Advanced trial under way for oral contraceptive
Could a new combined oral contraceptive (OC) be available to U.S. women? Organon is conducting two Phase 3a trials for the first monophasic oral contraceptive containing estradiol (E2) and a new progestin, nomegestrol acetate (NOMAC). Phase 3 development is scheduled to be completed in 2009, reports Monique Mols, an Organon spokeswoman.
The two trials, which involve 4,400 women, are the largest trials in contraception ever undertaken by the company.1 Recruitment for both trials was completed in May 2007. More than 180 centers in 24 countries, including the United States, are taking part in the trials. Mols declined to identify the U.S. sites.
Nomegestrol acetate is considered a new progestin, along with drospirenone, dienogest, trimegestone, and Nestorone.2 These new progestins have been designed to bind very specifically to the progesterone receptor and not to other steroid receptors in an effort to avoid androgenic, estrogenic, or glucocorticoid side effects.
Organon was granted development and marketing rights of NOMAC/E2 in 2005 by Laboratoire Théramex, an affiliate of Merck KGaA. Phase 2 research completed by Théramex indicates that the combination of NOMAC/E2 inhibits ovulation with an acceptable cyclic bleeding pattern and safety profile, says Mols.
Results from the Phase 2 program, which involved 265 women, indicates that a monophasic combination of 2.5 mg of NOMAC and 1.5 mg of E2 given in a cyclic regimen provides good ovulation inhibition and an acceptable monthly bleeding pattern and safety profile.3
Phase 2 studies for NOMAC/E2 looked at three doses of NOMAC (0.625 mg, 1.25 mg, and 2.5 mg) in combination with 1.5 mg of E2. Scientists studied suppression of ovarian function by measuring follicular growth via vaginal ultrasonography and circulating serum levels of luteinizing hormone (LH), follicle-stimulating hormone, E2, and progesterone. Research indicates daily dosages of 2.5 mg of NOMAC combined with 1.5 mg of E2 represents the optimal dose combination for suppression of ovarian activity.3
The NOMAC 2.5 mg /E2 1.5 mg combination appears to be associated with a cyclic and regular vaginal bleeding pattern. Results from a separate Phase 2 study indicate a consistent ovulation inhibition combined with a regular cyclic bleeding pattern in women who used the drug combination in a 24 days active tablet, four days placebo regimen. Full Phase 2 results will be published during the Phase 3 development program, Mols states.
Implant uses NOMAC
Nomegestrol acetate has been studied in use in a contraceptive implant form, Uniplant. Developed by South-to-South Cooperation in Reproductive Health, Uniplant is a single silicone rubber implant that is designed to slowly release the progestin over a year's time. A multicenter clinical trial of 1,803 women of reproductive age was conducted; 276 of the women discontinued prior to completing one year of study, with medical reasons for discontinuation principally menstrual-related. Fifteen pregnancies occurred during the one-year study period, which resulted in a 12-month net cumulative pregnancy rate of 0.94%.4 Uniplant is not commercially available.
In a separate study, researchers enrolled women of reproductive age to examine the effect of Uniplant on plasma levels of sex hormone-binding globulin (SHBG), testosterone, free testosterone, and androstenedione, as well as its impact on blood pressure, body weight, and the development of common acne.5 All changes observed in the study were within normal range, researchers report. SHBG was not affected by Uniplant use, and no significant increase was observed in androgen levels or in the development of acne vulgaris.5
Because of the lack of androgenic activity of NOMAC, the progestin does not modify glucose and insulin response in oral glucose tolerance tests and does not induce changes in the lipid profile.6,7
NOMAC also has been studied in use of perimenopausal women.8 In a study designed to evaluate whether progestin administration increases resting metabolic rate and influences body composition of perimenopausal women, results indicate cyclic NOMAC administration may contribute to reduce negative modification of body composition.8
- Organon. Pivotal phase IIIa trials for Organon's novel oral contraceptive, NOMAC/E2, complete recruitment. Press release. May 16, 2007. Accessed at www.organon.com.
- Sitruk-Ware R. New progestagens for contraceptive use. Hum Reprod Update 2006; 12:169-178.
- Organon. Phase III clinical studies for the novel oral contraceptive of Organon, NOMAC/E2, now in full swing — NOMAC/E2 Phase II clinical trial program indicated good ovulation inhibition combined with an acceptable monthly bleeding pattern and safety profile. Press release. Dec. 5, 2006. Accessed at www.organon.com.
- Coutinho EM, de Souza JC, Athayde C, et al. Multi-center clinical trial on the efficacy and acceptability of a single contraceptive implant of nomegestrol acetate, Uniplant. Contraception 1996; 53:121-125.
- Barbosa I, Coutinho E, Athayde C, et al. Androgen levels in women using a single implant of nomegestrol acetate. Contraception 1996; 53:37-40.
- Urquhart DR, Templeton AA, Shinewi F, et al. The efficacy and tolerance of mifepristone and prostaglandin in termination of pregnancy less than 63 days' gestation: UK Multicentre Study — Final results. Contraception 1997; 55:1-5.
- El-Refaey H, Rajasekar D, Abdalla M, et al. Induction of abortion with mifepristone (RU 486) and oral or vaginal misoprostol. N Engl J Med 1995; 332:983-987.
- Cagnacci A, De Toni A, Caretto S, et al. Cyclic progestin administration increases energy expenditure and decreases body fat mass in perimenopausal women. Menopause 2006; 13:197-201.