Subcutaneous progesterone versus vaginal progesterone gel for luteal phase support in in vitro fertilization a noninferiority randomized controlled study

Capsule:
Luteal phase supportwith a newsubcutaneous progesterone preparation provided pregnancy rates similar to progesterone vaginal gel in IVF patients. Safety and tolerability profile were equivalent.

Authors:
Gillian Lockwood, M.D., Georg Griesinger, M.D., Barbara Cometti, Ph.D.

Volume 101, Issue 1, Pages 112-119.e3, January 2014

Abstract:

Objective:
To compare the safety, efficacy, and tolerability of subcutaneous progesterone (Prolutex, 25 mg; IBSA Institut Biochimique SA) with vaginal progesterone gel (Crinone, 8%; Merck Serono) for luteal phase support (LPS) in assisted reproduction technologies (ART) patients.

Design:
Prospective, open-label, randomized, controlled, parallel-group, multicenter, two-arm, noninferiority study.

Setting:
Thirteen European fertility clinics.

Patient(s):
A total of 683 ART patients randomized to two groups: Prolutex, 25 mg subcutaneously daily (n = 339); and Crinone, 90 mg 8% gel daily (n = 344).

Intervention(s):
In vitro fertilization and embryo transfer were performed according to site-specific protocols. On the day of oocyte retrieval, Prolutex or Crinone gel was begun for LPS and continued for up to 10 weeks.

Main Outcome Measure(s):
Ongoing pregnancy rate.

Result(s):
The primary end point, ongoing pregnancy rates at 10 weeks of treatment were 27.4% and 30.5% in the Prolutex and Crinone groups, respectively (intention to treat [ITT]). The nonsignificant difference between the groups was −3.09% (95% confidence interval [CI] −9.91–3.73), indicating noninferiority of Prolutex to Crinone. Delivery and live birth rates resulted to be equivalent between the two treatments (26.8% vs. 29.9% in the Prolutex and Crinone groups, respectively [ITT]; difference −3.10 [95% CI −9.87–3.68]). No statistically significant differences were reported for any of the other secondary efficacy endpoints, including comfort of usage and overall satisfaction.

Conclusion(s):
Implantation rate, pregnancy rate, live birth rate, and early miscarriage rate for Prolutex were similar to those for Crinone. The adverse event profiles were similar and Prolutex was safe and well tolerated.

Clinical Trial Registration Number:
NCT00827983.

  • Gillian Lockwood

    Dear Dr Hill. Thank you for your encouraging comments on our paper about the new subcutaneous progesterone. The use of -10% as the lower limit was pre-specified to determine the sample size. I agree that -9.91% was close (but still the right side!)
    There was a lot of discussion among the centres about the optimum day for luteal phase support to be commenced. As the sub-cut progesterone was a novel medication, the decision was taken to start on the day of oocyte retrieval, so that the patients who had been randomised to Prolutex couled be supervised having their first injection. Accordingly, the Crinone patients were started on the same day to avoid bias.
    There was a lot of heterogeneity between the centres in what was a pan-European multi-centre study in terms of protocol choice, cleavage vs blastocyst stage transfer and background success rates. What was reassuring, in a non-inferiority study, was that there was a equivalence of outcome for each centre for trial drug and comparator.
    We believe that each individual clinician should determine the timing of luteal phase start for his/her patients. Our study, using 25mg of sub-cut progesterone demonstrated non-inferiority. Thank you again for your interest.

    • Micah Hill

      Thank you for answering all my questions and congratulations on the nice trial!

  • Micah Hill

    Thank you Dr. Lockwood for the very nice non-inferiority trial. I was impressed with the rigorous reporting in the paper! I did have 2 questions.
    1. Was the use of -10% in the lower limit of the 95% CI to demonstrate inferiority pre-specified? I couldn’t tell from the clinical trials registry if this was the case. The lower limit of the 95% CI ended up being -9.91.
    2. Were the Crinone and the Prolutex both started on the day of oocyte retrieval and was it an evening start? The Yanushpolsky study you cite and others have suggested that starting Crinone that early may have a negative effect on endometrial advancement and lead to lower pregnancy success. I’m curious on the authors thoughts about this point and do you think there was any risk that this may have lowered the success rates in the control group?

Translate »