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)?


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


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-


Paris, France


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-


Paris, France


Université Paris-


Paris, France


The needs for LPS





Parenteral Oral Vaginal Transdermic

Poor bioavailability

Poor permeability

First described


http://www.acclaimimages.com/usepolicy.html

P4Oral P4: Not efficacious due to hepatic metabolism

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

IM SC



P4

IM SCP4

first uterinepass effect

vaginal

Oral P4: Not efficacious due to hepatic metabolism


Vaginal P4: The only practical alternative to IM P4











P4

P4


IM SC vaginal

Uterine tissueSerum levels

IM

IMvag

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

IM

IMvag

vag




Parenteral

First described

5/5/13

IM



Vaginal

vag


Doses

Université Paris-


Paris, France


Doses

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

Ouch!



Vaginal Transdermic

cyclodextrin

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


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


cyclodextrin

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

2550

de Ziegler et al. Fertil Steril 2013

Université Paris-


Paris, France



cyclodextrin

2550

0

20

40

60

80

100

120

0 5 10 15 20hours (day 11)

Prog

este

rone

ng/

ml


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

Université Paris-


Paris, France



cyclodextrin

2550



Université Paris-


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


cyclodextrin

2550



Université Paris-


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



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-


Paris, France



Physiology: production of progesterone = 25 mg/day

Université Paris-


Paris, France



Physiologica

l

production of

progesterone

Université Paris-


Paris, France


LH

P4

P4: pulsatile production under the control of LH:

5ng/mL

Day LH +10


Université Paris-


Paris, France


Université Paris-


Paris, France


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


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

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)


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


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)


PP (per protocol) = patients with ET

Outcomes per ITT


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


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 (%)

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


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


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


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

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

0

10

20

30

40

50

Université Paris-


Paris, France


The needs for LPS





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

n

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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