Testing the Effects of Oxybutynin for the Treatment of Hot Flashes in Men Receiving Hormone Therapy for Prostate Cancer

Study Overview
=================
Brief Summary
-----------------
This phase II trial compares the effect of oxybutynin versus placebo for reducing hot flashes in men receiving androgen deprivation (hormone) therapy for the treatment of prostate cancer . Androgen deprivation therapy decreases testosterone and other androgens through medications or surgical removal of the testicles. Relative to placebo, low- or high-dose oxybutynin may reduce hot flashes in men receiving androgen deprivation therapy.

Detailed Description
-----------------
The primary and secondary objectives of the study: PRIMARY OBJECTIVE: I. To assess the effects of two doses of oxybutynin chloride (oxybutynin) on hot flash scores relative to placebo. SECONDARY OBJECTIVES: I. To assess study accrual rates and compliance with the therapy. II. To characterize the safety and adverse event profile of two doses of oxybutynin in the study population. III. To evaluate the consistency of the results across the various methods used to evaluate the efficacy of oxybutynin (i.e., hot flash scores versus hot flash frequencies, mean differences versus 50% or greater reduction since baseline, single day versus full week to define patients' baseline hot flash scores). IV. To compare patient-reported quality of life and hot flash interference, as measured by the Hot Flash Related Daily Interference Scale (HFRDIS), across arms. V. To compare other changes in patient symptoms, as measured by the Symptom Experience Questionnaire, across arms. OUTLINE: Patients are randomized to 1 of 4 arms in a 2:2:1:1 ratio according to the dynamic allocation scheme. Experimental Arm (low dose): Patients receive low-dose oxybutynin chloride orally (PO) twice daily (BID) on days 8-49 (6 weeks) in the absence of unacceptable toxicity. Experimental Arm (high dose): Patients receive high-dose oxybutynin chloride PO BID on days 8-49 (6 weeks) in the absence of unacceptable toxicity. Placebo Arm (low dose): Patients receive low-dose placebo PO BID on days 8-49 (6 weeks). After 6 weeks, patients may cross over to Experimental Arm (low dose) per physician discretion. Placebo Arm (high dose): Patients receive high-dose placebo PO BID on days 8-49 (6 weeks). After 6 weeks, patients may cross over to Experimental Arm (high dose) per physician discretion. There will be a 6-week follow-up for the Placebo Arm patients who participate in the optional crossover phase.

Official Title
-----------------
A Randomized, Double-Blind, Placebo-Controlled Phase II Study of Oxybutynin Versus Placebo for the Treatment of Hot Flashes in Men Receiving Androgen Deprivation Therapy

Conditions
-----------------
Prostate Carcinoma

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Men who are currently receiving androgen deprivation therapy (ADT) for the treatment of prostate cancer. ADT is defined by a history of orchiectomy, or ongoing usage of gonadotropin-releasing hormone agonists or antagonists. Men receiving abiraterone, but not enzalutamide, apalutamide, and darolutamide are eligible, as the latter three are metabolized by CYP3A4 and may affect oxybutynin serum concentrations. Patients must be on a stable dose of all hormone-directed therapies for at least 28 days prior to registration and must not be planning to discontinue this therapy for at least 42 days following registration. Patients receiving radiation therapy during the study period are eligible Eligible patient must have bothersome hot flashes for >= 14 days prior to registration, defined by an occurrence of >= 28 times per week and of sufficient severity to cause the patient to seek therapeutic intervention Life expectancy of greater than 6 months Eastern Cooperative Oncology Group (ECOG) performance status - 0, 1, or 2 In order to complete the mandatory patient-completed measures, participants must be able to speak and/or read English Exclusion Criteria: No current use or future planned use of any of the following agents during the study period: drugs that are not Food and Drug Administration (FDA) approved for use in humans, androgens, estrogens, progesterone analogs, gabapentin, selective serotonin reuptake inhibitor (SSRI)/serotonin and norepinephrine reuptake inhibitor (SNRI) anti-depressants, cholinergic agonists, cholinesterase inhibitors, or complementary/alternative medicine taken for the purpose of managing hot flashes. Prior use of these agents is permitted as long as they are discontinued before registration No current or prior use of oxybutynin Patients with a history of any of the following contraindications to oxybutynin are not eligible: gastroparesis or gastrointestinal obstructive disorders; significant gastric reflux symptoms not controlled by medication; ulcerative colitis; narrow-angle glaucoma; urinary retention requiring indwelling or intermittent self-catheterization within the prior 6 months; hypersensitivity to oxybutynin or any other components of the product; current uncontrolled hyperthyroidism; uncontrolled coronary artery disease or a history of myocardial infarction within the prior 12 months; New York Heart Association (NYHA) class II-IV congestive heart failure; symptomatic cardiac arrhythmias; current uncontrolled hypertension; myasthenia gravis; or dementia

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: low-dose oxybutynin<br>Patients receive low-dose oxybutynin chloride (2.5 mL twice daily) PO BID on days 8-49 (6 weeks) in the absence of unacceptable toxicity. | Drug: Oxybutynin Chloride<br>* Given PO<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Experimental: high-dose oxybutynin chloride<br>Patients receive high-dose oxybutynin chloride (5.0 mL twice daily) PO BID on days 8-49 (6 weeks) in the absence of unacceptable toxicity. | Drug: Oxybutynin Chloride<br>* Given PO<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Placebo Comparator: low-dose placebo<br>Patients receive a low-dose placebo (2.5 mL twice daily) PO BID on days 8-49 (6 weeks). After 6 weeks, patients may cross over to experimental arm - low-dose oxybutynin per physician discretion. | Drug: Placebo Administration<br>* Given PO<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Placebo Comparator: high-dose placebo<br>Patients receive a high-dose placebo (5.0 mL twice daily) PO BID on days 8-49 (6 weeks). After 6 weeks, patients may cross over to experimental arm - high-dose oxybutynin chloride per physician discretion. | Drug: Placebo Administration<br>* Given PO<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient-reported hot flash scores | Using patients' hot flash diaries, daily hot flash scores will be determined by multiplying the frequency of each defined hot flash grade by the severity and summing the values over a 24-hour period. Weekly hot flash scores will be computed by averaging these hot flash scores across 7 days. A mixed model will be estimated that includes baseline and weekly hot flash scores across the 6-week treatment period. Estimates from the mixed model will be used to construct 90% confidence intervals for mean differences in hot flash score reduction from baseline to 6 weeks between the oxybutynin and placebo arms. Contrasts estimated via the mixed model will involve a two-sided t-test with alpha = .10. At 6 weeks, the proportion of patients who experience a 50% or greater reduction in hot flash scores since baseline will be compared across the oxybutynin and placebo arms using Fisher's exact test or logistic regression. | Baseline up to 6 weeks post-randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient-reported hot flash frequency | Weekly hot flash frequencies will be determined by patients' hot flash diaries. A mixed model will be estimated that includes baseline and weekly hot flash frequencies across the 6-week treatment period. The mixed model and subsequent contrasts will account for the observed distribution of weekly hot flash frequencies. At 6 weeks, the proportion of patients who experience a 50% or greater reduction in hot flash frequency since baseline will be compared across the oxybutynin and placebo arms using Fisher's exact test or logistic regression. Consistency of the results will be assessed across the various methods used to evaluate the efficacy of oxybutynin in this trial (i.e., hot flash scores versus hot flash frequencies, mean differences versus 50% or greater reduction since baseline, single day versus full week to define patients' baseline hot flash scores). | Baseline up to 6 weeks post-randomization | 
| Incidence of adverse events | Grade 3 or higher adverse events will be assessed by the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 5.0 and summarized by arm. | Baseline up to 12 weeks post-randomization | 
| Patient-reported symptoms | Patient-reported symptoms will be assessed by the Symptom Experience Questionnaire. A mixed model will be estimated that includes baseline and weekly patient-reported symptoms across the 6-week treatment period. Estimates from the mixed model will be used to construct 90% confidence intervals for mean differences in patient-reported symptoms between the oxybutynin and placebo arms at 6 weeks. Contrasts estimated via the mixed model will involve a two-sided t-test with alpha = .10. | Baseline and at the end of each week of treatment, assessed up to 6 weeks post-randomization | 
| Patient accrual | The time required to accrue 87 patients will be reported. | Up to 2 years | 
| Treatment adherence rates | Treatment adherence rates will be calculated by dividing the number of patients who completed treatment per protocol by the number of patients who started treatment. Treatment adherence rates will be summarized by arm. | Up to 2 years | 
| Patient-reported quality of life: scale | A mixed model will be estimated that includes patients' scores on the Hot Flash Related Daily Interference Scale (HFRDIS) across the 6-week treatment period. Estimates from the mixed model will be used to construct 90% confidence intervals for mean differences in patient-reported quality of life between the oxybutynin and placebo arms at 6 weeks. Contrasts estimated via the mixed model will involve a two-sided t-test with alpha = .10. | Baseline and at the end of each week of treatment, assessed up to 6 weeks post-randomization | 
| Patient-reported hot flash interference | A mixed model will be estimated that includes patients' scores on the Hot Flash Related Daily Interference Scale (HFRDIS) across the 6-week treatment period. Estimates from the mixed model will be used to construct 90% confidence intervals for mean differences in patient-reported hot flash interference between the oxybutynin and placebo arms at 6 weeks. Contrasts estimated via the mixed model will involve a two-sided t-test with alpha = .10. | Baseline and at the end of each week of treatment, assessed up to 6 weeks post-randomization |