Conditions: Breast Carcinoma Ductal Breast Carcinoma In Situ Hot Flashes Lobular Breast Carcinoma In Situ No Evidence of Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 150
Healthy volunteers: no

Brief summary:
This randomized phase III trial studies how well oxybutynin chloride works in managing hot flashes in patients who are not candidates for, or not interested in hormone replacement therapy. Previous studies have shown that oxybutynin is effective in managing hot flashes, however doses used in prior studies have resulted in side effects. This trial is evaluating lower doses of oxybutynin with the goal of determining if they are efficacious with less side effects.

ADAM-VTE

Detailed description:
PRIMARY OBJECTIVES:

I. To determine whether oxybutynin chloride (oxybutynin) can diminish hot-flash activity in women with a history of breast cancer or in women who have a concern about taking estrogen for fear of breast cancer.

SECONDARY OBJECTIVES:

I. To perform a dose-response evaluation of two oxybutynin doses. II. To determine the toxicity of oxybutynin in the study population. III. To assess the impact of hot-flash activity on overall quality of life and to examine whether oxybutynin can diminish this impact on quality of life.

OUTLINE: Patients are randomized into 1 of 4 groups.

GROUP I (LOW-DOSE OXUBUTYNIN CHLORIDE): Patients receive lower dose oxybutynin chloride orally (PO) twice a day (BID) on days 8-49 in the absence of unacceptable toxicity.

GROUP II (LOW-DOSE PLACEBO): Patients receive lower dose placebo PO BID on days 8-49 in the absence of unacceptable toxicity.

GROUP III (HIGH-DOSE OXUBUTYNIN CHLORIDE): Patients receive lower dose oxybutynin chloride PO BID on days 8-14 and higher dose oxybutynin chloride on days 15-49 in the absence of unacceptable toxicity.

GROUP IV (HIGH-DOSE PLACEBO): Patients receive lower dose placebo PO BID on days 8-14 and higher dose placebo on days 15-49 in the absence of unacceptable toxicity.

Arms:
arm 1: Patients receive lower dose oxybutynin chloride PO BID on days 8-49 in the absence of unacceptable toxicity. arm 2: Patients receive lower dose placebo PO BID on days 8-49 in the absence of unacceptable toxicity. arm 3: Patients receive lower dose oxybutynin chloride PO BID on days 8-14 and higher dose oxybutynin chloride on days 15-49 in the absence of unacceptable toxicity. arm 4: Patients receive lower dose placebo PO BID on days 8-14 and higher dose placebo on days 15-49 in the absence of unacceptable toxicity.

Interventions: intervention 1: Oxybutynin Chloride intervention 2: Placebo 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 document:
Prot_SAP_000.pdf: 
ACCRU-SC-1603 
 
 
Academic and Community Cancer Research United (ACCRU) 
 
A Phase III, Double-Blind, Controlled Trial of Oxybutynin in the Management of Hot Flashes 
 
For any communications regarding this protocol, 
please contact the protocol resource person on the following page. 
Study Chairs 
ACCRU: 
Charles L. Loprinzi, M.D. 
Mayo Clinic 
507/284-4565 
507/284-5280 (FAX) 
loprinzi.charles@mayo.edu 
 
Roberto Leon-Ferre, M.D. 
Mayo Clinic 
507/284-4565 
LeonFerre.Roberto@mayo.edu 
 
Stephanie S. Faubion, M.D. 
Mayo Clinic 
507/284-4565 
Faubion.Stephanie@mayo.edu 
 
Statistician: 
  
Mayo 
Clinic 
 
 
Drug Availability 
Commercial Agents:  Oxybutynin (IND exempt) 
 
√ Study contributor(s) not responsible for patient care. 
 
Research Coordinating Center 
Academic and Community Cancer Research United 
200 First Street Southwest 
Rochester, MN 55905 
FAX# 507-538-0906 
 
 
 
Document History 
Effective Date 
Pre-activation ACCRU 
October 28, 2016 
Activation ACCRU 
December 9, 2016 
Amendment 1 
June 23, 2017 
Amendment 2 
September 08, 2017 




3  
A C C R U -S C -1 6 0 3  
 
 
Da ys 1 -7 ( Wee k 1)  
Baseli ne d oc u me ntati o n 1 
F oll o we d b y 
 
Da ys 8 -4 9 ( Wee ks 2 - 7) 
O x y b ut y ni n 2. 5 m L 
( oral) BI D x 4 2 da ys2, 3  
 
Da ys 1 -7 ( Wee k 1)  
Baseli ne d oc u me ntati o n 1 
F oll o we d b y 
 
Da ys 8 -4 9 ( Wee ks 2 -
7) O x y b ut y ni n 2. 5 m L 
( oral) BI D x 7 d a ys 
T he n 5 m L ( or al) BI D 
x 3 5  d a ys 2, 3  
 
Da ys 1 -7 ( Wee k 1)  
Baseli ne d oc u me ntati o n 1 
F oll o we d b y 
 
Da ys 8 -4 9 ( Wee ks 2 - 7) 
Place b o 2. 5 m L  
( oral) BI D x 4 2 da ys2, 3  
 
Da ys 1 -7 ( Wee k 1)  
Baseli ne d oc u me ntati o n 1 
F oll o we d b y 
 
Da ys 8 -4 9 ( Wee ks 2 - 7) 
Place b o 2. 5 m L ( oral) 
BI D x 7 da ys 
T he n 5 m L ( oral) BI D 
x 3 5 da ys 2, 3  
 
Sc he m a  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1Baseli ne s y m pt o m d oc u me ntati o n.  
2U nacce pta ble a d verse e ve nts (a dj ust d ose per secti o n 8).  
3Q uesti o n naires will c o nti n ue t o be a d mi nistere d after treat me nt i nitiati o n a n d f or t he d urati o n of t he st u d y. 
 
C ycle 1 = 7 da ys  
C ycle 2 = 7 da ys  
C ycle 3 = 7 da ys  
C ycle 4 = 7 da ys  
C ycle 5 = 7 da ys  
C ycle 6 = 7 da ys  
C ycle 7 = 7 da ys  
 
Ge neric  na me:  O x y b ut y ni n  c hl ori de 
Bra n d na me(s):  Ditr o pa n  
A vaila bilit y:  
Bi ol o gics  
Ge neric  na me:  Place b o 
Bra n d na me(s):  Place b o  
A vaila bilit y:  
Bi ol o gics  
 
Ra n d o mizati o n 
 
Off st u d y 
U nacce pta ble a d verse e ve nts or patie nt 
ref usal at a n y ti me → Off St u d y 


4 
ACCRU-SC-1603 
 
 
1.0 
Background 
 
1.1 
The Hot Flash Problem 
 
Vasomotor symptoms (VMS) continue to be the most common symptom associated with 
menopause and are experienced by about 75% of menopausal women. (Stearns V, et. al., 2002; 
Garcia C and Freeman E, 2004) The mean duration of VMS is 7-9 years; however, over 30% of 
women may experience moderate to severe VMS for 10 or more years. Stearns V, et. al., 2002) 
For women who are breast cancer survivors, the risk of long-term VMS is greater, as chemotherapy 
may result in premature ovarian function cessation. In addition, endocrine therapy is associated 
with hot flashes. Over 50% of women on tamoxifen and 34-58% of women on aromatase inhibitors 
(AIs) experience hot flashes. (Molina JR, et al., 2005; Loprinzi CL et al., 2000; Morales AJ et al., 
1994) 
 
VMS are not only disruptive and distressing to women, they are associated with a significant 
economic burden, both in term of medical costs and lost productivity. It has been reported that 
menopausal symptoms may be more severe in breast cancer survivors compared with healthy 
women experiencing natural menopause. (Carpenter JS, et. al., 2002) 
 
The most effective treatment for VMS, offering a 80-90% reduction, is estrogen and/or 
progesterone based therapy.Molina JR, et al., 2005; Bertelli G et al., 2002; MacGregor CA et al., 
2005; World Almanac and Book of Facts, 2005; Notelovitz M, et. al., 2000) However, hormonal 
therapy is not recommended for women with a history of hormone-responsive cancers, including 
breast cancer. (Stuenkel CA et. al., 2015) The most effective non-hormonal therapies 
(antidepressants and anticonvulsants) offer about a 50% reduction in VMS. (Loprinzi CL et. al., 
2000; Barton DL et al., 2010; Loprinzi CL et. al., 2009) However, these agents do have some 
unwanted side effects including dizziness, dry mouth, trouble sleeping, somnolence, nausea, and 
sexual dysfunction. (Barton D, Loprinzi CL, 2004) Furthermore, despite the potential efficacy of 
antidepressants for the management of VMS, these drugs have been shown to inhibit the CYP2D6 
enzyme system, which plays an essential role in the metabolic activation of tamoxifen. In women 
being treated with tamoxifen, use of CYP2D6 inhibitors has been shown to decrease the plasma 
concentrations of active tamoxifen metabolites and potentially decrease the anti-cancer efficacy of 
tamoxifen.(Hemeryck A, Belpaire FM, 2002; Jin Y, et. al., 2005; Borges S, et. al., 2006) Therefore, 
additional non-estrogenic treatment options for women with breast cancer and therapy-induced 
VMS would be welcomed. Options that do not interfere with tamoxifen metabolism are especially 
needed, as some women with breast cancer require endocrine therapy with tamoxifen or AIs for 
extended periods of time (up to 10 years). 
 
1.2 
Oxybutynin for Hot Flashes 
 
Oxybutynin is an anticholinergic agent that can be taken orally (as short or long-acting 
formulations) or transdermally. Oxybutynin is primarily metabolized by CYP3A4, and has no 
known inhibitory effect on CYP2D6, making it a therapeutic option for women concurrently using 
tamoxifen if is found to be effective for VMS management. Oxybutynin is FDA approved for 
overactive bladder symptoms. Due to the observation that patients treated for overactive bladder 
with oxybutynin experienced decreased sweating, a prospective, placebo-controlled trial of 
oxybutynin was conducted to assess its efficacy in the treatment of hyperhydrosis. (Wolosker N et. 
al., 2012) This trial demonstrated improvement in palmar and axillary hyperhydrosis in >70% of 
patients. Side effects were minor (dry mouth the most common), and quality of life was also found 
to be improved. 
 
There are data to suggest efficacy of oxybutynin in the treatment of VMS unresponsive to other 
treatments. (Sexton T et. al., 2007) In a retrospective review of a prospectively collected database, 
Sexton et al identified 52 patients with moderate-to-severe hot flashes that received treatment with 


5 
ACCRU-SC-1603 
 
 
oxybutynin. Of these, >90% had refractory symptoms, with 27% of patients having tried at least 3 
previous lines of therapy, including SSRIs, SNRIs, gabapentin, clonidine and hormone therapy. 
Seventy percent of patients treated with oxybutynin had a partial or excellent response, and more 
than half of patients continued treatment for at least six months. More than 90% of patients 
received 5 mg twice daily (BID) or less, although more “excellent responses” were seen in patients 
that took 5 mg BID. Although 62% of patients reported mild to moderate side effects, only 12% 
discontinued oxybutynin due to side effects. Dry mouth was the most common side effect (48%), 
followed by nausea (12%), cognitive/emotional symptoms (8%), blurred vision (2%) and 
constipation (2%). No clear correlation between dose and frequency of side effects or treatment 
discontinuation was noted. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.0 
Goals 
In addition, a prospective, double-blind clinical trial was developed to address the utility of 
oxybutynin for treating menopause-related VMS. While the results of this clinical trial were not 
published when this current protocol was conceived (only an internet report was available from 
2007; LaGuardia KD, 2007 patent), a published report of this trial appeared in late 2016 (Simon 
JA, 2016). This report revealed that higher doses of oxybutynin than are being studied in the 
current trial (i.e. 3 times the lowest dose in this current trial) resulted in significant reductions 
(P<.001) in both of the primary endpoints (daily frequency of moderate to severe VMS and daily 
severity of all VMS) in the 12th week compared to baseline. This was at the cost of higher toxicity 
in the treatment arm, including over 50% of patients reporting mouth dryness, as compared to 5% 
in the placebo arm. In addition, there was more dyspepsia (12% versus 1%), and diarrhea (10% vs 
0%), leading to 7% of patients discontinuing treatment. The authors of this publication 
recommended that lower doses of oxybutynin be studied for treating hot flashes, akin to what is 
outlined in the current trial. In addition, the current trial will be using a short-acting formulation, 
allowing for further dose reductions in the event of excess toxicity. 
2.1 
Primary 
 
2.11 
To determine whether oxybutynin can diminish hot-flash activity in women with a history 
of breast cancer or in women who have a concern about taking estrogen for fear of breast 
cancer. 
2.2 
Secondary 
2.21 
To perform a dose-response evaluation of two oxybutynin doses. 
2.22 
To determine the toxicity of oxybutynin in the study population. 
 
2.23 
To assess the impact of hot-flash activity on overall quality of life and to examine whether 
oxybutynin can diminish this impact on quality of life. 
 
3.0 
Patient Eligibility 
 
3.1 
Inclusion Criteria 
 
3.11 
Age ≥ 18 years. 
 
3.12 
Women with history of breast cancer, DCIS, or LCIS (currently without evidence of 
malignant disease) OR a concern about taking estrogen for fear of breast cancer. 
 
3.13 
Bothersome hot flashes (defined by their occurrence of ≥ 28 times per week and of 
sufficient severity to prompt the patient to seek therapeutic intervention). 
 
3.14 
Presence of hot flashes for >30 days prior to study entry. 


6 
ACCRU-SC-1603 
 
 
 
3.15 
Ability to complete questionnaire(s) by themselves or with assistance. 
 
3.16 
ECOG Performance Status (PS) = 0, 1. (Form is available on the ACCRU web 
site https://www.accru.org/accru/forms/NonProtocolSpecificForms/index.html). 
 
3.17 
Ability to provide informed written consent. 
 
3.18 
Life expectancy ≥6 months. 
 
3.19 a Willing to work with the enrolling institution for follow-up (during the Active Monitoring 
Phase of the study). 
 
3.2 
Exclusion Criteria 
 
3.21 
Any of the following current (≤4 weeks prior) or planned therapies: 
• 
Antineoplastic chemotherapy (anti-HER2 agents allowed) 
• 
Androgens 
• 
Estrogens (any delivery route) 
• 
Progestogens 
• 
Tamoxifen, raloxifene and aromatase inhibitors are allowed, but patient must have 
been on a constant dose for at least 28 days and must not be expected to stop the 
medication during the study period 
• 
SSRIs/SNRIs, when being used for hot flash management or other indications such as 
depression, is allowed, assuming the dose will remain unchanged for the study duration 
• 
Gabapentin/pregabalin, when being used for hot flash management (use for other 
indications, such as pain, is allowed, assuming the dose will remain unchanged for the 
study duration) 
• 
Clonidine 
• 
Agents with known potent anticholinergic activity as listed on Appendix VII. Agents 
with mild-moderate anticholinergic activity are allowed. 
 
3.22 
Prior use of oxybutynin during the period in which patient has had hot flashes. 
 
3.23 
Any of the following because this study involves an investigational agent whose genotoxic, 
mutagenic and teratogenic effects on the developing fetus and newborn are unknown: 
• 
Pregnant women 
• 
Nursing women 
 
3.24 
History of any of the following contraindications to oxybutynin: 
• 
Uncontrolled gastroesophageal reflux disease (GERD) despite appropriate therapy. If 
patient has history of GERD, but symptoms are well-controlled with medical treatment, 
patient is eligible. 
• 
Ulcerative colitis 
• 
Narrow-angle glaucoma 
• 
Urinary retention 
• 
Hypersensitivity to oxybutynin or any other components of the product 
• 
Current uncontrolled hyperthyroidism 
• 
Coronary heart disease (angina or prior myocardial infarction) 
• 
Congestive heart failure 
• 
Symptomatic cardiac arrhythmias 
• 
Current uncontrolled hypertension 
• 
Myasthenia gravis 
• 
Dementia 


7 
ACCRU-SC-1603 
 
 
4.0 
Test Schedule 
 
Tests and 
procedures 
Active Monitoring Phase 
≤ 60 days 
prior to 
registration 
End of 
week 
1 
(baseline) 
Daily during 
baseline 
week and 
during 
treatment 
(x7 weeks) 
End of each 
treatment 
week 
End of 
treatment  
(end of study) 
History and 
exam, weight, 
height, ECOG PS 
X 
Hot Flash 
Diary2,4 
(Appendix IV) 
X3 
Patient 
Questionnaire: 
Symptom 
Experience 
Questionnaire2 
(Appendix V) 
X3 
X3 
Hot Flash Daily 
Interference 
Scale2 (Appendix 
VI) 
X3 
X3 
Nurse/CRA 
phone contact 
(Appendix VIII) 
X1 
X1 
 
1Nurse/CRA to call patient at ends of weeks 1, 2, 3, 4, 5, 6 and 7 (AE assessment does not need to be done for 
end of week 1 call, however a form MUST be entered for forms tracking purposes). The CRA/Nurse Phone 
Call Script (Appendix VIII) may be used to assist in data collection. 
2Patient questionnaire booklets must be used. 
3Patient questionnaire booklets should be returned to the investigator at the end of the 1st and 7th study weeks. 
The patient should be supplied with addressed/stamped envelopes for returning the booklets. 
4Patient will be encouraged to carry a small notepad with them during the day to keep track of hot flashes and 
enhance accuracy of recording on Hot Flash Diary. 
 
 
5.0 
Stratification Factors: 
 
5.1 
Age:  18 - 49 vs ≥50. 
 
5.2 
Current tamoxifen use:  Yes vs no. 
 
5.3 
Current aromatase inhibitor use: Yes vs no. 
 
5.4 
Duration of flash symptoms (months):  <9 vs ≥9. 
 
5.5 
Average frequency of hot flashes per day:  4 - 9 vs ≥10. 


8 
ACCRU-SC-1603 
 
 
6.0 
Registration/Randomization Procedures 
 
6.1 
Registration Procedures 
 
6.11 
To register a patient, access the ACCRU web page 
at 
 click on “Training Page” and enter the 
registration/randomization application. The registration/randomization application is available 
24 hours a day, 7 days a week. Back up and/or system support contact information is available 
on the Web site. If unable to access the Web site, call the Academic and Community Cancer 
Research United (ACCRU) Registration Office at 
 between the hours of 8 a.m. 
and 4:30 p.m. Central Time (Monday through Friday). 
 
The instructions for the registration/randomization application are available using the Help 
button. Prior to initiation of protocol treatment, this process must be completed in its entirety 
and a ACCRU subject ID number must be available as noted in the instructions. It is the 
responsibility of the individual and institution registering the patient to confirm the process has 
been successfully completed prior to release of the study agent. Patient registration via the 
registration/randomization application can be confirmed in any of the following ways: 
• 
Contact the ACCRU Registration Office 
. If the patient was fully 
registered, the ACCRU Registration Office staff can access the information from the 
centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section “Finding/Displaying 
Information about A Registered Subject.” 
 
6.12 
Documentation of IRB approval must be on file with ACCRU before an investigator may 
register any patients. Approvals should be uploaded through the online ACCRU 
Regulatory Management System (ARMS). 
 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file with ACCRU (no less than annually). Approvals should be 
uploaded through the online ACCRU Regulatory Management System (ARMS). If the 
necessary documentation is not submitted in advance of attempting patient registration, the 
registration will not be accepted and the patient may not be enrolled in the protocol until 
the situation is resolved. 
 
Submission of annual IRB approvals to ACCRU is required until the study is closed 
through your IRB. 
 
6.13 
Prior to accepting the registration/randomization, the registration/randomization application 
will verify the following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information 
 
6.14 
Treatment cannot begin prior to registration and must begin ≤ 30 days after registration. 
 
6.15 
Pretreatment tests/procedures (see Section 4.0) must be completed within the guidelines 
specified on the test schedule. 
 
6.16 
Treatment on this protocol must commence at an ACCRU institution under the supervision 
of a health care professional. 


10 
ACCRU-SC-1603 
 
 
6.17 
Study drug is available on site. 
 
6.18 
Patient questionnaire booklet is available on site; copies are not acceptable 
for this submission. 
 
6.2 
Randomization Procedures 
 
6.21 
The factors defined in Section 5.0, together with the registering membership, will 
be used as stratification factors. 
 
6.22 
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 
which balances the marginal distributions of the stratification factors between the 
treatment groups (Pocock SJ, Simon R, 1975). 
 
• 
Oxybutynin 2.5 mL BID x 42 days 
• 
Oxybutynin 2.5 mL BID x 7 days followed by 5 mL BID x 35 days 
• 
Placebo 2.5 mL BID x 42 days 
• 
Placebo 2.5mL BID x 7 days followed by placebo 5mL  BID x 35 days 
 
6.3 
Procedures for Double-Blinding the Treatment Assignment 
 
6.31 
At the time that the site has registered/randomized the patient , the Registration 
Office will contact the designated site contact person with the assigned treatment 
as follows: 
 
• 
Oxybutynin 2.5mL oral BID x 42 days 
• 
Oxybutynin 2.5 mL oral BID x 7 days followed by 5 mL oral BID x 35 days 
• 
Placebo 2.5mL oral BID x 42 days 
• 
Placebo 2.5 mL oral BID x 7 days followed by placebo 5 mL oral BID x 35 
days 
 
The name of this person and his/her contact information will be entered on the 
Enrollment Form. This contact person may not be involved in assessing adverse 
events or any other outcome measure. The institutional pharmacist or designated 
contact person will maintain records that identify the patient and his/her 
corresponding treatment assignment. 
 
7.0 
Protocol Treatment 
 
7.1 
The patient will be instructed not to take any study medication for the first seven days but 
to complete their daily questionnaire 
 during this 
baseline period. At the end of the week, patients will complete Symptom Experience Form 
 and Hot Flash Daily Interference Scale 
. For the subsequent 
six weeks, patients will be instructed to take their study medication as illustrated below. 
 
• 
Oxybutynin 2.5mL oral BID Days 8 through 49  total of 42 days) 
• 
Oxybutynin 2.5 mL oral BID Days 8 through 14 (total of 7 days)  5 mL oral 
BID Days 15 through 49 (total of 35 days) 
• 
Placebo 2.5 mL oral BID Days 8 through 49 (total of 42 days) 
• 
Placebo 2.5mL oral BID Days 8 through 14 (total of 7 days)  5 mL oral BID 
Days 15 through 49 (total of 35 days) 
 
 
 
 


10 
ACCRU-SC-1603 
 
7.2 
At study entry, the patient will be given the following two booklets: 
 
• Double-Blind Week 1 (Baseline) that contains a Patient Instruction Sheet, Hot Flash 
definitions, a daily Hot Flash Diary, Symptom Experience Questionnaire, and a Hot Flash- 
Related Daily Interference Scale. 
• Double-Blind (Weeks 2-7) which contains Patient Instruction Sheet, Hot Flash Definitions, 
six daily Hot Flash Diaries, six Symptom Experience Questionnaires, and one Hot Flash- 
Related Daily Interference Scale. 
 
Procedures for completing and returning the booklets are to be carefully explained. Patient will be 
encouraged to carry a small notepad with them during the day to keep track of hot flashes and 
enhance accuracy of recording on Hot Flash Diary. 
 
7.21 
The page labeled “First Study Week (Baseline)” should be filled out during the first seven 
days following study entry, to document the patient’s baseline hot flashes 
 
 
7.22 
The next pages labeled “Week 2” should be filled out during the second seven days after 
study entry and so on for weeks 3-7 
 
 
7.23 
Evaluation procedures 
 
7.231 Each patient will be contacted by telephone at weekly intervals during the study 
weeks to document compliance, encourage completion of the questionnaires and 
address problems. Phone calls may be omitted in those weeks in which the patient 
is seen at the institution responsible for her primary care. The information obtained 
must be recorded on the Nurse/CRA Evaluation form in the forms packet. 
 
7.232 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. 
 
7.3 
Premature discontinuation of study 
 
7.31 
If the patient decides to discontinue the study medication because of unacceptable side 
effects, she is to call the study nurse. The patient should be asked to complete 
diaries/questionnaires to date and send them in. The patient can then be taken off study. 
 
7.32 
Patients wishing to discontinue the study medication because of perceived lack of benefit 
should be encouraged, whenever possible, to complete the study arm, since the full effect 
of treatment may not be evident for six weeks. 
 
7.33 
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. 
 
7.4 
Procedures at end of study. 
 
7.41 
Patients need to be contacted on their last scheduled day of the randomized, blinded study. 
It should be assured that the patient has completed her questionnaires. Then the patient 
should be told which dose of oxybutynin they were receiving and subsequently given the 
choice of whether she would like to continue with oxybutynin off study (or start it if she 
was on the placebo).  No further data submission is required. 
 
7.42 
If the patient chooses not to continue (or start) oxybutynin after the 7-week randomized 
period, then this is fine. 




12 
ACCRU-SC-1603 
 
• 
Any findings from epidemiological studies, pooled analysis of multiple studies, or 
clinical studies, whether or not conducted under an IND and whether or not conducted 
by the sponsor, that suggest a significant risk in humans exposed to the drug. 
• 
Any clinically important increase in the rate of a serious suspected adverse reaction over 
the rate stated in the protocol, package insert, or Investigator’s Brochure (IB). 
Definitions 
 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, whether or 
not considered drug related. 
 
Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the drug caused the adverse 
event. 
 
Expedited Reporting 
Events reported to sponsor within 24 hours, 5 days or 10 days of study team becoming aware of the 
event. 
 
Routine Reporting 
Events reported to sponsor via case report forms 
 
Events of Interest 
Events that would not typically be considered to meet the criteria for expedited reporting, but that 
for a specific protocol are being reported via expedited means in order to facilitate the review of 
safety data (may be requested by the FDA or the sponsor). 
 
10.1 
Adverse Event Characteristics 
 
CTCAE term (AE description) and grade: The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting. All appropriate treatment areas should have access to a copy of the 
CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web 
site: (http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm) 
 
a. Adverse event monitoring and reporting is a routine part of every clinical trial. 
 
b. Identify the grade and severity of the event using the CTCAE version 4.0. 
 
c. Determine whether the event is expected or unexpected (see Section 10.2). 
 
d. Determine if the adverse event is related to the study intervention (agent, treatment or 
procedure) (see Section 10.3). 
e. Determine whether the event must be reported as an expedited report. If yes, determine the 
timeframe/mechanism (see Section 10.4). 
f. Determine if other reporting is required (see Section 10.5). 
 
g. Note: All AEs reported via expedited mechanisms must also be reported via the routine data 
reporting mechanisms defined by the protocol (see Sections 10.6 and 18.0). 
Each CTCAE term in the current version is a unique representation of a specific event used for 
medical documentation and scientific analysis and is a single MedDRA Lowest Level Term 
(LLT). 
 


13 
ACCRU-SC-1603 
 
NOTE: A severe AE, as defined by the above grading scale, is NOT the same as serious AE 
which is defined in the table in Section 10.4. 
 
10.2 
Expected vs. Unexpected Events 
 
Expected events - are those described within the Section 15.0 of the protocol, the study specific 
consent form, package insert (if applicable), and/or the investigator brochure, (if an investigator 
brochure is not required, otherwise described in the general investigational plan). 
 
Unexpected adverse events or suspected adverse reactions are those not listed in Section 15.0 of the 
protocol, the study specific consent form, package insert (if applicable), or in the investigator 
brochure (or are not listed at the specificity or severity that has been observed); if an investigator 
brochure is not required or available, is not consistent with the risk information described in the 
general investigational plan. 
 
Unexpected also refers to adverse events or suspected adverse reactions that are mentioned in the 
investigator brochure as occurring with a class of drugs but have not been observed with the drug 
under investigation. 
 
10.3 
Assessment of Attribution 
 
When assessing whether an adverse event is related to a medical treatment or procedure, the 
following attribution categories are utilized: 
 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
Events determined to be possibly, probably or definitely attributed to a medical 
treatment suggest there is evidence to indicate a causal relationship between the 
drug/device and the adverse event. 
 
*Report any clinically important increase in the rate of a serious suspected adverse reaction (at 
your study) site over that which is listed in the protocol or investigator brochure as an expedited 
event. 
*Report an expected event that is greater in severity or specificity than expected as an 
expedited 
event 
*An investigational agent/intervention might exacerbate the expected AEs associated with a commercial 
agent.  Therefore, if an expected AE (for the commercial agent) occurs with a higher degree of severity 
or specificity, expedited reporting is required. 
A list of known/expected AEs is reported in the investigator brochure, package insert or the 
literature, including AEs resulting from a drug overdose. 


14 
ACCRU-SC-1603 
 
 
10.331 Death 
 
• 
Any death occurring within 30 days of the last dose, regardless of 
attribution to an agent/intervention under an IND/IDE requires 
expedited reporting within 24-hours. 
• 
Any death occurring greater than 30 days with an attribution of 
possible, probable, or definite to an agent/intervention under an 
IND/IDE requires expedited reporting within 24-hours. 
• 
Reportable categories of Death 
 
• 
Death attributable to a CTCAE term. 
 
• 
Death Neonatal: A disorder characterized by cessation of 
life during the first 28 days of life. 
• 
Death NOS: A cessation of life that cannot be attributed to a 
CTCAE term associated with Grade 5. 
• 
Sudden death NOS: A sudden (defined as instant or within one 
hour of the onset of symptoms) or an unobserved cessation of  
life that cannot be attributed to a CTCAE term associated with 
Grade 5. 
• 
Death due to progressive disease should be reported as Grade    
5 “Neoplasms benign, malignant and unspecified (including 
cysts and polyps) – Other (Progressive Disease)” under the 
system organ class (SOC) of the same name. 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. 
10.332 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. 
• 
All secondary malignancies that occur following treatment with an agent under 
an IND/IDE to be reported. Three options are available to describe the event: 
o Leukemia secondary to oncology chemotherapy (e.g., Acute Myeloid 
Leukemia [AML]) 
 
o Myelodysplastic syndrome (MDS) 
o Treatment-related  secondary malignancy 


15 
ACCRU-SC-1603 
 
 
• 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
 
10.333 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. 
 
10.335 Pregnancy 
 
Prior to obtaining private information about a pregnant woman and her infant, the 
investigator must obtain consent from the pregnant woman and the newborn infant’s parent 
or legal guardian before any data collection can occur. A consent form will need to be 
submitted to the IRB for these subjects if a pregnancy occurs. If informed consent is not 
obtained, no information may be collected. 
In cases of fetal death, miscarriage or abortion the mother is the patient. In cases where 
the child/fetus experiences a serious adverse event other than fetal death, the child/fetus is 
the patient. 
 
NOTE: When submitting ACCRU Adverse Event Report reports for “Pregnancy”, 
“Pregnancy loss”, or “Neonatal loss”, the potential risk of exposure of the fetus to the 
investigational agent(s) or chemotherapy agent(s) should be documented in the 
“Description of Event” section. Include any available medical documentation. 




1 7  
A C C R U -S C -1 6 0 3  
 
 
 
 
F oll o w site -s pecific re p orti n g g ui deli nes. 
 
C o m mercial a ge nt e x pe dit e d re p orts m ust be s u b mitte d t o t he F D A via 
Me d Watc h. 3 5 0 0 A htt p:// w w w.f da. g o v/ d o w nl oa ds/ A b o ut F D A/ Re p orts Ma n uals F or ms/ F or ms
/ U C M 0 4 8 3 3 4. p df or  
htt p:// w w w.f da. g o v/ A b o ut F D A/ Re p orts Ma n uals F or ms/ F or ms/ List F or ms Al p ha beticall y/ defa ult. ht m  
 
I nstr ucti o ns f or c o m pleti n g t he Me d Watc h 
3 5 0 0 A: htt p:// w w w.f da. g o v/ d o w nl oa ds/ Safet y/ Me d Watc h/ H o w T o Re p ort/ D o w nl oa d F or ms/ U C M 3 8 7 0 0 2. p df  
S u b mit c o pies t o t he A C C R U S A E C o or di nat or via fa x 
. T he A C C R U S A E C o or di nat or will 
f or war d t o (i nsert s p o ns or na me). 
 
1 0. 5  
Ot her Re q uire d  Re p orti n g  
 
1 0. 5 1  U na ntici pate d Pr o ble ms I n v ol vi n g Ris ks t o S u bjects or Ot hers ( U PI R T S O S) i n ge neral, 
i ncl u de a n y i nci de nt, e x perie nce, or o utc o me t hat meets all of t he f oll o wi n g  criteria: 
 
1.  U ne x pecte d (i n ter ms of nat ure, se verit y, or fre q ue nc y) gi ve n (a) t he researc h 
pr oce d ures t hat are descri be d i n t he pr ot oc ol- relate d d oc u me nts, s uc h as t he I R B- 
a p pr o ve d researc h pr ot oc ol a n d i nf or me d c o nse nt d oc u me nt; a n d ( b) t he c haracteristics 
of t he s u bject p o p ulati o n bei n g st u die d; 
 
2.  Relate d or p ossi bl y relate d t o partici pati o n i n t he researc h (i n t his g ui da nce d oc u me nt, 
p ossi bl y relate d mea ns t here is a reas o na ble p ossi bilit y t hat t he i nci de nt, e x perie nce, or 
o utc o me ma y ha ve bee n ca use d b y t he pr oce d ures i n v ol ve d i n t he researc h); a n d 
 
3.  S u g gests t hat t he researc h places s u bj ects or ot hers at a greater ris k of har m (i ncl u di n g 
p h ysical, ps yc h ol o gical, ec o n o mic, or s ocial har m) t ha n was pre vi o usl y k n o w n or 
rec o g nize d. 
 
S o me u na ntici pate d pr o ble ms i n v ol ve s ocial or ec o n o m ic har m i nstea d of t he p h ysical or 
ps yc h ol o gical har m ass ociate d wit h a d verse e ve nts. I n ot her cases, u na ntici pate d pr o ble ms 
place s u bjects or ot hers at i ncrease d risk of har m, b ut n o har m occ urs. 
 
N ote: If t here is n o la n g ua ge i n t he pr ot oc ol i n dicati n g t hat pre g na nc y is n ot c o nsi dere d a n 
a d verse e x perie nce f or t his trial, a n d if t he c o nse nt f or m d oes n ot i n dicate t hat s u bj ects  
1Seri o us a d verse e ve nts t hat occ ur m ore t ha n 3 0 da ys after t he last a d mi nistrati o n of i n vesti gati o nal 
a ge nt/i nter ve nti o n a n d ha ve a n attri b uti o n of p ossi ble, pr o ba ble, or defi nite re q uire re p orti n g as 
f oll o ws: 
E x pe dite d 2 4 -h o ur n otific ati o n f oll o we d b y c o m plete re p ort wit hi n 3 c ale n d ar d a ys f or:  
•
All Gra de 4, a n d Gra de 5 A Es  
E x pe dite d 7 c ale n d ar d a y re p orts f or:  
•
Gra de 2 a d verse e ve nts res ulti n g i n h os pitalizati o n or pr ol o n gati o n of h os pitalizati o n  
•
Gra de 3 a d verse  e ve nts 
2 F or st u dies usi n g P E T or S P E C T I N D a ge nts, t he A E re p orti n g peri o d is li mite d t o 1 0 ra di oacti ve 
half-li ves, r o u n de d U P t o t he nearest w h ole da y, after t he a ge nt/i nter ve nti o n was last a d mi nistere d. 
F o ot n ote “ 1” a b o ve a p plies after t his re p orti n g peri o d. 
Effecti ve Date:  Ma y 5, 2 0 1 1 


18 
ACCRU-SC-1603 
 
 
should not get pregnant/impregnate others, then any pregnancy in a subject/patient or a 
male patient’s partner (spontaneously reported) which occurs during the study or within 
120 days of completing the study should be reported as a UPIRTSO. 
If the event meets the criteria for an UPIRTSO, submit to your IRB as required by your 
institutional policies. 
 
10.52 Baseline and Adverse Events Evaluations 
 
Adverse event evaluations will be evaluated by the weekly questionnaires. If patients have 
significant toxicities, they will also be assessed with weekly phone calls. 
 
10.53 
Case Report Forms - Academic and Community Cancer Research United (ACCRU) 
 
Submit the following AEs not specified in Section 10.5 (paper or electronic, as applicable) 
 
10.521 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
 
10.522 Grade 3 and 4 AEs regardless of attribution to the study treatment or procedure. 
 
10.523 Grade 5 AEs (Deaths) 
 
10.5231 Any death within 30 days of the patient’s last study treatment or 
procedure regardless of attribution to the study treatment or 
procedure. 
 
10.5232   Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly treatment 
related must also be submitted as a Grade 5 AE, with a CTCAE 
type and attribution assigned. 
 
10.54 The Academic and Community Cancer Research United (ACCRU) Routine AE Data 
Submission Policy does not apply, as this study does not collect AE attribution. Submit 
Grade 2 or greater AEs via the AE Log when AEs experienced by the patient are not 
specified in Section 10.5. 
 
11.0 
Treatment Evaluation 
 
11.1 
During the seven-day baseline symptom documentation and the treatment periods of this study, 
patients will be instructed to complete a daily “Hot Flash Diary” 
 at roughly the 
same time each day to document severity and frequency of hot flashes. Patients will also complete 
a weekly “Symptom Experience Questionnaire 
 to document possible side effects. 
 
12.0 
Descriptive Factors 
 
12.1 
Duration of tamoxifen therapy (years): 0, <1, 1-5, >5 
 
12.2 
Duration of AI therapy (years). : 0, <1, 1-5, >5 
 
12.3 
Duration of hot flashes (years). :  <1, 1-5, >5 
 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient 


19 
ACCRU-SC-1603 
 
 
 
13.1 
A patient is deemed ineligible if after registration, it is determined that at the time of registration, 
the patient did not satisfy each and every eligibility criteria for study entry. The patient may 
continue treatment off-protocol at the discretion of the physician as long as there are no safety 
concerns, and the patient was properly registered. The patient will go directly off study. 
• 
If the patient received treatment, all data up until the point of confirmation of ineligibility must 
be submitted. 
• 
If the patient never received treatment, on-study material must be submitted. 
 
13.2 
A patient is deemed a major violation, if protocol requirements regarding treatment in cycle 1 of 
the initial therapy are so severely violated that evaluability for primary end point is questionable. 
All data up until the point of confirmation of a major violation must be submitted. The patient will 
go directly to the event-monitoring phase of the study. The patient may continue treatment off- 
protocol at the discretion of the physician as long as there are no safety concerns, and the patient 
was properly registered. 
13.3 
A patient is deemed a cancel if he/she is removed from the study for any reason before any study 
treatment is given. On-study material and the End of Active Treatment/Cancel Notification Form 
must be submitted.  No further data submission is necessary. 
 
14.0 
Body Fluid Biospecimens - Not Applicable 
 
15.0 
Drug Information 
 
Drug Package Insert: The most current version of the package insert will be maintained in the 
study folder on the ACCRU website. 
 
The study drug is IND exempt because: 
 
• 
The drug product is lawfully marketed in the United States. 
• 
The investigation is not intended to be reported to FDA as a well-controlled study in support of a 
new indication and there is no intent to use it to support any other significant change in the labeling 
of the drug. 
• 
In the case of a prescription drug, the investigation is not intended to support a significant change 
in the advertising for the drug. 
• 
The investigation does not involve a route of administration, dose, patient population, or other 
factor that significantly increases the risk (or decreases the acceptability of the risk) associated with 
the use of the drug product (21 CFR 312.2(b)(1)(iii)). 
• 
The investigation is conducted in compliance with the requirements of §312.7 (i.e., the 
investigation is not intended to promote or commercialize the drug product). 
 
15.1 
Oxybutynin chloride 
 
15.11 Formulation: Oxybutynin chloride is available as immediate release tablets of 5mg or oral 
syrup of 5mg/5mL. Extended release (XL) tablets of 5, 10 and 15 mg are also available. 
For the current study, we will use the oxybutynin chloride syrup 5 mg/5 mL, supplied in 
473 mL bottles. 
 
Each 5 mL, for oral administration, contains 5 mg of oxybutynin chloride. In addition, the 
following inactive ingredients are present: Artificial raspberry flavor; citric acid, USP; 
D&C Yellow No. 10; FD&C Blue No. 1; glycerin, USP; liquid sugar; methylparaben, NF; 
propylene glycol, USP; sodium citrate, USP and sorbitol solution, USP. 




21 
ACCRU-SC-1603 
 
 
15.15 Nursing guidelines: 
 
15.131 Patient may take medication with or without food. 
 
15.132 Monitor for potential mild nausea.  Treat accordingly. 
 
15.133 Warn patient of possible somnolence. If patient does experience somnolence, 
advise her to refrain from driving or operating machinery. 
 
15.134 Stress to patient the importance of avoiding medications listed on Appendix VII. 
Encourage patient to contact Nurse/CRA before initiation of new medications. 
 
15.135 Warn patient about possible urinary retention. If patience experiences this, she 
should hold the next dose and contact Nurse/CRA for next steps. 
 
 
15.2 
Placebo 
 
The liquid placebo, Ora-Sweet SF, will also be supplied free-of-charge. No toxicity is expected 
from the placebo. 
 
15.21 
Preparation and Storage 
 
Ora-Sweet SF will be used as the base solution for preparing the placebo doses. Ora- 
Sweet SF is a flavored sugar-free syrup vehicle available in 473mL (16 oz.) bottles. The 
product contains glycerin, sorbitol, sodium saccharin, xanthan bum, flavoring agent, and 
purified water. The solution is buffered with citric acid and sodium citrate and preserved 
with methylparaben, propylparaben, and potassium sorbate. 
 
Store at controlled room temperature (15º to 30º C, 59º to 86º F). A 473 mL (16 oz.) bottle 
is to be retained for the preparation of multiple patient’s dispenses. After the bottles have 
been opened for the first time, the site will assign an expiration date of one year, if this 
expiration date is shorter than the expiration date listed on the bottles. 
 
15.21 
Procurement: Refer to Section 15.14 for procurement instructions. 
 
Outdated or remaining drug is to be destroyed on-site as per procedures in place at each 
institution. 
 
16.0 
Statistical Considerations and Methodology 
 
16.1 
Study design 
 
16.11 This study is a randomized four-arm, double-blind, placebo-controlled phase III trial to 
assess the effectiveness and toxicity of oxybutynin as a treatment for hot flashes. Patients 
will be randomly assigned to oxybutynin at two target doses and placebo arms in 2:2:(1:1) 
ratios according to the dynamic allocation scheme. Patients assigned to the placebo arms 
will be equally divided to receive the same dose schedule as each of the two target doses of 
oxybutynin, so that double-blinding is maintained. 
 
16.12 We will adopt a modified intent-to-treat principle that excludes those patients who will be 
deemed ineligible, major violation, cancel after randomization or missing all repeated 
measures of primary endpoint after randomization. All statistical hypothesis testing will be 
carried out using a two-sided test with a significance level α=0.05. 


22 
ACCRU-SC-1603 
 
 
 
16.2 
Primary and secondary endpoints 
 
16.21 The primary endpoint is the intra-patient changes of weekly hot flash activity from baseline 
during the treatment period. The hot flash activity will be measured by the weekly average 
hot flash score (Sloan JA, et. al., 2001), which is a composite entity of both frequency and 
severity of hot flashes. The daily hot flash score is computed by the grade of severity 
multiplying the frequency of the same grade hot flashes according to the hot flash diary 
over a 24 hour period.  Taking the average of daily hot flash scores over a week produces 
the weekly average hot flash score. 
 
16.22 Secondary endpoints: There are a number of secondary endpoints that may be affected by 
oxybutynin treatment. Due to their exploratory nature, we will not adjust for multiple 
comparisons when performing these analyses. 
 
16.221 The change of weekly frequency and maximum grade of hot flashes as measured 
by the Hot Flash Diary during the treatment period. 
 
16.222 The change of frequency and maximum grade of adverse events reported via the 
CTCAE 4.0 during the treatment period. In particular, dry mouth is of interest. 
 
16.223 The change of severity of symptoms as measured the Symptom Experience 
Questionnaire from baseline to treatment termination. 
 
16.224 The change of daily interference as measured by the HFRDIS from baseline to 
treatment termination. 
 
16.225 The intra-patient changes of weekly hot flash activity from baseline during the 
treatment period between two placebo groups using different dosing. 
16.3 
Analysis plan 
 
16.31 Primary analysis 
 
16.331 The time-averaged intra-patient changes in hot flash activity from baseline during 
the treatment period will be compared between treatment and placebo arms using a 
repeated measures model of weekly hot flash score.  Patient baseline 
characteristics, prognostic factors and actual exposure to oxybutynin (exact dose) 
may be considered as covariate in the model. Estimates from this model will be 
used to construct a 95% confidence interval for the mean difference in intra-patient 
changed of hot flashes between the treatment and placebo arms. 
 
Because our two treatment arms represent different doses of the same drug, we will 
perform a fixed sequence of up to two hypothesis tests, rather than two 
simultaneous tests, as would generally be done for studies in which the primary 
analysis involves two independent hypotheses. This is based on the belief that the 
treatment effect of oxybutynin, if one exists, will change monotonically with 
respect to dose.  To control the overall type-I error for our primary analysis, we 
will employ a gatekeeping procedure. In particular, we will first use the time- 
averaged longitudinal model mentioned above to test the higher dose (2.5mg BID 
for one week, followed by 5mg BID for five weeks) vs placebo at the level 0.05, 
using a two-sided alternative. If and only if this test is significant, we will test the 
smaller dose oxybutynin arm (2.5mg BID for 6 weeks) vs placebo, again at the 
level 0.05, and using a two-sided alternative. If the test of the larger dose arm vs. 
placebo is not significant, we will not perform the test of the smaller dosing arm 


23 
ACCRU-SC-1603 
 
 
vs. placebo as part of our primary analysis.  If both of these tests are significant, 
we will conclude that the treatment effect of oxybutynin given at the dose 2.5mg 
BID or higher is significant (i.e. both the lower and higher dosing schedules are 
associated with a significant treatment effect). If only the higher dose arm test is 
significant, we will conclude that only the treatment effect for the higher dosing 
schedule is significant. If the higher dose arm is not found to differ significantly 
from placebo in the first test, we will conclude that neither of our treatment arms 
differ significantly from the placebo group. It should be noted that, if the higher 
dosing arm is not found to differ significantly from the placebo arms, we will still 
perform the test for the lower dosing arm, but as a secondary analysis, rather than a 
primary analysis. 
 
16.332 Supplementary analyses will be conducted to incorporate patient characteristics, 
baseline hot flash score and other baseline risk factors in the repeated measures 
model. Graphical procedures will include a stream plot of individual scores over 
time and a plot of average (or median) scores over time for the oxybutynin and 
placebo arms. 
 
16.32 Secondary analyses 
 
Secondary endpoints will be transformed to a 0-100 point scale where applicable to aid in 
ease of comparison. This transformation is standard practice in NCCTG Cancer Control 
trials with numerous secondary endpoints (Sloan JA, Dueck A, 2004). 
 
16.321 The change of frequency and maximum severity of hot flashes during the treatment 
period between treatment and placebo arms will be compared using repeated 
measures models.  Generalized estimating equations may be used to estimate 
model parameters, as these are likely to be count and ordinal endpoints. 
 
16.322 The frequency and maximum grade of adverse events reported via the CTCAE 
version 4 through treatment will be first summarized by descriptive statistics. For 
each adverse event, Chi-square tests (or Fisher’s exact tests) will be used to 
evaluate the difference between oxybutynin and placebo arms. 
 
16.323 The change of severity of symptoms as measured by the Symptom Experience 
Questionnaire from baseline to treatment termination will be first summarized by 
descriptive statistics and then compared across oxybutynin and placebo arms using 
Wilcoxon rank sum tests (or two sample t-tests). 
 
16.324 The change of daily interference as measured by the HFRDIS from baseline to 
treatment termination will be first summarized by descriptive statistics and then 
compared across oxybutynin and placebo arms using Wilcoxon rank sum tests (or 
two sample t-tests). 
 
16.325 The time-averaged intra-patient changes in hot flash activity from baseline during 
the treatment period will be compared between the two placebo arms using a 
repeated measures model of weekly hot flash score. 


24 
ACCRU-SC-1603 
 
 
16.4 
Power and sample size 
 
16.41 Sample size calculations are based on the primary analysis of using a time-averaged 
repeated measures model to compare oxybutynin and placebo arms. In particular, the 
number of evaluable patients needed per arm was obtained using Equation 2.4.2 in Diggle 
et al (2002): 
 
m = 2(zα + zQ )
2σ 
2[1+ (n −1)ρ] 
nd 
2 
 
 
 
where zα and zQ are the quantiles of standard normal distribution that corresponds to (one- 
sided) significance level α  and type II error Q , σ is the standard deviation, n is the 
number of repeated measures per subject, ρ is the correlation of repeated measures of 
weekly hot flash score, and d is the meaningful difference of interest. 
 
16.42 We assume the minimum meaningful difference (d) in the time-averaged intra-patient 
change in hot flash activity from baseline is half of a standard deviation (i.e. d/σ = 0.5), 
which is considered a moderate effect size by Cohen (Cohen J, 1988) and which has been 
described as clinically meaningful (Sloan J, et. al., 2003). A moderate correlation 
( ρ = 0.5 ) between repeated measures of weekly hot flash score over the six (n = 6) weeks 
is also assumed for the sample size calculation. 
 
16.43 For the two-sided test of the time-averaged hot flash scores at 5% significance level (note, 
this is two-sided significance, so we use α = 2.5% in the sample size formula above) in the 
primary analysis, we will need 42 evaluable patients per arm to provide 85% power to 
detect an effect size of one half standard deviation. The total sample size will be 126 
patients, as we have two oxybutynin arms. Assuming that as many as 15% of patients will 
be lost due to ineligibility, cancellation, or major violations, our target accrual will be 150 
patients (50 patients in each active treatment arm and 25 patients in each placebo arm). 
 
 
16.5 
Accrual rate and time to completion 
 
We anticipate accruing approximately 10 evaluable patients per month, based on our previous 
experience with similar hot flash trials. Thus, we expect to complete the primary accrual within 15 
months of study initiation and the double-blind data collection 17 months from study initiation. 
 
16.6 
Missing data 
 
16.61 We will examine the mechanisms of missing data if the proportion of missing assessments 
is not small (>=5%). Graphical presentation, correlation analysis (Kendall's) and logistic 
regression will be performed to examine whether the missing data mechanism depends on 
the covariates (patient characteristics and other baseline risk factors), observed patient- 
reported outcome (PRO) scores, and missing PRO scores. 
 
16.62 If we feel it is reasonable to assume that the missing data mechanism depends on the 
covariates only (missing completely at random, MCAR) or depends on the covariates and 
observed PRO scores only (missing at random, MAR) (Little R and Rubin D, 2002), we 
will enhance the primary analysis to incorporate these covariates in the repeated measures 
model.  Assuming the resulting model includes all observed data and covariates that 


25 
ACCRU-SC-1603 
 
 
explain the missing data mechanism, this should result in unbiased estimates under MCAR 
and MAR (Fairclough D, 2002). 
 
16.63 If the missing data mechanism depends on not only the covariates and observed PRO 
scores, but also on the missing HF score (missing not at random, MNAR) (Little R and 
Rubin D, 2002), we will explore advanced models that consider both longitudinal PRO 
assessments and missing data mechanism, such as pattern mixture model and selection 
model (Fairclough D, 2002). 
 
16.64 Simple and multiple imputations will be used as part of sensitivity analysis to examine the 
dependence of the results on specific assumptions about the PRO scores of individuals with 
missing assessments. Previous experience with imputation in NCCTG clinical trials have 
demonstrated that the use of various imputation methods compared to analysis of all 
available data provides evidence of the degree of robustness of the results relative to the 
assumptions of the analytical procedure. 
 
16.7 
Monitoring 
 
The efficacy and toxicity data for this study will be reviewed semiannually by the Mayo Clinic 
Data Safety Monitoring Board (DSMB). Early termination of accrual will be considered if there is 
evidence of unacceptable toxicity. 
 
 
16.8 
Adverse Event Stopping Rule 
 
The stopping rule specified below is based on the knowledge available at study development. We 
do 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 events that the study 
team considers to be at least possibly related to study treatment (i.e., an adverse event with attribute 
specified as “possible,” “probable,” or “definite”) that satisfy the following: 
 
If there are at least 2 events (so that the score is not just 1 versus 0) and a greater than 50% increase 
in grade 4 or higher non-hematologic adverse events (compared to the control arms) in the first 20 
treated patients; or a 25% increase in grade 4 or higher nonhematologic adverse events on the 
oxybutynin arms compared to the control arms after 20 patients total are accrued. 
 
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. 
 
16.9 
Minority accrual 
 
This study will be available to all eligible patients, regardless of race or ethnic origin. There is no 
information currently available regarding differential effects of oxybutynin in subsets defined by 
race or ethnicity, and there is no reason to expect such differences to exist. Nonetheless, the 
planned analyses will, as always, look for differences in treatment effect based on racial groupings. 
 
 
17.0 
Pathology Considerations/Tissue Biospecimens – Not applicable 






28 
ACCRU-SC-1603 
 
 
20.0 
References 
 
Barton DL, Lavasseur BI, Sloan JA, et al: Phase III, Placebo-Controlled Trial of Three Doses of 
Citalopram for the Treatment of Hot Flashes: NCCTG Trial N05C9. J Clin Oncol28:3278-83, 2010. 
 
Barton D, Loprinzi CL: Making sense of the evidence regarding nonhormonal treatments for hot flashes. 
Clinical Journal of Oncology Nursing 8:39-42, 2004. 
 
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