Oxybutynin Chloride in Managing Hot Flashes

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase III, Double-Blind, Controlled Trial of Oxybutynin in the Management of Hot Flashes

Conditions
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Breast Carcinoma, Ductal Breast Carcinoma In Situ, Hot Flashes, Lobular Breast Carcinoma In Situ, No Evidence of Disease

Intervention / Treatment
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* Drug: Oxybutynin Chloride
* Other: Placebo
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group I (low-dose oxybutynin chloride)<br>Patients receive lower dose oxybutynin chloride PO BID on days 8-49 in the absence of unacceptable toxicity. | Drug: Oxybutynin Chloride<br>* Given PO<br>* Other names: Oxybutynin Hydrochloride;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Placebo Comparator: Group II (low-dose placebo)<br>Patients receive lower dose placebo PO BID on days 8-49 in the absence of unacceptable toxicity. | Other: Placebo<br>* Given PO<br>* Other names: sham therapy;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Experimental: Group III (high-dose oxybutynin chloride)<br>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. | Drug: Oxybutynin Chloride<br>* Given PO<br>* Other names: Oxybutynin Hydrochloride;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Placebo Comparator: Group IV (high-dose placebo)<br>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. | Other: Placebo<br>* Given PO<br>* Other names: sham therapy;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline up to day 49 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline up to day 49 | 
| 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. | 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 | 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. | 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 | 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. | Baseline up to day 49 | 
| 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. | Up to 7 weeks |