Sub-cutaneous progesterone:

the best of both worlds ?

Dr Gillian Lockwood
Midland Fertility Services
Aldridge - West Midlands - United Kingdom

Il Simposio Reproduccion Asistida Madrid 20-21 Febrero 2014

Worldwide use of Luteal

Phase Support

Vaisbuch et al. ( 2012)

New aqueous progesterone preparation for i.m. and s.c. administration

Hydrosolubility of progesterone enhanced by -cyclodextrins (-CDs)

products of starch enzymatic degradation, containing six to eight glucose units joined in a ring by -14 glycosidic bonds These compounds are widely used to solubilise non-polar compounds and to improve the absorption and distribution of non-polar medicinal products

HPeta-Cyclodextrin Capping

Kinetic Profile of -cyclodextrins (CDs) after single dose administration of 100 mg of Progesterone in healthy female volunteers
250

200

i.m. s.c.

HPBCD conc (ug/ml)

15 0

10 0

50

0.25

0.5

2
Ti m e ( hour )

5 10

Clinical trials of Subcutaneous Progesterone EU and USA Studies

Study Design
European study Study design Test Reference USA Study

Prospective, multicentre, open-label, randomised, controlled trial, non-inferiority study Progesterone S.C., 25 mg, once daily Vaginal Prog Gel 90 mg, daily (Crinone) 672 patients 13 study sites Vaginal Prog Pessary 100 mg, twice daily (Endometrin) 800 patients 8 study sites

Sample size Centres

Study Sites
Germany: 1 site UK: 3 sites Hungary: 1 site

Switzerland: 2 sites

Italy: 6 sites

Total: 13 institutions

Seattle, WA

Study Sites
Boise, ID

Orlando, FL Stanford, CA Thousands Oaks, CA San Jose, CA Redondo Beach, CA

Bedford, TX

Total: 8 institutions

Primary Outcome Variable

Ongoing pregnancy rate at the end of the study (10 weeks of luteal support), defined as the percentage of embryotransferred patients with at least one fetal heartbeat. Statistical Analysis:
Non-inferiority was assessed by calculating the 95% confidence interval (CI) of the difference between the pregnancy rates for the two treatment group. If the lower bound of the 95% CI of the difference was greater than 0.10, then Progesterone 25 mg S.C. was considered non-inferior to the reference drug.

Secondary Outcome Variables

Implantation rate
Incidence of positive serum pregnancy tests

Clinical pregnancy rate

Live birth rate Early spontaneous abortions

Main Inclusion Criteria

BMI < 30 kg/m2;

Age 18 - 42 (upon starting COS); <3 prior ART cycles (IVF, ICSI and related procedures); Baseline (day 2-3 of cycling) FSH <15 IU/L and E2 <80 pg/mL;

Normal uterine cavity as per recent hysterosalpingogram, sonohystogram or hysteroscopic exam (i.e. no polyps or protruding submucosal fibroids).

Main Exclusion Criteria

Intramural uterine fibroids that distort the uterine cavity or polyps >1 cm; Stage III or IV endometriosis (no endometriomas); Hydrosalpinges; History of past poor response to COH resulting in cancelling ART; Uncontrolled adrenal or thyroid dysfunction; History of recurrent pregnancy loss defined as 3 or more spontaneous miscarriages, wherein pregnancy developed to a minimum of a gestational sac on TVUS

Study Protocol

IVF or ICSI
Any COH protocol Patients who provided at least 3 oocytes were randomised First dose administered on the day of OPU Daily treatment was continued for a total of 152 days, at which time a serum pregnancy test was performed In the event of a positive pregnancy test result and subsequent confirmation of ongoing pregnancy, treatment was to be continued for up to 10 weeks (i.e. up to the 12 weeks of gestation) Pregnancy outcome form following delivery

Baseline Characteristics

Variable Mean (SD) Prog s.c. (n=334)

EU study Prog Vag Gel (n=334) P Prog s.c. (n=392)

USA study P Vag Pessary (n=390) P

Age (years)

33.8 (4.3)

33.95 (4.3)
23.0 (3.14)

0.65

34.3 (4.3)

34.4 (4.5)
23.5 (3.0)

0.80
0.48

BMI (kg/m2) 22.8 (3.14)

0.43 23.4 (3.1)

Causes of Infertility

Variable (%) Male factor Tubal PCOS Anovulatory Endometriosis LPD Unexplained Other

European study Prog s.c. (n=334) 65.6 26.1 3.9 4.8 5.7 9.6 13.5 3.3 Prog Vag Gel (n=334) 67.7 22.8 3.6 3.6 6.6 9.0 14.4 4.2 p 0.57 0.32 0. 84 0.44 0.63 0.79 0.74 0.54 Prog s.c. (n=392) 48.5 23.0 10.7 8.4 11.2 0.5 14.0 27.8

USA study P Vag Pess (n=390) 49.7 22.6 7.4 7.2 7.2 0.8 16.9 28.2 p 0.78 0.93 0.14 0.59 0.06 0.69 0.28 0.94

Treatment Programming and Down-Regulation

Medication Type and Drug (%)

Cycle synchronisation Oral contraceptive Pituitary desensitisation

Prog. s.c. (n=334)

Prog. Vag Gel (n=334)

P value

3.9

3.9

1.00

GnRH agonist
GnRH antagonist

68.6
31.4

70.1
29.6

0.68

Treatment Programming and Down-Regulation

Medication Type And Drug (%) Cycle Synchronisation Oral Contraceptive Pituitary Desensitisation GnRH Agonist GnRH Antagonist 79.5 20.5 77.9 0.59 22.1 96 96 0.99 Prog s.c. (n=392) P Vag Pessary (n=390) P value

Ovarian Stimulation

Medication Type and Drug (%) Rec FSH h-FSH Rec-FSH + HMG Rec-FSH + Rec LH

Prog s.c. (n=334) 47.9 32.3 2.7 2.1

Prog Vag Gel (n=334) 45.5 35

P value

0.33 2.7 0.6

Ovarian Stimulation

Medication Type and Drug (%) Rec FSH + hMG Rec FSH only h-FSH + hMG Other

Prog s.c. (n=392) 88.3 5.1 4.1 2.6

Prog Vag Pessary (n=390) 85.1 8.2

P value

0.35 4.6 2.1

Retrieved oocytes

Variable [Mean (SD)] Total FSH, IU Nr oocytes retrieved Nr mature (MII) oocytes

Prog. s.c. (n=334) 2404.1 (1150.2) 9.6 (4.9) 7.9 (4.4)

Prog.Vag Gel (n=334) 2420.6 (1087.3) 9.8 (5.6) 8.1 (5.0)

p 0.85 0.72 0.52 0.23

Nr. of embr. transferred Endometrial thickness on the ET day (mm)

2.15 (0.61)

2.10 (0.61)

11.2 (2.1)

11.4 (2.4)

0.22

Retrieved oocytes

Variable [Mean (SD)] Total FSH, IU Nr oocytes retrieved

Prog s.c. (n=392) 2116 (1073) 16.5 (8.8)

Prog Vag Pessary (n=390) 2194 (1119) 15.6 (8.0)

P 0.32 0.17

Nr mature (MII) oocytes

11.9 (6.9)

11.6 (6.7)

0.57

Nr. of embr. transferred

Endometrial thickness on the ET day (mm)

2.2 (0.8) 10.9 (2.3)

2.2 (0.7) 10.9 (2.6)

0.60
0.95

Prog SC 25 mg
50 45 40 35 30 25 20 15 10 5 0
IR +bhCG Clinical PR

Vag Gel 90 mg

p=0.62

p=0.72 p=0.58 p=0.97 p=0.58

p=0.88
p=0.35

Ong PR

Biochemical P rate

EPL (%)*

LBR (%)

Prog SC 25 mg
70 60 50

Vag Pessaries 200 mg

p=0.47 p=0.31 p=0.54 p=0.42 p=0.61

40 30 20 10 0 IR +bHCG Clinical PR Ong PR Biochemical P Early Livebirth rate rate spontanous abortion

p=0.44

p=0.38

Why the difference?

Centre No. Prog N 1 2 3 4 5 41 29 19 35 24 sc % op 36.6 24.1 15.8 31.4 12.5 Vaginal N 42 30 21 39 23 Gel % op 26.2 33.3 33.3 24.2 30.4

6
7 8

16
31 64

6.3
32.3 31.3

17
28 64

23.5
42.9 29.7

9
10 11 12 13

13
22 5 28 7

46.2
4.6 0 53.6 14.3

13
23 5 27 8

69.2
26.1 20 80.5 12.5

Comfort

Assessment N (%) Comfort Very uncomfortable Uncomfortable Neutral Comfortable Very comfortable

Prog s.c.

Prog Vag Gel

P value

(0.7)

3 19

(1.0) (6.2) 0.829

23 (7.6) 62 (20.4) 171 (56.3) 46 (15.1)

69 (22.3) 165 (53.4) 53 (17.2)

Safety
Variable (%) Injection Site Reactions Vaginal Reactions AEs Related to IVF Procedure Abdominal Pain/Discomfort Vaginal Haemorrhage Prog s.c. (n=400) 22 0.8 Prog Vag Pessary (n=400) 0.0 14.5 p Value <0.001 <0.001

25.3
15.8 15.5 12.3 12.5 5.5

25.0
20.5 15.5 14.8 12.8 12.0

1.000
0.098 1.000 0.352 1.000 0.002

Headache
Nausea Breast Pain/Tenderness Constipation Vomiting Fatigue Insomnia

7.3
3.8 3.3 1.3

9.8
5.5 7.8 2.8

0.254
0.313 0.008 0.205

Conclusions

These two large, prospective randomised studies demonstrate that 25 mg subcutaneous progesterone administered once daily is both effective and well tolerated in a variety of COS protocols. Therefore, subcutaneous progesterone represents a valuable alternative option for luteal phase support in assisted reproduction, where parenteral administration is preferred or required.

Thank you for your attention.

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