Postmenopausal Symptoms
Conditions
Brief summary
The purpose of this study is to examine the effect of two different dose levels of estrogen or placebo in healthy postmenopausal women by measuring the changes in hormone levels and examining the changes in the uterine lining (endometrium).
Interventions
DRUGComparator: Estrace 0.5 mg
0.5 mg tablet taken once daily for 28 days
DRUGComparator: Estrace 2 mg
2 mg tablets taken once daily for 28 days.
DRUGComparator: Placebo
Placebo 0 mg capsule taken once daily for 28 days
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Patient is a healthy postmenopausal woman less than or equal to 65 years of age with onset of menopause less than or equal to 10 years prior to prestudy visit 1 * Patient has a uterus and no history of uterine bleeding in the past 3 months * Patient has not had a previous endometrial biopsy within the last 4 weeks * Patient has had a normal mammogram within the last 11 months * Patient has had a normal pap-smear within the past 3 years prior to screening * Patient has had a normal transvaginal ultrasound of the endometrium * Patient is willing to avoid strenuous physical activity such as strenuous or unaccustomed weight lifting, running, bicycling, etc for the duration of the study * Patient agrees to not consume grapefruit products beginning approximately 2 weeks prior to the first dose of study drug and throughout the study * Patient agrees to limit daily consumption of alcohol. During the study, daily alcohol consumption should not be more than 2 glasses * Patient agrees to limit daily consumption of caffeine. During the study, daily caffeine consumption should not exceed 3 cups of coffee * Patient is a non-smoker
Exclusion criteria
* Patient is mentally or legally incapacitated * Patient has a history of any first degree relatives with breast or endometrial cancer * Patient has a history of multiple and/or severe allergies to prescription or non-prescription drugs or food * Patient has used any type of estrogen or progesterone preparation unless followed by appropriate wash-out periods * Patient has had surgery, donated approximately 500 mL of blood or has participated in another investigational study within the last 4 weeks * Patient has a history of deep vein thromboses, coronary artery disease, heart attack or stroke * Patient is a current user of illegal drugs * Patient has a history of hypersensitivity to estrogen products * Patient is unable to refrain from using anti-coagulants
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Immunohistochemistry (IHC) Proliferative Effects Measurement | 4 weeks | Ratio of the total number of positively stained cell nuclei to the total number of cell nuclei. Proliferating endometrial cells express the Ki-67 antigen. The ratio was converted to a percent proliferating cells by taking the number of Ki-67 positive stained nuclei in a given field and dividing by the total number of nuclei in that field and multiplying by 100. At least 5 high power fields were scored in this manner and an aggregate percent Ki-67 positive cells was reported. Square root transformation was taken to make it approximately normally distributed for an ANOVA model to apply. |
Secondary
| Measure | Time frame |
|---|---|
| Mean Gene Expression Intensity After 4 Weeks of Either 0.5 or 2 mg Estrace Compared to Placebo. | 4 weeks |
Participant flow
Recruitment details
Patients were recruited through advertisement and review of patient databases at Comprehensive Phase I, USA, between December 2008 and April 2009.
Pre-assignment details
Major entry criteria - healthy postmenopausal women within 10 years of attaining menopause as determined by follicle-stimulating hormone (FSH) and estradiol levels within range of postmenopause, and other criteria. Normal transvaginal ultrasound at screening with endometrial thickening at \< 5.0 mm.
Participants by arm
| Arm | Count |
|---|---|
| 17β-estradiol 2.0 Milligrams Estrace 2.0 mg tablet | 9 |
| 17β-estradiol 0.5 Milligrams Estrace 0.5 mg tablet | 11 |
| Placebo | 9 |
| Total | 29 |
Baseline characteristics
| Characteristic | 17β-estradiol 2.0 Milligrams | 17β-estradiol 0.5 Milligrams | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 54.11 years STANDARD_DEVIATION 3.76 | 53.91 years STANDARD_DEVIATION 5.65 | 55.33 years STANDARD_DEVIATION 3.04 | 54.41 years STANDARD_DEVIATION 4.3 |
| Body Mass Index (BMI) | 27.87 kg/m^2 STANDARD_DEVIATION 3.95 | 28.69 kg/m^2 STANDARD_DEVIATION 2.74 | 27.43 kg/m^2 STANDARD_DEVIATION 1.98 | 28.05 kg/m^2 STANDARD_DEVIATION 2.92 |
| Race/Ethnicity, Customized Black | 1 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White | 8 participants | 11 participants | 9 participants | 28 participants |
| Sex: Female, Male Female | 9 Participants | 11 Participants | 9 Participants | 29 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 |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 7 / 9 | 6 / 11 | 6 / 9 |
| serious Total, serious adverse events | 0 / 9 | 0 / 11 | 0 / 9 |
Outcome results
Primary
Immunohistochemistry (IHC) Proliferative Effects Measurement
Ratio of the total number of positively stained cell nuclei to the total number of cell nuclei. Proliferating endometrial cells express the Ki-67 antigen. The ratio was converted to a percent proliferating cells by taking the number of Ki-67 positive stained nuclei in a given field and dividing by the total number of nuclei in that field and multiplying by 100. At least 5 high power fields were scored in this manner and an aggregate percent Ki-67 positive cells was reported. Square root transformation was taken to make it approximately normally distributed for an ANOVA model to apply.
Time frame: 4 weeks
Population: Though 29 subjects were enrolled, only 20 subjects had biopsy samples that were deemed adequate for Ki-67 immunohistochemical analysis at Week 4.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| 17β-estradiol 2.0 Milligrams | Immunohistochemistry (IHC) Proliferative Effects Measurement | 0.73 Square root of % positive stained cells |
| 17β-estradiol 0.5 Milligrams | Immunohistochemistry (IHC) Proliferative Effects Measurement | 0.43 Square root of % positive stained cells |
| Placebo | Immunohistochemistry (IHC) Proliferative Effects Measurement | 0.25 Square root of % positive stained cells |
p-value: <0.00195% CI: [0.31, 1]ANOVA
p-value: 0.03295% CI: [0.02, 1]ANOVA
Secondary
Mean Gene Expression Intensity After 4 Weeks of Either 0.5 or 2 mg Estrace Compared to Placebo.
Time frame: 4 weeks