Leiomyoma
Conditions
Keywords
Endometrium, Progesterone, Estrogen, Fibroid, Hysterectomy, Leiomyoma, Uterine Fibroids, Fibroids
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.
Interventions
DRUGulipristal 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
DRUGulipristal acetate 10 mg
10 mg given daily for three menstrual cycles or 90 - 102 days
DRUGplacebo
placebo given once daily for 3 menstrual cycles or 90 - 102 days
Sponsors
HRA Pharma
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
study agents were formulated in identical looking capsules
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
Eligibility
Sex/Gender
FEMALE
Age
25 Years to 50 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Pre-assignment details
Seventy-two women were screened for eligibility before being randomized to treatment. Of these only 42 were eligible to continue in the study.
Participants by arm
| Arm | Count |
|---|---|
| Placebo All women who received placebo | 14 |
| Ulipristal Acetate 10 mg All women who received Ulipristal Acetate - 20 mg | 14 |
| Ulipristal Acetate 20 mg All women who received Ulipristal Acetate - 20 mg | 14 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Treatment 1 (Months 2-4) | headache | 0 | 0 | 0 | 0 | 1 | 0 |
| Treatment 1 (Months 2-4) | Out of body experience | 0 | 0 | 0 | 1 | 0 | 0 |
| Treatment 1 (Months 2-4) | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Placebo | Ulipristal Acetate 10 mg | Ulipristal Acetate 20 mg | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 14 Participants | 14 Participants | 42 Participants |
| Region of Enrollment United States | 14 participants | 14 participants | 14 participants | 42 participants |
| Sex: Female, Male Female | 14 Participants | 14 Participants | 14 Participants | 42 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 |
| other Total, other adverse events | 11 / 14 | 14 / 14 | 12 / 14 | 10 / 14 | 13 / 14 | 10 / 14 |
| serious Total, serious adverse events | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 |
Outcome results
Primary
Shrinkage of Fibroids - Size of Fibroids
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)
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ulipristal Acetate -20mg | Shrinkage of Fibroids - Size of Fibroids | -0.27 logcm3 | Standard Error 0.07 |
| Ulipristal Acetate - 10 mg | Shrinkage of Fibroids - Size of Fibroids | -0.18 logcm3 | Standard Error 0.08 |
| Placebo | Shrinkage of Fibroids - Size of Fibroids | 0.07 logcm3 | Standard Error 0.78 |
p-value: 0.43t-test, 2 sided
Comparison: 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 groupp-value: 0.003ANOVA
Secondary
Short Form-36 and Uterine Fibroid Symptom Quality of Life
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)
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ulipristal Acetate -20mg | Short Form-36 and Uterine Fibroid Symptom Quality of Life | SF-36 Physical Component | 4.2 units on a scale | Standard Error 1.2 |
| Ulipristal Acetate -20mg | Short Form-36 and Uterine Fibroid Symptom Quality of Life | SF-36 Mental Component | 4.1 units on a scale | Standard Error 1.5 |
| Ulipristal Acetate -20mg | Short Form-36 and Uterine Fibroid Symptom Quality of Life | UFS Symptom Severity Score | -28.3 units on a scale | Standard Error 4.2 |
| Ulipristal Acetate -20mg | Short Form-36 and Uterine Fibroid Symptom Quality of Life | UFS Concern subscore | 46.1 units on a scale | Standard Error 4.5 |
| Ulipristal Acetate -20mg | Short Form-36 and Uterine Fibroid Symptom Quality of Life | UFS Energy/mood subscore | 19.2 units on a scale | Standard Error 3.7 |
| Ulipristal Acetate -20mg | Short Form-36 and Uterine Fibroid Symptom Quality of Life | UFS Control subscore | 20.3 units on a scale | Standard Error 4.3 |
| Ulipristal Acetate -20mg | Short Form-36 and Uterine Fibroid Symptom Quality of Life | UFS self-conscious subscore | 19.0 units on a scale | Standard Error 4.7 |
| Ulipristal Acetate -20mg | Short Form-36 and Uterine Fibroid Symptom Quality of Life | UFS sexual function subscore | 25.7 units on a scale | Standard Error 5.5 |
| Ulipristal Acetate -20mg | Short Form-36 and Uterine Fibroid Symptom Quality of Life | UFS activities subscore | 83.9 units on a scale | Standard Error 4.4 |
| Ulipristal Acetate -20mg | Short Form-36 and Uterine Fibroid Symptom Quality of Life | UFS composite bleeding subscore | 2.1 units on a scale | Standard Error 0.2 |
| Ulipristal Acetate -20mg | Short Form-36 and Uterine Fibroid Symptom Quality of Life | UFS Overall health related quality of life | 27.8 units on a scale | Standard Error 3.6 |
| Ulipristal Acetate - 10 mg | Short Form-36 and Uterine Fibroid Symptom Quality of Life | UFS sexual function subscore | 18.7 units on a scale | Standard Error 8.5 |
| Ulipristal Acetate - 10 mg | Short Form-36 and Uterine Fibroid Symptom Quality of Life | SF-36 Physical Component | -1.5 units on a scale | Standard Error 2 |
| Ulipristal Acetate - 10 mg | Short Form-36 and Uterine Fibroid Symptom Quality of Life | UFS Control subscore | 9.1 units on a scale | Standard Error 6.8 |
| Ulipristal Acetate - 10 mg | Short Form-36 and Uterine Fibroid Symptom Quality of Life | SF-36 Mental Component | -2.2 units on a scale | Standard Error 2.4 |
| Ulipristal Acetate - 10 mg | Short Form-36 and Uterine Fibroid Symptom Quality of Life | UFS composite bleeding subscore | 0.4 units on a scale | Standard Error 0.3 |
| Ulipristal Acetate - 10 mg | Short Form-36 and Uterine Fibroid Symptom Quality of Life | UFS Symptom Severity Score | -4.2 units on a scale | Standard Error 6.5 |
| Ulipristal Acetate - 10 mg | Short Form-36 and Uterine Fibroid Symptom Quality of Life | UFS Overall health related quality of life | 8.6 units on a scale | Standard Error 5.6 |
| Ulipristal Acetate - 10 mg | Short Form-36 and Uterine Fibroid Symptom Quality of Life | UFS self-conscious subscore | 15.8 units on a scale | Standard Error 7.5 |
| Ulipristal Acetate - 10 mg | Short Form-36 and Uterine Fibroid Symptom Quality of Life | UFS Concern subscore | 12.1 units on a scale | Standard Error 6.9 |
| Ulipristal Acetate - 10 mg | Short Form-36 and Uterine Fibroid Symptom Quality of Life | UFS activities subscore | 56.1 units on a scale | Standard Error 7 |
| Ulipristal Acetate - 10 mg | Short Form-36 and Uterine Fibroid Symptom Quality of Life | UFS Energy/mood subscore | 3.7 units on a scale | Standard Error 5.8 |
Comparison: No sample size calculation was made.p-value: <0.05ANOVA