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P Devroey
Participating clinics
25 clinics in 7 countries
Women 1834 years / BMI 1824.9 kg/m2 GnRH antagonist / No programming 150 IU starting dose ICSI Single blastocyst transfer on Day 5 2 weeks luteal support Vitrification Replacement of a single warmed blastocyst in a natural cycle
Trial design
GnRH antagonist 0.25 mg
HP-hMG or rFSH
150 IU x 5 days
Adjustment by 75 IU; minimum 4 days on dose
rhCG 250 g
Progesterone 3x200 mg
-hCG
Clin. P
Ong. P
6
3 follicles 17mm
OR
OR +5
ET
1 blastocyst
Post-trial follow-up
FER 1 blastocyst natural cycle Ongoing pregnancy No ongoing pregnancy
Ongoing pregnancy
No ongoing pregnancy
Endocrine profile / Follicular development Ovarian response Endometrial profile Pregnancy rates Oocyte maturation, fertilisation Blastocyst quality
Early-mid follicular phase endocrine profile Intrafollicular endocrine profile Uterine contractility Gene expression in cumulus cells
(mechanical dissection and enzymatic denudation)
METHODOLOGY
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%
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
EMBRYO ASSESSMENT
Embryo morphology assessment and grading Local embryologists only no central evaluation Interobserver agreement and intraobserver reproducibility were validated in the MERiT trial showing goodexcellent 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: 21412148 2. According to Gardner and Schoolcraft
Endometrial assessment
SUBJECT DISPOSITION
Consort diagram
Screened (N=810) Randomised and exposed (n=749)
HP-hMG (ITT; N=374) Oocyte retrieval N=362 Embryo transfer N=305 -hCG visit N=305
rFSH (ITT; N=375) Oocyte retrieval N=362 Embryo transfer N=316 -hCG visit N=316
BASELINE PARAMETERS
HP-hMG (N=374) 30.8 2.8 60.6 6.8 22.1 1.9 3.2 1.8 HP-hMG (N=374) 95% 49% 29%
rFSH (N=375) 30.4 2.6 59.9 7.0 21.9 2.0 3.1 1.7 rFSH (N=375) 95% 52% 31%
Age (years) Weight (kg) BMI (kg/m2) Duration of infertility (yrs) Treatment history
HP-hMG
Unexplained 40%
1st or 2nd COS cycle ever Previous IUI cycles, total Previous IUI cycles, with gonadotrophins
rFSH
ENDOCRINE PROFILE
Endocrine profile FSH (IU/L) LH (IU/L) Estradiol (pmol/L) Progesterone (nmol/L) Total testosterone (nmol/L) Inhibin B (ng/L) AMH (pmol/L)
Data are mean SD
HP-hMG (N=374) 7.5 2.3 6.2 2.3 180 106 2.2 1.1 1.6 0.8 87 40 27 19
rFSH (N=375) 7.4 2.4 6.2 2.2 177 100 2.2 1.1 1.7 0.8 85 35 27 20
ITT-population
HP-hMG rFSH
Day 1 Day 2 Day 2 Day 4 Day 1 Day 4 Day 4 Day 6 Day 1 Day 6
Median values
LH (IU/L) hCG (IU/L) Estradiol (pmol/L) Progesterone (nmol/L) Total testosterone (nmol/L) Inhibin B (ng/L)
Data are mean SD
4.9 5.0 1.7 0.6 2626 1405 2.2 1.9 1.9 0.9 604 324
5.5 6.0 2973 1702 2.8 10.8 1.9 0.9 722 424
rFSH (N=375) 2.1 1.6 7022 4945 3.1 3.3 2.1 1.0
2.8 2.8 2.1 0.8 8797 6030 3.1 3.4 2.5 1.2
Premature luteinization
HP-hMG (N=374) Premature luteinization* -LH 10 IU/L -Progesterone 1 ng/mL (3.18 nmol/L) 5.9%
ITT-population
Both LH and progesterone criteria to be met at the same visit (ie. Stimulation Day 6 or Last Stimulation Day)
TREATMENT EFFICIENCY
Follicular development
Stimulation Day 6
HP-hMG rFSH p<0.05
Mean data
ITT-population
Oocytes
0 0 0 0 0 0 0
Protocol target
HP-hMG (N=362) Oocytes retrieved 9.1 5.2
8 10
p value <0.001
t j b s f o ) % ( y c n u q e r F
0 0
HP-hMG
rFSH
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
PP ITT
30.0% 28.9%
27.0% 26.7%
Non-inferiority was demonstrated for both PP- and ITT-populations, as the lower limit of the 95% confidence interval was above the preestablished non-inferiority margin of -10%
PP-population
HP-hMG rFSH
HP-hMG
0 0
0 0 3 3 0 0 3 3
rFSH
3 3
0 0
0 0 3 3
0 0
0 0 0
0 0
Positive -hCG
Clinical pregnancy
Ongoing pregnancy
Significantly lower ongoing pregnancy rate in rFSH patients with higher progesterone levels at the end of stimulation
p=0.95
30
29
30
25 20 15 10 5 0
16
HP-hMG
rFSH
0% 0
0% 0 0(hatching blastocyst)
Ongoing pregnancy rate by quality of transferred blastocyst Expansion and hatching status 4-5 1-3
0(blastocoel filling 0 0 ) 0%
0% 0
0(expanded blastocyst)
0% 0
0% 0
0% 0
0% 0 0 %
0(blastocoel filling 0% 0)
0 %
0 %
0(early blastocoel)
Blastocyst expansion and hatching status
rFSH
Biochemical pregnancy N=14
37/374 = 10%
34/375 = 9%
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