Prostate Carcinoma
Conditions
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.
Interventions
Given PO
DRUGPlacebo Administration
Given PO
OTHERQuality-of-Life Assessment
Ancillary studies
OTHERQuestionnaire Administration
Ancillary studies
Sponsors
National Cancer Institute (NCI)
Alliance for Clinical Trials in Oncology
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
SUPPORTIVE_CARE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Weekly Patient-reported Hot Flash Scores | 6 weeks post-randomization | Using patients' hot flash diaries, daily hot flash scores will be determined by multiplying the frequency of each defined hot flash grade (mild=1, moderate=2, severe=3, very severe=4) 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 score of 0 would mean the patient experienced no hot flashes during the week, and every unit increase reflects more or more severe hot flashes experienced. 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients That Experienced a Grade 3+ Adverse Event | 12 weeks post-randomization | 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. |
| Patient-reported Symptoms | 6 weeks post-randomization | 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. The mean change in answers from baseline to week 6 to the item How Distressing Was Your Experience With Hot Flashes will be reported. Answers are given on a scale from 0 to 10 with higher scores being worse; therefore a positive number indicates a worse experience at week 6. |
| Change in Patient-reported Hot Flash Frequency | 6 weeks post-randomization | 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. |
| Patients That Completed Treatment | 4 months | 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. |
| Patient-reported Hot Flash Interference | 6 weeks post-randomization | 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. The mean change in answers from baseline to week 6 to the item Overall Quality of Life will be reported. Answers are given on a scale from 0 to 10 with higher scores being worse; therefore a positive number indicates a worse experience at week 6. |
| Patient Accrual | 26 months | The time required to accrue 87 patients will be reported. |
Countries
United States
Participant flow
Pre-assignment details
The placebo arms will be half the size as the oxybutynin arms, as they will be combined to have a placebo group with the same number of patients as the two different treatment groups. This allows all patients to be blinded as to whether they are receiving active drug or a placebo. Patients randomized to the two placebo arms will be combined to form a single placebo arm for analysis.
Participants by arm
| Arm | Count |
|---|---|
| Low-dose Oxybutynin 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.\>
\> Oxybutynin Chloride: Given PO\>
\> Quality-of-Life Assessment: Ancillary studies\>
\> Questionnaire Administration: Ancillary studies | 28 |
| High-dose Oxybutynin Chloride 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.\>
\> Oxybutynin Chloride: Given PO\>
\> Quality-of-Life Assessment: Ancillary studies\>
\> Questionnaire Administration: Ancillary studies | 28 |
| Placebo Patients receive a low-dose or high-dose placebo (2.5 or 5.0 mL twice daily) PO BID on days 8-49 (6 weeks). After 6 weeks, patients may cross over to experimental arm - low-dose or high-dose oxybutynin per physician discretion.\>
\> Placebo Administration: Given PO\>
\> Quality-of-Life Assessment: Ancillary studies\>
\> Questionnaire Administration: Ancillary studies | 25 |
| Total | 81 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Crossover Treatment | Adverse Event | 0 | 0 | 1 | 1 |
| Crossover Treatment | Withdrawal by Subject | 0 | 0 | 2 | 1 |
| Initial Treatment | Adverse Event | 0 | 2 | 0 | 0 |
| Initial Treatment | Other complicating disease | 0 | 0 | 1 | 0 |
| Initial Treatment | Withdrawal by Subject | 1 | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Low-dose Oxybutynin | High-dose Oxybutynin Chloride | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 67.7 years STANDARD_DEVIATION 7.3 | 68.9 years STANDARD_DEVIATION 7.6 | 68.8 years STANDARD_DEVIATION 5.8 | 68.5 years STANDARD_DEVIATION 6.9 |
| Daily hot flash frequency at baseline 10 or more hot flashes per day | 17 Participants | 16 Participants | 13 Participants | 46 Participants |
| Daily hot flash frequency at baseline 4 to 9 hot flashes per day | 11 Participants | 12 Participants | 12 Participants | 35 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 27 Participants | 27 Participants | 24 Participants | 78 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Hot flash duration at baseline 9 or more months | 12 Participants | 13 Participants | 10 Participants | 35 Participants |
| Hot flash duration at baseline less that 9 months | 16 Participants | 15 Participants | 15 Participants | 46 Participants |
| Number or prior hot flash therapies 0 | 22 Participants | 20 Participants | 19 Participants | 61 Participants |
| Number or prior hot flash therapies 1 or more | 6 Participants | 8 Participants | 6 Participants | 20 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 6 Participants | 2 Participants | 11 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 25 Participants | 21 Participants | 22 Participants | 68 Participants |
| Region of Enrollment United States | 28 Participants | 28 Participants | 25 Participants | 81 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 28 Participants | 28 Participants | 25 Participants | 81 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 28 | 0 / 28 | 0 / 15 | 0 / 11 | 0 / 11 | 0 / 8 |
| other Total, other adverse events | 17 / 28 | 23 / 28 | 1 / 15 | 4 / 11 | 5 / 11 | 8 / 8 |
| serious Total, serious adverse events | 2 / 28 | 1 / 28 | 0 / 15 | 0 / 11 | 1 / 11 | 0 / 8 |
Outcome results
Primary
Change in Weekly 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 (mild=1, moderate=2, severe=3, very severe=4) 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 score of 0 would mean the patient experienced no hot flashes during the week, and every unit increase reflects more or more severe hot flashes experienced. 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.
Time frame: 6 weeks post-randomization
Population: Patients that began treatment and were eligible were included in analysis
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Low-dose Oxybutynin | Change in Weekly Patient-reported Hot Flash Scores | -9.94 units on a scale |
| High-dose Oxybutynin Chloride | Change in Weekly Patient-reported Hot Flash Scores | -13.95 units on a scale |
| Placebo | Change in Weekly Patient-reported Hot Flash Scores | -4.85 units on a scale |
p-value: 0.001990% CI: [-13.76, -4.46]t-test, 2 sided
p-value: 0.073290% CI: [-9.7, -0.48]t-test, 2 sided
Secondary
Change in 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.
Time frame: 6 weeks post-randomization
Population: Patients that began treatment and were eligible were included in analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Low-dose Oxybutynin | Change in Patient-reported Hot Flash Frequency | -4.77 change in hot flashes per day |
| High-dose Oxybutynin Chloride | Change in Patient-reported Hot Flash Frequency | -6.89 change in hot flashes per day |
| Placebo | Change in Patient-reported Hot Flash Frequency | -2.15 change in hot flashes per day |
Secondary
Number of Patients That Experienced a Grade 3+ Adverse Event
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.
Time frame: 12 weeks post-randomization
Population: Patients that began treatment were included in analysis
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low-dose Oxybutynin | Number of Patients That Experienced a Grade 3+ Adverse Event | 2 Participants |
| High-dose Oxybutynin Chloride | Number of Patients That Experienced a Grade 3+ Adverse Event | 1 Participants |
| Placebo | Number of Patients That Experienced a Grade 3+ Adverse Event | 2 Participants |
Secondary
Patient Accrual
The time required to accrue 87 patients will be reported.
Time frame: 26 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low-dose Oxybutynin | Patient Accrual | 26 months |
Secondary
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. The mean change in answers from baseline to week 6 to the item Overall Quality of Life will be reported. Answers are given on a scale from 0 to 10 with higher scores being worse; therefore a positive number indicates a worse experience at week 6.
Time frame: 6 weeks post-randomization
Population: Patients that began treatment, were eligible, and completed their 6 week HFRDIS questionnaire.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low-dose Oxybutynin | Patient-reported Hot Flash Interference | -1.0 average change score from baseline | Standard Deviation 2.88 |
| High-dose Oxybutynin Chloride | Patient-reported Hot Flash Interference | -2.4 average change score from baseline | Standard Deviation 1.89 |
| Placebo | Patient-reported Hot Flash Interference | 0.0 average change score from baseline | Standard Deviation 2.7 |
p-value: 0.0057Kruskal-Wallis
Secondary
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. The mean change in answers from baseline to week 6 to the item How Distressing Was Your Experience With Hot Flashes will be reported. Answers are given on a scale from 0 to 10 with higher scores being worse; therefore a positive number indicates a worse experience at week 6.
Time frame: 6 weeks post-randomization
Population: Patients that began treatment, were eligible, and completed their 6 week PRO questionnaire were included in analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low-dose Oxybutynin | Patient-reported Symptoms | -1.8 average change score from baseline | Standard Deviation 2.74 |
| High-dose Oxybutynin Chloride | Patient-reported Symptoms | -3.0 average change score from baseline | Standard Deviation 2.68 |
| Placebo | Patient-reported Symptoms | -0.5 average change score from baseline | Standard Deviation 2.61 |
p-value: 0.012Kruskal-Wallis
Secondary
Patients That Completed Treatment
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.
Time frame: 4 months
Population: All patients that began treatment and were eligible were included in analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low-dose Oxybutynin | Patients That Completed Treatment | 27 Participants |
| High-dose Oxybutynin Chloride | Patients That Completed Treatment | 24 Participants |
| Placebo | Patients That Completed Treatment | 25 Participants |