Treatment of Uterine Fibroids With the Selective Progesterone Receptor Modulator CDB-2914

• ClinicalTrials.gov Identifier: NCT00290251
• Recruitment Status: Completed
• First Posted: February 10, 2006
• Results First Posted: December 18, 2012
• Last Update Posted: December 18, 2012
• Sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Collaborator: HRA Pharma
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) )

Tracking Information

• First Submitted Date: February 10, 2006
• First Posted Date: February 10, 2006
• Results First Submitted Date: October 28, 2011
• Results First Posted Date: December 18, 2012
• Last Update Posted Date: December 18, 2012
• Study Start Date: February 2006
• Actual Primary Completion Date: July 2009 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 14, 2012)

Shrinkage of Fibroids - Size of Fibroids [ Time Frame: 3 months (baseline to end of treatment) ]

The primary outcome, fibroid volume, was calculated by an ellipsoid formula (π/6xd1xd2xd3) using orthogonal three-dimensional measurements taken from pelvic MRI scan. Individual volumes were summed to assess total fibroid volume for each woman, which were log-transformed before analysis. Women with paired MRI results were included in this intent to treat analysis, even if they did not take all study medication. Fibroids were included if they were seen on both studies.The absolute change in cm3 between baseline and end of treatment was calculated and its log was used for statistics and reporting the results in the data table below.

• Original Primary Outcome Measures: Not Provided

Current Secondary Outcome Measures (submitted: November 14, 2012)

Quality of Life [ Time Frame: 3 months (Baseline to end of treatment 1) ]

The short form-36 (SF-36)and Uterine Fibroid Symptom Quality of Life (UFS-QOL) questionnaires were given before and at treatment end with scales of 0 - 100. SF-36 scales = mental and physical well-being. The UFS subscales are symptom severity, concern, activities, energy and mood, control, self-consciousness, sexual functioning compiled into an overall QOL score. Higher results indicate better QOL on all but symptom severity (higher = worse). The change in scores from baseline to end of treatment was calculated.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Leiomyoma

Intervention

• Drug: ulipristal acetate
  ulipristal acetate at a daily dose of 20 mg, given once daily for three menstrual cycles or 90 - 102 days if amenorrheic
  Other Name: VA2914; CDB-2914
• Drug: ulipristal acetate
  10 mg given daily for three menstrual cycles or 90 - 102 days
  Other Name: VA2914; CDB2914
• Drug: placebo
  placebo given once daily for 3 menstrual cycles or 90 - 102 days

Study Arms

• Active Comparator: ulipristal acetate -20 mg
  20 mg daily dose ulipristal acetate for three menstrual cycles or up to 102 days in each study phase
  Intervention: Drug: ulipristal acetate
• Active Comparator: ulipristal acetate - 10 mg
  10 mg daily dose ulipristal acetate for three menstrual cycles or up to 102 days in each study phase
  Intervention: Drug: ulipristal acetate
• Placebo Comparator: Placebo
  Placebo taken daily for three menstrual cycles or up to 102 days in each study phase
  Intervention: Drug: placebo

Publications *

• 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.
• 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.
• Cadepond F, Ulmann A, Baulieu EE. RU486 (mifepristone): mechanisms of action and clinical uses. Annu Rev Med. 1997;48:129-56. Review.
• 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.
• 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.
• 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.
• Lewis TD, Malik M, Britten J, Parikh T, Cox J, Catherino WH. Ulipristal acetate decreases active TGF-β3 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 14, 2012): 72
• Original Enrollment (submitted: February 9, 2006): 90
• Actual Study Completion Date: August 2010
• Actual Primary Completion Date: July 2009 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 25 Years to 50 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00290251
• Other Study ID Numbers: 060090; 1ZIAHD000637-17 ( U.S. NIH Grant/Contract ); 06-CH-0090
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: National Institutes of Health Clinical Center (CC) ( Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) )
• Study Sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Collaborators: HRA Pharma

Investigators

• Principal Investigator: Lynnette K Nieman, MD; NICHD, NIH

• PRS Account: National Institutes of Health Clinical Center (CC)
• Verification Date: November 2012