A prospective randomized multicentre study comparing vaginal progesterone gel and vaginal micronized progesterone tablets for luteal support after in vitro fertilization/intracytoplasmic sperm injection.

UNLABELLED SUMMARY QUESTION: Is vaginal progesterone gel equivalent to vaginal micronized progesterone tablets concerning ongoing pregnancy rate and superior concerning patient convenience when used for luteal support after IVF/ICSI? SUMMARY ANSWER Equivalence of treatments in terms of ongoing live intrauterine pregnancy rate has not been demonstrated; the 95% confidence interval (CI) for the difference in ongoing pregnancy rate (-8.2 to 0.1%) did not lie entirely within the pre-specified equivalence interval -7 to 7%. WHAT IS KNOWN ALREADY No significant differences in clinical pregnancy rates have been observed between vaginal progesterone gel and other vaginal progesterone products in earlier studies. However, all previous studies included a limited number of patients. STUDY DESIGN, SIZE AND DURATION This was a randomized, multicentre, controlled, assessor-blinded equivalence trial in 18 fertility centres in Denmark and Sweden between March 2006 and January 2010. A web-based randomization program was used with concealed allocation of patients. Patients were randomized to one of two groups: vaginal progesterone gel or vaginal micronized progesterone tablets. There was no blinding of patients. PARTICIPANTS AND SETTING A total of 2057 women ≤ 40 years of age were included and down-regulated, using the long agonist protocol and rFSH for stimulation. Luteal support was given for 19 days after embryo transfer or until a negative pregnancy test Day 14 after embryo transfer. Patient convenience was assessed using questionnaires to be filled in 14 days after embryo transfer, before pregnancy test. MAIN RESULTS AND THE ROLE OF CHANCE Ongoing intrauterine pregnancy rates were 299/991 (30.2%) (95% CI 27.3-33.0%) in the progesterone gel group and 324/992 (32.7%) (29.7-35.6%) in the micronized progesterone tablet group. The difference in ongoing pregnancy rates between the groups was -4.1% (-8.2 to 0.1%) and the difference in live birth rates was -3.4% (-7.4 to 0.7%), both calculated after correction for significant confounders. Patient convenience and ease of use (1 = very convenient, 10 = very inconvenient) was in favour of progesterone gel, as the overall score was 2.9 (2.7-3.0) for progesterone gel and 4.8 (4.7-5.0; P < 0.0001) for micronized progesterone tablets. This large equivalence trial shows that, even though equality could not be demonstrated, there is no substantial difference in ongoing pregnancy rate between vaginal progesterone gel and vaginal micronized progesterone tablets. It also shows that progesterone gel is considered more convenient by the patients. BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION Blinding of patients was not possible in this study, but since the outcome (pregnancy) is robust, blinding would have been unlikely to affect the results. Unfortunately, owing to an error in the randomization, the intended age distribution allocated older women to the micronized progesterone tablet group. In the analysis of results, adjustments were made for age and number of embryos transferred. GENERALIZABILITY TO OTHER POPULATIONS The results can be generalized to other women ≥ 18 and ≤ 40 years of age undergoing IVF/ICSI who have regular menstrual cycles (25-35 days), both ovaries present and no more than two previous failed IVF attempts. STUDY FUNDING/COMPETING INTEREST Merck Serono supported the study but had no influence on the design of the study and was not involved in the analysis of the results or preparation of the manuscript. TRIAL REGISTRATION NUMBER The trial was issued with the EudraCT number 2005-001248-22 with the Protocol code number 95576471.