Effects on Ovarian Function of the Combined Oral Contraceptive NOMAC-E2 Compared to a COC Containing DRSP/EE

Condition(s) targeted: Contraception

Intervention: Estradiol and Nomegestrol Acetate Tablets (1.5 mg / 2.5 mg) (Drug); Drospirenone and Ethinyl Estradiol Tablets (3 mg / 30 ug) (Drug)

Phase: Phase 3

Status: Completed

Sponsored by: Organon

Official(s) and/or principal investigator(s):
Carole Verhoeven, PhD, Study Director, Affiliation: NV Organon, a part of Schering-Plough Corporation

The primary purpose of this study is to evaluate the effects of the NOMAC-E2 combined oral contraceptive on ovarian function.

Official title: A Randomized, Open-Label, Comparative Trial to Evaluate the Effects on Ovarian Function of a Monophasic Combined Oral Contraceptive (COC) Containing 2.5 mg Nomegestrol Acetate (NOMAC) and 1.5 mg Estradiol (E2), Compared to a Monophasic COC Containing 3 mg Drospirenone (DRSP) and 30 ug Ethinyl Estradiol (EE)

Study design: Prevention, Randomized, Open Label, Active Control, Parallel Assignment, Pharmacodynamics Study

Primary outcome: Ovarian function as determined by blood sampling (P, FSH, LH and E2), and vaginal USS of the ovaries to assess follicular growth.

Secondary outcome:

Return of ovulation as determined by blood sampling (P levels) and vaginal USS of the ovaries to assess follicular growth.

Effects on cervical mucus as determined by Insler score.

Effects on endometrial thickness as determined by vaginal USS of the endometrium.

Effects on androgen, SHBG and folic acid levels as determined by blood sampling.

Contraceptive efficacy as determined by serum HCG pregnancy test (or home pregnancy test).

Drug safety as determined by [S]AE monitoring, cervical cytology, physical & gynecological exams, and monitoring vital signs.

Cycle control as determined by patient diary records.

Detailed description: This is an open-label, randomized, comparative single center trial of the NOMAC-E2 COC versus a COC containing 3 mg DRSP and 30 µg EE in healthy female volunteers. In total 48 subjects will be randomly allocated in a 2: 1 ratio to either the NOMAC-E2 COC or DRSP-EE COC, resulting in 32 women using NOMAC-E2 and 16 using DRSP-EE. Subjects will be treated for 6 consecutive cycles.

The trial will be conducted in an open-label fashion, as the differences in regimen between the NOMAC-E2 COC (24 active plus 4 placebo tablets per cycle) and comparator drug (21 active plus 7 placebo tablets per cycle) will lead to obvious differences in the timing of withdrawal bleeding, which will reveal the treatment. Moreover, the primary endpoint ovarian function, as judged by follicular development, and hormone levels, is not considered to be subject to bias. To exclude enrollment bias, the randomization process will be done by making use of an Interactive Voice Response System (IVRS).

In the trial the following phases relative to treatment can be distinguished: screening, one screening cycle, 6 treatment cycles and one post-treatment cycle. The screening phase serves to establish general eligibility for a contraception trial. During the pretreatment cycle, ovarian activity will be monitored in order to establish the occurrence of ovulation, which is an additional inclusion criterion for treatment as subjects must be at risk for ovulation. The treatment period will be 6 cycles, of which Cycles 1, 2 and 6 will be monitored in detail with respect to ovarian function parameters. Cycles 1 and 2 will be monitored to establish the onset and maintenance of ovulation inhibition, while monitoring of Cycle 6 serves to establish the maintenance of ovulation inhibition over a prolonged period of time. One post-treatment cycle will be monitored to assess return of ovulation and the timing thereof. Sampling frequency is such that the key-parameter of ovulation, i. e. progesterone levels >16 nmol/L sustained for at least 5 days cannot be missed. In addition to ovarian function, the mechanism of action will be investigated by the effects on cervical mucus and by ultrasonography of the endometrium.

To gain information on the androgenic status, SHBG and a panel of androgens will be determined at the end of the screening cycle, twice during treatment and at the end of the post-treatment cycle. Folic acid levels will be determined at the same time points, with a view on women wishing to conceive after having used the COC, for whom sufficient levels of folic acid are recommended for optimal early development of the fetus.

Bleeding pattern and tablet-intake will be assessed by means of a subject diary, to be completed on a daily basis. In addition, condom use and sexual intercourse during each cycle will be recorded at the end of each cycle, to assess whether the subject has been at risk for pregnancy. In addition, several safety assessments (vital signs, physical, gynecological and breast examinations, cervical smear, routine laboratory parameters and adverse events) will be performed.

Minimum age: 18 Years. Maximum age: 35 Years. Gender(s): Female.

Criteria:

Inclusion Criteria:

- Willing to use COC for at least 6 cycles.

- 18 - 35 years of age at screening.

- BMI of >/= 17 and

- Good physical and mental health.

- Willing to use condoms as the sole contraceptive method during screening cycle and 1

post-treatment cycle.

- Willing to give informed consent.

Exclusion Criteria:

- Contraindications for contraceptive steroids (general).

- Additional contraindications (renal, hepatic or adrenal insufficiency).

- Breastfeeding.

- Present use (or use within 2 months prior to start of the trial medication) of the

following drugs: phenytoin, barbiturates, primidone, carbamazepine, oxcarbazepine, topiramate, felbamate, rifampicin, nelfinavir, ritonavir, griseofulvin, ketoconazole, sex steroids (other than pre- and post treatment contraceptive method) and herbal remedies containing Hypericum perforatum (St. John's Wort0.

- Administration of any other investigational drugs and/or participation in another

clinical trial within 2 months prior to the start of the trial medication or during the trial period.

- Abnormal cervical smear at screening, or documentation of an abnormal smear performed

within 6 months before screening.

- Clinically relevant abnormal laboratory result at screening as judged by the

investigator.

Organon Study Site, Groningen, Netherlands

Starting date: October 2006
Ending date: April 2008
Last updated: May 30, 2008