Prometrium® (progesterone) 400mg soft vaginal capsules

PROMISE trial overview^{2, 3}

The PROMISE Trial was a multicenter, double-blind, placebo-controlled randomised trial investigating whether treatment with progesterone would increase the rates of live births and newborn survival among women with unexplained recurrent miscarriages. 

Efficacy 

• The live birth rate after 24 weeks of gestation was 65.8% (262/ 398) in the progesterone group as compared with 63.3% (271/428) in the placebo group (relative risk [RR], 1.04; 95% confidence interval [CI], 0.94-1.15; p-value = 0.45). The primary endpoint was not met
• While there was a slightly higher live birth rate in the progesterone group, the trial finding suggests that progesterone did not show a statistically significant difference in live birth rates after 24 weeks compared to placebo, nor did it significantly affect the secondary outcome measures.
• There were no significant between-group differences in the rates of clinical pregnancy (at 6 to 8 weeks), ongoing pregnancy (at 12 weeks), ectopic pregnancy, miscarriage, stillbirth, and neonatal outcomes, as well as in the median gestational age at miscarriage (secondary outcome measure). 

• The frequency of adverse events was not significantly different between the progesterone and placebo groups. In the progesterone group, there were 3 serious adverse events: an allergic reaction, neonatal seizures, and a diagnosis of hypoxic ischemic encephalopathy. In the placebo group, there were 2 serious adverse events: one case of appendicitis and a severe dermatological issue.

PRISM trial overview ^{3, 4}

The PRISM trial was a multicenter, randomised, double-blind, placebo-controlled trial to evaluate progesterone, as compared with placebo, in women with vaginal bleeding in early pregnancy.

Efficacy 
 

• The PRISM trial did not meet its primary endpoint of live birth after 24 completed weeks of gestation.
• The live birth rate after 34 weeks of gestation was 75% (1513/2025) in the progesterone group vs 72% (1459/2013) in the placebo group [RR, 1.03; 95% CI, 1.00–1.07, p=0.08]
• The following results are based on a subgroup analysis:
  • The live birth rates in the progesterone group was 74% (824/1111) and in the placebo group 75%, (840/1127) for women with no previous miscarriages [RR, 0.99; 95% CI, 0.95-1.04]
  • For women with three or more previous miscarriages, there was a 15% increase in live birth rates in the progesterone group (72%, 98/137) compared to the placebo group (57%, 85/148) [RR, 1.28; 95%; CI, 1.08 to 1.51; p=0.007]

Safety

• There was no significant between-group difference in the percentage of participants who had either a maternal or neonatal serious adverse event (5% [105/2025] in the progesterone group and 5% [98/2013] in the placebo group.

According to NICE guidelines, there is evidence to suggest that 400 mg of micronised vaginal progesterone, administered twice daily, improves live birth rates in women with early pregnancy bleeding and a history of miscarriage. ⁵
There was no evidence of benefit found for other progesterone formulations or doses, prompting a recommendation for further research into alternative progestogens for miscarriage prevention.⁵
The PRISM trial did not meet its primary endpoint of live birth after 24 completed weeks of gestation. However, vaginal micronised progesterone showed a modest but significant benefit in the outcome of live birth in women with early pregnancy bleeding and a history of three or more previous miscarriages⁵
The authors cautioned that the effectiveness of 400 mg twice daily of vaginal micronised progesterone cannot be assumed for other progesterone forms, doses, or routes, and it cannot be assumed that non-micronised preparations would behave in the same way as micronised progesterone as the preparation used in the study has identical molecular structure to endogenous progesterone.⁶ Further research is needed to compare micronised versus non-micronised options.
 

Common effects include:¹

• Vaginal itching or burning
• Oily discharge
• Transient tiredness or dizziness (typically within 1–3 hours post-dose)

Hypersensitivity to the active substance or to any of the excipients, jaundice, severe hepatic dysfunction, undiagnosed vaginal bleeding, mammary or genital tract carcinoma, thrombophlebitis, thromboembolic disorders, cerebral haemorrhage, porphyria, allergy to nuts or soya.¹Please refer to full summary of product characteristics for special warnings and precautions for use.¹

Prometrium 400mg soft vaginal capsules contains soybean lecithin and may cause hypersensitivity reactions (urticarial and anaphylactic shock in hypersensitive patients). As there is a possible relationship between allergy to soya and allergy to peanut, patients with peanut allergy should avoid using Prometrium 400mg soft vaginal capsules.¹