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