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The optimal choice of gonadotrophin in GnRH antagonist protocols Prof Dr P Devroey

The optimal choice of gonadotrophin in GnRH antagonist protocols Prof Dr P Devroey. Recent trends in ART practice. Increasing use of GnRH antagonists with lower doses of gonadotrophin Increasing use of ICSI over the last decade Increasing use of single embryo transfer

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The optimal choice of gonadotrophin in GnRH antagonist protocols Prof Dr P Devroey

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  1. The optimal choice of gonadotrophin in GnRH antagonist protocolsProf Dr P Devroey

  2. Recent trends in ART practice • Increasing use of GnRH antagonists with lower doses of gonadotrophin • Increasing use of ICSI over the last decade • Increasing use of single embryo transfer • Increasing use of embryo culture to blastocyst stage • Increasing use of vitrification instead of slow-freezing

  3. Why the MEGASET trial? • MEGASET compares HP-hMG (MENOPUR®) with rFSH (PUREGON®) in a setting that addresses these recent trends in ART practice • Randomised, assessor-blind, parallel groups, multi-centre trial to demonstrate non-inferiority of HP-hMG compared to rFSH with respect to ongoing pregnancy rates

  4. Participating clinics 25 clinics in 7 countries

  5. Key design features • Women 18–34 years • BMI 18–24.9 kg/m2 • GnRH antagonist • No programming • 150 IU starting dose • ICSI • Blastocyst culture • Single blastocyst transfer on Day 5 • 2 weeks luteal support • Vitrification • Replacement of a single warmed blastocyst in a natural cycle

  6. Trial design GnRH antagonist 0.25 mg HP-hMGorrFSH rhCG 250 μg Progesterone 3x200 mg 150 IU x 5 days Oocyte/embryo/blastocyst evaluation Adjustment by 75 IU; minimum 4 days on dose β-hCG Clin. P Ong. P 6 1 OR OR +5 13-15 days after ET 5-6 weeks after ET 10-11 weeks after ET ET1 blastocyst 3 follicles ≥ 17mm Post-trial follow-up No ongoing pregnancy Ongoing pregnancy FER1 blastocystnatural cycle Ongoing pregnancy No ongoing pregnancy Pregnancy outcome and neonatal health follow-up Pregnancy outcome and neonatal health follow-up

  7. Investigations: All patients • Endocrine profile • Follicular development • Ovarian response • Endometrial profile • Pregnancy rates • Cumulus mass appearance • Oocyte maturation, fertilisation • Embryo quality • Blastocyst quality

  8. Additional investigations: Subgroups of patients • Early-mid follicular phase endocrine profile • Intrafollicular endocrine profile • Uterine contractility • Modelling of follicles • Modelling of endometrium • Gene expression in cumulus cells (mechanical dissection and enzymatic denudation)

  9. METHODOLOGY

  10. Primary endpoint of the study • Ongoing pregnancy rates beyond 10–11 weeks after ET in a fresh cycle

  11. Power calculation • Estimated ongoing pregnancy rate of 30% was derived from previous studies on single blastocyst transfer • Non-inferiority margin was set at –10% (absolute) • At least 660 cycles was required to achieve a study power of 80%

  12. Analysis of data • Modified Intention-to-treat (ITT) analysis • All subjects who have been randomised and exposed to at least one dose of investigational medicinal product were analysed according to the actual treatment • Per protocol analysis • All subjects from the modified ITT, except those who are excluded because of a major protocol deviation were analysed

  13. EMBRYO ASSESSMENT

  14. Embryo morphology assessment and grading Local embryologists only; no central evaluation Interobserver agreement and intraobserver reproducibility were validated in the MERiT trial showing good–excellent agreement on overall embryo morphology assessment and grading1 Embryos were graded according to the Gardner and Schoolcraft classification system2 1. Arce et al. Hum Reprod 2006; 21: 2141–2148 2. Gardner and Schoolcraft. In: Towards reproductive certainty (Eds Jansen & Mortimer). The plenary proceedings of the 11th world congress on in vitro fertilization and human reproductive genetics. The Parthenon Publishing Group. 1999. Pp 378–388

  15. Endometrial assessment • Thickness • Triple-layer structure • Echogenicity pattern

  16. SUBJECT DISPOSITION

  17. Consort diagram Screened (N=810) Randomised and exposed (n=749) rFSH (ITT; N=375) HP-hMG (ITT; N=374) Oocyte retrieval N=362 Oocyte retrieval N=362 Embryo transfer N=305 Embryo transfer N=316 β-hCG visit N=305 β-hCG visit N=316 Ongoing pregnancy visit N=116 Ongoing pregnancy visit N=107

  18. BASELINE PARAMETERS

  19. Demographics and treatment history– ITT population Primary reason of infertility Unexplained 38% Mild male factor 62% HP-hMG Unexplained 40% Mild male factor 60% rFSH

  20. ENDOCRINE PROFILE

  21. Endocrine Profile – Stimulation day 1 Data are mean ± SD ITT-population

  22. Endocrine profile – stimulation day 6 ITT-population Data are mean ± SD

  23. Early-mid follicular phase: LH Change over time HP-hMG rFSH ITT-population / early-mid follicular phase sub-group Median values

  24. Endocrine profile – last stimulation day Mean ± SD ITT-population

  25. Premature luteinization ITT-population *Both LH and progesterone criteria to be met at the same visit (ie. Stimulation Day 6 or Last Stimulation Day)

  26. TREATMENT EFFICIENCY

  27. Follicular development Stimulation Day 6 Last Stimulation Day HP-hMG rFSH HP-hMG rFSH p<0.05 p<0.05 Mean data ITT-population

  28. Oocytes Protocol target 8 – 10 ITT-population with oocyte retrieval

  29. Exposure to gonadotrophins and GnRH antagonist ITT-population Percentages may not add to 100% due to rounding off

  30. Endometrial pattern– Day of embryo transfer ITT-population

  31. Availability of blastocysts on the day of ET

  32. Ongoing pregnancy rate per started cycle:Primary endpoint • Non-inferiority was demonstrated for both PP- and ITT-populations, as the lower limit of the 95% confidence interval was above the pre-established non-inferiority margin of -10%

  33. Pregnancy rates per started cycle ITT-population PP-population

  34. Progesterone ≤4nmol/L Progesterone >4nmol/L Significantly lower ongoing pregnancy rate in rFSH patients with higher progesterone levels at the endof stimulation p=0.95 p=<0.05 30 29 29 30 25 20 Ongoing pregnancy rate/cycle initiated (%) 16 15 10 5 0 HP-hMG rFSH

  35. Blastocyst quality and ongoing pregnancy rate Subjects according to their highest blastocyst quality Ongoing pregnancy rateby quality of transferred blastocyst ITT-population with embryo transfer Blastocyst expansion and hatching status ITT-population with blastocysts on Day 5

  36. Pregnancy loss HP-hMG rFSH Abortion N=8 Biochemical pregnancyN=18 Abortion N=7 Biochemical pregnancyN=14 Ectopic pregnancyN=1 Ectopic pregnancyN=1 Intrauterine pregnancy without heart beat N=10 Intrauterine pregnancy without heart beat N=12 37/374 = 10% 34/375 = 9%

  37. Conclusions Primary endpoint of MEGASET study was achieved Largest multicentre, multinational RCT of HP-hMG vs rFSH addressing new trends in ART in a robust, high quality innovative trial with ICSI Demonstrates single blastocyst transfer is effective with mild stimulation and lower number of oocytes Reinforces the importance of progesterone during the late follicular phase Higher pregnancy rate with HP-hMG than rFSH when progesterone >4 nmol/L

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