Clinical trial NCT00290251: Treatment of Uterine Fibroids With the Selective Progesterone Receptor Modulator CDB-2914
Official title: Evaluation of Whether the Selective Progesterone Receptor Modulator CDB-2914 Can Shrink Leiomyomata
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Leiomyoma
Keywords: Endometrium
Progesterone
Estrogen
Fibroid
Hysterectomy
Leiomyoma
Uterine Fibroids
Fibroids
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
Collaborators: name: HRA Pharma
First posted: 2006-02-10
Enrollment: 72
Sex: FEMALE
Minimum age (years): 25
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Subjects were studied during a single baseline menstrual cycle followed by a cross-over into three arms (active treatment at one of two doses, or placebo) given for three menstrual cycles
Primary purpose: TREATMENT

Brief summary: This study will evaluate whether the experimental drug ulipristal acetate can shrink uterine fibroids in pre-menopausal women.

Detailed description: Uterine leiomyomata (fibroids) are a common benign tumor of the uterine muscle in pre-menopausal women that may cause bleeding, pelvic pain and pressure. Because fibroids grow in the presence of estrogen, medical therapies that decrease estrogen levels (like Gonadotropin releasing hormone,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-flashes. Thus, many women with symptomatic fibroids choose to have them removed surgically, either individually or by removing the uterus via hysterectomy.

Women between 25 and 50 years of age who have regular menstrual cycles and a history of uterine fibroids that cause heavy bleeding, pressure, or pain may be eligible for this study. Candidates are screened with a medical history and physical examination, including breast and pelvic examination, blood and urine tests, a quality-of-life questionnaire, and a home urine test for leuteinizing hormone (LH) surge. They are given a diary to record the LH surge, days of vaginal spotting or bleeding, and symptoms. Participation includes the following:

Baseline Studies (First Menstrual Cycle)

* Magnetic resonance imaging (MRI): The subject lies in the MRI scanner, a narrow cylinder with a strong magnetic field, for imaging the uterus.
* Saline hysterosonogram: This is an ultrasound examination of the uterus. A speculum is placed in the vagina and a small amount of liquid is inserted into the uterus. A probe is then inserted into the vagina. The probe emits and receives sound waves that are used to visualize the fibroids and surrounding structures.

Study Drug Phase (Second through Fourth Menstrual Cycles)

* Subjects are randomly assigned to take ulipristal acetate or placebo (inactive compound) once a day by mouth on an empty stomach for three menstrual cycles or up to 102 days if menstrual cycles are irregular or stop.
* Pregnancy test on first or second day of every menstrual cycle.
* Blood tests every 2 weeks to measure effects of study medication on hormones, blood count, blood chemistries and liver function.
* 24-hour urine collections three times during the study, about once a month, to measure cortisol and check adrenal gland function.
* Repeat transvaginal ultrasound after 4-6 weeks of study drug to check fibroid growth.
* Repeat hysterosonogram and MRI within 2 weeks of surgery to count and measure the fibroids. or placebo (inactive compound) once a day by mouth on an empty stomach for three menstrual cycles or up to 102 days if menstrual cycles are irregular or stop.
* Pregnancy test on first or second day of every menstrual cycle.
* Blood tests every 2 weeks to measure effects of study medication on hormones, blood count, blood chemistries and liver function.
* 24-hour urine collections three times during the study, about once a month, to measure cortisol and check adrenal gland function.
* Repeat transvaginal ultrasound after 4-6 weeks of study drug to check fibroid growth.
* Repeat hysterosonogram and MRI within 2 weeks of surgery to count and measure the fibroids. or placebo (inactive compound) once a day by mouth on an empty stomach for three menstrual cycles or up to 102 days if menstrual cycles are irregular or stop.
* Pregnancy test on first or second day of every menstrual cycle.
* Blood tests every 2 weeks to measure effects of study medication on hormones, blood count, blood chemistries and liver function.
* 24-hour urine collections three times during the study, about once a month, to measure cortisol and check adrenal gland function.
* Repeat transvaginal ultrasound after 4-6 weeks of study drug to check fibroid growth.
* Repeat hysterosonogram and MRI within 2 weeks of surgery to count and measure the fibroids.

Eligibility criteria: INCLUSION CRITERIA:

* Female gender-to evaluate effects in the target population for clinical trials.
* History of uterine leiomyoma causing symptoms of bleeding, pressure, or pain, as defined by the American College of Obstetrics and Gynecology (ACOG) practice bulletin:
* 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.
* 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 (for those wishing surgery); iron may be administered to improve red blood cell counts.
* Willing and able to comply with study requirements.
* Age 25 to 50.
* Using mechanical (condoms, diaphragms) sterilization or abstinence methods of contraception for the duration of the study.
* Negative urine pregnancy test.
* Body mass index (BMI) less than or equal to 33, if a surgical candidate or less than or equal to 35, if not a surgical candidate.
* Creatinine less than 1.3 mg/dL.
* Liver function tests within 130% of upper limit.
* If interested in hysterectomy, no desire for fertility.

EXCLUSION CRITERIA:

* Significant abnormalities in the history, physical or laboratory examination.
* Pregnancy.
* Lactation.
* Use of oral, injectable or inhaled glucocorticoids or megestrol 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 induce hepatic P450 enzymes; use of imidazoles.
* Current use of Gonadotropin-releasing hormone (GnRH) analogs or other compounds that affect menstrual cyclicity.
* Follicle stimulating hormone (FSH) greater than 20 IU/mL.
* Untreated cervical dysplasia.
* Need for interval use of narcotics.
* Abnormal adnexal/ovarian mass.
* Use of herbal medication having estrogenic or antiestrogenic effects within the past 3 months.
* Contradiction to anesthesia, for women planning surgery.
* Genetic causes of leiomyomata.
* Previous participation in the study.
* Known recent rapid growth of fibroids, defined as a doubling in size in six months.

Primary outcomes:
measure: Shrinkage of Fibroids - Size of Fibroids
timeFrame: 3 months (baseline to end of treatment)
Secondary outcomes:
measure: Short Form-36 and Uterine Fibroid Symptom Quality of Life
timeFrame: 3 months (Baseline to end of treatment 1)
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: NIH Clinical Center
state: Maryland
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: NICHD, NIH
name: Lynnette K Nieman, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Batista MC, Cartledge TP, Zellmer AW, Merino MJ, Axiotis C, Loriaux DL, Nieman LK. Delayed endometrial maturation induced by daily administration of the antiprogestin RU 486: a potential new contraceptive strategy. Am J Obstet Gynecol. 1992 Jul;167(1):60-5. doi: 10.1016/s0002-9378(11)91627-5.
citation: Burroughs KD, Howe SR, Okubo Y, Fuchs-Young R, LeRoith D, Walker CL. Dysregulation of IGF-I signaling in uterine leiomyoma. J Endocrinol. 2002 Jan;172(1):83-93. doi: 10.1677/joe.0.1720083.
citation: Cadepond F, Ulmann A, Baulieu EE. RU486 (mifepristone): mechanisms of action and clinical uses. Annu Rev Med. 1997;48:129-56. doi: 10.1146/annurev.med.48.1.129.
citation: Levens ED, Wesley R, Premkumar A, Blocker W, Nieman LK. Magnetic resonance imaging and transvaginal ultrasound for determining fibroid burden: implications for research and clinical care. Am J Obstet Gynecol. 2009 May;200(5):537.e1-7. doi: 10.1016/j.ajog.2008.12.037. Epub 2009 Mar 9.
citation: Nieman LK, Blocker W, Nansel T, Mahoney S, Reynolds J, Blithe D, Wesley R, Armstrong A. Efficacy and tolerability of CDB-2914 treatment for symptomatic uterine fibroids: a randomized, double-blind, placebo-controlled, phase IIb study. Fertil Steril. 2011 Feb;95(2):767-72.e1-2. doi: 10.1016/j.fertnstert.2010.09.059. Epub 2010 Nov 5.
citation: Parikh TP, Malik M, Britten J, Aly JM, Pilgrim J, Catherino WH. Steroid hormones and hormone antagonists regulate the neural marker neurotrimin in uterine leiomyoma. Fertil Steril. 2020 Jan;113(1):176-186. doi: 10.1016/j.fertnstert.2019.08.090.
citation: Lewis TD, Malik M, Britten J, Parikh T, Cox J, Catherino WH. Ulipristal acetate decreases active TGF-beta3 and its canonical signaling in uterine leiomyoma via two novel mechanisms. Fertil Steril. 2019 Apr;111(4):806-815.e1. doi: 10.1016/j.fertnstert.2018.12.026. Epub 2019 Mar 11.
citation: Ng SSM, Jorge S, Malik M, Britten J, Su SC, Armstrong CR, Brennan JT, Chang S, Baig KM, Driggers PH, Segars JH. A-Kinase Anchoring Protein 13 (AKAP13) Augments Progesterone Signaling in Uterine Fibroid Cells. J Clin Endocrinol Metab. 2019 Mar 1;104(3):970-980. doi: 10.1210/jc.2018-01216.
citation: Levens ED, Potlog-Nahari C, Armstrong AY, Wesley R, Premkumar A, Blithe DL, Blocker W, Nieman LK. CDB-2914 for uterine leiomyomata treatment: a randomized controlled trial. Obstet Gynecol. 2008 May;111(5):1129-36. doi: 10.1097/AOG.0b013e3181705d0e.