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

• Sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00290251
• Collaborator: HRA Pharma (Industry)
• Enrollment: 72
• Locations: 2
• Arms: 6
• Duration (Months): 53.9
• Patients Per Site: 36
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Leiomyoma	Drug: ulipristal acetate 20 mg; Drug: ulipristal acetate 10 mg; Drug: placebo	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 72 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• 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 cyclesSubjects 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
• Masking: Double (Participant, Investigator)
• Masking Description: study agents were formulated in identical looking capsules
• Primary Purpose: Treatment
• Official Title: Evaluation of Whether the Selective Progesterone Receptor Modulator CDB-2914 Can Shrink Leiomyomata
• Study Start Date: Feb 1, 2006
• Actual Primary Completion Date: Jul 1, 2009
• Actual Study Completion Date: Aug 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: ulipristal acetate -20 mg 20 mg daily dose ulipristal acetate for three menstrual cycles or up to 102 days	Drug: ulipristal acetate 20 mg; ulipristal acetate at a daily dose of 20 mg, given once daily for three menstrual cycles or 90 - 102 days if amenorrheic; Other Names: VA2914; CDB-2914
Active Comparator: ulipristal acetate - 10 mg 10 mg daily dose ulipristal acetate for three menstrual cycles or up to 102 days	Drug: ulipristal acetate 10 mg; 10 mg given daily for three menstrual cycles or 90 - 102 days; Other Names: VA2914; CDB2914
Placebo Comparator: Placebo Placebo taken daily for three menstrual cycles or up to 102 days	Drug: placebo; placebo given once daily for 3 menstrual cycles or 90 - 102 days
No Intervention: Pre-ulipristal acetate 10 mg Subjects were studied during one baseline cycle without any intervention before entering ulipristal acetate 10 mg arm
No Intervention: Pre-ulipristal acetate 20 mg Subjects were studied during one baseline cycle without any intervention before entering ulipristal acetate 20 mg arm
No Intervention: Pre-placebo Subjects were studied during one baseline cycle without any intervention before entering placebo arm

Outcome Measures

Primary Outcome Measures

1. Shrinkage of Fibroids - Size of Fibroids [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.

Secondary Outcome Measures

1. Short Form-36 and Uterine Fibroid Symptom Quality of Life [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 25 Years to 50 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	NIH Clinical Center	Bethesda	Maryland	United States	20891
2	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• HRA Pharma

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

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.

• Responsible Party: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• ClinicalTrials.gov Identifier: NCT00290251
• Other Study ID Numbers: 060090; 1ZIAHD000637-17; 06-CH-0090
• First Posted: Feb 10, 2006
• Last Update Posted: Mar 8, 2022
• Last Verified: Nov 1, 2012

• Keywords provided by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): Endometrium; Progesterone; Estrogen; Fibroid; Hysterectomy; Leiomyoma; Uterine Fibroids; Fibroids
• Additional relevant MeSH terms: Leiomyoma; Myofibroma; Ulipristal acetate

Study Results

Participant Flow

Pre-assignment Detail	Seventy-two women were screened for eligibility before being randomized to treatment. Of these only 42 were eligible to continue in the study.

Arm/Group Title	Pre-ulipristal Acetate - 20 mg	Pre-ulipristal Acetate 10 mg	Pre-placebo	Ulipristal Acetate - 20 mg	Ulipristal Acetate- 10 mg	Placebo (PLC)
Arm/Group Description	Women received no intervention for one menstrual cycle before entering ulipristal acetate 20 mg group	Women received no intervention for one menstrual cycle before entering ulipristal acetate 20 mg group	Women received no intervention for one menstrual cycle before entering placebo group	Women received ulipristal acetate 20 mg/d	Women received ulipristal acetate at a daily dose of 10 mg for 90 - 102 days or three menstrual cycles.	Women received placebo capsules for 90 - 102 days or three menstrual cycles.
Period Title: Baseline (Month 1)
STARTED	14	14	14	0	0	0
COMPLETED	14	14	14	0	0	0
NOT COMPLETED	0	0	0	0	0	0
Period Title: Baseline (Month 1)
STARTED	0	0	0	14	14	14
COMPLETED	0	0	0	13	13	12
NOT COMPLETED	0	0	0	1	1	2

Baseline Characteristics

Arm/Group Title	Placebo	Ulipristal Acetate 10 mg	Ulipristal Acetate 20 mg	Total
Arm/Group Description	All women who received placebo	All women who received Ulipristal Acetate - 20 mg	All women who received Ulipristal Acetate - 20 mg	Total of all reporting groups
Overall Participants	14	14	14	42
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	14 100%	14 100%	14 100%	42 100%
>=65 years	0 0%	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	14 100%	14 100%	14 100%	42 100%
Male	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	14 100%	14 100%	14 100%	42 100%

Outcome Measures

1. Primary Outcome

Title	Shrinkage of Fibroids - Size of Fibroids
Description	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.
Time Frame	3 months (baseline to end of treatment)

Outcome Measure Data

Analysis Population Description

Per protocol, including women with two MRIs regardless of whether they took all study medication. The two ulipristal acetate arms, 10 mg and 20 mg, were not different from each other (see statistical analysis 1) so they were combined for analysis of outcomes (in statistical analysis 2).

Arm/Group Title	Ulipristal Acetate -20mg	Ulipristal Acetate - 10 mg	Placebo
Arm/Group Description	Women received ulipristal acetate at 20 mg/day for 90 - 102 days or three menstrual cycles.	Women received ulipristal acetate at 10 mg/day for 90 - 102 days or three menstrual cycles.	Women received placebo capsules for 90 - 102 days or three menstrual cycles.
Measure Participants	13	13	12
Mean (Standard Error) [logcm3]	-0.27 (0.07)	-0.18 (0.08)	0.07 (0.78)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ulipristal Acetate -20mg, Ulipristal Acetate - 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.43
	Comments
	Method	t-test, 2 sided
	Comments	performed on log-transformed delta change in total fibroid volume from baseline to end of treatment

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ulipristal Acetate -20mg, Ulipristal Acetate - 10 mg, Placebo
	Comments	Ulipristal acetate groups one and two were first compared and found to be similar (see statistical analysis 1), so they were combined into a single treatment group for comparison to placebo group
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	ANOVA
	Comments	Performed on log-transformed delta change

2. Secondary Outcome

Title	Short Form-36 and Uterine Fibroid Symptom Quality of Life
Description	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.
Time Frame	3 months (Baseline to end of treatment 1)

Outcome Measure Data

Analysis Population Description

All completers received a questionnaire at the end of the three-month study. One woman in the placebo group did not complete the questionnaire. All women receiving ulipristal acetate were combined for analysis of QOL, to parallel the combined analysis done for the primary outcome measure.

Arm/Group Title	Ulipristal Acetate -10 and 20mg	Placebo
Arm/Group Description	Women received ulipristal acetate at a daily dose of 10 or 20 mg for 90 - 102 days or three menstrual cycles.	Women received placebo capsules for 90 - 102 days or three menstrual cycles.
Measure Participants	26	11
SF-36 Physical Component	4.2 (1.2)	-1.5 (2.0)
SF-36 Mental Component	4.1 (1.5)	-2.2 (2.4)
UFS Symptom Severity Score	-28.3 (4.2)	-4.2 (6.5)
UFS Overall health related quality of life	27.8 (3.6)	8.6 (5.6)
UFS Concern subscore	46.1 (4.5)	12.1 (6.9)
UFS Energy/mood subscore	19.2 (3.7)	3.7 (5.8)
UFS Control subscore	20.3 (4.3)	9.1 (6.8)
UFS self-conscious subscore	19.0 (4.7)	15.8 (7.5)
UFS sexual function subscore	25.7 (5.5)	18.7 (8.5)
UFS activities subscore	83.9 (4.4)	56.1 (7.0)
UFS composite bleeding subscore	2.1 (0.2)	0.4 (0.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ulipristal Acetate -20mg, Ulipristal Acetate - 10 mg
	Comments	No sample size calculation was made.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	< 0.05
	Comments	The Delta of scores from treatment end to baseline was used to compare by ANOVA.
	Method	ANOVA
	Comments	Adjustment for age

Adverse Events

Time Frame	120 - 132 days
Adverse Event Reporting Description	Women recorded specific adverse events on a calendar; there was also a write-in field. The number of women with at least one day of each symptom is reported.
Arm/Group Title	Ulipristal Acetate -20mg		Ulipristal Acetate- 10 mg		Placebo		Pre-Ulipristal Acetate 20 mg		Pre-Ulipristal Acetate- 10 mg		Pre-Placebo
Arm/Group Description	Women received ulipristal acetate at a daily dose of 20 mg for 90 - 102 days or three menstrual cycles.		Women received ulipristal acetate at a daily dose of 10 mg for 90 - 102 days or three menstrual cycles.		Women received placebo capsules for 90 - 102 days or three menstrual cycles.		Women charted symptoms for one menstrual cycle before entering ulipristal acetate 20 mg group		Women charted symptoms for one menstrual cycle before entering ulipristal acetate 10 mg group		Women charted symptoms for one menstrual cycle before entering placebo group
All Cause Mortality
	Ulipristal Acetate -20mg		Ulipristal Acetate- 10 mg		Placebo		Pre-Ulipristal Acetate 20 mg		Pre-Ulipristal Acetate- 10 mg		Pre-Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/14 (0%)		0/14 (0%)		0/14 (0%)		0/14 (0%)		0/14 (0%)
Serious Adverse Events
	Ulipristal Acetate -20mg		Ulipristal Acetate- 10 mg		Placebo		Pre-Ulipristal Acetate 20 mg		Pre-Ulipristal Acetate- 10 mg		Pre-Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/14 (0%)		0/14 (0%)		0/14 (0%)		0/14 (0%)		0/14 (0%)
Other (Not Including Serious) Adverse Events
	Ulipristal Acetate -20mg		Ulipristal Acetate- 10 mg		Placebo		Pre-Ulipristal Acetate 20 mg		Pre-Ulipristal Acetate- 10 mg		Pre-Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/14 (78.6%)		14/14 (100%)		12/14 (85.7%)		10/14 (71.4%)		13/14 (92.9%)		10/14 (71.4%)
Blood and lymphatic system disorders
Lower extremity edema	0/14 (0%)	0	0/14 (0%)	0	0/14 (0%)	0	0/14 (0%)	0	1/14 (7.1%)	76	0/14 (0%)	0
Eye disorders
blurry vision	0/14 (0%)	0	1/14 (7.1%)	2	0/14 (0%)	0	0/14 (0%)	0	0/14 (0%)	0	0/14 (0%)	0
Gastrointestinal disorders
Nausea/vomiting	3/14 (21.4%)	4	2/14 (14.3%)	65	4/14 (28.6%)	10	0/14 (0%)	0	2/14 (14.3%)	2	1/14 (7.1%)	1
Decreased appetitie	1/14 (7.1%)	4	1/14 (7.1%)	4	2/14 (14.3%)	11	1/14 (7.1%)	1	0/14 (0%)	0	2/14 (14.3%)	7
Diarrhea	1/14 (7.1%)	4	3/14 (21.4%)	16	1/14 (7.1%)	5	2/14 (14.3%)	2	1/14 (7.1%)	2	0/14 (0%)	0
constipaton	2/14 (14.3%)	6	0/14 (0%)	0	0/14 (0%)	0	2/14 (14.3%)	9	0/14 (0%)	0	0/14 (0%)	0
General disorders
Abdominal pain	10/14 (71.4%)	110	9/14 (64.3%)	37	10/14 (71.4%)	77	9/14 (64.3%)	29	11/14 (78.6%)	33	8/14 (57.1%)	32
Pelvic pain	5/14 (35.7%)	16	7/14 (50%)	16	5/14 (35.7%)	23	7/14 (50%)	23	5/14 (35.7%)	12	2/14 (14.3%)	14
Fatigue	6/14 (42.9%)	25	8/14 (57.1%)	195	6/14 (42.9%)	75	9/14 (64.3%)	31	10/14 (71.4%)	76	6/14 (42.9%)	40
Headache	5/14 (35.7%)	13	7/14 (50%)	36	4/14 (28.6%)	24	2/14 (14.3%)	5	1/14 (7.1%)	2	2/14 (14.3%)	2
Abdominal cramps	2/14 (14.3%)	25	2/14 (14.3%)	9	3/14 (21.4%)	5	1/14 (7.1%)	4	1/14 (7.1%)	3	2/14 (14.3%)	6
Bloating	0/14 (0%)	0	1/14 (7.1%)	4	1/14 (7.1%)	8	0/14 (0%)	0	0/14 (0%)	0	0/14 (0%)	0
Leg swelling	0/14 (0%)	0	1/14 (7.1%)	47	0/14 (0%)	0	0/14 (0%)	0	0/14 (0%)	0	0/14 (0%)	0
Increased appetite	1/14 (7.1%)	1	0/14 (0%)	0	0/14 (0%)	0	1/14 (7.1%)	0	0/14 (0%)	0	0/14 (0%)	0
Depersonalization	1/14 (7.1%)	1	0/14 (0%)	0	0/14 (0%)	0	0/14 (0%)	0	0/14 (0%)	0	0/14 (0%)	0
weight gain	0/14 (0%)	0	1/14 (7.1%)	1	0/14 (0%)	0	0/14 (0%)	0	0/14 (0%)	0	0/14 (0%)	0
cold feet	1/14 (7.1%)	2	0/14 (0%)	0	0/14 (0%)	0	0/14 (0%)	0	0/14 (0%)	0	0/14 (0%)	0
Musculoskeletal and connective tissue disorders
Joint Pain	4/14 (28.6%)	33	1/14 (7.1%)	17	4/14 (28.6%)	40	5/14 (35.7%)	10	1/14 (7.1%)	1	3/14 (21.4%)	11
Calf or Thigh pain	4/14 (28.6%)	32	1/14 (7.1%)	6	4/14 (28.6%)	19	4/14 (28.6%)	4	1/14 (7.1%)	3	1/14 (7.1%)	6
Back pain	4/14 (28.6%)	10	2/14 (14.3%)	15	2/14 (14.3%)	6	3/14 (21.4%)	20	2/14 (14.3%)	7	1/14 (7.1%)	5
Nervous system disorders
weakness	0/14 (0%)	0	0/14 (0%)	0	1/14 (7.1%)	1	0/14 (0%)	0	0/14 (0%)	0	0/14 (0%)	0
Dizziness	0/14 (0%)	0	1/14 (7.1%)	4	0/14 (0%)	0	0/14 (0%)	0	0/14 (0%)	0	0/14 (0%)	0
food cravings	1/14 (7.1%)	1	0/14 (0%)	0	0/14 (0%)	0	0/14 (0%)	0	0/14 (0%)	0	0/14 (0%)	0
disrupted sleep	1/14 (7.1%)	5	0/14 (0%)	0	0/14 (0%)	0	0/14 (0%)	0	0/14 (0%)	0	0/14 (0%)	0
Psychiatric disorders
Mood changes	2/14 (14.3%)	3	0/14 (0%)	0	4/14 (28.6%)	16	1/14 (7.1%)	2	0/14 (0%)	0	1/14 (7.1%)	4
Reproductive system and breast disorders
Vaginal discharge	6/14 (42.9%)	69	6/14 (42.9%)	50	4/14 (28.6%)	64	6/14 (42.9%)	21	3/14 (21.4%)	13	2/14 (14.3%)	8
Non-menses Vaginal Bleeding	3/14 (21.4%)	5	7/14 (50%)	107	3/14 (21.4%)	12	0/14 (0%)	0	2/14 (14.3%)	40	2/14 (14.3%)	7
Breast pain	6/14 (42.9%)	25	5/14 (35.7%)	95	8/14 (57.1%)	44	7/14 (50%)	20	3/14 (21.4%)	14	3/14 (21.4%)	10
blood clots with menses	1/14 (7.1%)	3	1/14 (7.1%)	5	3/14 (21.4%)	15	2/14 (14.3%)	8	0/14 (0%)	0	3/14 (21.4%)	6
galactorrhea	1/14 (7.1%)	1	0/14 (0%)	0	0/14 (0%)	0	0/14 (0%)	0	0/14 (0%)	0	0/14 (0%)	0
breast engorgement	1/14 (7.1%)	1	0/14 (0%)	0	0/14 (0%)	0	0/14 (0%)	0	0/14 (0%)	0	0/14 (0%)	0
Skin and subcutaneous tissue disorders
Hot flashes	5/14 (35.7%)	14	1/14 (7.1%)	64	1/14 (7.1%)	11	0/14 (0%)	0	0/14 (0%)	0	0/14 (0%)	0
Skin Rash	1/14 (7.1%)	8	4/14 (28.6%)	43	2/14 (14.3%)	11	0/14 (0%)	0	0/14 (0%)	0	1/14 (7.1%)	6
Hair loss	0/14 (0%)	0	1/14 (7.1%)	2	0/14 (0%)	0	0/14 (0%)	0	0/14 (0%)	0	0/14 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.