prolutex the new progesterone
TRANSCRIPT
Université Paris-
Descartes,Hôpital Cochin
Paris, France
Charlers ChapronBruno BorgheseHervé FoulotAmin BititiPaul MazurkGuillaume PierreMarie Christine LafayFouzia DecupereFrançois X. Aubriot
Dominique de ZieglerVanessa GayetPietro Santulli
Rebecca MonffatPaul Pitrea
Corine MenezBander Kuttbi
Ann MarszalekAlessandra Fubini
Luteal phase support: a new progesterone option dose ranging issues and new perspectives
Université Paris-
Descartes,Hôpital Cochin
Paris, France
The options existing and doses used
The needs for LPS
A sub-cutaneous P4 preparation
Non-pelvic effects of P4?
Fresh or frozen embryo transfers (FET)?
Luteal phase support: a new progesterone option dose ranging issues and new perspectives
Université Paris-
Descartes,Hôpital Cochin
Paris, France
The options existing and doses used
The needs for LPS
A sub-cutaneous P4 preparation
Non-pelvic effects of P4?
Fresh or frozen embryo transfers (FET)?
Luteal phase support: a new progesterone option dose ranging issues and new perspectives
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
Start: 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
Stop:
On retrieval day or the day after, for minimizing UC at time of transfer. Earlier onset may advance closure of window of receptivity
Start:
Université Paris-
Descartes,Hôpital Cochin
Paris, France
Luteal phase support: a new progesterone option dose ranging issues and new perspectives
Stop:
On retrieval day or the day after, for minimizing UC at time of transfer. Earlier onset may advance closure of window of receptivity
Start:
Université Paris-
Descartes,Hôpital Cochin
Paris, France
Luteal phase support: a new progesterone option dose ranging issues and new perspectives
Stop: 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
Start:
Université Paris-
Descartes,Hôpital Cochin
Paris, France
Luteal phase support: a new progesterone option dose ranging issues and new perspectives
Université Paris-
Descartes,Hôpital Cochin
Paris, France
The options existing and doses used
The needs for LPS
A sub-cutaneous P4 preparation
Non-pelvic effects of P4?
Fresh or frozen embryo transfers (FET)?
Luteal phase support: a new progesterone option dose ranging issues and new perspectives
Parenteral Oral Vaginal Transdermic
Poor bioavailability
Poor permeability
First described
Luteal phase support: a new progesterone option dose ranging issues and new perspectives
P4Oral 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
P4
IM SCP4
first uterinepass 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
P4
P4
first uterinepass effect
IM SC vaginal
Uterine tissueSerum levels
IM
IMvag
vag IM vs. vaginalNo 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
P4IM SC vaginal
dose/effect
IM vs. vaginalNo differences: why?
P4Uterine tissueSerum levels
IM
IMvag
vag
first uterinepass effect
Luteal phase support: a new progesterone option dose ranging issues and new perspectives
Parenteral
First described
5/5/13
IM
Luteal phase support: a new progesterone option dose ranging issues and new perspectives
Vaginal
vag
Luteal phase support: a new progesterone option dose ranging issues and new perspectives
Doses
Université Paris-
Descartes,Hôpital Cochin
Paris, France
Luteal phase support: a new progesterone option dose ranging issues and new perspectives
Doses
Université Paris-
Descartes,Hôpital Cochin
Paris, France
Luteal phase support: a new progesterone option dose ranging issues and new perspectives
Doses
Hormone: P4
Confusion
physiology: 25mg/d
are all equally safe?
Université Paris-
Descartes,Hôpital Cochin
Paris, France
Luteal phase support: a new progesterone option dose ranging issues and new perspectives
Université Paris-
Descartes,Hôpital Cochin
Paris, France
The options existing and doses used
The needs for LPS
A sub-cutaneous P4 preparation
Non-pelvic effects of P4?
Fresh or frozen embryo transfers (FET)?
Luteal phase support: a new progesterone option dose ranging issues and new perspectives
Parenteral Oral Vaginal Transdermic
Poor bioavailability
Poor permeability
First described
Luteal phase support: a new progesterone option dose ranging issues and new perspectives
Parenteral Oral Vaginal Transdermic
Poor bioavailability
Poor permeability
First described
Ouch!
Luteal phase support: a new progesterone option dose ranging issues and new perspectives
Vaginal Transdermic
cyclodextrin
New self-injectable P4 (Prolutex®) (25mg/d)
Luteal phase support: a new progesterone option dose ranging issues and new perspectives
E2
progesterone
Monday 10 ds laterInclusion
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
BaselineGnRH-a
Luteal phase support: a new progesterone option dose ranging issues and new perspectives
cyclodextrin
25 & 50mg: 100% decidua-lized endomriumNo difference between the 2 doses tested
2550
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)
cyclodextrin
2550
0
20
40
60
80
100
120
0 5 10 15 20hours (day 11)
Prog
este
rone
ng/
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)
cyclodextrin
2550
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 treatmentPr
oges
tero
ne n
g/m
l
MEAN progesterone level(ng/ml)x 50 mgMEAN 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)
cyclodextrin
2550
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
Prog
este
rone
ng/
ml
MEAN progesterone level(ng/ml)x 50 mgMEAN progesterone level(ng/ml)x 25 mgsteady
state
Steady state pre-dose levels (11 days)
Selecting the progesterone dose: The “acid test” concept
cyclodextrin
2550
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 sitebruising
Injection siteerythema
Injection siteredness
Injection siteswelling
Other Total
AEs
/Nb
of in
ject
ions
(%) 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)
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
Physiology: production of progesterone = 25 mg/day
Physiologica
l
production of
progesterone
Université Paris-
Descartes,Hôpital Cochin
Paris, France
Luteal phase support: a new progesterone option dose ranging issues and new perspectives
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
Université Paris-
Descartes,Hôpital Cochin
Paris, France
Luteal phase support: a new progesterone option dose ranging issues and new perspectives
37
07EU/Prg06: European study• Randomised, open, multicenter, clinical trial
• sc P4: Prolutex®, (25 mg/day) IBSA• Reference: Crinone® 8% (90 mg)/day• 683 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
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
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
Pts screenedN=740
Oocyte retrieval performedN=683
Patients randomizedN=683
Screening failuresN=57
Patients withdrawn from the study without receiving any study drug
N=1
CrinoneN=344 (ITT)
Embryo transferN=319 (PP)
Embryo transfer N=321 (PP)
Embryo transfer not performed
N=16
Embryo transfer not performedN= 13
Protocol violatorsN= 3
Protocol violatorsN= 10
ProlutexN=339 (ITT)
Lockwood, Griesinger, Cometti et al., Fertil Steril 2013
Any stimulation
Prolutex 25mg/d s.c.
Crinone 90mg/d
OPU
randomize
hCG test
Study protocol
First dose on day of OPUAdministration 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
Primary end-point: ongoing PR
Prolutex CrinonePrimary end-pointOngoing 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
Outcomes per ITT
Lockwood, Griesinger, Cometti et al., Fertil Steril 2013
Positive
b-hCG Test
rate (
ITT)
Clinica
l preg
nancy
rate (
ITT)
Early
spontan
eous a
bortion (ITT)
Deliver
y and Liv
e birth
s rate
(ITT)
05
101520253035404550
39.5
30.4
4.1
26.8
43
32.9
4.1
29.9
ProlutexCrinone
Outcomes per ET (= PP)
Positive
b-hCG Test
rate (
PP)
Clinica
l preg
nancy
rate (
PP)
Early
spontan
eous a
bortion (PP)
Deliver
y and Liv
e birth
s rate
(PP)
05
101520253035404550
42
32.3
4.4
28.5
43.9
33.6
4.4
30.5
ProlutexCrinone
Lockwood, Griesinger, Cometti et al., Fertil Steril 2013
Tolerability & SatisfactionProg‑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
Non-serious adverse eventsProg‑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
Serious adverse events
Lockwood, Griesinger, Cometti et al., Fertil Steril 2013
Prog‑IBSA(N=339)
Vaginal P(N=344)
P value
Events Patients (%)
Events Patients (%)
Serious AEs: total 16 14 (4.1) 23 20 (5.8) 0.32
Abortion spontaneous‑all 5 5 (1.5) 5 5 (1.5) 1.00
Ectopic pregnancy 2 2 (0.6) - - 0.25
OHSS 4 4 (1.2) 7 7 (2.0) 0.55
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
Study Sites
Total: 8 institutions
Boise, IDSeattle, WA
Bedford, TX
Orlando, FL
Stanford, CAThousands Oaks, CASan Jose, CARedondo Beach, CA
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
RESULTS:Primary Endpoint: Ongoing Pregnancy Rate
Prog. s.c.n= 392
Prog. VaginalN = 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
Live Birth Rate
Variable
Prog. s.c.n= 392
Prog. VaginalN = 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
SafetyVariable (%) Prog - IBSA
(n=400)Prog. Vaginal
(n=400)p
ValueInjection Site Reactions 22 0.0 <0.001Vaginal Reactions 0.8 14.5 <0.001AEs Related to IVF Procedure 25.3 25.0 1.000Abdominal Pain/Discomfort 15.8 20.5 0.098Vaginal Haemorrhage 15.5 15.5 1.000Headache 12.3 14.8 0.352Nausea 12.5 12.8 1.000Breast Pain/Tenderness 5.5 12.0 0.002Constipation 7.3 9.8 0.254Vomiting 3.8 5.5 0.313Fatigue 3.3 7.8 0.008Insomnia 1.3 2.8 0.205
Lockwood, Griesinger, Cometti et al., Fertil Steril 2013
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
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
Université Paris-
Descartes,Hôpital Cochin
Paris, France
The options existing and doses used
The needs for LPS
A sub-cutaneous P4 preparation
Non-pelvic effects of P4?
Fresh or frozen embryo transfers (FET)?
Luteal phase support: a new progesterone option dose ranging issues and new perspectives
Université Paris-
Descartes,Hôpital Cochin
Paris, France
Non-pelvic effects of P’
Luteal phase support: a new progesterone option dose ranging issues and new perspectives
Université Paris-
Descartes,Hôpital Cochin
Paris, France
Luteal phase support: a new progesterone option dose ranging issues and new perspectives
Université Paris-
Descartes,Hôpital Cochin
Paris, France
Luteal phase support: a new progesterone option dose ranging issues and new perspectives
Université Paris-
Descartes,Hôpital Cochin
Paris, France
Luteal phase support: a new progesterone option dose ranging issues and new perspectives
Université Paris-
Descartes,Hôpital Cochin
Paris, France
01020304050
P <0.0001
CrinoneIM P4
Luteal phase support: a new progesterone option dose ranging issues and new perspectives
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
Université Paris-
Descartes,Hôpital Cochin
Paris, France
Non-pelvic effects of P’
Luteal phase support: a new progesterone option dose ranging issues and new perspectives
Université Paris-
Descartes,Hôpital Cochin
Paris, France
Université Paris-
Descartes,Hôpital Cochin
Paris, France
0
10
20
30
40
50
Université Paris-
Descartes,Hôpital Cochin
Paris, France
The options existing and doses used
The needs for LPS
A sub-cutaneous P4 preparation
Non-pelvic effects of P4?
Fresh or frozen embryo transfers (FET)?
Luteal phase support: a new progesterone option dose ranging issues and new perspectives
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
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
Université Paris-
Descartes,Hôpital Cochin
Paris, France
The options existing and doses used
The needs for LPS
A sub-cutaneous P4 preparation
Non-pelvic effects of P4?
Fresh or frozen embryo transfers (FET)?
Luteal phase support: a new progesterone option dose ranging issues and new perspectives
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
Conclusio
n
Université Paris-
Descartes,Hôpital Cochin
Paris, France
Charlers ChapronBruno BorgheseHervé FoulotAmin BititiPaul MazurkGuillaume PierreMarie Christine LafayFouzia DecupereFrançois X. Aubriot
Dominique de ZieglerVanessa GayetPietro Santulli
Rebecca MonffatPaul Pitrea
Corine MenezBander Kuttbi
Ann MarszalekAlessandra Fubini
Luteal phase support: a new progesterone option dose ranging issues and new perspectives