Clinical trial NCT04600336
Conditions: Prostate Carcinoma
Sponsor: Alliance for Clinical Trials in Oncology
Start date: 2021-10-28; Completion date: 2024-03-11
Enrollment: 88 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

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.

Arms: arm 1: 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. arm 2: 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. arm 3: 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. arm 4: 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.
Interventions: intervention 1: Oxybutynin Chloride intervention 2: Placebo Administration intervention 3: Quality-of-Life Assessment intervention 4: Questionnaire Administration
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Ancillary studies intervention 4: Ancillary studies

Protocol documents:
Prot_SAP_000.pdf: 
Alliance A222001 
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Update #02 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
ALLIANCE A222001 
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 
A limited access study 
Supplied agent: oxybutynin (Alliance IND: 152980, NSC 759108) 
ClinicalTrials.gov Identifier: NCT04600336 
 
Study Chair 
  
  
 
 
 
 
 
 
Community Oncology Co-chair 
Study Co-chair 
Study Co-chair 
 
 
 
 
  
 
 
 
 
 
 
 
 
Symptom Intervention Committee 
and Study Co-chair 
Health Disparities Co-chairs 
 
 
 
  
  
 
 
 
 
 
 
 
 
Primary Statistician 
Secondary Statistician 
 
 
 
 
 
 
 
Data Manager 
Protocol Coordinator 
 
 
  
 
 
 
 
Limited Access Institutions: See page 2-3 
 
Participating Organizations:  
Alliance/Alliance for Clinical Trials in Oncology (lead), ECOG-ACRIN/ECOG-ACRIN Cancer Research Group, 
NRG/NRG Oncology, SWOG/SWOG  
 


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Limited access institutions 
Abbott-Northwestern Hospital, MN008 
Altru Cancer Center, ND028 
 
Arizona Breast Cancer Specialists, AZ118  
Arizona Breast Cancer Specialists-Gilbert, AZ147  
Arizona Breast Cancer Specialists-Phoenix, AZ125 
Arizona Breast Cancer Specialists-Scottsdale, AZ146 
Arizona Cancer Care-Surprise, AZ149 
 
Arizona Center for Cancer Care-Peoria, AZ127  
Ascension All Saints Hospital, WI061 
 
Ascension Calumet Hospital, WI204 
 
Ascension Colombia Saint Mary’s Hosp-Milwaukee, 
WI161  
Ascension Colombia Saint Mary’s Hosp-Ozaukee, 
WI140   
Ascension Med Group SE Wisc.-Mayfair Road, 
WI169  
Springfield Clinic, IL194 
Ascension Mercy Hospital, WI038  
Ascension Saint Elizabeth Hospital, WI039  
Ascension Saint Francis-Reiman Cancer Center, 
WI137  
Ascension Saint Joseph Hospital, MI364 
Ascension Saint Mary’s Hospital, MI142   
Ascension SE Wisc. Hospital-Elmbrook Campus, 
WI145  
Ascension SE Wisc. Hospital-St Joseph Campus, 
WI043  
Aspirus Cancer Care-Wisconsin Rapids, WI093  
Aspirus Langlade Hospital, WI146  
Aspirus Regional Cancer Center, WI028 
 
AtlantiCare Cancer Care Institute, NJ237 
AtlantiCare Health Park-Cape May Court House, 
NJ287  
Baptist MD Anderson Cancer Center, FL003 
Cancer Care Specialists of IL-Decatur, IL185 
 
Cancer Center at Saint Joseph’s, AZ151 
 
Carle Cancer Center, IL168 
 
Carle on Vermillion, IL405 
 
Carle Physician Group-Effingham, IL406 
 
Carle Physician Group-Mattoon/Charleston, IL393 
 
Crossroads Cancer Center, IL208  
Decatur Memorial Hospital, IL094  
Delbert Day Cancer Institute at PCRMC, MO052 
Fairview Clinics and Surgery Center-Maple Grove, 
MN113  
Fairview Lakes Medical Center, MN132  
Fairview Ridges Hospital, MN070  
Fairview Southdale Hospital, MN031 
Fremont-Rideout Cancer Center, CA564 
Gene Upshaw Memorial Tahoe Forest Therapy Ctr, 
CA690 
Genesee Cancer and Blood Disease Treatment Ctr, 
MI347 
Genesee Hematology Oncology, MI348 
Genesys Hurley Cancer Center, MI149 
Grand Valley Oncology, CO138 
Hawaii Cancer Care Inc, HI022 
Hawaii Cancer Care-Westridge, HI049 
Heartland Oncology and Hematology, IA147 
Hennepin County Medical Center, MN013 
Iowa Methodist Medical Center, IA004 


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Jennie Edmundson Memorial Hospital, IA055 
Lakeview Hospital, MN119 
 
Mary Greeley Medical Center, IA067 
Mayo Clinic, MN026 
McFarland Clinic-Ames, IA003 
McFarland Clinic-Boone, IA106 
McFarland Clinic-Jefferson, IA105 
 McFarland Clinic-Marshalltown, IA104 
McFarland Clinic-Trinity Cancer Center, IA107 
Medical Oncology Hematology Assoc-Des Moines, 
IA072 
Mercy Hospital, MN019 
Mercy Medical Center-Des Moines, IA008 
Messino Cancer Centers, NC053 
Minnesota Oncology Hematology-Maplewood, 
MN075  
Minnesota Oncology Hematology-Woodbury, 
MN098  
Minnesota Oncology-Burnsville, MN145 
 
Montefiore Medical Center-Moses Campus, NY045 
Montefiore Medical Center-Einstein Campus, NY313 
Montefiore Medical Center-Weiler Hosp, NY043 
Monticello Cancer Center, MN141 
Nebraska Cancer Specialists-MECC, NE074  
Nebraska Methodist Hospital, NE007 
 
New Ulm Medical Center, MN121 
North Memorial Medical Health Center, MN054 
NYP/Weill Cornell Medical Center, NY018  
Ohio State University Comprehensive Cancer Center, 
OH007  
Oncology Hematology Assoc of Saginaw, MI364 
Park Nicollet Clinic-St Louis Park, MN014 
ProHealth D N Greenwald Center, WI143 
ProHealth Oconomowoc Memorial Hospital, WI087 
Regions Hospital, MN001 
Rice Memorial Hospital, MN028 
Ridgeview Medical Center, MN059 
Saint Francis Regional Medical Center, MN064 
Saint John’s Hospital-Healtheast, MN041 
Sanford Broadway Medical Center, ND003 
Sanford Cancer Center Oncology Clinic, SD004 
Sanford Roger Maris Cancer Center, ND005 
Sanford USD Medical Center, SD003 
Southeastern Medical Oncology Center-Clinton, 
NC254 
Southeastern Medical Oncology Center-Goldsboro, 
NC065 
Southeastern Medical Oncology Center-Jacksonville, 
NC231 
Southern Illinois School of Medicine, IL096 
Sovah Health Martinsville, VA043 
Sparta Community Hospital, IL413 
Springfield Memorial Hospital, IL097 
United Hospital, MN002 
Unity Hospital, MN018 
University of Arizona Cancer Center-North Campus, 
AZ110 
University of Mississippi Medical Center, MS005 
University of Missouri-Ellis Fischel, MO036 
UW Cancer Center at ProHealth Care, WI207 
Westfields Hosp/Cancer Center of Western WI, 
WI196  
Zablocki Veterans Administration Medical Cetner, 
WI004 
 


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Study Resources: 
Expedited Adverse Event Reporting 
 
Medidata Rave iMedidata portal 
 
OPEN (Oncology Patient Enrollment Network) 
 
Biospecimen Management System 
 
 
Protocol Contacts: 
A222001 Nursing Contacts 
 
 
 
 
 
A222001 Pharmacy Contact 
 
  
   
  
 
Drug Distribution Contact 
  
 
 
 
 
Protocol-related questions may be directed as follows: 
Questions 
Contact (via email) 
Questions regarding patient eligibility, treatment, 
and dose modification: 
Study Chair, Nursing Contact, Protocol 
Coordinator, and (where applicable) Data 
Manager 
Questions related to data submission, RAVE or 
patient follow-up: 
Data Manager  
Questions regarding the protocol document and 
model informed consent: 
Protocol Coordinator 
Questions related to IRB review 
Alliance Regulatory Inbox 
 
Questions regarding CTEP-AERS reporting: 
Alliance Pharmacovigilance Inbox 
 
Questions regarding drug supply 
McKesson Clinical Research Services  
Questions regarding drug administration 
Pharmacy Contact 
 
 
 
 


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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
CONTACT INFORMATION 
 
For regulatory requirements: 
For patient enrollments: 
For data submission: 
Regulatory documentation must 
be submitted to the Cancer 
Trials Support Unit (CTSU) via 
the Regulatory Submission 
Portal. 
 (Sign in at 
 and select 
the Regulatory > Regulatory 
Submission.)  
 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately by phone or email: 
 
to 
receive further instruction and 
support. 
 
Contact the CTSU Regulatory 
Help Desk at 1
 
for regulatory assistance. 
Refer to the patient enrollment 
section of the protocol for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN). OPEN is 
accessed at 
 
 
Contact the CTSU Help Desk 
with any OPEN related questions 
by phone or email : 
 
 
 
 
Data collection for this study 
will be done exclusively through 
Medidata Rave. Refer to the data 
submission section of the 
protocol for further instructions.  
 
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific page located on the CTSU members’ website 
Access 
to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program - 
Identity and Access Management (CTEP-IAM) registration system and requires log in with a CTEP-
IAM username and password.  
 
Permission to view and download this protocol and its supporting documents is restricted and is based 
on person and site roster assignment housed in the CTSU Regulatory Support System (RSS).   
 
Supplies can be ordered by downloading and completing the CTSU Supply Request Form (available on 
the protocol-specific page on the CTSU website) and submitting it as instructed on the form. 
 
For clinical questions (i.e. patient eligibility or treatment-related) see the Protocol Contacts, Page 4. 
 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) Contact the CTSU Help Desk by phone or email:  
CTSU General Information Line – 
All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
 
 


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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 
Eligibility Criteria (see Section 3.0) 
Required Initial Laboratory Values 
• 
Men who are currently receiving androgen 
deprivation therapy (ADT) for the treatment of 
prostate cancer. (See §3.2.1) 
None  
• 
Patients must be on a stable dose of all hormone-directed therapies for at least 28 days prior to 
registration. Patients receiving radiation therapy are eligible. (See §3.2.2) 
• 
Eligible patient must have bothersome hot flashes for ≥ 14 days prior to registration. (See §3.2.3) 
• 
No current or future planned use of any of the agents listed in Section 3.2.4 during the study period. 
(See §3.2.4) 
• 
No current or prior use of oxybutynin as a treatment for hot flashes. (See §3.2.5)  
• 
Patients with a history of any of the contraindications to oxybutynin listed in Section 3.2.6 are not 
eligible. (See §3.2.6) 
• 
IPSS score < 20 (See §3.2.8) 
• 
Life expectancy of greater than 6 months. (See §3.2.9) 
• 
Age ≥ 18 years. (See §3.2.10) 
• 
ECOG Performance Status 0, 1 or 2. (See §3.2.11) 
• 
Participants must be able to speak and read English. (See §3.2.12) 
 
Schema 
 
 
Initial Blinded Phase  
 
 
 
Optional Unblinded Phase  
R 
 
Oxybutynin 2.5 mL** p.o. BID for 42 days*** 
 
R 
 
 
A 
 
 
E 
 
 
N 
 
 
 
R
 
Oxybutynin 2.5 mL*** 
p.o. BID for 42 days 
D 
 
Placebo 2.5 mL** p.o. BID for 42 days*** 
 
E 
 
O 
 
 
G
 
M 
 
 
 
I 
 
 
I 
 
Oxybutynin 5.0 mL** p.o. BID for 42 days*** 
 
S 
 
 
Z 
 
 
T 
 
 
E* 
 
 
 
E  
Oxybutynin 5.0 mL*** 
p.o. BID for 42 days 
 
 
Placebo 5.0 mL p.o.**  BID for 42 days*** 
 
 
R 
 
* 
Days 1-7 of study will involve collection of BSD (Baseline Symptom Documentation). Study treatment 
is to be administered from Days 8-49.  
** The concentration of oxybutynin is 1 mg per 1 mL, so that placebos and active treatments will maintain 
blinding. 
*** Following 6 weeks of study treatment, the patient will be given the option of being unblinded (Section 
8.3.2), and if he was on placebo, will be allowed to cross-over, be re-registered (See Section 4.7), 
receive either 2.5 or 5.0 mL of oxybutynin, equivalent to the amount of the placebo the patient had 
received prior to unblinding, for 6 weeks..  
Please refer to the full protocol text for a complete description of the eligibility criteria and 
treatment plan. 
If the Group credited for enrollment is a non-Alliance Group, then other requirements from the credited 
Group may apply. 
 


Alliance A222001 
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Table of Contents 
Section 
Page 
1.0 
BACKGROUND AND RATIONALE .......................................................................................... 9 
1.1 
Treatment of Hot Flashes in Men ................................................................................................. 9 
1.2 
Oxybutynin for Hot Flashes .......................................................................................................... 9 
1.3 
Study Design ............................................................................................................................... 10 
2.0 
OBJECTIVES ............................................................................................................................... 11 
2.1 
Primary objective ........................................................................................................................ 11 
2.2 
Secondary objectives .................................................................................................................. 11 
3.0 
PATIENT SELECTION............................................................................................................... 12 
3.1 
On-Study Guidelines ................................................................................................................... 12 
3.2 
Eligibility Criteria ....................................................................................................................... 12 
4.0 
PATIENT REGISTRATION ....................................................................................................... 14 
4.1 
Investigator and Research Associate Registration with CTEP ................................................... 14 
4.2 
CTSU Site Registration Procedures ............................................................................................ 15 
4.3 
Patient Registration Requirements .............................................................................................. 17 
4.4 
Patient Enrollment (registration/randomization procedures (Step 1)) ........................................ 17 
4.5 
Stratification Factors and Treatment Assignments ..................................................................... 18 
4.6 
Procedures for Double-Blinding the Treatment Assignment ...................................................... 19 
4.7 
Cross-Over Re-registration (step 2) Procedures ......................................................................... 19 
5.0 
STUDY CALENDAR ................................................................................................................... 20 
6.0 
DATA SUBMISSION ................................................................................................................... 21 
6.1 
Data Collection and Submission ................................................................................................. 21 
6.2 
Submission of Patient Completed Measures ............................................................................... 22 
7.0 
TREATMENT PLAN/INTERVENTION ................................................................................... 23 
7.1 
Baseline Symptom Documentation ............................................................................................. 23 
7.2 
Oxybutynin/Placebo .................................................................................................................... 23 
7.3 
Patient Unblinding and optional crossover ................................................................................. 23 
8.0 
DOSE AND TREATMENT MODIFICATIONS, UNBLINDING ........................................... 24 
8.1 
Ancillary Therapy, Concomitant Medications, and Supportive Care ......................................... 24 
8.2 
Dose Modifications ..................................................................................................................... 24 
8.3 
Unblinding Procedures ................................................................................................................ 25 
9.0 
ADVERSE EVENTS .................................................................................................................... 26 
9.1 
Routine Adverse Event Reporting .............................................................................................. 26 
9.2 
CTCAE Routine Reporting Requirements .................................................................................. 26 
9.3 
Expedited Adverse Event Reporting (CTEP-AERS) .................................................................. 27 
10.0 
DRUG INFORMATION .............................................................................................................. 29 
10.1 
Oxybutynin Chloride Oral Syrup (Ditropan) .............................................................................. 29 
10.2 
Placebo Oral Solution ................................................................................................................. 33 
11.0 
MEASURES .................................................................................................................................. 34 
11.1 
Baseline Symptom Determination (Appendix II) ....................................................................... 34 
11.2 
International Prostate Symptom Score (IPSS) (Appendix III) .................................................... 34 
11.3 
Hot Flash Diary (Appendix IV) .................................................................................................. 34 
11.4 
Symptom Experience Questionnaire (Appendix V) ................................................................... 34 
11.5 
Hot Flash Related Daily Interference Scale (HRFDIS) (Appendix VI) ...................................... 35 


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11.6 
Nurse Telephone Contact (Appendix VII) .................................................................................. 35 
12.0 
END OF TREATMENT/INTERVENTION .............................................................................. 35 
12.1 
Duration of Protocol Treatment .................................................................................................. 35 
12.2 
Criteria for Discontinuation of Protocol Treatment/Intervention ............................................... 35 
12.3 
Follow-up .................................................................................................................................... 36 
12.4 
Extraordinary Medical Circumstances ........................................................................................ 36 
12.5 
Managing ineligible patients and registered patients who never receive protocol intervention . 36 
13.0 
STATISTICAL CONSIDERATIONS ........................................................................................ 37 
13.1 
Overview ..................................................................................................................................... 37 
13.2 
Study Design ............................................................................................................................... 37 
13.3 
Study Endpoints .......................................................................................................................... 37 
13.4 
Analysis Plan .............................................................................................................................. 37 
13.5 
Sample Size and Power ............................................................................................................... 39 
13.6 
Accrual Time and Study Duration .............................................................................................. 40 
13.7 
Data and Safety Monitoring ........................................................................................................ 40 
13.8 
Minority Accrual ......................................................................................................................... 40 
13.9 
Inclusion of Minorities ................................................................................................................ 41 
14.0 
GENERAL REGULATORY CONSIDERATIONS AND CREDENTIALING ..................... 42 
14.1 Limited Access Requirements ........................................................................................................ 42 
15.0 
MONITORING PLAN ................................................................................................................. 42 
16.0 
REFERENCES .............................................................................................................................. 43 
APPENDIX I HOT FLASH DEFINITIONS FOR THE MALE PATIENT ....................................... 46 
APPENDIX II BASELINE SYMPTOM DOCUMENTATION ........................................................... 47 
APPENDIX III INTERNATIONAL PROSTATE SYMPTOM SCORE (IPSS) ................................ 48 
APPENDIX IV HOT FLASH DIARY (SAMPLE INCLUDED ON THE NEXT PAGE) ................. 50 
APPENDIX V SYMPTOM EXPERIENCE QUESTIONNAIRE ........................................................ 52 
APPENDIX VI HOT FLASH RELATED DAILY INTERFERENCE SCALE (HFRDIS)............... 56 
APPENDIX VII NURSE/CRP PHONE CONTACT GUIDE ............................................................... 57 
APPENDIX VIII: PATIENT MEDICATION DIARY – OXYBUTYNIN/PLACEBO ...................... 58 
APPENDIX IX PATIENT INFORMATION SHEETS......................................................................... 60 
APPENDIX X PATIENT CLINICAL TRIAL WALLET CARD ........................................................ 62 
APPENDIX XI PATIENT THANK YOU LETTERS ........................................................................... 63 
 
 
 
 


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1.0 
BACKGROUND AND RATIONALE 
Therapies to decrease testosterone and other androgens are frequently utilized in men diagnosed with 
prostate cancer, and also in certain salivary gland tumors.[1, 2] Additionally, medications to block 
estrogen signaling are also commonly employed in men with estrogen and/or progesterone receptor 
positive breast cancer.[3] Although these therapies can have significant clinical efficacy, a rapid 
change in the circulating hormone levels can commonly cause patients to experience symptomatic 
hot flashes. Approximately 60-80% of prostate cancer patients being treated with either surgical (i.e. 
orchiectomy) or medical androgen deprivation therapy (ADT) will experience hot flashes.[4, 5] Hot 
flashes have been associated with negative impacts on patients’ reported quality of life, fatigue, and 
sleep disturbance.[6-11]  Additionally, patients with bothersome hot flashes may be less likely to 
complete the recommended course of ADT, which can negatively influence cancer prognosis. Given 
the prevalence of this symptom and the significance of associated toxicity, further study of potentially 
effective interventions is warranted. 
1.1 
Treatment of Hot Flashes in Men  
A variety of different therapies have been investigated for reducing hot flashes in men. Two 
progesterone analogs, megestrol and medoxyprogesterone, have randomized trial evidence 
demonstrating a significant reduction in hot flashes, with acceptable toxicity profiles.[12, 13] 
Both of these trials demonstrated that greater than 70% of patients receiving the study agents 
reported significant reductions in hot flashes. However, some oncologists are hesitant to 
prescribe these agents due to overexpression of progesterone receptors in a subset of patients 
with prostate cancer, and the uncertain clinical effects of these medication on oncologic 
outcomes.[14-16] Megestrol has also been associated with a decrease in prostate-specific 
antigen (PSA) after withdrawal suggesting some potential therapeutic effect by the drug.[17] 
Gabapentin, a gamma-aminobutyric acid analog, has also been shown to be effective at reducing 
hot flash frequency compared to placebo in men receiving ADT.[18] In that study, a dose-
dependent response to gabapentin was noted, with only patients receiving the highest dose (900 
mg/day) demonstrating a statistically significant moderate improvement in hot flash scores and 
frequencies, compared to placebo. However, there was only a 20% reduction and that only 
appeared after 3 weeks. A randomized trial assessing the efficacy of both venlafaxine, a 
serotonin-norepinephrine reuptake inhibitor (SNRI), and soy protein revealed that neither agent 
was effective at reducing hot flashes in men with prostate cancer.[19] This result is notable 
because venlafaxine has been shown, in multiple randomized studies, to improve hot flashes in 
women [20, 21], thus demonstrating the importance of investigating gender-specific responses 
to interventions for managing hot flashes. While there are evidence-based options for treating 
male hot flashes, further study is warranted to identify additional interventions that provide both 
providers and patients with more effective means of hot flash management, with tolerable side 
effects.  
1.2 
Oxybutynin for Hot Flashes  
Oxybutynin is an anti-cholinergic agent which is available in both oral and transdermal 
formulations. Currently, oxybutynin is approved by the Food and Drug Administration (FDA) 
for use in managing overactive bladder symptoms. Additionally there are randomized trial data 
supporting off label use for the management of hyperhidrosis, with studies showing that this 
effect is equal across both genders.[22-24] Oxybutynin has a very good safety profile, with the 
most common reported adverse effects being xerostomia, drowsiness, dizziness, mild cognitive 
effects, and urinary retention, which are typically mild in severity and resolve with 
discontinuation, if not tolerable.[25] 
In 2007, a manuscript reported retrospective data that supported the efficacy of oxybutynin for 
managing refractory hot flash symptoms in 52 cancer patients, including four men with ADT-


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induced hot flashes.[26] The promising results of this study, which suggested a 70% response 
rate to oxybutynin with acceptable toxicity, led to the development of Phase III, double-blind, 
randomized trials comparing oxybutynin to placebo in women with hot flashes.[27, 28] One 
such trial demonstrated that moderate doses of oxybutynin substantially decreased hot flashes 
with mild to moderate toxicity. [27] More recently, our group completed another study which 
compared oxybutynin at doses of 2.5 and 5.0 mg BID to placebo in women with symptomatic 
hot flashes. These results were presented as an oral abstract at the 2018 San Antonio Breast 
Cancer Symposium, and showed that hot flash scores were significantly reduced from baseline 
in both the 2.5 mg (-10.6, SD 7.7) and 5.0 mg (-16.9, SD 15.6) treatment arms compared to 
placebo (-5.7, SD 10.2). Additionally, hot flash frequency was significantly improved for 
patients receiving both dose levels of oxybutynin (2.5 mg=60% reduction, 5.0 mg=77% 
reduction) over those treated with placebo (27% reduction). Reported treatment-related adverse 
effects for participants were typically mild and there was no difference in the discontinuation of 
the study drug between the oxybutynin and placebo arms. [28] 
Additionally, a recent letter to the editor in the New England Journal of Medicine highlighted a 
case study of a man with hot flashes related to ADT which were refractory to high doses of 
gabapentin and venlafaxine, who then experienced a dramatic improvement after starting 
oxybutynin 2.5 mg twice daily.[29]  Furthermore, members of our study team have anecdotally 
noted positive effects on hot flash symptoms when prescribing oxybutynin to manage urinary 
symptoms in men with prostate cancer. These observations, coupled with the positive effect of 
oxybutynin on hot flashes in women, support the conduct of a double-blind, placebo-controlled 
trial of oxybutynin for the management of hot flashes in men receiving ADT with a primary 
endpoint assessing the change in hot flash scores from baseline.  
1.3 
Study Design 
1.3.1 
Baseline period:  
We will utilize a one week period to obtain data regarding baseline hot flashes.  
1.3.2 
Hot flash measurement 
Patient reported outcome (PRO) measurements will be used as per the methodology that 
we described 18 years ago,[30] and that has also been used in trials conducted by other 
investigators. The primary endpoint of this study will assess the effects of the study 
interventions on patient reported hot flash scores. The calculation of this metric is defined 
in Section 2.1.1. Definitions of hot flash severity in men will be provided, based on data 
we collected from male patients who participated in a previous hot flash trial, and published 
25 years ago.[31] Previous studies for hot flashes in men have utilized the same outcome 
measures to assess the study drug’s efficacy and the hot flash score represents an ideal tool 
for quantitating multiple aspects of hot flash symptomatology.[12, 18, 30-32] We plan to 
use the Hot Flash Related Daily Interference Scale (HFRDIS), a tool developed by Dr. 
Janet Carpenter.[33]  We recently assessed face validity by asking 10 men with androgen 
deprivation hot flashes to review this tool.  All of the HFRDIS items were assessed as clear, 
appropriate, and easy to interpret. The items related to work and sexuality were identified 
as potentially difficult to answer if the individual was retired or not sexually active, 
however all of the men were able to provide a numeric score for these items. We also 
discussed the above with Dr. Janet Carpenter, who developed the HFRDIS tool and have 
identified other studies that have used the HFRDIS in men receiving androgen deprivation 
therapy.[34-36] These studies provide additional data supporting the reliability and validity 
of the 10-item instrument in this population. For example, Gonzalez, et al., (2015) provided 
evidence of construct validity in this population by demonstrating significant differences 
in scores between men receiving androgen deprivation therapy and men who only undergo 


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prostatectomy. [34] Beer, et al. (2010) demonstrated decreasing scores on both the HFD 
and HFRDIS following acupuncture in men undergoing androgen deprivation therapy, 
supporting concurrent validity of the HFRDIS [34]. 
1.3.4 
Cognitive effects  
One potential concern when using anti-cholinergic agents, such as oxybutynin, for 
extended periods is the potential negative impact on cognition via interaction with 
muscarinic receptors within the central nervous system. Prospective studies, conducted 
primarily in elderly patients with overactive bladder symptoms, have demonstrated 
conflicting findings with regard to the effects of oxybutynin on neuro-cognition relative to 
placebo.[37-40] Questions relating to patient-reported cognition will be asked via the 
Symptom Experience Questionnaire (Appendix V) at baseline and weekly during the 6-
week treatment period to help ascertain the effects of oxybutynin relative to placebo. These 
data will ultimately provide insight regarding the potential for cognitive toxicity with 
oxybutynin, which can be useful when considering the therapeutic index of this medication 
for treating hot flashes.  
2.0 
OBJECTIVES 
2.1 
Primary objective 
2.1.1 
To assess the effects of two doses of oxybutynin on hot flash scores (determined by 
multiplying the frequency of each defined hot flash grade by the severity [grade 0: none, 
1: mild, 2: moderate, 3: severe, and 4: very severe] and summing the values over a 24-
hour period) relative to placebo. 
2.2 
Secondary objectives 
2.2.1 
To assess study accrual rates and compliance with the therapy. 
2.2.2 
To characterize the safety and adverse event profile of two doses of oxybutynin in the 
study population. 
2.2.3 
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). 
2.2.4 
To compare patient-reported quality of life and hot flash interference, as measured by the 
HFRDIS, across arms. 
2.2.5 
To compare other changes in patient symptoms, as measured by the Symptom Experience 
Questionnaire, across arms. 
 
 


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Update #02 
3.0 
PATIENT SELECTION 
For questions regarding eligibility criteria, see the Study Resources page. Please note that the Study 
Chair cannot grant waivers to eligibility requirements.  
3.1 
On-Study Guidelines 
This clinical trial can fulfill its objectives only if patients appropriate for this trial are enrolled. 
All relevant medical and other considerations should be taken into account when deciding 
whether this protocol is appropriate for a particular patient. Physicians should consider the risks 
and benefits of any therapy, and therefore only enroll patients for whom this treatment is 
appropriate.  
Physicians should consider whether any of the following may render the patient inappropriate 
for this protocol: 
• 
Psychiatric illness which would prevent the patient from giving informed consent. 
• 
Medical condition such as uncontrolled infection (including HIV), uncontrolled 
diabetes mellitus or cardiac disease which, in the opinion of the treating physician, 
would make this protocol unreasonably hazardous for the patient. 
3.2 
Eligibility Criteria  
Use the spaces provided to confirm a patient’s eligibility by indicating Yes or No as appropriate. 
It is not required to complete or submit the following page(s). 
When calculating days of tests and measurements, the day a test or measurement is done is 
considered Day 0. Therefore, if a test were done on a Monday, the Monday one week later would 
be considered Day 7. 
___ 
3.2.1 
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. 
___ 
3.2.2 
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.  
___ 
3.2.3 
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. 
___ 
3.2.4 
No current use or future planned use of any of the following agents during the 
study period: drugs that are not FDA approved for use in humans, drugs with 
category X interactions with oxybutynin [e.g. other anti-cholinergic agents, 
eluoxadloline, and potassium chloride], androgens, estrogens, progesterone analogs, 
gabapentin, 
cholinergic 
agonists, 
cholinesterase 
inhibitors, 
or 
complementary/alternative medicine taken for the purpose of managing hot flashes. 
No current or future planned use of strong CYP3A4 inhibitors (e.g. antipsychotic 
agents or macrolide antibiotics) during the study. 
Prior use of these agents is permitted as long as they are discontinued before registration.  


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____ 
3.2.5 
No current or prior use of oxybutynin for the treatment of hot flashes.  Prior 
use of oxybutynin for other purposes (e.g. bladder symptoms) is allowed, as long as 
the patient has not taken any oxybutynin for 30 days prior to registration. 
___ 
3.2.6 
Comorbid conditions 
Patients with a history of any of the following contraindications to oxybutynin are not 
eligible: gastroparesis or gastrointestinal obstructive disorders; severe constipation defined 
as 2 or fewer bowel movements per week; significant gastric reflux symptoms not 
controlled by medication; ulcerative colitis; narrow-angle glaucoma; 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; NYHA Class II-IV congestive heart failure; symptomatic cardiac arrhythmias; 
current uncontrolled hypertension (average systolic >140 mm Hg and diastolic >90 mm 
Hg); myasthenia gravis; Parkinson’s disease; or dementia. 
___ 
3.2.7 
Patients with urinary retention requiring indwelling or intermittent self-
catheterization within the prior 6 months are not eligible. 
___ 
3.2.8 IPSS (Appendix III) score < 20, unless they have a post void residual 
confirmation of less than 300 cc residual in the bladder (that is that the patient is 
eligible with a higher IPSS score if a subsequent PVR test looks good).    
____ 
3.2.9 
Life Expectancy of greater than 6 months. 
___ 
3.2.10 Age ≥ 18 years  
___ 
3.2.11 ECOG Performance Status- 0, 1, or 2 
___ 
3.2.12 Language: In order to complete the mandatory patient-completed measures, 
participants must be able to speak and/or read English. 
___ 
3.2.13 Required Initial Laboratory Values: None  
 
 


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4.0 
PATIENT REGISTRATION 
4.1 
Investigator and Research Associate Registration with CTEP 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and renew their 
registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation 
Program 
(CTEP) 
Identity 
and 
Access 
Management 
(IAM) 
account 
at 
 In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must complete their annual 
registration using CTEP’s web-based Registration and Credential Repository (RCR) at 
    
RCR utilizes five person registration types. 
• 
IVR — MD, DO, or international equivalent; 
• 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level researchers 
(e.g., PhD); 
• 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications 
such as the Roster Update Management System [RUMS], OPEN, Rave, acting as a 
primary site contact, or with consenting privileges; 
• 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials; 
and 
• 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
RCR requires the following registration documents: 
Documentation Required 
IVR NPIVR AP 
A 
AB 
FDA Form 1572 
✔ 
✔ 
 
 
 
Financial Disclosure Form 
✔ 
✔ 
✔ 
NCI Biosketch (education, training, employment, 
license, and certification) 
✔ 
✔ 
✔ 
GCP training 
✔ 
✔ 
✔ 
 
 
Agent Shipment Form (if applicable) 
✔ 
CV (optional) 
✔ 
✔ 
✔ 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and Cancer Trials Support Unit (CTSU) websites and applications. In addition, IVRs and 
NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) covering 
their practice sites on the FDA Form 1572 in RCR to allow the following: 
• 
Addition to a site roster; 
• 
Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
• 
Act as the site-protocol Principal Investigator (PI) on the IRB approval; and 
• 
Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).  


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In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, or as the CI on the DTL 
must be rostered at the enrolling site with a participating organization.  
Additional 
information 
is 
located 
on 
the 
CTEP 
website 
at 
 For questions, please contact the 
RCR Help Desk by email at 
 
4.2 
CTSU Site Registration Procedures 
Permission to view and download this protocol and its supporting documents is restricted and is 
based on person and site roster assignment housed in the CTSU Regulatory Support System 
(RSS). 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval   
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical Trials 
Network (NCTN) and NCI Community Oncology Research Program (NCORP) Research Bases 
after March 1, 2019, all U.S.-based sites must be members of the NCI Central Institutional 
Review Board (NCI CIRB). In addition, U.S.-based sites must accept the NCI CIRB review to 
activate new studies at the site after March 1, 2019. Local IRB review will continue to be 
accepted for studies that are not reviewed by the CIRB, or if the study was previously open at 
the site under the local IRB. International sites should continue to submit Research Ethics Board 
(REB) approval to the CTSU Regulatory Office following country-specific regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for Local 
Context (SSW) to the CIRB using IRBManager to indicate their intent to open the study locally. 
The NCI CIRB’s approval of the SSW is automatically communicated to the CTSU Regulatory 
Office, 
but 
sites 
are 
required 
to 
contact 
the 
CTSU 
Regulatory 
Office 
at 
 to establish site preferences for applying NCI CIRB approvals 
across their Signatory Network. Site preferences can be set at the network or protocol level. 
Questions about establishing site preferences can be addressed to the CTSU Regulatory Office 
by email or calling 
 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the IRB/REB 
approval) must meet the following criteria in order for the processing of the IRB/REB 
approval record to be completed: 
• 
Holds an active CTEP status; 
• 
Active status at the site(s) on the IRB/REB approval (applies to US and Canadian sites 
only) on at least one participating organization’s roster; 
• 
If using NCI CIRB, active on the NCI CIRB roster under the applicable CIRB Signatory 
Institution(s) record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile;  
• 
Lists all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in the 
RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol.  
 


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4.2.1 Additional Requirements 
Additional site requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization (PO);  
• 
An active roster affiliation with the NCI CIRB roster under at least one CIRB Signatory 
Institution (US sites only); and 
• 
Compliance with all protocol-specific requirements (PSRs). 
4.2.2 
Protocol specific requirements for A222001 site registration  
Limited access information 
This is a limited access study. Institutions that are interested in participating in this study 
must first contact 
 to review study requirements and 
procedures. See Section 14.1 for instructions regarding how to be added to this trial.  
4.2.3 
Downloading Site Registration Documents 
Download the site registration forms from the protocol-specific page located on the 
CTSU members’ website. Permission to view and download this protocol and its 
supporting documents is restricted to institutions and its associated investigators and staff 
on a participating roster. To view/download site registration forms:   
• 
Log in to the CTSU members’ website 
 using your CTEP-IAM 
username and password; 
• 
Click on Protocols in the upper left of the screen: 
o Enter the protocol number in the search field at the top of the protocol tree; or 
o Click on the By Lead Organization folder to expand, then select [Alliance], 
and protocol number [A222001]. 
Click on Documents, Protocol Related Documents, and use the Document Type filter and 
select Site Registration to download and complete the forms provided. (Note: For sites 
under the CIRB, IRB data will load automatically to the CTSU.) 
4.2.4 
Submitting Regulatory Documents  
Submit required forms and documents to the CTSU Regulatory Office using the 
Regulatory Submission Portal on the CTSU members’ website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to 
the Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission 
Portal should alert the CTSU Regulatory Office immediately by phone or email: 
 in order to receive further 
instruction and support. 
4.2.5 
Checking your site’s registration status  
Site registration status may be verified on the CTSU members’ website.  
• 
Click on Regulatory at the top of the screen; 


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• 
Click on Site Registration; and 
• 
Enter the sites 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, 
Protocol Status, and/or IRB Type. 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling investigator’s 
status with NCI or their affiliated networks. 
4.3 
Patient Registration Requirements 
4.3.1 
Informed consent 
The patient must be aware of the neoplastic nature of his/her disease and willingly consent 
after being informed of the procedure to be followed, the experimental nature of the 
therapy, alternatives, potential benefits, side-effects, risks, and discomforts. Current human 
protection committee approval of this protocol and a consent form is required prior to 
patient consent and registration. 
This study includes the use of the mandatory patient completed measures. The patient 
reported measures are available in English. Participation in Alliance A222001 is restricted 
to patients who are able to speak, understand and read English. 
Patient questionnaire booklets 
Patient questionnaire booklets are to be ordered prior to the registration of any patients. 
Patient completed booklets can be ordered by downloading and completing the CTSU 
supply request form (located under the site registration documents section of the A222001 
CTSU web site) and submitting it through the CTSU regulatory portal. Samples of the 
booklets are found in Appendices I-VII, which are to be used for reference and IRB 
submission only. They are not to be used for patient completion. 
4.4 
Patient Enrollment (registration/randomization procedures (Step 1)) 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and 
with the LPOs registration/randomization systems or the Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/randomization assignment. 
OPEN will populate the patient enrollment data in NCI’s clinical data management 
system, Medidata Rave. 
Requirements for OPEN access:   
• 
A valid CTEP-IAM account; 
• 
To perform enrollments or request slot reservations: Must be on an LPO roster, 
ETCTN corresponding roster, or participating organization roster with the role of 


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Registrar. Registrars must hold a minimum of an Associate Plus (AP) registration 
type; 
• 
If a Delegation of Tasks Log (DTL) is required for the study, the registrars must hold 
the OPEN Registrar task on the DTL for the site; and 
• 
Have an approved site registration for the protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR. If a DTL is required for the study, the IVR or 
NPIVR must be assigned the appropriate OPEN-related tasks on the DTL. 
    Prior to accessing OPEN, site staff should verify the following: 
• 
Patient has met all eligibility criteria within the protocol stated timeframes; and  
• 
All patients have signed an appropriate consent form and Health Insurance Portability 
and Accountability Act (HIPAA) authorization form (if applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. You may print this confirmation for your records.  
Access OPEN at 
or from the OPEN link on the CTSU members’ website. 
Further instructional information is in the OPEN section of the CTSU website at 
For any additional questions, contact the CTSU 
Help Desk at 
 
 
4.5 
Stratification Factors and Treatment Assignments 
The randomization routine is found in Section 13 (Statistical Considerations). 
4.5.1 
Stratification Factors 
Stratification factors include: 
4.5.1.1 Daily hot flash frequency at baseline: 4 to 9 hot flashes per day versus 10 
or more hot flashes per day 
4.5.1.2 Hot flash duration at baseline: less than 9 months versus 9 or more months, 
and 
4.5.1.3 Number of prior hot flash therapies (0 versus 1 or more). 
4.5.2 
Treatment Assignments  
The factors defined in Section 4.5.1 will be used as stratification factors. 
After the patient has been registered into the study, the values of the stratification factors 
will be recorded, and the patient will be assigned to one of the following treatment groups 
using the Pocock and Simon dynamic allocation procedure [41] which balances the 
marginal distributions of the stratification factors between the treatment groups.  
• 
Oxybutynin: 2.5 mL oral BID Days 8 through 49 (total of 42 days) 
• 
Oxybutynin: 5 mL oral BID Days 8 through 49 (total of 42 days)  
• 
Placebo: 2.5 mL oral BID Days 8 through 49 (total of 42 days)  
• 
Placebo: 5 mL oral BID Days 8 through 49 (total of 42 days) 


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Note: Oxybutynin concentration = 1mg/mL.  
4.6 
Procedures for Double-Blinding the Treatment Assignment 
After the treatment assignment has been ascertained by randomization, the Registration 
Specialist will notify the designated unblinded data manager/nurse/pharmacist at the patient’s 
institution. The name of this designated unblinded contact person is to be indicated in the OPEN 
registration system at the time of registration. This contact person may not be involved in 
assessing adverse events or any other outcome measure and should not be the same person 
listed on page one of the OPEN registration form as the person completing the form. The OPEN 
registration form should provide the source of communication, either fax or e-mail, and the 
appropriate contact information. The Registration Specialist will then communicate the 
treatment assignment “Oxybutynin 2.5 mL, Placebo 2.5 mL, Oxybutynin 5 mL or Placebo 5 
mL” to designated contact at the patient’s institution. 
Once the treatment assignment has been communicated, the designated contact should prepare 
the dose of drug or placebo for delivery to the patient.  
The dose will be prepared and labeled as “oxybutynin/placebo” so that the contents are not 
discernible to the person administering the treatment. 
The pharmacist or designated contact person will maintain records that indicate the identity of 
the patient and their corresponding treatment assignment. The pharmacist or designated contact 
person at the treating site will maintain records that indicate the identity of the patient and their 
corresponding study medication code number. 
4.7 
Cross-Over Re-registration (step 2) Procedures  
Patients who complete 6 weeks of study treatment and submit their questionnaires will be 
unblinded per the unblinding procedures in Section 8.3.2. In order to unblind the patient, site 
staff must call the Alliance Registration Office (507-284-4130) during regular business hours to 
find out if the patient was receiving oxybutynin or placebo. Site staff must ensure that the 
questionnaires associated with the initial cycle of treatment have been completed and sent to the 
study staff by the patient before proceeding with unblinding, as these are related to the 
assessment of the primary endpoint of the study.  
If the patient was receiving placebo, he will be allowed to cross over and receive oxybutynin at 
the discretion of the treating physician. 
Patients who choose to enter the cross-over phase will be re-registered as follows:   
1. Site staff will log into the OPEN registration system and select the appropriate patient. 
2. Then select the next registration step. (Step 2) 
3. Complete the OPEN Enrollment Form for the patient to be re-registered for the 
continuation phase. The patient will be re-registered to oxybutynin 2.5 or 5.0 mL, 
equivalent to whichever dose of placebo the patient was receiving prior to unblinding. 
4. Verify the patient turned in their questionnaires for the initial cycle of treatment, yes/no. 
5. Once the re-registration to the crossover phase is successfully completed, a confirmation 
email will be sent to the CRP. 
If assistance is needed with this process, contact the Alliance Registration Office at 
 
Following re-registration, the designated contact will be notified by the CRP so that s/he can 
prepare drug for delivery to the patient. Patient should be told that he may need to come back to 
the clinic to pick up open label supplies.  
 


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5.0 
STUDY CALENDAR 
Pre-study Testing Intervals: 
The pre-study testing intervals are guidelines only. Laboratory and clinical parameters during 
treatment are to be followed using individual institutional guidelines and the best clinical judgment 
of the responsible physician. It is expected that patients on this study will be cared for by physicians 
experienced in the treatment and supportive care of patients on this trial.  
When calculating days of tests and measurements, the day a test or measurement is done is considered 
Day 0. Therefore, if a test were done on a Monday, the Monday one week later would be considered 
Day 7. 
To be completed ≤ 60 DAYS before registration: History and physical.  
 
Prior to 
Registration 
Baseline 
booklets 
(Days 1-7) 
Daily during 
treatment 
(Days 8-49) 
 
End of each week 
of treatment 
 
Tests & Observations 
 
 
 
 
History and physical, 
including Vital signs  
X 
 
 
 
Height, Weight, ECOG PS 
X 
 
 
 
Baseline Symptom 
Documentation (Appendix 
II) 
 
X (1) 
 
 
International Prostate 
Symptom Score- 
(Appendix III) 
X 
 
 
X 
Hot Flash Diary 
(Appendix IV) 
 
 
X 
 
Symptom Experience 
Questionnaire  
(Appendix V) 
 
A (1) 
 
X 
Hot Flash Related Daily 
Interference Scale 
(HFRDIS) (Appendix VI) 
 
A (1) 
 
B(2) 
Telephone Contact and AE 
assessment  
(Appendix VII) 
 
 
 
X (2) 
1 
Nurse/research coordinator should call the patient, to remind him to send in the baseline 
questionnaire booklets to the site, which are required to be completed prior to start of study 
treatment.  
2 
All patients will receive weekly phone calls from study staff (nurse or research coordinator), to 
document compliance with study drug, encourage completion of patient questionnaires, assess 
adverse events, and address any patient concerns or problems. They will also remind the patient to 
return the completed questionnaire booklets. For patients who choose to cross over, nurse phone 
calls will occur weekly to assess adverse events during the unblinded cross over phase. (See 
Section 7.3) 
A 
To be completed on Day 7.  
B 
To be completed at the end of Weeks 2, 4 and 6 only (Weeks 3, 5 and 7 when measured from 
registration).  


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6.0 
DATA SUBMISSION 
6.1 
Data Collection and Submission 
6.1.1 
Data submission schedule 
A Data Submission Schedule (DSS) is available on the Alliance study webpage, within the 
Case Report Forms section. The Data Submission Schedule is also available on the CTSU 
site within the study-specific Case Report Forms folder.  
6.1.2 
Medidata Rave 
Medidata Rave is a clinical data management system being used for data collection for 
this trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system 
and role assignments.  
Requirements to access Rave via iMedidata: 
• 
A valid CTEP-IAM account; and  
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, 
Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
Rave role requirements: 
• 
Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate 
Plus (AP) registration type; 
• 
Rave Investigator role must be registered as an Non-Physician Investigator (NPIVR) 
or Investigator (IVR); and 
• 
Rave Read Only role must have at a minimum an Associates (A) registration type. 
Refer to 
 for registration types 
and documentation required. 
 
This study has a Delegation of Tasks Log (DTL). Therefore, those requiring write access 
to Rave must also be assigned the appropriate Rave tasks on the DTL. 
 
Upon initial site registration approval for the study in Regulatory Support System (RSS), 
all persons with Rave roles assigned on the appropriate roster will be sent a study invitation 
email from iMedidata. To accept the invitation, site staff must either click on the link in 
the email or log in to iMedidata via the CTSU members’ website  under Data Management 
> Rave Home and click to accept the invitation in the Tasks pane located in the upper right 
corner of the iMedidata screen. Site staff will not be able to access the study in Rave until 
all required Medidata and study specific trainings are completed. Trainings will be in the 
form of electronic learnings (eLearnings) and can be accessed by clicking on the eLearning 
link in the Tasks pane located in the upper right corner of the iMedidata screen. If an 
eLearning is required for a study and has not yet been taken, the link to the eLearning will 
appear under the study name in the Studies pane located in the center of the iMedidata 
screen; once the successful completion of the eLearning has been recorded, access to the 
study in Rave will be granted, and a Rave EDC link will replace the eLearning link under 
the study name.  
Site staff that have not previously activated their iMedidata/Rave account at the time of 
initial site registration approval for the study in RSS will receive a separate invitation 
from iMedidata to activate their account. Account activation instructions are located on 


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the CTSU website in the Data Management section under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). Additional information 
on iMedidata/Rave is available on the CTSU members’ website in the Data Management 
> Rave section at 
or by contacting the CTSU Help Desk at 
or by email at 
   
6.1.3 
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to 
manage unanswered queries and form delinquencies, monitor data quality and 
timeliness, generate reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management. 
The Rave Home section displays a table providing summary counts of Total 
Delinquencies and Total Queries. DQP Queries, DQP Delinquent Forms, DQP 
Form Status and the DQP Reports modules are available to access details and 
reports of unanswered queries, delinquent forms, forms with current status and 
timeliness reports. Review the DQP modules on a regular basis to manage 
specified queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to 
the CTSU website. Staff that have Rave study access can access the Rave study 
data using a direct link on the DQP. 
To learn more about DQP use and access, click on the Help icon displayed on the 
Rave Home, DQP Queries, DQP Delinquent Forms, DQP Form Status, and DQP 
Reports modules. 
 
6.2 
Submission of Patient Completed Measures 
Patient-completed questionnaire booklets for this study are to be ordered prior to the registration 
of any patients (see Section 4.3). Samples of questionnaire booklets are available in Appendices 
I-VII for reference and IRB submission only. They are not to be used for patient completion. 
Booklets must be given to patients to complete and patients should be instructed to return the 
booklets to site staff either in person or by mail and site staff will enter patient responses into 
Medidata Rave. At visits in which booklets are to be completed, the booklet should be given to 
the patient before any discussion of the patient’s health status or test results. The PRO 
submission schedule is provided in the Study Calendar.  
Weekly Booklets: Six booklets to be completed weekly must be given to patients to complete 
at home and patients should be instructed to return the booklets by mail weekly or to return the 
booklets at their regularly scheduled clinic visit. Institutions must provide patients with 
sufficient self-addressed stamped envelopes for this purpose. Site staff will enter patient 
responses into Rave upon receipt of the completed booklets. 
Verbal administration of the measures for visually impaired patients is permitted if the verbal 
administration of the measure is conducted in a language understandable to the patients.  
6.2.1 
Patient Language Considerations 
The patient reported measures are available in English. Participation in Alliance A222001 
is restricted to patients who are able to speak, understand and read English. Ad-hoc 
translation of patient-completed measures is not permitted.  
 
 


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7.0 
TREATMENT PLAN/INTERVENTION 
Protocol treatment is to begin ≤ 8 days of registration.  
For questions regarding treatment, please see the study contacts page. 
This is a randomized, double-blind trial. The pharmacist or designated contact (see Section 4.6) at 
the institution will be informed of the patient’s randomization, so that they may prepare oxybutynin 
or placebo for delivery to the patient (see Section 10.0). 
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 dose groups. This allows all 
patients to be blinded as to whether they are receiving active drug or a placebo. 
Patients will be assigned to one of the following treatment groups, and continue to receive treatment 
for 6 weeks (i.e., 42 days): 
 
Days 1-7 
Days 8-49 
Oxybutynin 2.5 mL  
Patients on all arms will be 
asked to complete 
questionnaires as baseline 
symptom documentation on 
Days 1-7, before starting 
study treatment on Day 8. 
Oxybutynin 2.5 mL* PO twice a day 
Placebo 2.5 mL 
Placebo 2.5 mL* PO twice a day 
Oxybutynin 5 mL 
Oxybutynin 5.0 mL* PO twice a day 
Placebo 5.0 mL 
Placebo 5.0 mL* PO twice a day 
* 
Note that the concentration of oxybutynin is 1 mg per 1 ml, so that placebos and active 
treatments will maintain blinding. 
Upon completion of the 6-week study period, patients will be contacted to ensure they have 
completed all required questionnaires. 
7.1 
Baseline Symptom Documentation 
The patient will be instructed not to take any study medication for the first seven days of the 
study, but to complete their daily questionnaires (Baseline Symptom Documentation – 
Appendix II) during this baseline period. At the end of the week, patients will complete 
Symptom Experience Questionnaire (Appendix V) and Hot Flash Related Daily Interference 
Scale (Appendix VI). 
7.2 
Oxybutynin/Placebo 
Beginning on Day 8 of the study, and for the subsequent six weeks, patients will be instructed 
to take their study medication as illustrated below.  
• 
Oxybutynin: 2.5 mL oral BID Days 8 through 49 (total of 42 days) 
• 
Placebo: 2.5 mL oral BID Days 8 through 49 (total of 42 days)  
• 
Oxybutynin: 5.0 mL oral BID Days 8 through 49 (total of 42 days)  
• 
Placebo: 5.0 mL oral BID Days 8 through 49 (total of 42 days) 
7.3 
Patient Unblinding and optional crossover  
Patients will be contacted on their last scheduled day of the study treatment.  It should be assured 
that the patient has completed his questionnaires. Then the patient may be unblinded per the 
procedures described in Section 8.3.  


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If the patient was receiving placebo, he may choose to crossover to oxybutynin 2.5 or 5.0 mL, 
equivalent to whichever dose of placebo the patient was receiving prior to unblinding. This 
crossover will require a second registration (see Section 4.7 for re-registration instructions). The 
duration of treatment for patients who crossover will be 6 weeks.  
8.0 
DOSE AND TREATMENT MODIFICATIONS, UNBLINDING  
8.1 
Ancillary Therapy, Concomitant Medications, and Supportive Care 
8.1.1 
Patients should not receive any other treatment or participate in trials which would 
be considered treatment for hot flashes or impact the primary endpoint. 
Simultaneous enrollment on other treatment studies is not allowed during the 7 week 
study period.  
8.1.2 
Patients should receive full supportive care while on this study.  This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions.  All blood products and concomitant medications such as 
antidiarrheals, analgesics, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose will be recorded in the medical 
records. 
8.1.3 
Treatment of the patient’s cancer should not be influenced by this study. If the 
patient stops ADT while participating in the study, it should be recorded on the study 
forms. 
8.2 
Dose Modifications 
Dose modifications to the patient’s cancer treatment are up to the discretion of the treating 
physician.  During participation in the study, if the patient develops any symptoms attributed to 
the drug that are considered to be of unacceptable severity by the patient and/or physician, 
oxybutynin/placebo doses will be adjusted as follows: 
Dose modifications for adverse events 
Low Dose 
(2.5 mL BID) 
Maintain prescribed dose, but decrease frequency from BID to once 
daily. 
If symptoms are still unacceptable by the patient and/or physician, 
drug will be discontinued and patient will be taken off study. 
High Dose 
(5.0 mL BID) 
If toxicity occurs, decrease dose from 5 mL BID to 2.5 mL BID. If 
symptoms persist, decrease dose from 2.5 mL BID to 2.5 mL once 
daily. If symptoms are still unacceptable by the patient and/or 
physician, the drug will be discontinued and patient will be asked to 
complete questionnaires to date and then be taken off study. 
Urinary retention:  For patients on both doses, if at any time during treatment, the patient 
develops severe urinary symptoms, he should immediately discontinue study treatment and get 
a post void residual ultrasound assessment as clinically indicated.  
 
 


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8.3 
Unblinding Procedures  
Unblinding can be done only in cases of an emergency or at the end of study treatment. Follow 
the directions below to unblind patient treatment. Please note that if a treatment assignment is 
unblinded, the patient must discontinue protocol therapy. 
8.3.1 
Emergency Unblinding Procedures 
Examples of emergencies include 1) a life-threatening unexpected adverse event that is at 
least possibly related to the investigational agent and for which unblinding would influence 
treatment decisions; or 2) medication error, such as accidental overdose. Expected adverse 
events are listed in the “Toxicities” section below.  
Contact the Alliance Executive Officer on call by calling 
 
  
The institution must provide the following information to the Alliance Executive Officer:  
• 
Alliance study ID (i.e., “A222001”)  
• 
Alliance patient ID number (e.g., “999999”)  
• 
Patient initials (e.g., “L,F,M”)  
• 
Institution name  
• 
Name and telephone number of treating physician  
• 
Name and contact information of person requesting the unblinding procedure  
• 
Name and contact information of person to inform of treatment assignment  
• 
Reason for emergency unblinding  
Please remember that emergency unblinding request may be authorized only by an Alliance 
Executive Officer, and emergency unblinding applies only if unblinding would influence 
management of the medical situation. After the Executive Officer deems unblinding is 
warranted, the treatment assignment will be provided to the contact person at the treating 
site. 
8.3.2 
Protocol-specified unblinding—Crossover Unblinding at end of treatment 
The steps for unblinding a patient upon completion of study treatment are as follows:  
1. Patient has completed 6 weeks of study treatment.  
2. Site completes the form documenting end of treatment in Rave. 
3. Site calls the registration office to unblind the patient; registration office confirms 
receipt of the end of treatment form with statistics and data center in order to 
communicate patient treatment assignment to site. 
Contact the Alliance Registration Office at 
during regular business hours. 
Upon confirmation by the Primary Statistician (or designee) that the criteria for unblinding 
have been met, the treatment assignment may be unblinded. No Alliance Executive Officer 
(or designee) approval is required.  
 
 


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9.0 
ADVERSE EVENTS 
The prompt reporting of adverse events is the responsibility of each investigator engaged in clinical 
research, as required by Federal Regulations. Adverse events must be described and graded using the 
terminology and grading categories defined in the NCI’s Common Terminology Criteria for Adverse 
Events 
(CTCAE), 
Version 
5.0. 
The 
CTCAE 
is 
available 
at 
 
Attribution 
to 
protocol 
treatment for each adverse event must be determined by the investigator and reported on the required 
forms. Please refer the NCI Guidelines: Adverse Event Reporting Requirements for further details 
on AE reporting procedures.  
9.1 
Routine Adverse Event Reporting 
Adverse event data collection and reporting, which are required as part of every clinical trial are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at scheduled 
times according to the study calendar in Section 5.0.  
9.1.1 
Solicited adverse events 
There are no additional solicited adverse events for this trial.  
9.2 
CTCAE Routine Reporting Requirements 
The following table outlines the combinations of time points, grades and attributions of AEs that 
require routine reporting to the Alliance Statistics and Data Center. Questions about routine 
reporting should be directed to the Data Manager. 
Combinations of CTCAE Grade & Attribution Required for Routine AE Data Submission on 
Case Report Forms (CRFs) 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
 
 
a 
a 
a 
Unlikely 
 
 
a 
a 
a 
Possible 
 
a 
a, b 
a, b 
a, b 
Probable 
 
a 
a, b 
a, b 
a, b 
Definite 
 
a 
a, b 
a, b 
a, b 
a) Adverse Events: Other CRF - Applies to AEs occurring between registration and within 
30 days of the patient’s last treatment date, or as part of the Clinical Follow-Up Phase. 
b) Adverse Events: Late CRF - Applies to AEs occurring greater than 30 days after the 
patient’s last treatment date. 
 
 


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9.3 
Expedited Adverse Event Reporting (CTEP-AERS) 
Investigators are required by Federal Regulations to report serious adverse events as defined in 
the table below. The descriptions and grading scales found in the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting.  The CTCAE 
is 
identified 
and 
located 
on 
the 
CTEP 
website 
at: 
 
All 
appropriate 
treatment areas should have access to a copy of the CTCAE. All reactions determined to be 
“reportable” in an expedited manner must be reported using the Cancer Therapy Evaluation 
Program Adverse Event Reporting System (CTEP-AERS). 
For further information on the NCI requirements for SAE reporting, please refer to the ‘NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements’ document published by 
the NCI.  
Note:  All deaths on study require both routine and expedited reporting regardless of causality.  
Attribution to treatment or other cause should be provided. 
9.3.1 
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last 
Administration of the Investigational Agent/Intervention1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 
10 calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 


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agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
9.3.2 
Expedited AE reporting timelines defined 
• 
“24 hours; 5 calendar days” – The investigator must initially report the AE via 
CTEP-AERS ≤ 24 hours of learning of the event followed by a complete CTEP-
AERS report ≤ 5 calendar days of the initial 24-hour report. 
• 
“10 calendar days” - A complete CTEP-AERS report on the AE must be submitted 
≤ 10 calendar days of the investigator learning of the event.  
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization 
(or prolongation of existing hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected with the exception of any events identified as 
protocol-specific expedited adverse event reporting exclusions (see below). 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported via CTEP-AERS if the event occurs following 
treatment with an agent under an IND. 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
9.3.3 
Additional Instructions or Exclusions to CTEP-AERS Expedited Reporting 
Requirements  
All adverse events reported via CTEP-AERS (i.e., serious adverse events) should also be 
forwarded to your local IRB. 
Alliance A222001 uses a drug under an Alliance IND. The reporting requirements for 
investigational agents under a CTEP IND should be followed for all agents (any arm) in 
this trial. 
Treatment expected adverse events include those listed in Section 10.0 and in the package 
insert. 
CTEP-AERS reports should be submitted electronically. 
Death 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in 
the system organ class (SOC) “General disorders and administration site conditions.” 
Evidence that the death was a manifestation of underlying disease (e.g., radiological 
changes suggesting tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted.  
Any death occurring within 30 days of the last dose, regardless of attribution to the 
investigational agent/intervention requires expedited reporting within 24 hours.  


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Any death occurring greater than 30 days after the last dose of the investigational 
agent/intervention requires expedited reporting within 24 hours only if it is possibly, 
probably, or definitely related to the investigational agent/intervention. 
New Malignancies 
All new malignancies must be reported via CTEP-AERS whether or not they are thought 
to be related to either previous or current treatment. All new malignancies should be 
reported, i.e. solid tumors (including non-melanoma skin malignancies), hematologic 
malignancies, myelodysplastic syndrome/acute myelogenous leukemia, and in situ tumors.  
Whenever possible, the CTEP-AERS reports for new malignancies should include tumor 
pathology, history or prior tumors, prior treatment/current treatment including duration, 
any associated risk factors or evidence regarding how long the new malignancy may have 
been present, when and how the new malignancy was detected, molecular characterization 
or cytogenetics of the original tumor (if available) and of any new tumor, and new 
malignancy treatment and outcome, if available. 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent 
under an NCI IND/IDE be reported via CTEP-AERS. Three options are available to 
describe the event:  
• 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• 
Myelodysplastic syndrome (MDS)  
• 
Treatment-related secondary malignancy  
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via Rave.  
Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT 
a metastasis from the initial malignancy).  Second malignancies require ONLY routine 
reporting unless otherwise specified. 
10.0 DRUG INFORMATION 
10.1 
Oxybutynin Chloride Oral Syrup (Ditropan) 
IND: Alliance A222001 uses Oxybutynin under an Alliance IND. 
Procurement  
Oxybutynin Chloride 5mg/5 mL oral syrup (473 mL) and ORA-Sweet® Solution (473 mL) stock 
bottles will be provided and shipped by McKesson Clinical Research Services to sites.  
After receiving IRB approval for this study, each participating institution will order a starter 
supply of three bottles of oxybutynin oral syrup and two bottles of ORA-Sweet® solution from 
McKesson Clinical Research Services by faxing or emailing the Alliance Clinical Drug 
Order/Return Form to: 


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The A222001 Oxybutynin/Placebo Order Form can be found on the A222001 study page of the 
Alliance and CTSU websites. 
Each site is responsible for monitoring their inventory and ordering additional bottles as needed.  
Each site will provide their own 16 oz. amber bottles. 
Sites are also expected to provide each patient with an oral syringe to measure and take their 
medication, along with instructions for rinsing and reusing it for the duration of the study.  
Main member institutions will be provided a per patient reimbursement by the Alliance for their 
rebottling services and supplies.   
Within ninety days after the last patient is treated at the institution, any expired or remaining 
supplies should be destroyed according to institutional procedure. 
Preparation 
The designated unblinded person at each institution will transfer either oxybutynin chloride 5 
mg/5 mL oral syrup or ORA-Sweet® solution into one 16 oz amber bottles based on the patient’s 
treatment assignment.  This should be a sufficient supply for the entire 42 days of treatment.  
The bottles will be labeled “oxybutynin 5 mg/5 mL or placebo solution”.  A maximum 
expiration date of 6 months should be assigned to the dispensed bottles. If drug supply will 
expire less than 6 months from the dispense date, then site must confirm that sufficient in-date 
supply is available for the duration of intervention.  
 
Below is the label template for the blinded phase: 
RX#___________________DATE_________________ 
PT NAME ____________________________________ 
INVESTIGATOR ______________________________ 
 
Study A222001: Take by mouth twice daily for 42 days as directed by the study team.  
 
Oxybutynin 5mg/5ml or Placebo Oral Syrup 
Dispense: 473ml       Expiration Date:  ____________ 
Store at room temperature, 15– 30 °C (59 to 86°F) 
Sponsor: 
 
 
CAUTION: NEW DRUG -LIMITED BY FEDERAL (OR UNITED STATES) LAW TO 
INVESTIGATIONAL USE ONLY 
 
For patients who are re-registered to the cross over phase, the bottles need to be open label 
“Oxybutynin 2.5 or 5.0 mL” depending on which dose the patient is assigned to receive.  
 


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Below is the label template for the cross over phase: 
 
RX#___________________DATE_________________ 
PT NAME ____________________________________ 
INVESTIGATOR ______________________________ 
 
Study A222001: Take by mouth twice daily for 42 days as directed by the study team.  
 
Oxybutynin 5mg/5ml Oral Syrup 
Dispense: 473ml       Expiration Date:  ____________ 
Store at room temperature, 15– 30 °C (59 to 86°F) 
Sponsor: 
 
 
CAUTION: NEW DRUG -LIMITED BY FEDERAL (OR UNITED STATES) LAW TO 
INVESTIGATIONAL USE ONLY 
 
Drug Accountability 
Drug accountability logs must be kept for the oxybutynin 5 mg/5 mL oral syrup and the ORA-
Sweet® oral solution. 
Investigator Brochure Availability 
The current version of the package insert for the agents will be accessible to site investigators 
and research staff through the Alliance office. 
Availability 
Oxybutynin oral syrup is available as 5 mg/5mL concentration with raspberry flavor.  The 
solution contains citric acid, D&C Yellow No 10, FD&C Blue No 1, glycerin, liquid sugar, 
methylparaben, propylene glycol, sodium citrate, and sorbitol solution.   
Storage and Stability 
Store at Controlled Room Temperature, 15–30°C (59–86°F). 
Administration 
Oxybutynin/placebo will be administered at a dosage of either 2.5mg/2.5ml or 5mg/5ml two 
times daily. Study medication can be taken with or without food.  
Drug Interactions 
The concomitant use of oxybutynin with other anticholinergic drugs or with other agents 
which produce dry mouth, constipation, somnolence (drowsiness), and/or other 
anticholinergic-like effects may increase the frequency and/or severity of such effects. 
Anticholinergic agents may potentially alter the absorption of some concomitantly 
administered drugs due to anticholinergic effects on gastrointestinal motility. Anticholinergic 
agents may also antagonize the effects of prokinetic agents, such as metoclopramide.  
Mean oxybutynin plasma concentrations were approximately 3 to 4 fold higher when 
oxybutynin chloride tablets were administered with ketoconazole, a potent CYP3A4 inhibitor.  


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Other CYP3A4 inhibitors, such as antimycotic agents (e.g., itraconazole and miconazole) or 
macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter oxybutynin mean 
pharmacokinetic parameters. The clinical relevance of such potential interactions is not 
known. Caution should be used when such drugs are co-administered. 
Pharmacokinetics  
Time to peak concentration: Oral: 0.89 + 0.34 hours. Oxybutynin contains both the R- and S-
isomers, the R-isomer contributes most to the antimuscarinic activity of oxybutynin. 
Bioavailability: The absolute bioavailability of oxybutynin is 6%, although there is wide 
interindividual variation following oral administration. Food slightly delays absorption and 
increases bioavailability by 25%. 
Metabolism: Hepatic, extensive particularly the CYP3A4 isoenzyme 
Half-life elimination: Normal renal function: 2-3 hours 
Excretion: Renal, less than 0.1% unchanged as parent compound or as the metabolite N-
desethyloxybutynin.  
Adverse Events 
Consult the package insert for the most current and complete information.  
Following administration of oxybutynin chloride, the following symptoms may occur:  
Cardiovascular: Palpitations, tachycardia, vasodilatation  
Dermatologic: Decreased sweating, rash  
Gastrointestinal/Genitourinary: Constipation, decreased gastrointestinal motility, dry mouth, 
nausea, urinary hesitance and retention  
Nervous System: Asthenia, dizziness, drowsiness, hallucinations, insomnia, restlessness  
Ophthalmic: Amblyopia, cycloplegia, decreased lacrimation, mydriasis  
Other: Impotence, suppression of lactation 
Nursing Guidelines 
1. Use extreme caution when oxybutynin is administered with any other anticholinergic 
agents as increased side effects can occur (i.e. dry mouth, constipation, somnolence).  
2. Instruct patients to report any palpitations or tachycardia to the study team. 
3. Patients may experience rash. Inform patients to report skin changes to the study team. 
4. Warn patients that they may have decreased sweating abilities. They should use caution 
if out in the heat and to avoid becoming overheated.  
5. Gastrointestinal effects can be seen including constipation, decreased GI motility, 
nausea, vomiting, and dry mouth. Treat symptomatically and monitor for effectiveness. 
6. Warn patients of possible urinary hesitation and retention. If patient has difficulty 
voiding they should report this to the study team immediately. 
7. Patients may experience neurologic side effects including dizziness, hallucinations, 
drowsiness and/or insomnia. Instruct patients to use caution when operating a vehicle 
or other activities that require close attention until they know how they respond to agent. 


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8. Effects on the eye can include amblyopia (lazy eye), cycloplegia (paralysis of ciliary 
muscle-leading to inability to focus on close objects), decreased tears and mydriasis 
(abnormal pupil dilation).  Instruct patient to report any of these to the study team. 
9. Warn men that this agent can cause impotence and suppress lactation in women. 
10.2 
Placebo Oral Solution  
Procurement 
Please see ordering instructions in Section 10.1, for both active agent and placebo.  
The placebo for this study will be ORA-Sweet® SF and ORA-Sweet® .  ORA-Sweet® SF and 
ORA-Sweet® are a berry citrus flavored inert syrup vehicle. The ORA-Sweet® SF contains 
purified water, sorbitol, sodium saccharin, xanthan gum, and flavoring. It is buffered with 
citric acid and sodium phosphate, and preserved with methylparaben, propylparaben, and 
potassium sorbate. ORA-Sweet® SF contains FD&C Red#40 and is sugar-free and alcohol-
free. ORA-Sweet® contains purified water, sucrose, glycerin, sorbitol, and flavoring. It is 
buffered with citric acid and sodium phosphate, and preserved with methylparaben and 
potassium sorbate.  
Storage and Stability 
Store at Controlled Room Temperature, 15–30°C (59–86°F). Store in original container, 
protected from direct sunlight and moisture.  
 
 


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11.0 MEASURES 
Before they start treatment and during the course of study treatment, patients will be asked to assess 
the severity of their hot flashes (descriptions provided in Appendix I) and complete a baseline 
symptoms determination (Appendix II) (Week 1 only),  daily Hot Flash Diaries (Appendix IV), along 
with weekly Symptom Experience Questionnaires (Appendix V). The Hot Flash Related Daily 
Interference Scale (HFRDIS) (Appendix VI) will be completed prior to initiation of and at the 
conclusion of study treatment. All patients will receive weekly phone calls from study staff 
(Appendix VII) to document compliance with study drug, encourage completion of requisite study 
questionnaires, collect adverse events and address any patient concerns or problems. 
11.1 
Baseline Symptom Determination (Appendix II) 
The baseline symptoms determination is completed after registration and randomization but 
prior to initiation of study treatment. This form has patients record the number of total hot flashes 
they experience on a daily basis, along with the number of hot flashes according to severity 
(mild, moderate, severe, or very severe) over the first 7 days of the study period. It is estimated 
that completing the baseline symptom determination will take 3-5 minutes daily. Questionnaires 
should be returned to the investigator at the end of the baseline week (week 1) and at the end of 
treatment (i.e., after the 7th week following study entry).  The patient should be supplied with 
two addressed/stamped envelopes for returning the forms. 
11.2 
International Prostate Symptom Score (IPSS) (Appendix III) 
This tool has been added to this study at screening and to be completed at the end of every week 
of treatment in response to FDA recommendations to ensure that patients do not have urinary 
retention issues. This is an 8-item scale, widely used in clinical practice, which measures lower 
urinary tract symptoms. It includes questions encompassing incomplete bladder emptying, 
frequent urination, urgency, nocturia, intermittency, weak stream, straining, and quality of life 
related to urinary symptoms[42]. 
There are robust data to suggest that prostate cancer patients on active surveillance experience 
significantly decreased urinary health relative to men without prostate cancer. In a cohort 
analysis of 6,000 community dwelling older men, we observed that compared to men without 
prostate cancer, men with prostate cancer on active surveillance (i.e. those who had not 
undergone treatment) reported a significantly diminished quality of life due to urinary 
symptoms[43]. 
11.3 
Hot Flash Diary (Appendix IV) 
The Hot Flash Diary is completed daily during each of the 6 weeks that patients are taking the 
study treatment. Like the Baseline Symptom Determination, the form has patients report the 
number and severity of their daily hot flashes. Additionally, it has them report how many doses 
of the study drug they took on each day. Completion of the Hot Flash Diary is anticipated to 
take less than a minute per day. 
11.4 
Symptom Experience Questionnaire (Appendix V) 
The Symptom Experience Questionnaire is collected at the end each of the 7 weeks of the study 
period. This form collects patient reported toxicity and quality of life data using a 0-10 scale, 
with one question that allows an unstructured response to report symptoms not captured in the 
questions provided. Estimated completion time for the Symptom Experience Questionnaire is 
10-15 minutes each week.  


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11.5 
Hot Flash Related Daily Interference Scale (HRFDIS) (Appendix VI) 
Hot Flash Related Daily Interference Scale (HFRDIS), a tool developed by Dr. Janet 
Carpenter.[33]  We recently asked 10 men with androgen deprivation hot flashes, to review this 
tool.  All of the HFRDIS items were assessed as clear, appropriate, and easy to interpret. The 
items related to work and sexuality were identified as potentially difficult to answer if the 
individual was retired or not sexually active, however all of the men were able to provide a 
numeric score for these items. We also discussed the above with Dr. Janet Carpenter, who 
developed the HFRDIS tool and have identified other studies that have used the HFRDIS in men 
receiving androgen deprivation therapy [34-36]. These studies provide additional data 
supporting the reliability and validity of the 10-item instrument in this population.  
The Hot Flash Related Daily Interference Scale is to be completed by all participants at baseline 
(Week 1) and at the conclusion of the study (Week 7). It will also be completed at the end of 
Weeks 2 and 4 of study treatment, as it asks questions related to hot flashes over the past two 
weeks.  This 10-item questionnaire uses a 1-10 scale to assess the interference caused by hot 
flash symptoms with specific aspects of patients’ personal lives. Each completion of the 
HFRDIS is expected to take 5 minutes. 
11.6 
Nurse Telephone Contact (Appendix VII)  
All patients will receive weekly phone calls from study staff, to document compliance with 
study drug, encourage completion of requisite study questionnaires, and address any patient 
concerns or problems and assess adverse events. The nurse weekly phone calls will continue 
during the optional cross over phase, to assess and collect adverse events during this time.  
12.0 END OF TREATMENT/INTERVENTION 
12.1 
Duration of Protocol Treatment  
Protocol treatment is to continue for 6 weeks from the time of start of treatment. Please see the 
study calendar (Section 5.0) and the treatment section (Section 7.0) for treatment and follow up 
time periods. 
12.2 
Criteria for Discontinuation of Protocol Treatment/Intervention 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
• 
Disease progression (if applicable) 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patient decides to withdraw from the study 
• 
General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
• 
Patient non-compliance 
• 
Termination of the study by sponsor 
• 
The drug manufacturer can no longer provide the study agent (if applicable) 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 


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12.3 
Follow-up  
12.3.1 Duration of Follow-up  
Protocol treatment is to continue for 6 weeks. Please follow the data submission 
requirements outlined in the study calendar (Section 5.0). There is no further clinical or 
survival follow up beyond the 6-week study period. For patients who participate in the 
optional crossover phase, there will be a 6-week follow up.  
12.3.2 Follow-up for Patients who Stop Study Treatment Early  
Protocol treatment is to continue for 6 weeks. Patients who do not complete 6 weeks of 
protocol treatment for any reason will still be expected to follow the data submission 
requirements outlined in the study calendar (Section 5.0) and will thus be followed up until 
6 weeks post-randomization. 
Follow up for patients who stop due to toxicity 
If the patient decides to discontinue the study medication because of unacceptable side 
effects, he is to call the study nurse.  The patient should be encouraged to complete 
diaries/questionnaires to date and send them in. The patient can then be taken off study. 
The off-study date to be used is either (1) the day after the patient took some study 
medication OR (2) the day after the patient last recorded some research data on the patient 
questionnaire--whichever occurred last. 
12.4 
Extraordinary Medical Circumstances 
If, at any time the constraints of this protocol are detrimental to the patient's health and/or the 
patient no longer wishes to continue protocol therapy, protocol therapy shall be discontinued. In 
this event: 
• 
Document the reason(s) for discontinuation of therapy on data forms. 
• 
Follow the patient for protocol endpoints as required by the Study Calendar. 
12.5 
Managing ineligible patients and registered patients who never receive protocol 
intervention  
Definition of ineligible patient 
A study participant who is registered to the trial but does not meet all of the eligibility criteria 
is deemed to be ineligible.  
Follow-up for ineligible patients who continue with protocol treatment 
Patients who are deemed ineligible after registering may continue protocol treatment, provided 
the treating physician, study chair, and executive officer agree there are no safety concerns if 
the patient continues protocol treatment. All scans, tests, and data submission are to continue as 
if the patient were eligible. Notification of the local IRB may be necessary per local IRB 
policies. 
Follow-up for ineligible patients who discontinue protocol treatment 
For patients who are deemed ineligible after registering to the trial, who start treatment, but then 
discontinue study treatment, the same data submission requirements are to be followed as for 
those patients who are eligible and who discontinue study treatment. 
Follow-up for patients who are registered, but who never start study treatment 
For all study participants who are registered to the trial but who never receive study intervention 
(regardless of eligibility), the follow-up requirements are specified below:  


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Baseline and off-treatment notice data submission required. See the Data Submission Schedule 
accompanying the All Forms Packet. 
13.0 STATISTICAL CONSIDERATIONS 
13.1 
Overview 
This randomized four-arm, double-blind, placebo-controlled phase II trial will assess the 
efficacy and safety of oxybutynin for reducing hot flash scores in men receiving androgen 
deprivation therapy. The primary endpoint of this phase II trial is hot flash scores at 6 weeks 
post-randomization. All analyses will follow an intent-to-treat approach that includes all 
randomized patients who meet eligibility criteria. 
13.2 
Study Design 
Patients will be randomly assigned to oxybutynin at 2.5 mL twice daily, oxybutynin at 5.0 mL 
twice daily, placebo at 2.5 mL twice daily, or placebo at 5.0 ml twice daily in a 2:2:1:1 ratio 
according to the dynamic allocation scheme. Stratification factors will include daily hot flash 
frequency at baseline (4 to 9 hot flashes per day versus 10 or more hot flashes per day), hot flash 
duration at baseline (less than 9 months versus 9 or more months), and number of prior hot flash 
therapies (0 versus 1 or more). The study design includes two placebo arms to match the dose 
of the two oxybutynin arms; however, patients randomized to the two placebo arms will be 
combined to form a single placebo arm for analysis. All analyses will follow an intent-to-treat 
approach that includes all randomized patients who meet eligibility criteria. 
13.3 
Study Endpoints 
Important endpoints for this phase II trial relate to (1) efficacy of oxybutynin as measured by 
hot flash scores (primary) and hot flash frequency, (2) safety as measured by the presence of 
CTCAE v5.0-determined grade 3 or higher adverse events, (3) tolerability as measured by 
relevant patient-reported symptoms on the Symptom Experience Questionnaire (Appendix V), 
(4) feasibility regarding the conduct of this trial as measured by patient accrual and treatment 
adherence, and (5) patient-reported quality of life and hot flash interference as measured by the 
Hot Flash Related Daily Interference Scale (HFRDIS; Appendix VI). 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. Hot flash scores and frequencies will be measured 
by patients’ hot flash diaries (Appendix IV). Daily hot flash scores will be computed by 
multiplying the frequency of each hot flash grade within a 24-hour period by the severity of the 
hot flash (grade 0: none, 1: mild, 2: moderate, 3: severe, and 4: very severe) and then summing 
all the values. Weekly hot flash scores will be computed by averaging these hot flash scores 
across the 7 days of each week. Weekly hot flash scores will be computed as long as hot flash 
scores from at least 1 of the 7 days of each week are available. However, the number of missing 
(daily) hot flash scores each week will be tabulated. 
13.4 
Analysis Plan 
To assess efficacy, a mixed model will be estimated that includes baseline and weekly hot flash 
scores across the 6-week treatment period. The mixed model will include a fixed intercept; fixed 
effect for time, arm, and arm by time interaction; and residual covariance matrix based on the 
observed covariances. Alternative structures will be investigated for the residual covariance 
matrix, with final selection based on convergence of the mixed model and minimization of the 
Akaike information criterion. Stratification factors used in the randomization as well as baseline 
patient characteristics and prognostic factors may be included in the mixed model as covariates 
if imbalances across arms occur. For this mixed model, time will be treated as nominal (not 
continuous), such that the mixed model will not be making assumptions about the trajectory of 


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patients’ hot flash scores over time. 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 post-randomization between the oxybutynin and placebo arms (i.e., Arm A versus Arms 
C and D combined; Arm B versus Arms C and D combined). To control the Type I error rate, a 
fixed sequence procedure will be employed such that the following two tests will be sequenced 
rather than conducted simultaneously. Hot flash score reduction from baseline to 6 weeks will 
be compared across patients assigned to oxybutynin at 5.0 mL twice daily (Arm B) and patients 
assigned to placebo (Arms C and D combined) using a contrast estimated via the mixed model. 
The contrast will involve a two-sided t-test with a nominal significance level of α = .10. If and 
only if this test is significant, hot flash score reduction from baseline to 6 weeks will be formally 
compared across patients assigned to oxybutynin at 2.5 mL twice daily (Arm A) and patients 
assigned to placebo (Arms C and D combined) using a second contrast estimated via the mixed 
model. This contrast will also involve a two-sided t-test with a nominal significance level of 
α = .10. The proposed sequencing is based on the assumption that the effect of oxybutynin will 
increase monotonically with respect to dose. If p ≤ .10 for both tests, we will conclude that both 
dosing schedules significantly improved hot flash scores at 6 weeks relative to placebo. If 
p ≤ .10 for the first test but p > .10 for the second test, we will conclude that the higher dosing 
schedule significantly improved hot flash scores at 6 weeks relative to placebo but that the lower 
dosing schedule did not significantly improve hot flash scores at 6 weeks relative to placebo. 
Finally, if p > .10 for the first test, we will conclude that neither dosing schedule significantly 
improved hot flash scores at 6 weeks relative to placebo. In practice, if p > .10 for the first test, 
we will still conduct the second test, but as an exploratory analysis rather than as a primary 
analysis. We will also conduct a responder analysis at 6 weeks comparing the proportion of 
patients who experience a clinically significant improvement in hot flash scores since baseline 
across the oxybutynin and placebo arms using Fisher’s exact test, χ2 test, or logistic regression. 
Stratification factors used in the randomization as well as baseline patient characteristics and 
prognostic factors may be included in the logistic regression model as covariates if imbalances 
across arms occur. A clinically significant improvement will be defined as a 50% or greater 
reduction in hot flash scores since baseline based on preliminary evidence suggesting that 
patients consider a 50% or greater reduction in frequency of moderate to severe hot flashes to 
be a meaningful improvement.[41, 42] Patients who experience a 50% or greater reduction in 
hot flash scores since baseline will be deemed responders, while the remaining patients 
(including those with missing hot flash scores) will be deemed non-responders. As an 
exploratory analysis, we will investigate whether these efficacy results differ when using a 
single day rather than a full week to define patients’ baseline hot flash scores. 
Weekly hot flash frequencies (as opposed to weekly hot flash scores) will be compared across 
the oxybutynin and placebo arms in a manner similar to above using a mixed model that 
accounts for the observed distribution of weekly hot flash frequencies. A fixed sequence 
procedure will be employed. For the responder analysis, patients who experience a 50% or 
greater reduction in hot flash frequency since baseline will be deemed responders, while the 
remaining patients (including those with missing hot flash frequencies) will be deemed non-
responders. Finally, 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). 
To assess safety, the proportion of patients experiencing a grade 3 or higher adverse event will 
be summarized by arm. We expect this proportion to be extremely low for all arms. 
To assess tolerability, mixed models similar to the one described above will be estimated that 
include baseline and weekly patient-reported symptoms as measured by the Symptom 


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Experience Questionnaire (Appendix V) across the 6-week treatment period. A single mixed 
model will be developed for each patient-reported symptom. Estimates from the mixed models 
will be used to construct 90% confidence intervals for mean differences in patient-reported 
symptoms between the oxybutynin and placebo arms (i.e., Arm A versus Arms C and D 
combined; Arm B versus Arms C and D combined) at 6 weeks post-randomization. Contrasts 
estimated via the mixed models will involve a two-sided t-test with a nominal significance level 
of α = .10. 
To assess feasibility, the time required to accrue 87 patients will be reported. To move forward 
with a phase III trial, an average accrual rate of 4 patients per month (starting 4 months after 
enrollment begins, to account for the time required for multiple institutions to activate the trial) 
would be desired. The treatment adherence rate (i.e., the number of patients who completed 
treatment per protocol divided by the number of patients who started treatment) will be 
summarized by arm. 
To assess patient-reported quality of life and hot flash interference, mixed models similar 
to the one described above will be estimated that include patients’ scores on the HFRDIS 
(Appendix VI) across the 6-week treatment period. A single mixed model will be developed for 
each HFRDIS item. Estimates from the mixed models will be used to construct 90% confidence 
intervals for mean differences in patient-reported quality of life and hot flash interference 
between the oxybutynin and placebo arms (i.e., Arm A versus Arms C and D combined; Arm B 
versus Arms C and D combined) at 6 weeks post-randomization. Contrasts estimated via the 
mixed models will involve a two-sided t-test with a nominal significance level of α = .10. 
Attempts to minimize missing data will be made through site training and data monitoring (e.g., 
form delinquency notifications, queries; see Section 6.1.3). The proportion of, and reported 
reasons for, missing data will be presented by time point and arm. Correlation analysis and 
logistic regression analysis will be used to examine whether baseline patient characteristics and 
prognostic factors predict missingness. The primary analysis will provide unbiased parameter 
estimates under a missing completely at random or missing at random mechanism. However, a 
sensitivity analysis will be conducted to assess the robustness of the results across various 
assumptions about the missing data. 
13.5 
Sample Size and Power 
As this is a pilot trial, the sample size was determined based on feasibility and logistical 
considerations rather than on power for hypothesis testing. We aim to enroll 26 evaluable 
patients per oxybutynin arm and 13 evaluable patients per placebo arm (i.e., 78 evaluable 
patients total). For the primary aim, 26 evaluable patients per oxybutynin arm and 13 evaluable 
patients per placebo arm with 6 weekly hot flash scores provide 76% power to detect a mean 
difference in hot flash score reduction from baseline when comparing each oxybutynin arm (5.0 
mL twice daily or 2.5 mL twice daily  to the placebo arm (both placebo arms combined) based 
on a two-sided t-test estimated via a mixed model, nominal significance level of α = .10, 
intraclass correlation of .50, and population standardized mean difference of 0.50 (i.e., Cohen’s 
convention for a moderate effect size)[44]. In a similar study in women, Cohen’s d equaled 0.85 
when comparing the higher dose oxybutynin arm (2.5 mL twice daily escalated to 5.0 mL twice 
daily) to the placebo arm, and Cohen’s d equaled 0.54 when comparing the lower dose 
oxybutynin arm (2.5 mL twice daily) to the placebo arm [45]. An additional 9 patients will be 
accrued to account for a 10% loss in sample size due to ineligibility, major treatment violation, 
or cancellation. Maximum projected accrual is, therefore, 87 patients. 


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13.6 
Accrual Time and Study Duration 
The anticipated accrual rate is approximately 7 patients per month, based on our most-recent 
previous male hot flash trial (conducted 15 years ago to evaluate gabapentin) and recent survey 
information. Therefore, the accrual period for this phase II trial is expected to be 13 months. 
The final analysis is predicted to begin approximately 15 months after the trial begins (i.e., as 
soon as the last patient has been observed for 6 weeks). 
13.7 
Data and Safety Monitoring 
The study chair(s) and the study statistician will review the study at regular intervals to identify 
accrual and adverse events. The Alliance Data Safety Monitoring Board (DSMB) is responsible 
for reviewing accrual and safety data for this trial at least twice a year, based on reports provided 
by the Alliance Statistics and Data Management Center (SDMC). 
Required submission of patient demographic data for this study will be submitted automatically 
via OPEN.   
Note: Serious adverse events must be submitted via CTEP-AERS per protocol guidelines. 
13.7.1 Adverse Event Stopping Rules 
The stopping rules specified below are based on the knowledge available at study 
development. We note that the adverse event stopping rule may be adjusted in the event of 
either (1) the study re-opening to accrual or (2) at any time during the conduct of the trial 
and in consideration of newly acquired information regarding the adverse event profile of 
the treatment(s) under investigation. The study team may choose to suspend accrual 
because of unexpected adverse event profiles that have not crossed the specified rule 
below. 
Accrual will be temporarily suspended to this study if at any time we observe adverse 
events considered at least possibly related to study treatment (i.e., an adverse event with 
attribute specified as “possible”, “probable”, or “definite”) that satisfy either of the 
following: 
• 
if 2 or more patients in the first 10 treated patients experience a grade 3 or higher 
adverse event felt to be attributed to the study agent and the event rate is higher in 
the treatment arms than the placebo arm. 
• 
if after the first 10 patients have been treated, 10% of all patients experience a 
grade 3 or higher adverse event felt to be attributed to the study agent and the event 
rate is higher in the treatment arms than the placebo arm. 
We note that we will review grade 4 and 5 adverse events deemed “unrelated” or “unlikely 
to be related,” to verify their attribution and to monitor the emergence of a previously 
unrecognized treatment-related adverse event. 
13.8 
Minority Accrual 
Enrollment will be open to all eligible patients, regardless of race or ethnicity. There is no 
information currently available regarding differential effects of oxybutynin by race or ethnicity, 
and there is no reason to expect such differences to exist. Therefore, although the planned 
analysis will, as always, look for differences in treatment effect based on race and ethnicity, the 
sample size is not increased in order to provide additional power for subset analyses. However, 
it is well known that the incidence of prostate cancer is greater in African American men. Given 
this, an Alliance Health Disparities Committee member was added as a study co-chair to 


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facilitate appropriate accrual of minority patients. Efforts will be made to accrue a substantial 
number of African American men to this trial. 
Based on prior Alliance studies involving similar disease sites, expected sizes of racial and 
ethnic subsets for patients registered to this study are shown in the following table: 
13.9 
Inclusion of Minorities 
PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ 
Alaska Native 
0 
1 
0 
0 
1 
Asian 
0 
1 
0 
0 
1 
Native Hawaiian or 
Other Pacific 
Islander 
0 
1 
0 
0 
1 
Black or African 
American 
0 
9 
0 
0 
9 
White 
0 
70 
0 
4 
74 
More Than One 
Race 
0 
1 
0 
0 
1 
Total 
0 
83 
0 
4 
87 
Ethnic Categories: 
 
• 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
• 
Not Hispanic or Latino 
Racial Categories: 
• 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
• 
Asian – a person having origins in any of the original peoples of the Far East, Southeast 
Asia, or the Indian subcontinent including, for example, Cambodia, China, India, Japan, 
Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and Vietnam. (Note: 
Individuals from the Philippine Islands have been recorded as Pacific Islanders in 
previous data collection strategies.)  
• 
Black or African American – a person having origins in any of the black racial groups 
of Africa.  
• 
Native Hawaiian or other Pacific Islander – a person having origins in any of the original 
peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
• 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 
 
 


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14.0 GENERAL REGULATORY CONSIDERATIONS AND CREDENTIALING 
14.1 Limited Access Requirements 
Institutions that are interested in participating in this study must be able to rebottle liquid formulation 
of drug and placebo into patient specific supplies. In order for the Alliance to monitor starter supply 
distribution, institutions are asked to document their commitment to the requirements of the study as 
follows:  
• 
In order for a site to be considered for the study, a “Site Participation Form” must be completed.  
The form can be requested from and once completed returned to 
   
• 
Upon approval, the site will be added to the list of limited access institutions with the next update 
to this protocol.  
Sites will receive extra per patient reimbursement for the effort involved with rebottling liquid 
formulations of the drug. 
15.0 MONITORING PLAN 
Use standard Alliance monitoring procedures, including regular review by the Alliance Data Safety 
Monitoring Board (DSMB) as outlined in Section 13.7. 
 


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16.0 REFERENCES 
1. 
Nguyen, P.L., et al., Adverse effects of androgen deprivation therapy and strategies to mitigate 
them. Eur Urol, 2015. 67(5): p. 825-36. 
2. 
Boon, E., et al., Androgen deprivation therapy for androgen receptor-positive advanced salivary 
duct carcinoma: A nationwide case series of 35 patients in The Netherlands. Head Neck, 2018. 
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3. 
Khan, M.H., R. Allerton, and L. Pettit, Hormone Therapy for Breast Cancer in Men. Clin Breast 
Cancer, 2015. 15(4): p. 245-50. 
4. 
Thompson, C.A., T.D. Shanafelt, and C.L. Loprinzi, Andropause: symptom management for 
prostate cancer patients treated with hormonal ablation. Oncologist, 2003. 8(5): p. 474-87. 
5. 
Jones, J.M., M. Kohli, and C.L. Loprinzi, Androgen deprivation therapy-associated vasomotor 
symptoms. Asian J Androl, 2012. 14(2): p. 193-7. 
6. 
Clark, J.A., et al., Dimensions of quality of life expressed by men treated for metastatic prostate 
cancer. Soc Sci Med, 1997. 45(8): p. 1299-309. 
7. 
Challapalli, A., et al., Evaluating the prevalence and predictive factors of vasomotor and 
psychological symptoms in prostate cancer patients receiving hormonal therapy: Results from a 
single institution experience. Clin Transl Radiat Oncol, 2018. 10: p. 29-35. 
8. 
Gonzalez, B.D., et al., Sleep disturbance in men receiving androgen deprivation therapy for 
prostate cancer: The role of hot flashes and nocturia. Cancer, 2018. 124(3): p. 499-506. 
9. 
Hunter, M.S. and E. Stefanopoulou, Vasomotor symptoms in prostate cancer survivors 
undergoing androgen deprivation therapy. Climacteric, 2016. 19(1): p. 91-7. 
10. 
Savard, J., S. Hervouet, and H. Ivers, Prostate cancer treatments and their side effects are 
associated with increased insomnia. Psychooncology, 2013. 22(6): p. 1381-8. 
11. 
Sharpley, C.F., V. Birsika, and J.W. Denham, Factors associated with feelings of loss of 
masculinity in men with prostate cancer in the RADAR trial. Psychooncology, 2014. 23(5): p. 
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12. 
Loprinzi, C.L., et al., Megestrol acetate for the prevention of hot flashes. N Engl J Med, 1994. 
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13. 
Irani, J., et al., Efficacy of venlafaxine, medroxyprogesterone acetate, and cyproterone acetate for 
the treatment of vasomotor hot flushes in men taking gonadotropin-releasing hormone analogues 
for prostate cancer: a double-blind, randomised trial. Lancet Oncol, 2010. 11(2): p. 147-54. 
14. 
Bonkhoff, H., et al., Progesterone receptor expression in human prostate cancer: correlation 
with tumor progression. Prostate, 2001. 48(4): p. 285-91. 
15. 
Sartor, O. and J.A. Eastham, Progressive prostate cancer associated with use of megestrol 
acetate administered for control of hot flashes. South Med J, 1999. 92(4): p. 415-6. 
16. 
Geller, J., J. Albert, and S.S. Yen, Treatment of advanced cancer of prostate with megestrol 
acetate. Urology, 1978. 12(5): p. 537-41. 
17. 
Burch, P.A. and C.L. Loprinzi, Prostate-specific antigen decline after withdrawal of low-dose 
megestrol acetate. Journal of clinical oncology, 1999. 17(3): p. 1086a-1086a. 
18. 
Loprinzi, C.L., et al., A phase III randomized, double-blind, placebo-controlled trial of 
gabapentin in the management of hot flashes in men (N00CB). Ann Oncol, 2009. 20(3): p. 542-9. 
19. 
Vitolins, M.Z., et al., Randomized trial to assess the impact of venlafaxine and soy protein on hot 
flashes and quality of life in men with prostate cancer. J Clin Oncol, 2013. 31(32): p. 4092-8. 
20. 
Joffe, H., et al., Low-dose estradiol and the serotonin-norepinephrine reuptake inhibitor 
venlafaxine for vasomotor symptoms: a randomized clinical trial. JAMA Intern Med, 2014. 
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21. 
Evans, M.L., et al., Management of postmenopausal hot flushes with venlafaxine hydrochloride: a 
randomized, controlled trial. Obstet Gynecol, 2005. 105(1): p. 161-6. 


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22. 
Artzi, O., et al., Topical Oxybutynin 10% Gel for the Treatment of Primary Focal Hyperhidrosis: 
A Randomized Double-blind Placebo-controlled Split Area Study. Acta Derm Venereol, 2017. 
97(9): p. 1120-1124. 
23. 
Wolosker, N., et al., Oxybutynin treatment for hyperhidrosis: a comparative analysis between 
genders. Einstein (Sao Paulo), 2012. 10(4): p. 405-8. 
24. 
Campanati, A., et al., Oxybutynin for the Treatment of Primary Hyperhidrosis: Current State of 
the Art. Skin Appendage Disord, 2015. 1(1): p. 6-13. 
25. 
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26. 
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27. 
Simon, J.A., et al., Extended-release oxybutynin therapy for vasomotor symptoms in women: a 
randomized clinical trial. Menopause, 2016. 23(11): p. 1214-1221. 
28. 
Leon-Ferre, R.A., et al., A randomized, doubleblind, placebo-controlled trial of oxybutynin (Oxy) 
for hot flashes (HF): ACCRU study SC-1603. Cancer Research, 2019. 79(4). 
29. 
Smith, T.J., C.L. Loprinzi, and C. Deville, Oxybutynin for Hot Flashes Due to Androgen 
Deprivation in Men. N Engl J Med, 2018. 378(18): p. 1745-1746. 
30. 
Sloan, J.A., et al., Methodologic lessons learned from hot flash studies. J Clin Oncol, 2001. 
19(23): p. 4280-90. 
31. 
Quella, S., C.L. Loprinzi, and A.M. Dose, A qualitative approach to defining "hot flashes" in 
men. Urol Nurs, 1994. 14(4): p. 155-8. 
32. 
Loprinzi, C.L., et al., Transdermal clonidine for ameliorating post-orchiectomy hot flashes. J 
Urol, 1994. 151(3): p. 634-6. 
33. 
Carpenter, J.S., The Hot Flash Related Daily Interference Scale: a tool for assessing the impact 
of hot flashes on quality of life following breast cancer. J Pain Symptom Manage, 2001. 22(6): p. 
979-89. 
34. 
Gonzalez, B.D., et al., Course and Moderators of Hot Flash Interference during Androgen 
Deprivation Therapy for Prostate Cancer: A Matched Comparison. J Urol, 2015. 194(3): p. 690-
5. 
35. 
Beer, T.M., et al., Acupuncture for hot flashes in patients with prostate cancer. Urology, 2010. 
76(5): p. 1182-8. 
36. 
Rich, T., et al., Intermittent 96-Hour Auricular Electroacupuncture for Hot Flashes in Patients 
with Prostate Cancer: A Pilot Study. Med Acupunct, 2017. 29(5): p. 313-321. 
37. 
Kay, G., et al., Differential effects of the antimuscarinic agents darifenacin and oxybutynin ER on 
memory in older subjects. Eur Urol, 2006. 50(2): p. 317-26. 
38. 
Wagg, A., et al., Randomised, multicentre, placebo-controlled, double-blind crossover study 
investigating the effect of solifenacin and oxybutynin in elderly people with mild cognitive 
impairment: the SENIOR study. Eur Urol, 2013. 64(1): p. 74-81. 
39. 
Katz, I.R., et al., Identification of medications that cause cognitive impairment in older people: 
the case of oxybutynin chloride. J Am Geriatr Soc, 1998. 46(1): p. 8-13. 
40. 
Lackner, T.E., et al., Randomized, placebo-controlled trial of the cognitive effect, safety, and 
tolerability of oral extended-release oxybutynin in cognitively impaired nursing home residents 
with urge urinary incontinence. J Am Geriatr Soc, 2008. 56(5): p. 862-70. 
41. 
Pocock, S.J. and R. Simon, Sequential treatment assignment with balancing for prognostic 
factors in the controlled clinical trial. Biometrics, 1975: p. 103-115. 
42. 
Barry, M. and F. Fowler Jr, O’Leary MP et al. The American Urological Association symptom 
index for benign prostatic hyperplasia. The Measurement Committee of the American Urological 
Association. J Urol, 1992. 148(5): p. 1549-1557. 
43. 
Parsons, J.K., et al., 494 PROSTATE CANCER AND LOWER URINARY TRACT SYMPTOMS IN 
COMMUNITY DWELLING OLDER MEN. The Journal of Urology, 2010. 183(4S): p. e195-e195. 


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44. 
Cohen, J., Statistical Power Analysis for the Behavioral Sciences (2nd edn), 411 Lawrence 
Erlbaum Associates. Hillsdale, NJ, 1988. 412. 
45. 
Leon-Ferre, R.A., et al., Oxybutynin vs Placebo for Hot Flashes in Women With or Without 
Breast Cancer: A Randomized, Double-Blind Clinical Trial (ACCRU SC-1603). JNCI Cancer 
Spectrum, 2020. 4(1): p. pkz088. 
 
 
 


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APPENDIX I HOT FLASH DEFINITIONS FOR THE MALE PATIENT 
Patient Information Sheet 
____________________________________________________________________________________  
Please refer to these examples of hot flashes that have been given by cancer survivors in 
previous studies when describing their hot flash severity. One or more of these 
descriptions may help to categorize your hot flash as mild, moderate, severe, or very 
severe. 
 
MILD 
Duration: Lasting less than 3 minutes 
Physical symptoms: Very light perspiration, generalized warmth or a flushed 
sensation  
Emotional symptoms: None or rare 
Action needed: Usually no action taken 
 
MODERATE 
 Duration: Lasting up to 5 minutes 
Physical symptoms: Light-to-moderate perspiration, moderate warmth and/or 
perspiration  
Emotional symptoms: Mild anxiety, some irritability, loss of concentration 
Action needed: Needed to use a fan, needed to loosen clothing, needed to remove clothing, 
needed to remove bedding 
 
SEVERE  
Duration: Lasting up to 10 minutes 
Physical symptoms: Described as feeling “hotter” or “very hot,” heavy perspiration, 
dizziness, nausea, shortness of breath, weakness, extreme discomfort 
Emotional symptoms: Moderate anxiety, moderate irritability 
Action needed: Needed to loosen clothing, needed to change clothing, needed to change bedding 
 
VERY SEVERE 
Duration: Lasting up to 30 minutes 
Physical symptoms: Described as feeling “very hot,” drenching perspiration, dizziness, 
nausea, shortness of breath, weakness, chest discomfort, extreme discomfort 
Emotional symptoms: Severe anxiety, severe irritability, restlessness, totally out of control 
Action needed: Needed to change clothing, needed to towel off, needed to change 
bedding, used wet towels, took a bath or shower, needed a rest 


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APPENDIX II BASELINE SYMPTOM DOCUMENTATION  
___________________________________________________________________________________ 
 
Directions:  
• 
The baseline symptom determination is divided into 7 rows, one for each day of the week.  
• 
Enter the day and the date your week started.  
• 
Start in the row for Day 1.  
• 
Write in the number of mild, moderate, severe and very severe hot flashes experienced in the 
boxes.  
• 
Repeat for each day of the week.  
• 
See page 2 of this booklet for the definitions of each type of hot flashes.  
 
Day week started: _____________________ Date week started: __ __ / __ __ / __ __ __ __  
 
 
 
 
 
 
 
 
m m     d d       y   y    y   y 
 
 
Day 
Number of mild 
hot flashes 
Number of 
moderate hot 
flashes 
Number of 
severe hot 
flashes 
Number of 
very severe 
hot flashes 
Day 1 
 
 
 
 
Day 2 
 
 
 
 
Day 3 
 
 
 
 
Day 4 
 
 
 
 
Day 5 
 
 
 
 
Day 6 
 
 
 
 
Day 7 
 
 
 
 
 
*A day should be considered a 24-hour period (i.e. 7 a.m. to 7 a.m. or midnight to midnight). 
 
 


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APPENDIX III INTERNATIONAL PROSTATE SYMPTOM SCORE (IPSS)  
(To be completed at screening and at the end of each week of treatment)  
INTERNATIONAL-PROSTATE SYMPTOM SCORE 
Question 
Not at all 
Less than 
1 time in 5 
Less than 
half the 
time 
About half 
the time 
More than 
half the 
time 
Almost 
always 
1. Over the past week, how 
often have you had a 
sensation of not emptying 
your bladder completely 
after you finished 
urinating? 
0 
1 
2 
3 
4 
5 
2. Over the past week, how 
often have you had to 
urinate again less than two 
hours after you finished 
urinating? 
0 
1 
2 
3 
4 
5 
3. Over the past week, how 
often have you found you 
stopped and started again 
several times when you 
urinated? 
0 
1 
2 
3 
4 
5 
4. Over the past week, how 
often have you found it 
difficult to postpone 
urination? 
0 
1 
2 
3 
4 
5 
5. Over the past week, how 
often have you had a weak 
urinary stream? 
0 
1 
2 
3 
4 
5 
6. Over the past week, how 
often have you had to push 
or strain to begin urination? 
0 
1 
2 
3 
4 
5 
 
None 
1 time 
2 times 
3 times 
4 times 
5 or more 
times 
7. Over the past week, how 
many times did you most 
typically get up to urinate 
from the time you went to 
bed at night until the time 
you got up in the morning? 
0 
1 
2 
3 
4 
5 
I-PSS - United States/English 
ID 5070 / I-PSS1a_AU1.0_eng-USori.doc 
 
 
 
 


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INTERNATIONAL-PROSTATE SYMPTOM SCORE (cont'd) 
QUALITY OF LIFE DUE TO URINARY SYMPTOMS 
Question 
Delighted 
Pleased 
Mostly 
satisfied 
Mixed about 
equally 
satisfied and 
dissatisfied 
Mostly 
dissatisfied 
Unhappy 
Terrible 
1. If you were to 
spend the rest of 
your life with your 
urinary condition just 
the way it is now, 
how would you feel 
about that? 
0 
1 
2 
3 
4 
5 
6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I-PSS - United States/English 
ID 5070 / I-PSS1a_AU1.0_eng-USori.doc 
 


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APPENDIX IV HOT FLASH DIARY (SAMPLE INCLUDED ON THE NEXT PAGE)  
_____________________________________________________________________________________ 
 
Directions:  
 
The hot flash diary is divided into 7 rows, one for each day* of the week.  
Enter the day and the date your week started.  
Start in the row for Day 1.  
Write in the number of mild, moderate, severe and very severe hot flashes experienced in the 
boxes.  
Repeat for each day of the week.  
See page 2 of this booklet for the definitions of each type of hot flashes.  
 
Day week started: _____________________ Date week started: __ __ / __ __ / __ __ __ __  
 
 
 
 
 
 
 
 
m m     d d       y   y    y   y 
 
 
Day 
Number of mild 
hot flashes 
Number of 
moderate hot 
flashes 
Number of 
severe hot 
flashes 
Number of 
very severe 
hot flashes 
How many 
doses of study 
medication 
did you take? 
(circle one) 
Day 1 
 
 
 
 
0   1    2 
Day 2 
 
 
 
 
0   1    2 
Day 3 
 
 
 
 
0   1    2 
Day 4 
 
 
 
 
0   1    2 
Day 5 
 
 
 
 
0   1    2 
Day 6 
 
 
 
 
0   1    2 
Day 7 
 
 
 
 
0   1    2 
 
*A day should be considered a 24-hour period (i.e. 7 a.m. to 7 a.m. or midnight to midnight). 
 


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APPENDIX V SYMPTOM EXPERIENCE QUESTIONNAIRE 
Completed at baseline and weekly for six weeks 
 
Date completed:  
 
 
INSTRUCTIONS: Please complete at the end of each study week by circling the one 
number for each item below that best describes you. 
 
1. Over the past week, have you experienced stomach pain or cramps? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Not 
at all 
As bad as 
it can be 
 
2. Over the past week, have you experienced diarrhea (loose stools)? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Not 
at all 
As bad as 
it can be 
 
3. Over the past week, have you experienced constipation? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Not 
at all 
As bad as 
it can be 
 
 
4. Over the past week, have you experienced nausea? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Not 
at all 
As bad as 
it can be 
 
5. Over the past week, have you experienced any vomiting? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Not at 
all 
As bad as it 
can be 
 
 
6. Over the past week, have you experienced dry mouth? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Not 
at all 
As bad as 
it can be 
 
 


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7. Over the past week, have you experienced dizziness? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Not 
at all 
As bad as 
it can be 
 
8. Over the past week, have you experienced decrease in appetite? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Not 
at all 
As bad as 
it can be 
 
9. Over the past week, have you experienced headaches? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Not 
at all 
As bad as 
it can be 
 
10. Over the past week, have you experienced fatigue? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Not 
at all 
As bad as 
it can be 
 
11. Over the past week, have you experienced excessive somnolence (sleepiness)? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Not 
at all 
As bad as 
it can be 
 
12. Over the past week, have you experienced blurry vision? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Not 
at all 
As bad as 
it can be 
 
13. Over the past week, have you experienced dry eyes? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Not 
at all 
As bad as 
it can be 
 
 
 


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14. Over the past week, have you experienced episodes of confusion? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Not 
at all 
As bad as 
it can be 
15. Over the past week, have you had a skin rash? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Not 
at all 
As bad as 
it can be 
 
16. Over the past week, did you experience any muscle/joint aches or pains? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Not 
at all 
As bad as 
it can be 
 
17. Over the past week, did you experience trouble sleeping? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Not 
at all 
As bad as 
it can be 
 
18. Over the past week, have you had trouble concentrating? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Not 
at all 
As bad as 
it can be 
 
19. Over the past week, have you experienced any difficulties with your memory? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Not 
at all 
As bad as 
it can be 
 
20. Over the past week, have you experienced difficulties urinating (difficulties emptying your bladder)? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Not 
at all 
As bad as 
it can be 
 
21. Over the past week, have you experienced any trouble with urine incontinence (leaking)? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Not 
at all 
As bad as 
it can be 
 
 
 


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22. Over the past week, how distressing was your experience with hot flashes? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Not 
at all 
As bad as 
it can be 
 
23. Did you experience any other symptoms this past week that were not mentioned above? 
 
No  
Yes  
 
If so, please describe 
The following question will ONLY be asked at baseline: 
 
23a. 
How much do you think the study medication will be able to help hot flashes? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Probably 
won’t 
work 
Will work 
extremely 
well 
 
 
The following question will NOT be asked at baseline: 
 
23b. 
Over the past week, how satisfied are you with the control of your hot flashes? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Extremely 
Satisfied 
Extremely 
Dissatisfied 
 
 
23c  
Given your experience with the study medication on this trial would you want to continue 
it after the trial is over if given the choice?  
 
No  
Yes  
 
 
 
 


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APPENDIX VI HOT FLASH RELATED DAILY INTERFERENCE SCALE (HFRDIS) 
Completed on Day 7, at the end of Weeks 3, 5, and 7 (i.e., Days 21, 35, and 49 
Please circle one number to the right of each phrase to describe how much DURING THE 
PAST TWO WEEKS hot flashes INTERFERED with each aspect of your life. 
 
 Did not 
Completely 
 interfere 
interfered 
1. Work (work outside the 
home and housework) 
 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
2. Social activities (time 
spent with family, friends, 
etc) 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
3. Leisure activities (time 
spent relaxing, doing 
hobbies, etc.) 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
4. Sleep 
 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
5. Mood 
 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
6. Concentration 
 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
7.   Relations with others 
 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
8.   Sexuality 
 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
9.   Enjoyment of life 
 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
10. Overall quality of life 
 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
HFRDIS © 2001 Janet S. Carpenter 
 
 
 


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APPENDIX VII NURSE/CRP PHONE CONTACT GUIDE 
 
 
Patient Phone No.__________________ 
Best Dates/Times to call_____________ 
 
FOLLOW UP: 
 
1. Please make an appointment to call the patient at home the end of each study 
week. The purpose of this contact is to remind the patient of dose schedule, 
document compliance, encourage completion of the booklet, and address 
problems. 
 
• 
It is important to reinforce daily completion of diary as well as 
weekly side effects on symptom experience questionnaire. 
Regarding potential side effects, please ask about dry mouth, 
nausea, vomiting, dizziness, blurred vision, dry eyes, urinary 
retention, and urinary incontinence. If there are any significant 
toxicities, then refer to protocol  Section 8.2 for potential dose 
modifications. In addition, determine whether there are any 
reportable adverse events (Section 9.0). 
 
2. Items to document on the Nurse/CRP Evaluation form in the forms packet include, but 
are not limited to the following: 
• 
Date of phone call 
• 
Study week 
• 
Side effects: 
➢ Type of side effect, severity and attribution, if applicable 
• 
Any changes in medications or other treatments (i.e. behavioral, diet, etc.) 
• 
Has the participant taken the proper amount of study 
medication each day? (Choose one: Always  
, 
Usually  
, Rarely  
, or Never  ) 
• 
Questions/Comments 
 
3. Reinforce compliance with study medication.  
 
4. Reinforce completion of questionnaires and request return of them at end of weeks 1 and 4. 
 
Note – If patient decides to stop study before week 7, ask them to fill out the questionnaires up to 
that point at the end of the booklet and return in the envelope provided. 
 
 


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APPENDIX VIII: PATIENT MEDICATION DIARY – OXYBUTYNIN/PLACEBO  
(For patient and site convenience only)  
Today’s date ______________________________ 
 
Patient Name___________________ (initials acceptable)  
Patient Study ID ____________ 
 
 
INSTRUCTIONS FOR THE PATIENT: 
1. 
Complete this form while you take oxybutynin/placebo.  This form is a 7 day diary.  You may 
need to complete more than one form between clinic visits, for each week of treatment. 
2. 
You will take your dose of oxybutynin/placebo twice daily.  You will be given an oral syringe to 
measure and take your medication, which you will clean and reuse during the course of the 
study. 
3 
Take the oxybutynin/placebo at least one hour before a meal or at least two hours afterwards. 
4. 
Record the date, the dose you took, and when you took it. Record doses as soon as you take 
them; do not batch entries together at a later time. 
5. 
If a dose is missed, do not make up that dose; resume dosing with the next scheduled dose. 
6. 
Use extreme caution when oxybutynin is administered with any other anticholinergic agents as 
increased side effects can occur (i.e dry mouth, constipation, somnolence).  
2. 
Report any unusual rapid heart rates to your doctor. 
3. 
Report skin changes like rash to your doctor.  
4. 
You may have decreased sweating abilities. Use caution if out in the heat and to avoid becoming 
overheated.  
5. 
Gastrointestinal effects can be seen including constipation, decreased GI motility, nausea, 
vomiting, and dry mouth.  
6. 
If you have trouble urinating, report this to your doctor. 
7. 
Use caution when operating a vehicle or other activities that require close attention. 
8. 
Effects on the eye can include amblyopia (lazy eye), cycloplegia (paralysis of ciliary muscle-
leading to inability to focus on close objects), decreased tears and mydriasis (abnormal pupil 
dilation).  Report any of these to your doctor.  
9. 
If you have any comments or notice any side effects, please record them in the comments 
column. If you make a mistake while you write, please cross it out with one line, put your initials 
next to it, and then write the corrected information next to your initials.   
10. Please return this form to your doctor or study staff. You may need to return more than one form 
per clinic visit.  
 
 


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WEEK: __________ 
 
 
 
Day 
Date 
Time of daily dose 
Dose#1 
Dose#2 
Comments 
1 
 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
 
6 
 
 
 
 
 
7 
 
 
 
 
 
Patient’s Signature 
 
 
Date 
 
 


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APPENDIX IX PATIENT INFORMATION SHEETS   
PATIENT INFORMATION SHEET 
BASELINE 
 
Patient Completed Quality of Life Booklet (Baseline/Week 1) 
________________________________________________________________________ 
 
You have been given a booklet to complete for this study.  The booklet contains some questions 
about your ‘quality of life’ as a patient receiving treatment for hot flashes.  Your answers will help 
us to better understand how the treatment you are receiving is affecting the way you feel. 
 
Do not take any study medication this week.  
 
1. This booklet is to be completed before you start study treatment. 
 
2. The booklet contains 3 set of questions: 
a. Baseline Symptom Documentation (Days 1-7). This should be completed daily. 
On page 2 of this booklet, you will find examples of the different hot flash intensities: 
mild, moderate, severe, and very severe hot flash. This is to help you to decide the 
intensity of your hot flash, but it is not an absolute rule. Your hot flashes may differ in 
some ways or may fall just between two descriptions. Try to get as close as you can, but 
do not worry if your hot flashes do not match exactly what is given. 
b. Symptom Experience Questionnaire (Day 7) 
c. Hot Flash Related Daily Interference Scale (HFRDIS) (Day 7)  
 
3. Directions on how to complete this set of questions are written on the top of the page. 
 
4. Please return your booklet, in the envelope provided or in person when you are finished. 
 
 
Thank you for taking the time to help us. 
 
 


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PATIENT INFORMATION SHEET 
TREATMENT 
Patient Completed Quality of Life Booklet (Weeks 2-7) 
________________________________________________________________________ 
 
You have been given a booklet to complete for this study.  The booklet contains some questions 
about your ‘quality of life’ as a patient receiving treatment for hot flashes.  Your answers will help 
us to better understand how the treatment you are receiving is affecting the way you feel. 
 
 
1. This booklet is to be completed on days 8-49, while you are receiving treatment. It is divided up 
into 6 weeks.  
 
2. The booklet contains 4 set of questions: 
a. Hot Flash Diary (every day during treatment): This should be completed daily. 
On page 2 of this booklet, you will find examples of the different hot flash intensities: 
mild, moderate, severe, and very severe hot flash. This is to help you to decide the 
intensity of your hot flash, but it is not an absolute rule. Your hot flashes may differ in 
some ways or may fall just between two descriptions. Try to get as close as you can, but 
do not worry if your hot flashes do not match exactly what is given. 
b. Symptom Experience Questionnaire (at the end of every week) 
c. International Prostate Symptom Score tool (at the end of every week)  
d. Hot Flash Related Daily Interference Scale (HFRDIS) (at the end of Weeks 2 and 4 of 
treatment, and at the end of treatment)  
 
3. Directions on how to complete this set of questions are written on the top of the page. 
 
4. You may call a member of the study team to answer any questions you might have.  You will be 
given a name and telephone number.  You can call anytime with any concerns or questions. A 
nurse/research coordinator will also call you at the end of every week and they can answer 
questions you might have.  
 
5. It is very important that you return the booklet to us, whether you finish the study or not. 
 
6. When the booklet is complete, return it in the provided envelope. 
 
 
Thank you for taking the time to help us.  
 
 


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APPENDIX X PATIENT CLINICAL TRIAL WALLET CARD 
 
 
 
CLINICAL TRIAL WALLET CARD 
Show this card to all of your 
healthcare providers and keep 
it with you in case you go to 
the emergency room. 
Patient Name:        
Diagnosis:        
Study Doctor:       
Study Doctor Phone #:       
NCI Trial #:  04600336 
Study Drug(S):  oxybutynin or Placebo 
 
 
 
 
For more information: 1-800-4-CANCER 
 
 
 


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APPENDIX XI PATIENT THANK YOU LETTERS 
 
Guidance for Disseminating 
Thank You Letters to Trial Participants 
 
Trial Participant Thank You Letter  
We ask that the physician use the template to prepare a letter thanking the participant for 
enrolling in this Alliance trial. The template is intended as a guide and can be downloaded from 
the study page on the Alliance website at 
As this is a personal letter, 
physicians may elect to further tailor the text to their situation.  
This small gesture is a part of a broader program being undertaken by Alliance and the NCI to 
increase awareness of the importance of clinical trials and improve accrual and follow-through.  
We appreciate your help in this effort.  
____________________________________________________________________  
Sample Template 
[PARTICIPANT NAME] [DATE] [PARTICIPANT ADDRESS]  
Dear [PARTICIPANT SALUTATION],  
Thank you for agreeing to take part in this important research study. With the help of people like 
you who participate in clinical trials, we will achieve our goal of effectively treating and ultimately 
curing cancer.  
There are many reasons why individuals choose to participate in a clinical trial. Sometimes it is 
because they want access to a specific medication or because they want to do whatever they 
can to help someone else with cancer.  Whatever your reason for participating, you are making 
a contribution towards finding better treatments and ultimately eliminating this disease for future 
patients. 
You will receive high quality care while participating in this clinical trial. My research staff and I 
will maintain very close contact with you. This will allow me to provide you with the best care 
while learning as much as possible to help you and other participants.  
On behalf of [INSTITUTION] and the Alliance for Clinical Trials in Oncology, we thank you again 
for your participation in this clinical trial and look forward to partnering with you.  
Sincerely, [PHYSICIAN NAME]