Breast Carcinoma, Ductal Breast Carcinoma In Situ, Hot Flashes, Lobular Breast Carcinoma In Situ, No Evidence of Disease
Conditions
Brief summary
This randomized phase III trial studies how well oxybutynin chloride works in managing hot flashes in patients who are not candidates for, or not interested in hormone replacement therapy. Previous studies have shown that oxybutynin is effective in managing hot flashes, however doses used in prior studies have resulted in side effects. This trial is evaluating lower doses of oxybutynin with the goal of determining if they are efficacious with less side effects. ADAM-VTE
Detailed description
PRIMARY OBJECTIVES: I. To determine whether oxybutynin chloride (oxybutynin) can diminish hot-flash activity in women with a history of breast cancer or in women who have a concern about taking estrogen for fear of breast cancer. SECONDARY OBJECTIVES: I. To perform a dose-response evaluation of two oxybutynin doses. II. To determine the toxicity of oxybutynin in the study population. III. To assess the impact of hot-flash activity on overall quality of life and to examine whether oxybutynin can diminish this impact on quality of life. OUTLINE: Patients are randomized into 1 of 4 groups. GROUP I (LOW-DOSE OXUBUTYNIN CHLORIDE): Patients receive lower dose oxybutynin chloride orally (PO) twice a day (BID) on days 8-49 in the absence of unacceptable toxicity. GROUP II (LOW-DOSE PLACEBO): Patients receive lower dose placebo PO BID on days 8-49 in the absence of unacceptable toxicity. GROUP III (HIGH-DOSE OXUBUTYNIN CHLORIDE): Patients receive lower dose oxybutynin chloride PO BID on days 8-14 and higher dose oxybutynin chloride on days 15-49 in the absence of unacceptable toxicity. GROUP IV (HIGH-DOSE PLACEBO): Patients receive lower dose placebo PO BID on days 8-14 and higher dose placebo on days 15-49 in the absence of unacceptable toxicity.
Interventions
Given PO
OTHERPlacebo
Given PO
OTHERQuality-of-Life Assessment
Ancillary studies
OTHERQuestionnaire Administration
Ancillary studies
Sponsors
National Cancer Institute (NCI)
Academic and Community Cancer Research United
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* History of breast cancer, ductal breast carcinoma in situ (DCIS), or lobular carcinoma in situ (LCIS) (currently without evidence of malignant disease) OR a concern about taking estrogen for fear of breast cancer * Bothersome hot flashes (defined by their occurrence of \>= 28 times per week and of sufficient severity to prompt the patient to seek therapeutic intervention) * Presence of hot flashes for \> 30 days prior to study entry * Ability to complete questionnaire(s) by themselves or with assistance * Eastern Cooperative Oncology Group (ECOG) performance status (PS) = 0, 1 * Ability to provide informed written consent * Life expectancy \>= 6 months * Willing to work with the enrolling institution for follow-up (during the active monitoring phase of the study)
Exclusion criteria
* Any of the following current (=\< 4 weeks prior) or planned therapies: * Antineoplastic chemotherapy (anti-HER2 agents allowed) * Androgens * Estrogens (any delivery route) * Progestogens * Tamoxifen, raloxifene and aromatase inhibitors are allowed, but patient must have been on a constant dose for at least 28 days and must not be expected to stop the medication during the study period * Selective serotonin reuptake inhibitors (SSRIs)/serotonin?norepinephrine reuptake inhibitors (SNRIs), when being used for hot flash management or other indications such as depression, is allowed, assuming the dose will remain unchanged for the study duration * Gabapentin/pregabalin, when being used for hot flash management (use for other indications, such as pain, is allowed, assuming the dose will remain unchanged for the study duration) * Clonidine * Agents with known potent anticholinergic activity; agents with mild-moderate anticholinergic activity are allowed * Prior use of oxybutynin during the period in which patient has had hot flashes * Pregnant women * Nursing women * History of any of the following contraindications to oxybutynin: * Uncontrolled gastroesophageal reflux disease (GERD) despite appropriate therapy; if patient has history of GERD, but symptoms are well-controlled with medical treatment, patient is eligible * Ulcerative colitis * Narrow-angle glaucoma * Urinary retention * Hypersensitivity to oxybutynin or any other components of the product * Current uncontrolled hyperthyroidism * Coronary heart disease (angina or prior myocardial infarction) * Congestive heart failure * Symptomatic cardiac arrhythmias * Current uncontrolled hypertension * Myasthenia gravis * Dementia
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Average Change in Hot Flash Activity Score From Baseline to Week 7 for Low Dose Oxybutynin vs Placebo and for High Dose Oxybutynin vs Placebo | Baseline up to day 49 | Average change in hot flash activity score from baseline to Week 7 for Low Dose Oxybutynin vs Placebo. The hot flash activity will be measured by the weekly average hot flash score (Sloan JA, et. al., 2001), which is a composite entity of both frequency and severity of hot flashes (The Hot Flash Diary collects the following information for Day 1- Day 7 of each week: Number of mild hot flashes, Number of moderate hot flashes, Number of severe hot flashes, Number of very severe hot flashes). This is a count, so it can range from 0 to infinity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Average Change in Hot Flash Score From Week 1 to Week 7 Comparing Low Dose Oxybutynin to Placebo | Baseline up to day 49 | Average change in Hot Flash Score from Week 1 to Week 7 Comparing Low Dose Oxybutynin to Placebo. The least squares (LS) mean was estimated from a mixed-effects model with repeated measures (MMRM) that included low dose oxybutynin, weeks 1-7, no current aromatase inhibitor, age group 18-49, no tamoxifen, hot flash symptom duration \< 9 months, and 4-9 hot flashes/day as fixed effects, and participant and error as random effects. The mean change in Hot Flash Score from Week 1 to Week 7 is reported below for the low-dose oxybutynin and placebo groups. |
| Average Change in Hot Flash Score From Week 1 to Week 7 Comparing High Dose Oxybutynin to Placebo | Baseline up to day 49 | Average change in Hot Flash Score from Week 1 to Week 7 Comparing High Dose Oxybutynin to Placebo. The least squares (LS) mean was estimated from a mixed-effects model with repeated measures (MMRM) that included low dose oxybutynin, weeks 1-7, no current aromatase inhibitor, age group 18-49, no tamoxifen, hot flash symptom duration \< 9 months, and 4-9 hot flashes/day as fixed effects, and participant and error as random effects. The mean change in Hot Flash Score from Week 1 to Week 7 is reported below for the high-dose oxybutynin and placebo groups. |
| Average Change of Severity of Stomach Pain/Cramps Symptoms as Measured by the Symptom Experience Questionnaire From Baseline to Week 7 for Low Dose Oxybutynin vs Placebo and for High Dose Oxybutynin vs Placebo | Baseline up to day 49 | Average Change of severity of Stomach pain/cramps symptoms as measured by the Symptom Experience Questionnaire From Baseline to Week 7 for Low Dose Oxybutynin vs Placebo and for High Dose Oxybutynin vs Placebo The Symptom Experience Questionnaire stomach pain/cramps item (Over the past week, have you experienced stomach pain or cramps?) is scored from 0 to 10 with higher values being worse symptoms. So a negative value means the symptom is improving and a positive score means the symptom is getting worse. |
| Average Change of Daily Interference (Work) From Baseline to Week 7 as Measured by the Hot Flash-Related Daily Interference Scale (HFRDIS) Comparing Low Dose Oxybutynin vs Placebo and High Dose Oxybutynin vs Placebo | Baseline up to day 49 | Average Change of daily interference (Work) from baseline to Week 7 as measured by the Hot Flash-Related Daily Interference Scale (HFRDIS) comparing Low dose oxybutynin vs Placebo and High dose oxybutynin vs Placebo. HFRDIS Work item (Work (work outside the home and housework)) Interference scores run from 0 to 10 with 0 being no interference and 10 being complete interference. |
| Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (v4) | Up to 7 weeks | The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns within patient groups. In addition, we will review all adverse event data that is graded as 3, 4, or 5 and classified as either unrelated or unlikely to be related to study treatment in the event of an actual relationship developing. The overall toxicity rates (percentages) for grade 3 or higher adverse events considered at least possibly related to treatment are reported below. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| High-dose Oxybutynin Chloride Group Patients receive lower dose oxybutynin chloride PO BID on days 8-14 and higher dose oxybutynin chloride on days 15-49 in the absence of unacceptable toxicity. | 35 |
| Low-dose Oxybutynin Chloride Group Patients receive lower dose oxybutynin chloride PO BID on days 8-49 in the absence of unacceptable toxicity. | 40 |
| High-dose Placebo Group Patients receive lower dose placebo PO BID on days 8-14 and higher dose placebo on days 15-49 in the absence of unacceptable toxicity. | 18 |
| Low-dose Placebo Group Patients receive lower dose placebo PO BID on days 8-49 in the absence of unacceptable toxicity. | 20 |
| Total | 113 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Canceled | 4 | 5 | 1 | 4 |
| Overall Study | without baseline data | 4 | 0 | 1 | 0 |
| Overall Study | without post baseline data | 7 | 6 | 4 | 1 |
Baseline characteristics
| Characteristic | Low-dose Oxybutynin Chloride Group | High-dose Oxybutynin Chloride Group | Total | Low-dose Placebo Group | High-dose Placebo Group |
|---|---|---|---|---|---|
| Age, Continuous | 55.6 years STANDARD_DEVIATION 8 | 57.6 years STANDARD_DEVIATION 8.4 | 57.1 years STANDARD_DEVIATION 8.2 | 58.8 years STANDARD_DEVIATION 8.7 | 57.5 years STANDARD_DEVIATION 8.2 |
| ECOG Performance Status 0 | 36 Participants | 33 Participants | 105 Participants | 20 Participants | 16 Participants |
| ECOG Performance Status 1 | 4 Participants | 2 Participants | 8 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 0 Participants | 3 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 36 Participants | 34 Participants | 108 Participants | 20 Participants | 18 Participants |
| Sex: Female, Male Female | 40 Participants | 35 Participants | 113 Participants | 20 Participants | 18 Participants |
| Sex: Female, Male Male | 0 Participants | 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 | 0 / 46 | 0 / 48 | 0 / 44 |
| other Total, other adverse events | 19 / 46 | 13 / 48 | 8 / 44 |
| serious Total, serious adverse events | 2 / 46 | 0 / 48 | 0 / 44 |
Outcome results
Primary
Average Change in Hot Flash Activity Score From Baseline to Week 7 for Low Dose Oxybutynin vs Placebo and for High Dose Oxybutynin vs Placebo
Average change in hot flash activity score from baseline to Week 7 for Low Dose Oxybutynin vs Placebo. The hot flash activity will be measured by the weekly average hot flash score (Sloan JA, et. al., 2001), which is a composite entity of both frequency and severity of hot flashes (The Hot Flash Diary collects the following information for Day 1- Day 7 of each week: Number of mild hot flashes, Number of moderate hot flashes, Number of severe hot flashes, Number of very severe hot flashes). This is a count, so it can range from 0 to infinity.
Time frame: Baseline up to day 49
Population: Patients who received high-dose oxybutynin, low-dose oxybutynin or placebo and completed the Hot Flash Diary at baseline and Week 7 are included in this analysis. Low-dose and high-dose placebo groups were combined to serve as a control/placebo group to compare with the low-dose and high-dose oxybutynin chloride groups.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High-dose Oxybutynin Chloride Group | Average Change in Hot Flash Activity Score From Baseline to Week 7 for Low Dose Oxybutynin vs Placebo and for High Dose Oxybutynin vs Placebo | -16.9 score on a scale | Standard Deviation 15.6 |
| Low-dose Oxybutynin Chloride Group | Average Change in Hot Flash Activity Score From Baseline to Week 7 for Low Dose Oxybutynin vs Placebo and for High Dose Oxybutynin vs Placebo | -10.6 score on a scale | Standard Deviation 7.7 |
| Placebo Group | Average Change in Hot Flash Activity Score From Baseline to Week 7 for Low Dose Oxybutynin vs Placebo and for High Dose Oxybutynin vs Placebo | -5.7 score on a scale | Standard Deviation 10.2 |
p-value: 0.0041Kruskal-Wallis
p-value: 0.0001Kruskal-Wallis
Secondary
Average Change in Hot Flash Score From Week 1 to Week 7 Comparing High Dose Oxybutynin to Placebo
Average change in Hot Flash Score from Week 1 to Week 7 Comparing High Dose Oxybutynin to Placebo. The least squares (LS) mean was estimated from a mixed-effects model with repeated measures (MMRM) that included low dose oxybutynin, weeks 1-7, no current aromatase inhibitor, age group 18-49, no tamoxifen, hot flash symptom duration \< 9 months, and 4-9 hot flashes/day as fixed effects, and participant and error as random effects. The mean change in Hot Flash Score from Week 1 to Week 7 is reported below for the high-dose oxybutynin and placebo groups.
Time frame: Baseline up to day 49
Population: Patients who received higher dose oxybutynin or placebo and completed the Hot Flash Diary at baseline and Week 7 are included in this analysis. Low-dose and high-dose placebo groups were combined to serve as a control/placebo group to compare with the high-dose oxybutynin chloride group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| High-dose Oxybutynin Chloride Group | Average Change in Hot Flash Score From Week 1 to Week 7 Comparing High Dose Oxybutynin to Placebo | 9.8 score on a scale | Standard Error 0.82 |
| Low-dose Oxybutynin Chloride Group | Average Change in Hot Flash Score From Week 1 to Week 7 Comparing High Dose Oxybutynin to Placebo | 16.2 score on a scale | Standard Error 0.82 |
p-value: <0.0001Mixed Models Analysis
Secondary
Average Change in Hot Flash Score From Week 1 to Week 7 Comparing Low Dose Oxybutynin to Placebo
Average change in Hot Flash Score from Week 1 to Week 7 Comparing Low Dose Oxybutynin to Placebo. The least squares (LS) mean was estimated from a mixed-effects model with repeated measures (MMRM) that included low dose oxybutynin, weeks 1-7, no current aromatase inhibitor, age group 18-49, no tamoxifen, hot flash symptom duration \< 9 months, and 4-9 hot flashes/day as fixed effects, and participant and error as random effects. The mean change in Hot Flash Score from Week 1 to Week 7 is reported below for the low-dose oxybutynin and placebo groups.
Time frame: Baseline up to day 49
Population: Patients who received low-dose oxybutynin or placebo and completed the Hot Flash Diary at baseline and Week 7 are included in this analysis. Low-dose and high-dose placebo groups were combined to serve as a control/placebo group to compare with the low-dose oxybutynin chloride group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| High-dose Oxybutynin Chloride Group | Average Change in Hot Flash Score From Week 1 to Week 7 Comparing Low Dose Oxybutynin to Placebo | 8.1 score on a scale | Standard Error 0.63 |
| Low-dose Oxybutynin Chloride Group | Average Change in Hot Flash Score From Week 1 to Week 7 Comparing Low Dose Oxybutynin to Placebo | 15.6 score on a scale | Standard Error 0.66 |
p-value: <0.0001Mixed Models Analysis
Secondary
Average Change of Daily Interference (Work) From Baseline to Week 7 as Measured by the Hot Flash-Related Daily Interference Scale (HFRDIS) Comparing Low Dose Oxybutynin vs Placebo and High Dose Oxybutynin vs Placebo
Average Change of daily interference (Work) from baseline to Week 7 as measured by the Hot Flash-Related Daily Interference Scale (HFRDIS) comparing Low dose oxybutynin vs Placebo and High dose oxybutynin vs Placebo. HFRDIS Work item (Work (work outside the home and housework)) Interference scores run from 0 to 10 with 0 being no interference and 10 being complete interference.
Time frame: Baseline up to day 49
Population: Patients who completed the Hot Flash-Related Daily Interference Scale (HFRDIS) Work item at baseline and week 7 are included in this analysis. Low-dose and high-dose placebo groups were combined to serve as a control/placebo group to compare with the low-dose and high-dose oxybutynin chloride groups.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High-dose Oxybutynin Chloride Group | Average Change of Daily Interference (Work) From Baseline to Week 7 as Measured by the Hot Flash-Related Daily Interference Scale (HFRDIS) Comparing Low Dose Oxybutynin vs Placebo and High Dose Oxybutynin vs Placebo | -2.3 change in score on a scale | Standard Deviation 3.4 |
| Low-dose Oxybutynin Chloride Group | Average Change of Daily Interference (Work) From Baseline to Week 7 as Measured by the Hot Flash-Related Daily Interference Scale (HFRDIS) Comparing Low Dose Oxybutynin vs Placebo and High Dose Oxybutynin vs Placebo | -2.9 change in score on a scale | Standard Deviation 3.2 |
| Placebo Group | Average Change of Daily Interference (Work) From Baseline to Week 7 as Measured by the Hot Flash-Related Daily Interference Scale (HFRDIS) Comparing Low Dose Oxybutynin vs Placebo and High Dose Oxybutynin vs Placebo | -0.2 change in score on a scale | Standard Deviation 3.2 |
p-value: 0.0011Kruskal-Wallis
p-value: 0.0025Kruskal-Wallis
Secondary
Average Change of Severity of Stomach Pain/Cramps Symptoms as Measured by the Symptom Experience Questionnaire From Baseline to Week 7 for Low Dose Oxybutynin vs Placebo and for High Dose Oxybutynin vs Placebo
Average Change of severity of Stomach pain/cramps symptoms as measured by the Symptom Experience Questionnaire From Baseline to Week 7 for Low Dose Oxybutynin vs Placebo and for High Dose Oxybutynin vs Placebo The Symptom Experience Questionnaire stomach pain/cramps item (Over the past week, have you experienced stomach pain or cramps?) is scored from 0 to 10 with higher values being worse symptoms. So a negative value means the symptom is improving and a positive score means the symptom is getting worse.
Time frame: Baseline up to day 49
Population: Patients who completed baseline and week 7 Symptom Experience Questionnaire Stomach pain/cramps item were included in this analysis. Low-dose and high-dose placebo groups were combined to serve as a control/placebo group to compare with the low-dose and high-dose oxybutynin chloride groups.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High-dose Oxybutynin Chloride Group | Average Change of Severity of Stomach Pain/Cramps Symptoms as Measured by the Symptom Experience Questionnaire From Baseline to Week 7 for Low Dose Oxybutynin vs Placebo and for High Dose Oxybutynin vs Placebo | 0.0 change in score on a scale | Standard Deviation 1.3 |
| Low-dose Oxybutynin Chloride Group | Average Change of Severity of Stomach Pain/Cramps Symptoms as Measured by the Symptom Experience Questionnaire From Baseline to Week 7 for Low Dose Oxybutynin vs Placebo and for High Dose Oxybutynin vs Placebo | -0.3 change in score on a scale | Standard Deviation 1.5 |
| Placebo Group | Average Change of Severity of Stomach Pain/Cramps Symptoms as Measured by the Symptom Experience Questionnaire From Baseline to Week 7 for Low Dose Oxybutynin vs Placebo and for High Dose Oxybutynin vs Placebo | -1.4 change in score on a scale | Standard Deviation 2.5 |
p-value: 0.0174Kruskal-Wallis
p-value: 0.0279Kruskal-Wallis
Secondary
Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (v4)
The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns within patient groups. In addition, we will review all adverse event data that is graded as 3, 4, or 5 and classified as either unrelated or unlikely to be related to study treatment in the event of an actual relationship developing. The overall toxicity rates (percentages) for grade 3 or higher adverse events considered at least possibly related to treatment are reported below.
Time frame: Up to 7 weeks
Population: Patients who received at least one cycle of treatment and were assessed for adverse events were included in this analysis. Low-dose and high-dose placebo groups were combined to serve as a control/placebo group to compare with the low-dose and high-dose oxybutynin chloride groups.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| High-dose Oxybutynin Chloride Group | Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (v4) | grade 3 | 1 Participants |
| High-dose Oxybutynin Chloride Group | Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (v4) | grades 4/5 | 0 Participants |
| Low-dose Oxybutynin Chloride Group | Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (v4) | grade 3 | 1 Participants |
| Low-dose Oxybutynin Chloride Group | Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (v4) | grades 4/5 | 0 Participants |
| Placebo Group | Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (v4) | grade 3 | 0 Participants |
| Placebo Group | Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (v4) | grades 4/5 | 0 Participants |