Treatment of Uterine Fibroids With CDB-2914, an Experimental Selective Progesterone Receptor Antagonist

Uterine leiomyomata (fibroids) are a common benign tumor of the uterine muscle in premenopausal women. These tumors may cause bleeding, pelvic pain and pressure. Because fibroids grow in the presence of estrogen, medical therapies that decrease estrogen levels (like GnRH analog) cause fibroids to shrink and so may relieve symptoms. However, such medication can only be given short-term and has inconvenient side effects such as hot-flushes. Thus, many women with symptomatic fibroids choose to have them removed surgically, either individually or by removing the uterus via hysterectomy.

The study evaluates a new medical treatment for fibroids using the progesterone receptor modulator CDB-2914. A similar compound, mifepristone (Registered Trademark), reduced fibroid size when given for twelve weeks. This study will compare fibroid size, hormone levels and symptoms before and during daily administration of CDB-2914 (10 or 25 mg) or placebo for 10 - 14 weeks. To do this, women will undergo MRI and a saline hysterosonogram (ultrasound with fluid) of the uterus before and at the end of the treatment; they will have blood drawn every 7 - 14 days, and will fill out a symptom calendar at home. Hysterectomy will be performed at the end of the treatment to evaluate the effects of the medication on the uterine and fibroid tissues, and to provide treatment for the study participant. Women will be randomly assigned to the treatment groups; during the treatment period neither the participants nor the investigators will know the type of treatment that a woman receives.

• GENERAL INCLUSION CRITERIA:

Women receiving insulin or thyroid hormone replacement may participate if well-controlled; use of vitamins and calcium under RDA is allowed.

Female gender-to evaluate effects in the target population for clinical trials.

In good health. Chronic medication use is acceptable except for glucocorticoid use. Other chronic medication use may be acceptable at the discretion of the research team. Interval use of over-the counter drugs is acceptable but must be recorded.

Menstrual cycles of 24 - 35 days.

Hemoglobin greater than 10 g/dL.

Willing and able to comply with study requirements.

Age 33 to 50.

Using mechanical (condoms, diaphragms), sterilization or abstinence methods of contraception for the duration of the study.

Negative urine pregnancy test.

BMI less than or equal to 33.

Able to read and speak English fluently to allow accurate self-administration of medication, recording of symptoms and unassisted completion of questionnaire.

Normal glomerular filtration rate.

Liver function tests within 130% of upper limit.

Inclusion criteria

FOR WOMEN WITH LEIOMYOMA:

History of uterine leiomyoma causing symptoms of bleeding, pressure, or pain, as defined by the ACOG practice bulletin (ACOG Practice Bulletin 1994):

Excessive uterine bleeding will be evidenced by either of the following-profuse bleeding with flooding or clots or repetitive periods lasting for more than 8 days; or anemia due to acute or chronic blood loss; OR

Pelvic discomfort caused by leiomyomata, either acute and severe or chronic lower abdominal or low back pressure or bladder pressure with urinary frequency not due to urinary tract infection.

Uterine leiomyoma(ta) of at least 2 cm size.

No desire for fertility; willing to undergo hysterectomy.

GENERAL EXCLUSION CRITERIA:

Significant abnormalities in the history, physical or laboratory examination.

Pregnancy.

Lactation.

Use of oral, injectable or inhaled glucocorticoids or megesterol within the last year.

Unexplained vaginal bleeding.

History of malignancy within the past 5 years.

Use of estrogen or progesterone-containing compounds, such as oral contraceptives and hormone replacement therapy, within 8 weeks of study entry, including transdermal, injectable, vaginal and oral preparations.

Use of agents known to induct hepatic P450 enzymes; use of imidazoles.

Current use of GnRH analogs or other compounds that affect menstrual cyclicity.

FSH greater than 20 IU/mL.

Significant medical disorders.

Cervical dysplasia.

Need for interval use of narcotics.

Abnormal adnexal/ovarian mass.

Intrauterine device.

Exclusion criteria

FOR WOMEN WITH FIBROIDS:

Use of herbal medication having estrogenic or antiestrogenic effects within the past 3 months.

Contradiction to anesthesia

Genetic causes of leiomyomata.

Previous participation in the study.

Known recent rapid growth of fibroids, defined as a doubling in size in six months.