Healthy Volunteer, Female, Breast
Conditions
Brief summary
To evaluate whether administration of denosumab results in a decrease compared to the control group in proliferation of mammary epithelial cells as measured by the Ki-67 proliferation index.
Interventions
DRUGDenosumab
Single sucutaneous dose
PROCEDUREPercutaneous core needle breast biopsy
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Willing to use, in combination with her partner, 2 non-hormonal methods of effective contraception or practice sexual abstinence. Subjects who are surgically sterile (eg, history of hysterectomy) or whose sexual partner is sterile (eg, history of vasectomy) are not required to use contraceptive measures * Laboratory tests are within clinically acceptable range * Clinically acceptable physical exam and no history or evidence of any clinically significant medical disorder that would pose a risk to subject safety or interfere with study evaluations or procedures.
Exclusion criteria
* Female subject with a prior history of breast cancer; breast implant in the breast to be biopsied; Known history of fibrocystic breast disease * Subject is unable or unwilling to provide breast biopsy tissue from the upper outer quadrant of her breast * Pregnant or plans to become pregnant while exposed to investigational product * Lactating/breastfeeding or plans to breastfeed while exposed to investigational product * Recent use of any non-approved medications or devices * Uncontrolled thyroid disorder * Significant dental/oral disease * Planned invasive dental procedures * Positive urine screen for alcohol and/or drugs
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Log Ratio of Post-baseline to Baseline Ki-67 Index in Mammary Epithelial Cells | Baseline and Day 28 | Ki-67 is a marker for cell proliferation. Participants underwent percutaneous core needle breast biopsies on Day 1 (Baseline, prior to treatment) and Day 28. Levels of Ki67 were measured using immunohistochemical staining and digital imaging. The proliferation index was calculated as the percentage of Ki-67 positive terminal ductal lobular unit (TDLU) and duct epithelial cells. The higher the percentage, the higher the rate of epithelial cell proliferation. |
Countries
United States
Participant flow
Pre-assignment details
On study day 1, eligible participants were randomized into 1 of 3 treatment assignments. Randomization was stratified by average length of menstrual cycle (\< 28 days, equal to 28 days, and \> 28 days).
Participants by arm
| Arm | Count |
|---|---|
| No Treatment Participants received no treatment and underwent percutaneous core needle breast biopsies on Day 1 and Day 28. | 27 |
| Denosumab 60 mg Participants received 60 mg denosumab by subcutaneous injection on Day 1 and underwent percutaneous core needle breast biopsies on Day 1 and Day 28. | 27 |
| Denosumab 120 mg Participants received 120 mg denosumab by subcutaneous injection on Day 1 and underwent percutaneous core needle breast biopsies on Day 1 and Day 28. | 28 |
| Total | 82 |
Baseline characteristics
| Characteristic | No Treatment | Denosumab 60 mg | Denosumab 120 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 29.9 years STANDARD_DEVIATION 7.3 | 32.2 years STANDARD_DEVIATION 7.6 | 32.8 years STANDARD_DEVIATION 8.8 | 32.5 years STANDARD_DEVIATION 8.2 |
| Race/Ethnicity, Customized Asian | 0 participants | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Black (or African American) | 4 participants | 8 participants | 10 participants | 22 participants |
| Race/Ethnicity, Customized Multiple | 1 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 participants | 0 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Whte | 21 participants | 19 participants | 16 participants | 56 participants |
| Sex: Female, Male Female | 27 Participants | 27 Participants | 28 Participants | 82 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 | 4 / 27 | 6 / 27 | 11 / 28 |
| serious Total, serious adverse events | 0 / 27 | 0 / 27 | 0 / 28 |
Outcome results
Primary
Log Ratio of Post-baseline to Baseline Ki-67 Index in Mammary Epithelial Cells
Ki-67 is a marker for cell proliferation. Participants underwent percutaneous core needle breast biopsies on Day 1 (Baseline, prior to treatment) and Day 28. Levels of Ki67 were measured using immunohistochemical staining and digital imaging. The proliferation index was calculated as the percentage of Ki-67 positive terminal ductal lobular unit (TDLU) and duct epithelial cells. The higher the percentage, the higher the rate of epithelial cell proliferation.
Time frame: Baseline and Day 28
Population: Pharmacodynamic analysis set with non-missing data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| No Treatment | Log Ratio of Post-baseline to Baseline Ki-67 Index in Mammary Epithelial Cells | 0.084 log ratio | Standard Deviation 0.645 |
| Denosumab 60 mg | Log Ratio of Post-baseline to Baseline Ki-67 Index in Mammary Epithelial Cells | -0.100 log ratio | Standard Deviation 1.048 |
| Denosumab 120 mg | Log Ratio of Post-baseline to Baseline Ki-67 Index in Mammary Epithelial Cells | -0.081 log ratio | Standard Deviation 0.918 |
Comparison: An ANCOVA analysis was performed on the log ratio of post-baseline to baseline Ki-67 index. Independent variables included treatment, stratification factor, and log transformed baseline Ki-67 index.p-value: 0.296695% CI: [-0.136, 0.441]ANCOVA
Comparison: An ANCOVA analysis was performed on the log ratio of post-baseline to baseline Ki-67 index. Independent variables included treatment, stratification factor, and log transformed baseline Ki-67 index.p-value: 0.276995% CI: [-0.447, 0.13]ANCOVA
Comparison: An ANCOVA analysis was performed on the log ratio of post-baseline to baseline Ki-67 index. Independent variables included treatment, stratification factor, and log transformed baseline Ki-67 index.p-value: 0.523895% CI: [-0.373, 0.191]ANCOVA
Comparison: An ANCOVA analysis was performed on the log ratio of post-baseline to Baseline Ki-67 index. Independent variables included treatment, stratification factor, and log transformed baseline Ki-67 index.p-value: 0.134395% CI: [-0.72, 0.098]ANCOVA
Comparison: An ANCOVA analysis was performed on the log ratio of post-baseline to Baseline Ki-67 index. Independent variables included treatment, stratification factor, and log transformed baseline Ki-67 index.p-value: 0.234595% CI: [-0.646, 0.161]ANCOVA