Postmenopause
Conditions
Keywords
Biomarkers of estrogen receptor beta activation
Brief summary
This study will develop a model for the assessment of successful activation/engagement of estrogen receptor beta using salivary biomarkers.
Interventions
DRUGComparator: placebo
placebo capsule once daily for 7 days.
DRUGComparator: Estrace
Estrace 0.5 mg or 2 mg tablets once daily for 7 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
40 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Subject is healthy, postmenopausal woman at least 40 years of age with onset of menopause within 10 years of screening * Subject has a normal mammogram at screening * Subject has had a normal Pap-smear within 3 years of screening. Subjects who have not had a Pap-smear in the last 3 years will have the option to have the test at screening * Subject agrees to avoid medications that cause dry mouth or otherwise affect saliva flow * Subject is willing to avoid strenuous exercise during the study * Subject is willing to avoid use of mouthwash or salt water rinses during the study * Subject is willing to avoid use of teeth whitening products * Subject is willing to avoid eating and/or drinking grapefruit products * Subject is willing to limit alcohol consumption to 2 drinks a day * Subject is willing to limit caffeine consumption to 3 cups of coffee (or equivalent) per day * Subject is a non-smoker
Exclusion criteria
* Subject has a history of multiple and/or severe allergies to drugs or food * Subject has a cold or viral infection within 2 weeks of Visit 2 * Subject is taking antibiotics within 2 weeks of Visit 2 * Subject needs dental work or procedures during the study * Subject has used any estrogen or progesterone preparation or product containing phytoestrogens within 3 months of screening * Subject is unable to discontinue anti-coagulants
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Estrogen Receptor Beta (ERbeta) -Specific Gene Signature After Treatment With 2 mg, 0.5 mg, or no Estradiol (Placebo) at Day 7 | Baseline and Day 7 | Subset of genes on the log ratio intensity scale from a microarray platform - signature was pre-specified from an internally conducted study in knock-out mice treated with estrogens- quantified as a ratio of up regulated versus down regulated genes |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Minor Gland Salivary Flow Rate After Treatment With 2 mg Estradiol vs Placebo at Day 7. | Baseline and Day 7 | Change from baseline in unstimulated labial gland saliva flow rate at Day 7 |
Participant flow
Recruitment details
This was a randomized, double-blind, placebo-controlled parallel group study in healthy postmenopausal women. Enrollment occurred from May 2008 through October 2008 across two US Phase I clinical research centers.
Participants by arm
| Arm | Count |
|---|---|
| 17β-estradiol 2.0 Milligrams Estrace 2 mg tablets once daily for 7 days. | 10 |
| 17β-estradiol 0.5 Milligrams Estrace 0.5 mg tablets once daily for 7 days. | 6 |
| Placebo Placebo capsule once daily for 7 days. | 11 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | non-compliance | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | 17β-estradiol 2.0 Milligrams | 17β-estradiol 0.5 Milligrams | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 54.3 years STANDARD_DEVIATION 5 | 53.8 years STANDARD_DEVIATION 4.4 | 54.4 years STANDARD_DEVIATION 4.8 | 54.2 years STANDARD_DEVIATION 4.6 |
| Body Mass Index (BMI) | 29.1 kg/m^2 STANDARD_DEVIATION 6.1 | 28.7 kg/m^2 STANDARD_DEVIATION 3.2 | 29.2 kg/m^2 STANDARD_DEVIATION 4.8 | 29.0 kg/m^2 STANDARD_DEVIATION 4.9 |
| Sex: Female, Male Female | 10 Participants | 6 Participants | 11 Participants | 27 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 | 8 / 10 | 4 / 6 | 7 / 11 |
| serious Total, serious adverse events | 0 / 10 | 0 / 6 | 0 / 11 |
Outcome results
Primary
Change From Baseline in Estrogen Receptor Beta (ERbeta) -Specific Gene Signature After Treatment With 2 mg, 0.5 mg, or no Estradiol (Placebo) at Day 7
Subset of genes on the log ratio intensity scale from a microarray platform - signature was pre-specified from an internally conducted study in knock-out mice treated with estrogens- quantified as a ratio of up regulated versus down regulated genes
Time frame: Baseline and Day 7
Population: All subjects with salivary gland tissue with RNA of acceptable quality based on pre-specified QC criteria
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 17β-estradiol 2.0 Milligrams | Change From Baseline in Estrogen Receptor Beta (ERbeta) -Specific Gene Signature After Treatment With 2 mg, 0.5 mg, or no Estradiol (Placebo) at Day 7 | 0.028 Fold change | Standard Error 0.036 |
| 17β-estradiol 0.5 Milligrams | Change From Baseline in Estrogen Receptor Beta (ERbeta) -Specific Gene Signature After Treatment With 2 mg, 0.5 mg, or no Estradiol (Placebo) at Day 7 | -0.011 Fold change | Standard Error 0.048 |
| Placebo | Change From Baseline in Estrogen Receptor Beta (ERbeta) -Specific Gene Signature After Treatment With 2 mg, 0.5 mg, or no Estradiol (Placebo) at Day 7 | 0.080 Fold change | Standard Error 0.039 |
p-value: 0.345ANOVA
p-value: 0.166ANOVA
Secondary
Change From Baseline in Minor Gland Salivary Flow Rate After Treatment With 2 mg Estradiol vs Placebo at Day 7.
Change from baseline in unstimulated labial gland saliva flow rate at Day 7
Time frame: Baseline and Day 7
Population: All subjects with salivary flow rate measured at baseline and 7 days
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| 17β-estradiol 2.0 Milligrams | Change From Baseline in Minor Gland Salivary Flow Rate After Treatment With 2 mg Estradiol vs Placebo at Day 7. | -0.26 μL/min |
| 17β-estradiol 0.5 Milligrams | Change From Baseline in Minor Gland Salivary Flow Rate After Treatment With 2 mg Estradiol vs Placebo at Day 7. | -0.64 μL/min |
p-value: 0.1290% CI: [-0.16, 0.92]ANCOVA