1. Université
Paris-
Descartes,
Hôpital
Cochin
Paris,
France
Charlers Chapron
Bruno Borghese
Hervé Foulot
Amin Bititi
Paul Mazurk
Guillaume Pierre
Marie Christine Lafay
Fouzia Decupere
François X. Aubriot
Dominique de Ziegler
Vanessa Gayet
Pietro Santulli
Rebecca Monffat
Paul Pitrea
Corine Menez
Bander Kuttbi
Ann Marszalek
Alessandra Fubini
Luteal phase support: a new progesterone option
dose ranging issues and new perspectives
4. Defective luteal support in ART due to high hormone levels,
GnRH analogues and hCG.
Université
Paris-
Descartes,
Hôpital
Cochin
Paris,
France
Luteal phase support: a new progesterone option
dose ranging issues and new perspectives
5.
6.
7.
8. On retrieval day or the day after, for minimizing UC
at time of transfer. Earlier onset may advance
closure of window of receptivity
Université
Paris-
Descartes,
Hôpital
Cochin
Paris,
France
Luteal phase support: a new progesterone option
dose ranging issues and new perspectives
9. On retrieval day or the day after, for minimizing UC
at time of transfer. Earlier onset may advance
closure of window of receptivity
Université
Paris-
Descartes,
Hôpital
Cochin
Paris,
France
Luteal phase support: a new progesterone option
dose ranging issues and new perspectives
10. On retrieval day or the day after, for minimizing UC
at time of transfer. Earlier onset may advance
closure of window of receptivity
Université
Paris-
Descartes,
Hôpital
Cochin
Paris,
France
Luteal phase support: a new progesterone option
dose ranging issues and new perspectives
11. At time of luteo-placental shift or as early as the
time of the positive pregnancy test.
On retrieval day or the day after, for minimizing UC
at time of transfer. Earlier onset may advance
closure of window of receptivity
Université
Paris-
Descartes,
Hôpital
Cochin
Paris,
France
Luteal phase support: a new progesterone option
dose ranging issues and new perspectives
14. P4
Oral P4: Not efficacious
due to hepatic metabolism
Trans dermal P4: Not possible
due to quantities (25mg/day) and
skin metabolism
IM SC
Luteal phase support: a new progesterone option
dose ranging issues and new perspectives
15. P4
IM SC
P4
first uterine
pass effect
vaginal
Oral P4: Not efficacious
due to hepatic metabolism
Trans dermal P4: Not possible
due to quantities (25mg/day) and
skin metabolism
Vaginal P4:
The only practical alternative to
IM P4
Luteal phase support: a new progesterone option
dose ranging issues and new perspectives
16. P4
P4
first uterine
pass effect
IM SC vaginal
0
5
10
15
20
25
30
0
0.2
0.4
0.6
0.8
1
1.2
Uterine tissueSerum levels
IM
IM
vag
vag IM vs. vaginal
No differences: why?
Oral P4: Not efficacious
due to hepatic metabolism
Trans dermal P4: Not possible
due to quantities (25mg/day) and
skin metabolism
Vaginal P4:
The only practical alternative to
IM P4
Luteal phase support: a new progesterone option
dose ranging issues and new perspectives
17. P4
IM SC vaginal
IM vs. vaginal
No differences: why?
P4
0
5
10
15
20
25
30
0
0.2
0.4
0.6
0.8
1
1.2
Uterine tissueSerum levels
IM
IM
vag
vag
first uterine
pass effect
Luteal phase support: a new progesterone option
dose ranging issues and new perspectives
27. E2
progesterone
Monday
10 ds later
Inclusion
before starting E2
V0 V1 V2
1-3 weeks
Measure
progesterone
EMBpredecidualization
E2
n=12
n=12
25 mg/day
50 mg/day
V3
Study
conclusion
EMBpredecidualization
3rd Friday
After menses
Baseline
GnRH-a
Luteal phase support: a new progesterone option
dose ranging issues and new perspectives
28. cyclodextrin
25 & 50mg: 100% decidua-lized
endomrium
No difference between the 2
doses tested
25
50
de Ziegler et al. Fertil Steril 2013
Université
Paris-
Descartes,
Hôpital
Cochin
Paris,
France
Luteal phase support: a new progesterone option
dose ranging issues and new perspectives
New self-injectable P4
(Prolutex®) (25mg/d)
29. cyclodextrin
25
50
0
20
40
60
80
100
120
0 5 10 15 20
hours (day 11)
Progesteroneng/ml
de Ziegler et al. Fertil Steril 2013
Sator et al. Gyn End 2013;29:205-8.
Université
Paris-
Descartes,
Hôpital
Cochin
Paris,
France
Luteal phase support: a new progesterone option
dose ranging issues and new perspectives
New self-injectable P4
(Prolutex®) (25mg/d)
30. cyclodextrin
25
50
de Ziegler et al. Fertil Steril 2013
Sator et al. Gyn End 2013;29:205-8.
Université
Paris-
Descartes,
Hôpital
Cochin
Paris,
France
0
2
4
6
8
10
12
0 1 2 3 4 5 6 7 8 9 10 11
Days since the beginning of treatmentProgesteroneng/ml
MEAN progesterone level
(ng/ml)x 50 mg
MEAN progesterone level
(ng/ml)x 25 mg
steady state
Steady state pre-dose levels (11 days)
Selecting the progesterone dose:
The “acid test” concept
New self-injectable P4
(Prolutex®) (25mg/d)
31. cyclodextrin
25
50
de Ziegler et al. Fertil Steril 2013
Sator et al. Gyn End 2013;29:205-8.
Université
Paris-
Descartes,
Hôpital
Cochin
Paris,
France
New self-injectable
P4 (25mg/d)
0
2
4
6
8
10
12
0 1 2 3 4 5 6 7 8 9 10 11
Days since the beginning of treatment
Progesteroneng/ml
MEAN progesterone level
(ng/ml)x 50 mg
MEAN progesterone level
(ng/ml)x 25 mgsteady
state
Steady state pre-dose levels (11 days)
Selecting the progesterone dose:
The “acid test” concept
32. cyclodextrin
25
50
de Ziegler et al. Fertil Steril 2013
Sator et al. Gyn End 2013;29:205-8.
AEs related to study drug:
Nb of AEs recorded durigng the 14 days of treatment /tot Nb of injections per group (%)
0,00
10,00
20,00
30,00
40,00
50,00
60,00
70,00
Injection site
bruising
Injection site
erythema
Injection site
redness
Injection site
swelling
Other Total
AEs/Nbofinjections(%)
Prog IBSA 50 mg IM
Oily Prog 50 mg IM
tolerability
Université
Paris-
Descartes,
Hôpital
Cochin
Paris,
France
Luteal phase support: a new progesterone option
dose ranging issues and new perspectives
New self-injectable P4
(Prolutex®) (25mg/d)
33. Physiology: production of progesterone = 25 mg/day
Université
Paris-
Descartes,
Hôpital
Cochin
Paris,
France
Luteal phase support: a new progesterone option
dose ranging issues and new perspectives
34. Physiology: production of progesterone = 25 mg/day
Université
Paris-
Descartes,
Hôpital
Cochin
Paris,
France
Luteal phase support: a new progesterone option
dose ranging issues and new perspectives
35. LH
P4
P4: pulsatile production under the control of LH:
5ng/mL
Day LH +10
Physiology: production of progesterone = 25 mg/day
Université
Paris-
Descartes,
Hôpital
Cochin
Paris,
France
Luteal phase support: a new progesterone option
dose ranging issues and new perspectives
38. study sites: total n =13
UK: 3 sites
Germany: 1 site
Italy: 6 sites
Switzerland:
2 sites
Hungary: 1 site
Lockwood, Griesinger, Cometti et al., Fertil Steril 2013
39. Inclusion Criteria
• 18-42 years
• BMI≤30 kg/m2
• <3 prior assisted reproductive technology
(ART) cycles
• baseline (Day 2-3) FSH level ≤15 IU/L and
E2<80 pg/mL
• normal uterine cavity
• at least 3 retrieved oocytes
Lockwood, Griesinger, Cometti et al., Fertil Steril 2013
40. Pts screened
N=740
Oocyte retrieval performed
N=683
Patients randomized
N=683
Screening failures
N=57
Patients withdrawn from the study
without receiving any study drug
N=1
Crinone
N=344 (ITT)
Embryo transfer
N=319 (PP)
Embryo transfer
N=321 (PP)
Embryo transfer not
performed
N=16
Embryo transfer not performed
N= 13
Protocol violators
N= 3
Protocol violators
N= 10
Prolutex
N=339 (ITT)
Lockwood, Griesinger, Cometti et al., Fertil Steril 2013
41. Any stimulation
Prolutex 25mg/d s.c.
Crinone 90mg/d
OPU
randomize
hCG
test
Study protocol
First dose on day of OPU
Administration for 15±2 days
if pregnancy test is positive treatment until GW 10
follow-up of all pregnancies
Lockwood, Griesinger, Cometti et al., Fertil Steril 2013
42. Primary end-point: ongoing PR
Prolutex Crinone
Primary end-point
Ongoing pregnancy rate (ITT) N (%) 93 (27.4) 105 (30.5)
Difference versus Crinone
(95% CI)
-3.09
(-9.91 - 3.73)
Ongoing pregnancy rate (PP) N (%) 93 (29.2) 100 (31.2)
Difference versus Crinone
(95% CI)
-2.00
(-9.12 – 5.13)
Lockwood, Griesinger, Cometti et al., Fertil Steril 2013
PP (per protocol) = patients with ET
43. Outcomes per ITT
Lockwood, Griesinger, Cometti et al., Fertil Steril 2013
39.5
30.4
4.1
26.8
43
32.9
4.1
29.9
0
5
10
15
20
25
30
35
40
45
50
Positive b-hCG Test
rate (ITT)
Clinical pregnancy
rate (ITT)
Early spontaneous
abortion (ITT)
Delivery and Live
births rate (ITT)
Prolutex
Crinone
44. Outcomes per ET (= PP)
42
32.3
4.4
28.5
43.9
33.6
4.4
30.5
0
5
10
15
20
25
30
35
40
45
50
Positive b-hCG
Test rate (PP)
Clinical pregnancy
rate (PP)
Early spontaneous
abortion (PP)
Delivery and Live
births rate (PP)
Prolutex
Crinone
Lockwood, Griesinger, Cometti et al., Fertil Steril 2013
45. Tolerability & Satisfaction
Prog-IBSA
(N=339)
Vaginal P
(N=344)
P value
Injection site discomfort including
irritation, pain, pruritus, swelling,
induration, haematoma
57% 0 <0.0001
Vaginal discomfort including dryness,
irritation, pain, pruritus, swelling,
inflammation, vaginal discharge
10.4% 50.8% 0.0001
Treatment rating as comfortable or
very comfortable
71.4% 70.3% 0.77
Satisfied or very satisfied with
treatment
77.6% 78.7% 0.75
Lockwood, Griesinger, Cometti et al., Fertil Steril 2013
46. Non-serious adverse events
Prog-IBSA
(N=339)
Vaginal P
(N=344)
P value
Treatment related non-serious
adverse events (any)
42.3% 45.4% 0.425
AEs of reproductive tract including
breast
29.3% 40.4% 0.002
AEs of the gastrointestinal system 0% 2.3% 0.03
Genital tract infections 1.5% 3.8% 0.09
Lockwood, Griesinger, Cometti et al., Fertil Steril 2013
48. 48
Study 07US/prg05: US study
• Randomised, open, multicenter, clinical trial
• sc P: Progesterone IBSA 25 mg/day
• Reference: Endometrin 100mg b.i.d.
• 800 patients randomised
• Primary end-point: Ongoing pregnancy rate 10
weeks after treatment start
• Non-inferiority study design
Lockwood, Griesinger, Cometti et al., Fertil Steril 2013
49. 49
Study Sites
Total: 8 institutions
Boise, ID
Seattle, WA
Bedford, TX
Orlando, FL
Stanford, CA
Thousands Oaks, CA
San Jose, CA
Redondo Beach, CA
50. 50
Disposition of Patients
• 800 patients randomized
– 400 per treatment group
• 782 embryo transfer (Evaluable population)
– 392 in the P4 SC group, Prolutex®
– 390 in the Progesterone Vaginal insert group
Lockwood, Griesinger, Cometti et al., Fertil Steril 2013
51. 51
RESULTS:
Primary Endpoint: Ongoing Pregnancy Rate
Prog. s.c.
n= 392
Prog. Vaginal
N = 390
Difference versus
Control
(95% CI)
P
value1
n (%)
Ongoing
Pregnancy Rate
41.6% 44.6% -3.0 (-10.0 to 3.9) 0.43
1 Chi square test
Lockwood, Griesinger, Cometti et al., Fertil Steril 2013
52. Live Birth Rate
Variable
Prog. s.c.
n= 392
Prog. Vaginal
N = 390
Difference versus
Control
(95% CI)
P
Value1
% (n/n)
Live Birth Rate
40.8
(160/392)
43.3
(169/390)
-2.5 (-9.4 to 4.4) 0.52
1 Chi squared test
Lockwood, Griesinger, Cometti et al., Fertil Steril 2013
54. Conclusions I
• The clinical non-inferiority of Progesterone
IBSA (Prolutex®) compared to vaginal
treatment was established for the primary
efficacy endpoint of ongoing pregnancy rates
at 10 weeks in two independent studies
• No significant differences were found for any
secondary outcome (miscarriage rate, live
birth rate etc.)
Lockwood, Griesinger, Cometti et al., Fertil Steril 2013
55. Conclusions II
• Subcutaneous progesterone administered
once daily (Prolutex®) is well tolerated and
found convenient to use by the patients
• Thus s.c. Progesterone, Prolutex, has now
been established as a valid alternative as
luteal phase support in IVF
Lockwood, Griesinger, Cometti et al., Fertil Steril 2013
62. There appears to be a superiority of IM over
vaginal progesterone for frozen embryo transfers
(FET)
The difference may result from non-pelvic effects
of progesterone (immuno-suppression and/or
Vasopressin/oxytocin)
Université
Paris-
Descartes,
Hôpital
Cochin
Paris,
France
Luteal phase support: a new progesterone option
dose ranging issues and new perspectives
67. The differed ET option (Dif-ET)
the GnRH trigger option
Luteal phase support: a new progesterone option
dose ranging issues and new perspectives
Université
Paris-
Descartes,
Hôpital
Cochin
Paris,
France
68. The differed ET option (Dif-ET)
the GnRH trigger option
Luteal phase support: a new progesterone option
dose ranging issues and new perspectives
Université
Paris-
Descartes,
Hôpital
Cochin
Paris,
France
70. Université
Paris-
Descartes,
Hôpital
Cochin
Paris,
France
LPS is necessary in ART because CL support by
LH is deficient
Progesterone production during the luteal
phase is of ~25ng/mL
A new sub cutaneous progesterone preparation
is available: Prolutex® (25mg/day)
Endometrial effects of vag and injectable
progesterone are equivalent.
In FET, injectable progesterone results in higehr
PR possibly, through non-pelvic effects.
Luteal phase support: a new progesterone option
dose ranging issues and new perspectives
71. Université
Paris-
Descartes,
Hôpital
Cochin
Paris,
France
Charlers Chapron
Bruno Borghese
Hervé Foulot
Amin Bititi
Paul Mazurk
Guillaume Pierre
Marie Christine Lafay
Fouzia Decupere
François X. Aubriot
Dominique de Ziegler
Vanessa Gayet
Pietro Santulli
Rebecca Monffat
Paul Pitrea
Corine Menez
Bander Kuttbi
Ann Marszalek
Alessandra Fubini
Luteal phase support: a new progesterone option
dose ranging issues and new perspectives
