Vaginal rings with progesterone receptor modulators for …...PRMs for regular contraception RCT: oral daily Mifepristone 5 mg (n=74) vs LNG 30 mcg (n=23) for 24 weeks – Better bleeding

Vaginal Rings with Progesterone Receptor Modulators for Regular

Contraception

Jeffrey T. Jensen, MD, MPH

Oregon Health & Science University

PRMs for regular contraception

• Mechanism: Suppression of ovulation – 90-95% with oral mifepristone (2-5mg daily)*

• Opportunity: Elimination of estrogen-related adverse effects

• Risk: New nontarget effects – Endometrial changes

– Antiglucocorticoid effect

* Brown et al JCEM, 2002;87(1):63-70.

Presenter

Presentation Notes

One potential adverse interaction is non-target binding to the cortisol receptor. This antiglucocorticoid effect varies between the different SPRMs, but is not clinically important with single dose or short term treatments even with mifepristone [16]. Longer term studies of high dose mifepristone (200mg) for meningioma have also not revealed clinical significant changes although the diagnosis of hypoadrenalism is difficult because serum cortisol levels are normal or even increased due to this blockade [17]. Hypoadrenalism has not been observed with low dose mifepristone in contraceptive studies [15].

PRMs for regular contraception RCT: oral daily Mifepristone 5 mg (n=74)

vs LNG 30 mcg (n=23) for 24 weeks

– Better bleeding pattern with mifepristone

• 49% vs. 0% amenorrhea

• 4% vs 39% with > 5 days bleeding/spotting

– Thicker endometrium • Mife 10.3mm;LNG 4.0 mm (p <.001)

• PAECs on biopsy

– 2 pregnancies with mifepristone

Lakha et al. Human Reproduction Vol.22, No.9 pp. 2428–2436, 2007

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Presenter

Presentation Notes

BACKGROUND: The acceptability and continuation rate of oral contraceptive steroids are limited by unpredictable bleeding and the fear of long-term risks such as breast cancer. By inhibiting ovulation and by altering the receptivity of the endometrium, antagonists of progesterone, such as mifepristone, could be developed as estrogen-free novel contraceptives. METHODS: Multicentre, double-blind, randomized controlled trial comparing frequency of amenorrhoea (primary outcome), bleeding patterns, side effects and efficacy in women taking daily 5 mg mifepristone (n 5 73) or 0.03 mg levonorgestrel (progestogen-only pill; POP, n 5 23) for 24 weeks. RESULTS: More women were amenorrhoeic while taking mifepristone than POP (49 versus 0% P < 0.001), and fewer women bled or spotted for >5 days per month (4 versus 39% P < 0.001). Forty-eight percent of women who took mifepristone for 6 months had cystic glandular dilatation of the endometrium but none showed hyperplasia or atypia. There were no pregnancies in 356 months of exposure in women who used only mifepristone for contraception. Two pregnancies occurred in women taking mifepristone who were also using condoms for dual protection. CONCULSIONS: Daily mifepristone (5 mg) is an effective oral contraceptive pill which has a better pattern of menstrual bleeding than an existing POP (levonorgestrel FIG. 1. Excretion of metabolites of ovarian steroids in women taking either 2 or 5 mg mifepristone per day for 120 d. E1G and pregnanediol glucuronide are expressed per mol Cr. f, Menses. A, Persistent follicular activity but no ovulation in a woman in Edinburgh on 2 mg/d. B, Single ovulatory episode in Edinburgh woman on 2 mg/d. C, Complete suppression of ovarian activity in Edinburgh women on 5 mg/d. D, single ovulatory cycle in woman in Shanghai on 5 mg/d.

Ulipristal acetate

• Receptor binding affinity – Progesterone receptor UPA = Mife= P4

– Glucocorticoid receptor UPA < Mife

• Approved for use as an oral emergency contraceptive pill and in the EU for uterine fibroid treatment

• Results with short term oral dosing 5-10 mg – Ovulation suppression in 80%

– Amenorrhea in 81% -90% Chabbert-Buffet et al. JCEM 2007;92:3582-9

UPA Contraceptive Vaginal Ring • Developed by Population Council

– Support • NICHD NIH U54 HD 29990

• HRA Pharma, Paris, France.

• Goal: A highly effective continuous use estrogen-free and bleed-free contraceptive method

Ulipristal Acetate Vaginal Ring (~2.5 mg VA/CDB-2914/day)

Slicone elastomer fusion technology of a ring within a ring

International patent application number PCT/US2005/024474 to Sitruk-Ware and Tsong, for “Sustained Release Compositions Containing Progesterone Receptor Modulators” filed July 8, 2005

Presenter

Presentation Notes

Nuvaring 54 mm x 4 mm

UPA CVR 600-800 µg/day; 12 weeks

Ovarian Activity % of cycles UPA (ng/mL)

Ovulation 32% (25/78) 4.7

Ovulatory dysfunction 1% (1/78) 5.7

LUF 13% (10/78) 5.5

Persistent follicle 31% (24/78) 5.6

No follicular resolution 14% (11/78) 4.7

No follicular development >10 mm

9% (7/78) 7.6

Brache et al, Contraception 85 (2012): 480-488

Bleeding days (mean) = 4.2 Spotting days (mean) = 7.5 Episodes (mean) = 1.4

Presenter

Presentation Notes

3.4. Bleeding patterns The mean number of bleeding onsets during the 12 weeks of treatment was 1.19, while the mean number of bleeding and spotting onsets was 1.41. These values are significantly below the minimum expected value of two onsets in the three 4-week periods (pb.05). The mean days of bleeding and of bleeding and spotting in the 12 weeks of ring use for all 37 subjects were, respectively, 4.16 and 7.51. These overall values are about 33% to 50% of what one may expect over a 12-week period in normally menstruating women. The Santiago clinic had the lowest average number of days with a bleeding and/or spotting event. Progesterone increase and drop were followed by a withdrawal bleeding with few exceptions (4/51).

Classification of Ovarian Activity

Each 28 day cycle of observation • Ovulation

• follicular rupture • P ≥ 10 nmol/L next 2 samples

• Ovulatory Dysfunction • Rupture with abnormal endocrine profile

• Luteinized unruptured follicle (LUF) • No rupture, P ≥ 5 nmol/L x 2

• Persistent Follicle • No Follicular Development • No Follicular Resolution

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Prot 422: Estradiol, progesterone and follicular diameter means of control cycles

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Brache et al Contraception 85 (2012): 480-488

Presenter

Presentation Notes

Ovulatory dysfunction Follicular rupture with abnormal endocrine profile: preceded by progesterone levels >10 nmol/L not followed by a luteal phase ( No P > 5 nmol/L) not followed by adequate luteal phase (P not > 10 nmol/L in at least two consecutive samples). Also associated with follicle > 30 mm Luteinized unruptured follicle (LUF) no follicular rupture P ≥ 5 nmol/L in at least two consecutive samples. Persistent follicle a follicle developing beyond 15 mm and persisting for ≥ 7 days without rupture and without P increase No follicular development No follicle > 10 mm with growth No follicular resolution Fate not determined in 30 d interval

Ovulation Follicular rupture P ≥ 10 nmol/L next 2

-14-10 -7 -3 0 3 7 10 140

200400600800

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Prot 422: Estradiol, progesterone and follicular diameter means of control cycles

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Presenter

Presentation Notes

Abrupt decrease of at least 50% of a ≥ 15 mm follicle, or change to corpus luteum at the next US measurement done 3-4 days later

– Follicular rupture with abnormal endocrine profile:

• preceded by progesterone levels >10 nmol/L

• not followed by a luteal phase ( No P > 5 nmol/L)

• not followed by adequate luteal phase (P not > 10 nmol/L in at least two consecutive samples).

• Also associated with follicle > 30 mm

Ovulatory dysfunction


Luteinized unruptured follicle (LUF) – no follicular rupture

– P ≥ 5 nmol/L in at least two consecutive samples.

Persistent follicle – a follicle developing beyond 15 mm and persisting

for ≥ 7 days without rupture and without P increase

No follicular development – No follicle > 10 mm with growth

No follicular resolution – Fate not determined in 30 d interval

Brache et al, Contraception 85 (2012): 480-488

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Protocol 422: A Phase 2, randomized study to evaluate the safety and efficacy of two Contraceptive Vaginal Rings delivering a daily dose of 1500 or 2500 μg

of CDB-2914 on inhibition of ovulation, endometrial changes and bleeding patterns in normal cycling women

• Randomized, dose-finding, multicenter trial

• CDB-2914 CVR ( 3 month) 1500 µg or 2500 µg

• 3 ICCR sites

– Santo Domingo, Santiago, Portland (n = 20/site)

• Primary Objective: To develop a UPA CVR that will suppress ovulation in 90% of cycles

• Secondary Objectives: To assess bleeding patterns, endometrial effects, and clinical safety

Documents

Vaginal rings with progesterone receptor modulators for …...PRMs for regular contraception RCT: oral daily Mifepristone 5 mg (n=74) vs LNG 30 mcg (n=23) for 24 weeks – Better bleeding