (PTB) in women with a prior spontaneous PTB (SPTB)
    • Relative risk [RR] 0.66 (95% CI, 0.54–0.81)
• The current PROLONG study was a ‘confirmatory trial’, performed with FDA input as a requirement for the FDA accelerated approval pathway

PROLONG Methods

• Double-blind randomized controlled trial (RCT)
• Participants
  • ≥18 years
  • Singleton pregnancy
  • Currently 16w0d to 20w6d
  • Previous history of singleton SPTB (birth between 20w0d and 36w6d following preterm labor or PROM)
• Groups (IM injection 1 in upper outer quadrant of the gluteus maximus) weekly until delivery or 36 weeks
  • 17-OHPC (250 mg)
  • Placebo
• Stratified by
  • Study site
  • GA at randomization
• Primary outcomes
  • PTB < 35 weeks
  • Composite neonatal morbidity and mortality index

PROLONG Results

• PTB < 35w0d (p=0.72)
  • 17-OHPC: 11.0%
  • Placebo: 11.5%
  • Relative risk (RR) 0.95 (95% CI, 0.71–1.26)
• Neonatal composite index (p=0.73)
  • 17-OHPC 5.6%
  • Placebo 5.0%
  • RR 1.12 (95% CI, 0.70–1.66)
  • Note: No differences seen in any of the individual components that were part of the composite index

KEY POINTS:

SMFM Response

SMFM has responded to the PROLONG trial results and makes the following substantive points comparing current data to Meis et. al. study

• Difference in population when analyzing Meis et al., vs PROLONG
  • Higher rate of black women: 59% vs 7%
  • Smoking (tobacco): >20% vs 8%
  • >1 prior PTB: 32% vs 12%
  • Additional PTB risk factors aside from prior history: 91% vs 48%
• Difference in results may be a result of high vs average risk but “population differences do not completely explain the discrepancy” due to complexity of PTB
• Concerns related to 17-OHPC include
  • Healthcare costs
  • Injection-site pain
  • Additional patient visits
• Additional research required to (1) determine long-term maternal and neonatal side effects (2) “identify populations in which administration of 17-OHPC may provide needed benefit in the reduction of recurrent sPTB”
• SMFM states that

…it is reasonable for providers to use 17-OHPC in women with a profile more representative of the very high-risk population reported in the Meis trial. For all women at risk of recurrent sPTB, the risk/benefit discussion should incorporate a shared decision-making approach, taking into account the lack of short-term safety concerns but uncertainty regarding benefit

ACOG Response

ACOG has likewise responded to the PROLONG trial with a Practice Advisory | Guidance remains unchanged following the FDA decision

• Similar to SMFM, ACOG notes that while eligibility criteria were similar between the Meis trial and PROLONG, the populations are different and preterm birth rate in the current study is approximately 50% lower than the earlier study
• The study authors acknowledge that
  • PROLONG may be underpowered for the population under study
  • Selection bias may have played a role, as women at higher risk would not have agreed to possibility of receiving placebo
• Additional studies, including a meta-analysis, are planned
• ACOG Guidance (Practice Bulletin 130) states

A woman with a singleton gestation and a prior spontaneous preterm singleton birth should be offered progesterone supplementation starting at 16–24 weeks of gestation, regardless of transvaginal ultrasound cervical length, to reduce the risk of recurrent spontaneous preterm birth

• The Practice Advisory response to the PROLONG trial states that ACOG

is not changing our clinical recommendations at this time and continues to recommend offering hydroxyprogesterone caproate as outlined in Practice Bulletin # 130

Sibai et al. Obstet Gynecol, 2020

Meis Trial

• Well designed and conducted
• Highly statistically significant results
  • Prespecified criterion threshold of alpha=0.015 was met regarding benefit of 17-OHPC
  • Preterm birth <37 weeks: Relative risk (RR) 0.66 (95% CI, 0.54 to 0.81; P<.001)
  • Preterm births <35 weeks: RR 0.67 (95% CI, 0.48 to 0.93)
  • Preterm birth <32 weeks: RR 0.58 (95% CI, 0.37–0.91)
• Subgroup analysis: Number of prior preterm birth | Race | Marital status | Smoking or substance use
  • Confirmed generalizability

Prolong Trial

• Population studied was very different from that of the Meis trial (non-US)
• Trial is underpowered based on observed event rates
  • For 90% power, PROLONG required 3,600 women for preterm birth <35 weeks and 6,000 women for neonatal composite outcome
• PROLONG not powered for subgroup analysis, but Meis et al. did look at US subgroup and found that while not statistically significant
  • Direction and magnitude of effect <32 weeks and neonatal composite index were similar to the Meis trial

Authors’ Conclusion

We assert PROLONG was underpowered, based on substantially lower observed preterm birth rates than anticipated, and therefore was a false-negative study, rather than the Meis trial being a false-positive study

Careful assessment of these two trials is critical as removal of 17α-hydroxyprogesterone caproate from the U.S. marketplace may have substantial effects on public health

Learn More – Primary Sources:

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

Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. (NEJM, 2003)

SMFM Statement: Use of 17-alpha hydroxyprogesterone caproate for prevention of recurrent preterm birth

ACOG Practice Advisory: Clinical guidance for integration of the findings of the PROLONG study: Progestin’s Role in Optimizing Neonatal Gestation

ACOG Statement on FDA Proposal to Withdraw 17p Hydroxyprogesterone Caproate

ACOG Practice Bulletin 130: Prediction and Prevention of Preterm Birth

Meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee Meeting Announcement: MAKENA supplemental new drug application

FDA (October 2020): CDER proposes withdrawal of approval for Makena

Re-examining the Meis Trial for Evidence of False-Positive Results (Sibai et al. Obstetrics & Gynecology, 2020)

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