Avemere Meeting Caracas 2012 Resultados Del Estudio Megaset
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Transcript of Avemere Meeting Caracas 2012 Resultados Del Estudio Megaset
RESULTADOS DEL ESTUDIO MEGASET
P Devroey
Megaset The clinical trial
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
• Increasing use of embryo culture to blastocyst stage
• Increasing use of vitrification instead of slow-freezing
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
Participating clinics
25 clinics in 7 countries
Key design features
• Women 18–34 years / BMI 18–24.9 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
rhCG 250 μg
OR6
HP-hMG or rFSH
1
3 follicles ≥ 17mmET1 blastocyst
Oocyte/embryo/blastocyst evaluation
β-hCG
150 IU x 5 daysAdjustment by 75 IU; minimum 4 days on dose
Clin. P
Progesterone 3x200 mg
GnRH antagonist 0.25 mg
OR +5
13-15 days after ET
5-6 weeks after ET
10-11 weeks after ET
Ong. P
Trial design
Post-trial follow-up
FER1 blastocyst
natural cycle
Ongoingpregnancy
No ongoingpregnancy
Ongoingpregnancy
No ongoingpregnancy
Pregnancy outcomeand neonatal health follow-up
Pregnancy outcome andneonatal health follow-up
Investigations: All patients
• Endocrine profile / Follicular development
• Ovarian response
• Endometrial profile
• Pregnancy rates
• Oocyte maturation, fertilisation
• Blastocyst quality
Additional investigations: Subgroups of patients
• Early-mid follicular phase endocrine profile
• Intrafollicular endocrine profile
• Uterine contractility
• Gene expression in cumulus cells (mechanical dissection and enzymatic denudation)
METHODOLOGY
Primary endpoint of the study
Ongoing pregnancy rates beyond 10–11 weeks
after ET in a fresh cycle
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 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. According to Gardner and Schoolcraft
Endometrial assessment
• Thickness
• Triple-layer structure
• Echogenicity pattern
SUBJECT DISPOSITION
Consort diagram
Screened (N=810)
Randomised and exposed (n=749)
Oocyte retrieval N=362
rFSH (ITT; N=375)
Embryo transfer N=305
β-hCG visit N=305
Ongoing pregnancy visit N=116
Ongoing pregnancy visit N=107
β-hCG visit N=316
Embryo transfer N=316
Oocyte retrieval N=362
HP-hMG (ITT; N=374)
BASELINE PARAMETERS
Demographics and treatment history– ITT population
Demographics HP-hMG(N=374)
rFSH(N=375)
Age (years) 30.8 ± 2.8 30.4 ± 2.6
Weight (kg) 60.6 ± 6.8 59.9 ± 7.0
BMI (kg/m2) 22.1 ± 1.9 21.9 ± 2.0
Duration of infertility (yrs) 3.2 ± 1.8 3.1 ± 1.7
Treatment history HP-hMG(N=374)
rFSH(N=375)
1st or 2nd COS cycle ever 95% 95%
Previous IUI cycles, total 49% 52%
Previous IUI cycles, with gonadotrophins
29% 31%
Unexplained 38%
Primary reason of infertility
Mild male factor 62%
Unexplained 40% Mild male
factor 60%
rFSH
HP-hMG
ENDOCRINE PROFILE
Endocrine Profile – Stimulation day 1
Endocrine profile HP-hMG(N=374)
rFSH(N=375)
FSH (IU/L) 7.5 ± 2.3 7.4 ± 2.4
LH (IU/L) 6.2 ± 2.3 6.2 ± 2.2
Estradiol (pmol/L) 180 ± 106 177 ± 100
Progesterone (nmol/L) 2.2 ± 1.1 2.2 ± 1.1
Total testosterone (nmol/L) 1.6 ± 0.8 1.7 ± 0.8
Inhibin B (ng/L) 87 ± 40 85 ± 35
AMH (pmol/L) 27 ± 19 27 ± 20
ITT-populationData are mean ± SD
Early-mid follicular phase: LH
HP-hMG(N=49)
rFSH(N=50)
Day 1 → Day 2
-22% -26%
Day 2 → Day 4
-42% -47%
Day 1 → Day 4
-60% -61%
Day 4 → Day 6
10% 24%
Day 1 → Day 6
-50% -57%
Change over time
Median valuesITT-population / early-mid follicular phase
sub-group
HP-hMGrFSH
Endocrine profile – stimulation day 6
HP-hMG(N=374)
rFSH(N=375)
p value
LH (IU/L) 4.9 ± 5.0 5.5 ± 6.0 0.558
hCG (IU/L) 1.7 ± 0.6 - -
Estradiol (pmol/L) 2626 ± 1405 2973 ± 1702 0.003
Progesterone (nmol/L) 2.2 ± 1.9 2.8 ± 10.8 0.025
Total testosterone (nmol/L) 1.9 ± 0.9 1.9 ± 0.9 0.169
Inhibin B (ng/L) 604 ± 324 722 ± 424 <0.001
ITT-populationData are mean ± SD
HP-hMG(N=374)
rFSH(N=375)
p value
LH (IU/L) 2.8 ± 2.8 2.1 ± 1.6 <0.001
hCG (IU/L) 2.1 ± 0.8 - -
Estradiol (pmol/L) 8797 ± 6030 7022 ± 4945 <0.001
Progesterone (nmol/L) 3.1 ± 3.4 3.1 ± 3.3 0.630
Total testosterone (nmol/L) 2.5 ± 1.2 2.1 ± 1.0 <0.001
ITT-populationMean ± SD
Endocrine profile – last stimulation day
HP-hMG(N=374)
rFSH(N=375)
Premature luteinization*
-LH ≥ 10 IU/L -Progesterone ≥ 1 ng/mL (3.18 nmol/L)
5.9% 6.1%
ITT-population
*Both LH and progesterone criteria to be met at the same visit (ie. Stimulation Day 6 or Last Stimulation Day)
Premature luteinization
TREATMENT EFFICIENCY
Stimulation Day 6 Last Stimulation Day
ITT-populationMean data
p<0.05
p<0.05
Follicular development
HP-hMG
rFSH
HP-hMG
rFSH
Oocytes
0
0
0
0
0
00
00
0 0 0 0 0 0 0 0 0 0 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00
Frequency (%) of subjects
Number of oocytes retrieved
HP-hMG rFSH
ITT-population with oocyte retrieval
Protocol target 8 – 10HP-hMG(N=362)
rFSH(N=362)
p value
Oocytes retrieved
9.1 ± 5.2 10.7 ± 5.8 <0.001
Exposure to gonadotrophins and GnRH antagonist
HP-hMG(N=374)
rFSH(N=375)
p value
Duration of gonadotrophin use (days)
8.8 ± 1.6 8.5 ± 1.3 0.077
Total gonadotrophin dose (IU) 1433 ± 371 1353 ± 296 0.009
Dose on Day 6
Decreased 1% 2%
Maintained 67% 73%
Increased 31% 25%
ITT-populationPercentages may not add to 100% due to rounding off
Endometrial pattern– Day of embryo transfer
HP-hMG(N=374)
rFSH(N=375)
p value
Endometrial thickness (mm) 11.1 ± 2.1 11.1 ± 2.2 -
Triple-layer structure 53% 54% 0.873
Echogenic pattern
Hypoechogenic 5% 6% 0.983
Isoechogenic 17% 17%
Hyperechogenic 73% 73%
Not possible to evaluate
5% 4%
ITT-population
Availability of blastocysts on the day of ET
ITT-population HP-hMG rFSH
Subjects with blastocysts 82% 85%
Subjects with frozen blastocysts 55% 58%
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%
Ongoing pregnancy rate per started cycle:Primary endpoint
HP-hMG rFSH HP-hMG – rFSH
Difference (95% CI)
PP 30.0% 27.0% 3.0% (-3.8; 9.8)
ITT 28.9% 26.7% 2.2% (-4.2; 8.6)
Pregnancy rates per started cycle
00
0000
33
3333
0
00
00
00
00
Positive β-hCG
Clinicalpregnancy
Ongoingpregnancy
Percentage (%)
HP-hMG
rFSH
PP-population
00
3300
33
0033
0
00
00
00
00
Positive β-hCG
Clinicalpregnancy
Ongoingpregnancy
Percentage (%)
HP-hMGrFSH
ITT-population
p=0.95p=<0.05
0
5
10
15
20
25
30
HP-hMG rFSH
On
go
ing
pre
gn
an
cyra
te/c
ycle
in
itia
ted
(%
)
29
16
29 30
Progesterone >4nmol/L
Progesterone ≤4nmol/L
Significantly lower ongoing pregnancy rate in rFSH patients with higher progesterone levels at the endof stimulation
Blastocyst quality and ongoing pregnancy rate
Expansion and hatching status
HP-hMG(N=304)
rFSH(N=315)
4-5 46% 41%
1-3 13% 14%
Ongoing pregnancy rateby quality of transferred blastocyst
%0
%0
%00
%00
%00
%0
%00
%00
%00
%00
%000
(hatching blastocyst)0
(expanded blastocyst)0
(blastocoel filling %)0 000
(blastocoel filling ≥ %)0 00
(early blastocoel)0
ITT-population with blastocysts on Day 5
ITT-population with embryo transfer
Subjects according to their highest blastocyst quality
Blastocyst expansion and
hatching status
Pregnancy loss
Biochemical pregnancy
N=14
Ectopic pregnancy
N=1
Intrauterine pregnancy without heart beat
N=12@
Abortion N=7
Biochemical pregnancy
N=18
Ectopic pregnancy
N=1
Intrauterine pregnancy without heart beat
N=10
Abortion N=8
HP-hMG
37/374 = 10%
rFSH
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