PROLUTEX THE NEW progesterone

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-

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)?

Université Paris-

Paris, France

The needs for LPS

Defective luteal support in ART due to high hormone levels, GnRH analogues and hCG.

Université Paris-

Paris, France

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-

Paris, France

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-

Paris, France

Start:

Université Paris-

Paris, France

Stop: At time of luteo-placental shift or as early as the time of the positive pregnancy test.

Start:

Université Paris-

Paris, France

Université Paris-

Paris, France

The needs for LPS

Parenteral Oral Vaginal Transdermic

Poor bioavailability

Poor permeability

First described

P4Oral P4: Not efficacious due to hepatic metabolism

Trans dermal P4: Not possible due to quantities (25mg/day) and skin metabolism

IM SCP4

first uterinepass effect

vaginal

Oral P4: Not efficacious due to hepatic metabolism

Vaginal P4: The only practical alternative to IM P4

IM SC vaginal

Uterine tissueSerum levels

vag IM vs. vaginalNo differences: why?

Oral P4: Not efficacious due to hepatic metabolism

Vaginal P4: The only practical alternative to IM P4

P4IM SC vaginal

dose/effect

IM vs. vaginalNo differences: why?

P4Uterine tissueSerum levels

Parenteral

First described

5/5/13

Vaginal

Université Paris-

Paris, France

Université Paris-

Paris, France

Hormone: P4

Confusion

physiology: 25mg/d

are all equally safe?

Université Paris-

Paris, France

Université Paris-

Paris, France

The needs for LPS

Poor permeability

First described

Poor permeability

First described

Vaginal Transdermic

cyclodextrin

New self-injectable P4 (Prolutex®) (25mg/d)

progesterone

Monday 10 ds laterInclusion

before starting E2

V0 V1 V2

1-3 weeks

Measure progesterone

EMBpredecidualization

25 mg/day

50 mg/day

Study conclusion

EMBpredecidualization

3rd Friday After menses

BaselineGnRH-a

cyclodextrin

25 & 50mg: 100% decidua-lized endomriumNo difference between the 2 doses tested

de Ziegler et al. Fertil Steril 2013

Université Paris-

Paris, France

cyclodextrin

0 5 10 15 20hours (day 11)

Sator et al. Gyn End 2013;29:205-8.

Université Paris-

Paris, France

cyclodextrin

Université Paris-

Paris, France

0 1 2 3 4 5 6 7 8 9 10 11

Days since the beginning of treatmentPr

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

cyclodextrin

Université Paris-

Paris, France

New self-injectable P4 (25mg/d)

0 1 2 3 4 5 6 7 8 9 10 11

Days since the beginning of treatment

MEAN progesterone level(ng/ml)x 50 mgMEAN progesterone level(ng/ml)x 25 mgsteady

Steady state pre-dose levels (11 days)

Selecting the progesterone dose: The “acid test” concept

cyclodextrin

AEs related to study drug: Nb of AEs recorded durigng the 14 days of treatment /tot Nb of injections per group (%)

Injection sitebruising

Injection siteerythema

Injection siteredness

Injection siteswelling

Other Total

(%) Prog IBSA 50 mg IM

Oily Prog 50 mg IM

tolerability

Université Paris-

Paris, France

Physiology: production of progesterone = 25 mg/day

Université Paris-

Paris, France

Physiologica

production of

progesterone

Université Paris-

Paris, France

P4: pulsatile production under the control of LH:

5ng/mL

Day LH +10

Université Paris-

Paris, France

Université Paris-

Paris, France

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

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

Pts screenedN=740

Oocyte retrieval performedN=683

Patients randomizedN=683

Screening failuresN=57

Patients withdrawn from the study without receiving any study drug

CrinoneN=344 (ITT)

Embryo transferN=319 (PP)

Embryo transfer N=321 (PP)

Embryo transfer not performed

Embryo transfer not performedN= 13

Protocol violatorsN= 3

Protocol violatorsN= 10

ProlutexN=339 (ITT)

Any stimulation

Prolutex 25mg/d s.c.

Crinone 90mg/d

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

Primary end-point: ongoing PR

Prolutex CrinonePrimary end-pointOngoing pregnancy rate (ITT) N (%) 93 (27.4) 105 (30.5)

Difference versus Crinone

(95% CI)

(-9.91 - 3.73)

Ongoing pregnancy rate (PP) N (%) 93 (29.2) 100 (31.2)

Difference versus Crinone

(95% CI)

(-9.12 – 5.13)

PP (per protocol) = patients with ET

Outcomes per ITT

Positive

b-hCG Test

rate (

Clinica

l preg

rate (

spontan

eous a

bortion (ITT)

Deliver

y and Liv

e birth

s rate

101520253035404550

ProlutexCrinone

Outcomes per ET (= PP)

Positive

b-hCG Test

rate (

Clinica

l preg

rate (

spontan

eous a

bortion (PP)

Deliver

y and Liv

e birth

s rate

101520253035404550

ProlutexCrinone

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

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

Serious adverse events

Prog‑IBSA(N=339)

Vaginal P(N=344)

P value

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

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

Study Sites

Total: 8 institutions

Boise, IDSeattle, WA

Bedford, TX

Orlando, FL

Stanford, CAThousands Oaks, CASan Jose, CARedondo Beach, CA

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

RESULTS:Primary Endpoint: Ongoing Pregnancy Rate

Prog. s.c.n= 392

Prog. VaginalN = 390

Difference versus Control (95% CI)

P value1

Ongoing Pregnancy Rate 41.6% 44.6% -3.0 (-10.0 to 3.9) 0.43

1 Chi square test

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

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

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.)

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

Université Paris-

Paris, France

The needs for LPS

Université Paris-

Paris, France

Non-pelvic effects of P’

Université Paris-

Paris, France

Université Paris-

Paris, France

Université Paris-

Paris, France

Université Paris-

Paris, France

01020304050

P <0.0001

CrinoneIM P4

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-

Paris, France

Université Paris-

Paris, France

Non-pelvic effects of P’

Université Paris-

Paris, France

Université Paris-

Paris, France

Université Paris-

Paris, France

The needs for LPS

The differed ET option (Dif-ET)

the GnRH trigger option

Université Paris-

Paris, France

The differed ET option (Dif-ET)

the GnRH trigger option

Université Paris-

Paris, France

Université Paris-

Paris, France

The needs for LPS

Université Paris-

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.

Conclusio

Université Paris-

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

PROLUTEX THE NEW progesterone

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