Clinical trial NCT02822573
Conditions: Cognitive Dysfunction Memory Impairment
Keywords: Donepezil Cognition Breast Cancer
Sponsor: Wake Forest University Health Sciences
Start date: 2017-05-30; Completion date: 2022-07-29
Enrollment: 276 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is to compare the safety and effects of donepezil (Aricept) for patients reporting cognitive or memory issues after receiving chemotherapy for breast cancer. Patients will receive either donepezil or placebo for 24 weeks. The primary objective is to see if memory improves with the use of donepezil during the study.

Detailed description:
Randomized, double-blind, placebo-controlled study with 24 weeks of exposure to drug or placebo followed by a 12 week wash-out period. Patients who meet the eligibility criteria will be stratified by age (\<50, 50-59, 60-69, ≥70) and randomized to donepezil or placebo with equal probability. A total of 276 patients will be enrolled (138 per arm). We expect an accrual rate of 7-10 participants per month based on our prior feasibility study. We expect the study to be complete within 40 months.

Participants will be asked to take one 5mg tablet of donepezil or one tablet of matching placebo orally once a day for 6 weeks followed by two 5mg tablets (10mg total) of donepezil or two placebo tablets orally once a day for 18 weeks. After 24 weeks, participants will begin a 12 week wash-out period.

Time points for performing study assessments. Participants will be administered the cognitive battery of tests and questionnaires at baseline, week 12, week 24 and week 36. In addition, a single vial of blood will be drawn at baseline for apolipoprotein E (APOE) genotyping and subsequent bioassays (pending supplemental funding).

Arms: arm 1: Participants will be asked to take one 5 mg tablet of donepezil daily for 6 weeks followed by two 5 mg tablets daily for 18 weeks. After 24 weeks, participants will begin a 12 week wash-out period. arm 2: Participants will be asked to take one tablet of matching placebo daily for 6 weeks followed by two tablets daily for 18 weeks. After 24 weeks, participants will begin a 12 week wash-out period.
Interventions: intervention 1: Donepezil 5 mg intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will be asked to take one 5 mg tablet of donepezil daily for 6 weeks followed by two 5mg tablets daily for 18 weeks. After 24 weeks, participants will begin a 12 week wash-out period. intervention 2: Participants will be asked to take one tablet of matching placebo daily for 6 weeks followed by two tablets daily for 18 weeks. After 24 weeks, participants will begin a 12 week wash-out period.

Protocol documents:
Prot_SAP_001.pdf: 
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COVER PAGE 
DCP Protocol #: WF-97116 
Local Protocol #: WF-97116 
A Phase 3 Randomized Placebo Controlled Clinical Trial of Donepezil in Chemotherapy 
Exposed Breast Cancer Survivors with Cognitive Impairment (REMEMBER) 
Research Base Name: 
Wake Forest NCORP Research Base  
Name of Research Base Principal  
 
Investigator: 
Glenn Lesser, MD 
 
Wake Forest School of Medicine 
 
Department of Internal Medicine, 
 
Section on Hematology and Oncology 
 
Medical Center Boulevard 
 
Winston-Salem, NC 27157 
 
Telephone: (336) 716-0891 
 
Fax: (336) 716-6275 
 
E-mail address: glesser@wakehealth.edu  
Organization: 
Wake Forest School of Medicine 
Protocol Principal Investigator: 
Stephen R. Rapp, PhD 
 
Psychiatry and Behavioral Medicine 
 
Medical Center Boulevard 
 
Winston-Salem, NC 27157 
 
Telephone: (336) 716-6995 
 
Fax: (336) 716-6830 
 
E-mail address: srapp@wakehealth.edu 
Organization: 
Wake Forest School of Medicine 
Co-Investigator: 
Heidi Klepin, MD 
 
Department of Internal Medicine  
 
Section on Hematology and Oncology 
 
Medical Center Boulevard 
 
Winston-Salem, NC 27157 
 
Telephone: (336) 716-5772 
 
Fax: (336) 716-5687 
 
E-mail address: hklepin@wakehealth.edu 
Organization:  
Wake Forest School of Medicine  
Co-Investigator: 
Edward G. Shaw, MD, MA 
 
Department of Internal Medicine  
 
Section of Geriatrics and Gerontology 
 
Medical Center Boulevard 
 
Winston-Salem, NC 27157 
 
Telephone: (336) 716-1034 
 
Fax: (336) 713-5927 
 
E-mail address: eshaw@wakehealth.edu 
 


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Organization: 
Wake Forest School of Medicine 
Statistician: 
Emily V. Dressler, PhD 
 
Department of Public Health Sciences 
 
Department of Biostatistical Sciences 
 
Medical Center Boulevard 
 
Winston-Salem, NC 27157 
 
Telephone: (336) 713-0917 
 
Fax: (336) 716-6427 
 
E-mail address: edressle@wakehealth.edu 
 
Grant: 
1UG1CA189824 
 
NCI/Division of Cancer Prevention 
 
Community Oncology & Prevention Trials Research Group 
 
9609 Medical Center Drive, Room 5E502 
 
Rockville, MD  20850 
 
(240) 276-7050 
IND#: 
Exempt - 131660 
Agent(s)/Supplier: 
Donepezil: Vensun Pharmaceuticals  
 
Placebo: Catalent Pharma Solutions 
Protocol Amendment #: 
4 
Protocol Version Date: 
06/07/2019 
Protocol History: 
Initial 
Version 10/10/2016 
Not Activated 
Amendment 1 
Version 03/23/2017 
Activated 05/12/2017 
Amendment 2 
Version 11/29/2017 
Released 02/12/2018 
Amendment 3 
Version 04/02/2019 
Released 05/16/2019 
 
 
 
 
 
Participating Organizations 
 
WAKE/ Wake Forest NCORP Research Base 
 


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CONTACT INFORMATION 
 
For regulatory requirements: 
For patient enrollments: 
For study data submission: 
Regulatory documentation must 
be submitted to the CTSU via 
the Regulatory Submission 
Portal. 
Regulatory Submission Portal: 
(Sign in at www.ctsu.org,            
and select the Regulatory > 
Regulatory Submission.)  
 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately at 1-866-651-2878 
to receive further instruction 
and support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 
for regulatory assistance. 
Refer to the patient enrollment 
section of the protocol for 
detailed instructions. 
Data will be submitted to the WF 
NCORP Research Base.  
Address: 
Wake Forest NCORP Research 
Base 
Wake Forest Baptist Medical 
Center 
Building 525@Vine, 4th Floor 
Medical Center Boulevard 
Winston-Salem, NC 27157  
 
Phone:  (336) 716-0891 
Fax:       (336) 713-6476  
Email:  
NCORP@wakehealth.edu  
 
Do not submit study data or 
forms to CTSU Data Operations. 
Do not copy the CTSU on data 
submissions. 
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific page of the CTSU Members’ Web site located at https://www.ctsu.org.  
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 user log on with 
CTEP-IAM username and password.  
For clinical questions (i.e. patient eligibility or treatment-related) contact the Site Coordinator at the 
Wake Forest NCORP Research Base Protocol Information Office at NCORP@wakehealth.edu or 
(336)716-0891.  
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Website is located at https://www.ctsu.org. 
 
 


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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
*Select patients will have an ECG or heart rate taken 3-7 days post start of intervention, at the 3 Week study time point, and 3-7 days post study 
agent dose increase. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stratification: Age (<50, 50-59, 60-69, ≥70) 
Study Sample: N=276 (138 per group) 
Study Duration: Approximately 40 months 
Brief Eligibility Criteria:  ≥18 years old, female, history of invasive breast cancer, completed adjuvant/neo-adjuvant 
chemotherapy between 1-5 years prior to enrollment, received ≥ 4 cycles of cytotoxic chemotherapy, self-reported cognitive 
complaint, documented memory deficit. 
 
Baseline Data Collection 
 
Clinic visit for medical history and study assessments. 
 
Baseline Assessment Booklet: 
o 
Neurocognitive test battery: HVLT-R-Form 1, Digit Span Backwards, Digit Symbol Coding, Trail Making Test, 
Controlled Oral Word Association Test  
o 
Patient-Reported Outcomes: Functional Assessment of Cancer Therapy-Cognition (v3), PROMIS Fatigue scale, 
PROMIS Sleep Disturbance scale, Patient Health Questionnaire-9.  
o 
Cognitive Reserve: Shipley-2 Vocabulary Test 
Endpoints 
Primary: 
Memory: HVLT-R Immediate Recall score 
Secondary: Other cognitive domains: Executive function, working memory, processing speed, verbal fluency, global cognitive 
function,  
Patient-reported outcomes: cognitive problems 
Other: toxicities, adverse events.  
Pre-Screening: Verbal consent for Eligibility:  
Self-reported cognitive symptoms; poor memory performance (Hopkins Verbal Learning 
Test-Revised (HVLT-R)-Form 3 Score  ≤7) 
Enrollment / Randomization 
Placebo tablets x 24 weeks 
Weeks 1-6: one tablet orally once a day  
Weeks 7-24: two tablets orally once a day  
Donepezil tablets x 24 weeks 
Weeks 1-6: one 5mg tablet orally once a day 
Weeks 7-24: two 5mg tablets (10mg total) orally once 
a day 
Informed Consent / Screening 
Intervention* 
Week 3: 
Phone interview for assessment of toxicities  
Week 6: 
Phone interview for assessment of toxicities; if indicated, increase dose to two 5mg tablets of donepezil daily or 
two placebo tablets starting at week 7 
Week 12: 
Clinic visit for study assessment, Neurocognitive test battery, Patient Reported Outcomes, Toxicity assessment, 
Verify dosage and continued compliance with study medication 
Week 24: 
End of drug administration; beginning of wash-out. Clinic visit for study assessment, Neurocognitive test battery, 
Patient Reported Outcomes, Toxicity assessment 
Week 36: 
End of wash-out. Clinic visit for study assessment, Neurocognitive test battery, Patient Reported Outcomes, 
Toxicity assessment 


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Table of Contents 
 
COVER PAGE................................................................................................................................... 1 
SCHEMA ........................................................................................................................................... 4 
1. OBJECTIVES ................................................................................................................................ 6 
2. BACKGROUND ........................................................................................................................... 6 
3. SUMMARY OF STUDY PLAN ................................................................................................... 10 
4. PARTICIPANT SELECTION ....................................................................................................... 12 
5. AGENT ADMINISTRATION ...................................................................................................... 16 
6. PHARMACEUTICAL INFORMATION ...................................................................................... 18 
7. CLINICAL EVALUATIONS AND PROCEDURES ................................................................... 21 
8. OFF-AGENT/OFF-STUDY .......................................................................................................... 28 
9. SPECIMEN MANAGEMENT ...................................................................................................... 29 
10. REPORTING ADVERSE EVENTS ........................................................................................... 29 
11. STUDY MONITORING ............................................................................................................. 34 
12. STATISTICAL CONSIDERATIONS ......................................................................................... 36 
13. SITE REGISTRATION ............................................................................................................... 41 
REFERENCES .................................................................................................................................. 44 
Appendix A – Moderate Risk QTc Prolonging Medications ............................................................. 49 
Appendix B – Moderate Risk Bradycardia Causing Agents .............................................................. 50 
Appendix C – Succinylcholine/Acetylcholinesterase Inhibitors ........................................................ 51 
Appendix D – High Risk QTc Prolonging Medications .................................................................... 52 
Appendix E – Guidelines for Reconsenting Patients ......................................................................... 53 
 
 
Data Form Appendices 
 
1. 
Data Submission Checklist 
2. 
Flow Sheet 
3. 
Pre-Screen 
4. 
Decline Form 
5. 
Eligibility-Enrollment Form 
6. 
Baseline Assessment Booklet 
7. 
Concomitant Medication Form 
8. 
Donepezil Medication Diary 
9. 
Telephone Contact 
10. 
12 Week Assessment Booklet 
11. 
24 Week Assessment Booklet 
12. 
36 Week Assessment Booklet 
13. 
Patient Status Form 
14. 
AE Report Form 
15. 
Cardiac Monitoring Form 
 
 
 


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1. 
OBJECTIVES 
 
1.1 
Primary Objective 
 
Aim 1: Determine whether randomization to a 24-week course of treatment with donepezil compared to 
placebo improves memory performance in women who have received chemotherapy for breast cancer 1 to 
5 years previously.  Hypothesis: Women randomized to donepezil for 24 weeks will have better memory 
performance than women receiving placebo. 
 
1.2 
Secondary Objectives 
 
Aim 2: Determine whether a 24-week course of treatment with donepezil compared to placebo improves 
executive functions (working memory, verbal fluency, set shifting), processing speed and global cognitive 
performance in women who have received chemotherapy for breast cancer 1 to 5 years previously. 
Hypothesis: Women randomized to donepezil for 24 weeks will have better executive function, 
processing speed and global cognitive performance than women receiving placebo. 
 
Aim 3: Determine if a 24-week course of treatment with donepezil reduces self-reported cognitive 
problems in women who have received chemotherapy for breast cancer 1 to 5 years previously compared 
to placebo. Hypothesis: Women randomized to donepezil for 24 weeks will report fewer cognitive 
problems than women receiving placebo. 
 
Aim 4: To determine the effect of a 24-week course of treatment with donepezil on toxicities and adverse 
events.  Hypothesis: No group difference. 
 
1.3 
Tertiary (Exploratory) Objectives 
 
Aim 5: Determine whether APOE genotype (1 or 2, ε4 alleles v none) is associated with poorer pre-
randomization cognitive performance and more cognitive complaints in women who have received 
chemotherapy for breast cancer 1 to 5 years previously and to determine if APOE predicts who will 
respond to treatment. Hypothesis: Women who are carriers of the APOE ε4 alleles will have poorer pre-
randomization cognitive performance, more cognitive complaints, and respond better to donepezil than 
women without the ε4 alleles. 
 
Aim 6: Determine whether low cognitive reserve (CR) is associated with poorer pre-randomization 
cognitive performance and more cognitive complaints in women who have received chemotherapy for 
breast cancer 1 to 5 years previously and determine if cognitive reserve predicts who will respond to 
treatment. Hypothesis: Women with lower CR will have poorer pre-randomization cognitive 
performance, more cognitive complaints, and respond better to donepezil than women high in CR. 
  
2. 
BACKGROUND 
 
2.1 
Study Disease 
 
 
 
Cancer-related cognitive dysfunction (CRCD) frequently occurs in breast cancer survivors following 
cytotoxic adjuvant or neo-adjuvant chemotherapy and will be the focus of this study.  
 
 
2.2 
Study Agent 
 
Donepezil hydrochloride (Aricept®) is a reversible inhibitor of the enzyme acetyl cholinesterase.  It is 
currently FDA approved for use in the treatment of mild to moderate dementia of the Alzheimer’s type.  


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Donepezil hydrochloride is available for oral administration in 5 or 10mg film-coated tablets. The 
donepezil are not dispersible tablets as such, the donepezil and placebo are over encapsulated and must be 
swallowed. Donepezil was initially manufactured and marketed by Eisai Inc., Teaneck NJ and distributed 
by Roerig Division of Pfizer Inc., New York, NY.  Generic donepezil is now available and will be 
purchased from Vensun Pharmaceuticals, Inc., Cranbury, NJ.  Drug and matching placebo will be 
purchased in bulk and provided at no cost for participants participating in this study. Drug/placebo will be 
packaged and distributed by RxCrossroads by McKesson Inc., Irving, Texas.  
 
IND Status: We have conducted several controlled trials involving cancer patients using the proposed 
dosages of donepezil and consistently found a very low risk profile.  In a feasibility study for this 
proposal with 62 female breast cancer survivors enrolled between 7/24/2012 and 1/24/2013 and randomly 
assigned to receive the same dosages as proposed in this study (5mg x 6 weeks increased to  10mg x 18 
weeks) or placebo, we had excellent compliance (98% in the donepezil group), few withdrawals from the 
study due to toxicities (4 in the donepezil group), and only four adverse events (3 in the Control arm and 
1 in the Donepezil arm).  All were unrelated to the study treatment (Lawrence et al., 2015). In other 
published studies we reported a similar profile of few toxicities with this agent.  In a phase 3 RCT with 
198 brain tumor survivors ≥6 months post brain irradiation treatment who were randomized to the same 
dosage of donepezil (5mg x 6 weeks increased to 10mg x 18 weeks) or placebo, only 14 donepezil 
participants discontinued treatment due to toxicity compared to 5 control participants (p = .030) and 19 
SAEs were reported (10 for the donepezil arm and 9 for the control arm); only two of the donepezil 
events and one control were coded as possibly or probably related to the study drug.  Toxicities were 
queried at 6, 12 and 24 weeks. Fatigue was the most common complaint, experienced to some degree by 
58% of the donepezil participants and 67% of the control participants (p = .241).  Anorexia occurred in 
21% and 15% of the donepezil and control group, respectively (p = .301), nausea in 14% and 21% (p = 
.171), and diarrhea in 25% and 9% (p = .005)(Rapp, Case, Peiffer, Naughton, & Shaw, 2013).  A very 
similar toxicity profile was reported in a pilot study with brain tumor survivors following brain irradiation 
randomized to donepezil or placebo (Shaw et al., 2006).  Thus the risk profiles associated with the 
proposed dosages of donepezil when used with cancer patients including breast cancer survivors 
following chemotherapy is minimal and supports not requiring an IND.  The study will be submitted to 
the FDA for IND exemption request as described in the DCP memo dated January 14, 2013. 
 
The recommended dosage for patients with dementia is donepezil 5mg/day for 6 weeks escalated to 
donepezil 10mg/day if well-tolerated.  Participants will be randomized 1:1 to either one tablet of 
donepezil 5mg or one tablet of matching placebo orally once a day for 6 weeks followed by an escalation 
to two 5mg tablets (10mg total) or two tablets of matching placebo orally once a day for 18 weeks. This 
dose and schedule has been used in our previous phase 2 and phase 3 studies of donepezil and is similar to 
regimens used in the treatment of cognitive impairment associated with neurodegenerative disease.  A 12-
week wash-out phase will occur immediately following the 24 week active intervention phase. 
 
We recently completed a phase II, placebo-controlled, double-blind feasibility study comparing a standard 
dose of oral donepezil (5mg for 6 weeks followed by 10mg daily for 18 weeks) to placebo in breast 
cancer survivors who had completed adjuvant chemotherapy 1-5 years prior to enrollment and who 
reported cognitive dysfunction (WF NCORP Research Base study #97211).  The study was open at 16 
sites within the WF NCORP Research Base. We enrolled 62 women between 7/24/11 and 1/24/12 for an 
excellent accrual rate of 10.2 subjects per month.  Of the women who completed study (76% of those 
enrolled), self-reported compliance to study drug was 98% and completion of all assessments was 98%.  
Participant toxicities were minimal (mostly Grade 1 and 2; p>.05).   
 
In addition, the identical dosage and regimen was used successfully in a phase 2 study (WF NCORP 
Research Base study #97100) (N=35 of brain tumor patients who had completed a course of ≥30 Gray of 
brain radiotherapy at least 6 months prior to enrollment as well as in a subsequent phase 3 study (WF 


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NCORP Research Base study #91105) (N=198) with the same patient population. In both studies 
tolerance of donepezil was quite good and self-reported adherence was >90%.  
 
2.3 
Rationale 
 
There are 2.5 million breast cancer survivors in the United States today,1 and the number is increasing as 
treatments increase life expectancy.  Some of the most important late effects of cancer treatment to 
patients are the negative impact on cognition, energy and mood which result in decreased quality of life 2.   
 
Chemotherapeutic agents lack tissue selectivity resulting in damage to non-targeted organs. Despite the 
protection offered by the blood-brain barrier, some agents penetrate the central nervous system and 
adversely affect brain tissue resulting in cognitive dysfunction for a substantial number of patients. CRCD 
can range from mild to severe, often is chronic and affects social and occupational functioning and life 
quality 3-6.  
 
The specific phenotype and course of CRCD remain unclear. 70% of longitudinal studies of non-CNS 
cancer patients treated with chemotherapy show some cognitive deficits with point estimates ranging 
from 17% to 70% 7. CRCD is often reported by patients long after chemotherapy has ended 5, 8-12.  For 
example, among breast cancer patients treated with chemotherapy 21% exhibited CRCD before 
chemotherapy, 65% exhibited cognitive changes during or shortly after treatment, and 61% showed 
decline approximately 1 year after treatment ended with approximately 2/3 of these patients showing 
deficits that were not previously detected13.  Breast cancer survivors who were assessed between 1 to 5 
years following a course of chemotherapy showed significantly poorer learning and memory performance 
compared with women who were treated with local therapy (surgery and radiation)10.  Late CRCD effects 
including poorer memory, processing speed and executive functioning in breast cancer survivors have 
been observed up to 21 years following treatment14.  In our recently completed phase II feasibility study 
(#97211) conducted through the Wake Forest CCOP Research Base, we documented deficits in learning 
and memory, verbal fluency, processing speed, executive function and motor speed and dexterity in 62 
breast cancer survivors 1-5 years after completing chemotherapy15 relative to non-cancer norms. Across 
studies of breast cancer patients receiving chemotherapy, cognitive domains commonly affected are 
learning and memory, attention and processing speed5 but other patterns have also been reported16.  
   
The mechanisms underlying chemotherapy-induced cognitive dysfunction remain unclear17.  Anticancer 
agents can affect brain function through direct (neurotoxicity) and indirect pathways (treatment induced 
metabolic and hormonal abnormalities, inflammatory cytokine activation, medical comorbidities, fatigue 
and injury to other body organs)18. Structural and functional CNS changes occur in as many as 70% of 
patients19.  These changes can include periventricular white matter lesions, necrosis, ventriculomegaly 
and cortical atrophy20.  Alterations in metabolism and cerebral blood flow have been observed21 along 
with atrophy22.   
 
Damage to the hippocampus may be particularly important in CRCD. The hippocampus, a brain 
region critical to learning, memory and mood, is rich in cholinergic neurons and highly susceptible to 
radiotherapy and chemotherapy23. Rodents exposed to methotrexate, which crosses the blood brain 
barrier, exhibit impairment in spatial memory function which is correlated with decreased hippocampal 
cell proliferation24.  Smaller gray and white matter volumes in prefrontal, hippocampal and 
parahippocampal regions in humans have been documented 1 year following chemotherapy and volumes 
were positively correlated with cognitive performance22. Thus, cognitive impairment seen following 
chemotherapy may be related to neuronal damage in the hippocampus. Cognitive enhancing treatments 
that operate on hippocampal processes like cholinergic enhancers may offer benefit to patients who have 
received chemotherapy.  
 


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Interventions:  A potential role for neurotransmitter modulators 
Acetylcholine esterase inhibitors (AChEIs) are the standard of care for individuals with Alzheimer’s 
dementia,25, 26 and vascular dementia27 and are frequently used for milder forms of impairment such as 
Mild Cognitive Impairment syndrome28. Furthermore, there is evidence of AChEIs efficacy in treating 
cognitive impairment associated with Parkinson’s disease29, multiple sclerosis30, and traumatic brain 
injury31, 32.  AChEIs have also improved cognitive functioning in young, healthy adults33.  In addition to 
the known direct effects on neuronal function, donepezil, the most commonly prescribed AChEI, also 
increases cerebral perfusion in critical brain areas related to cognitive processing34. Advantages of 
donepezil are its availability in generic form, its high tolerance profile and a simple dosing regimen.   
 
Preliminary studies 
 
Our research group has tested donepezil in several cancer survivor populations.   
 
Brain tumor patients following brain irradiation. Shaw et al. reported significant improvement in 
cognitive function, cognitive complaints, mood and quality of life among brain tumor patients treated 
with 5mg/10mg daily dose of donepezil at least 6 months following completion of brain irradiation 
therapy35.  A comprehensive cognitive test battery assessing major domains of cognition (attention, 
language, episodic memory, working memory, visuomotor speed and dexterity, processing speed, 
executive function) and standardized questionnaires were used. That uncontrolled phase 2 study was 
followed by our recently completed phase 3 study (5R01NR009675, Rapp PI) of brain tumor patients 
who were ≥6 months post partial or whole brain irradiation, in which we found randomization to 
donepezil did not improve overall cognitive function but cognitive function in individuals with poorer 
baseline cognitive functioning did improve significantly compared to placebo36.   
 
Breast cancer patients following chemotherapy. In our recently completed phase 2 feasibility study of 
62 breast cancer survivors 1-5 years following chemotherapy who reported moderate to severe cognitive 
symptoms using the same comprehensive cognitive battery, we found participants randomized to 24 
weeks of donepezil (5mg x 6 wk. + 10mg x 18 wk.) had better memory (HVLT-R Total recall, p = 0.03; 
HVLT-R Discrimination, p = 0.04) scores after 24 weeks than participants assigned to placebo15.  
Sensitivity analyses revealed that participants with lower baseline memory scores  (≤7 on Trial 1 of 
HVLT-R) who were randomized to donepezil showed greater improvement relative to controls than 
participants with better memory function assigned to donepezil (p = 0.002) and a similar pattern was 
observed for executive function  (p = .007).  Participant reported treatment compliance was 98%, and 
toxicities were minimal (mostly Grade 1 and 2; p>.05).  Accrual was robust (62 participants from 16 sites 
in 6 months or 10 participants per month), and 24-week retention was very good (76%).  There were no 
significant group differences in subjective cognitive functioning or quality of life. There was a suggestion 
that those participants on anti-estrogen hormonal therapy (HT) did somewhat worse than participants who 
were not receiving HT (e.g., composite LS mean .2 vs -.05 at 24 weeks, p = .14).  However, there was 
very little evidence that the treatment effect differed for those who were and were not receiving HT 
(interaction p-values ranged from .36 to .97 for the memory tests and composite). Finally, member sites of 
the WF NCORP Research Base were surveyed before the phase 2 feasibility study and indicated a keen 
interest in it and in a larger phase 3 trial. 
 
Thus, studies conducted by our research group demonstrate that donepezil can improve cognitive 
function, particularly memory and executive function, among brain and breast cancer survivors following 
both brain irradiation and chemotherapy.   
 
 
 
 


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Correlative science: Finding markers of susceptibility  
 
There is wide variability in the severity of CRCD among breast cancer survivors treated with 
chemotherapy. Scores on standardized cognitive tests often range from severely impaired to normal 
levels.  To better understand and treat CRCD, it will be important to identify markers of susceptibility.  
Factors studied in relation to other diseases associated with cognitive impairment may offer insights into 
CRCD6.  For example, Apolipoprotein E (APOE) genotype, older age, and lower ‘cognitive reserve’ 
are all associated with a greater risk of developing Alzheimer’s dementia (AD) and of transition from 
mild cognitive impairment to AD and thus may also identify breast cancer survivors who are at greater 
risk of developing CRCD.  
 
APOE genotype is a multifunctional lipoprotein synthesized by many body organs and is thought to have 
a role in neuronal repair after injury. The APOE polymorphism is a risk factor for both Alzheimer’s 
dementia and vascular dementia with carriers of the ε4 allele at higher risk than non-carriers37, 38.   Ahles 
et al. reported an increased susceptibility to the adverse cognitive effects of chemotherapy among breast 
cancer survivors an average of 8 years post-treatment among carriers of the APOE ε4 alleles compared to 
non-carriers39.  Ahles et al. also recently reported poorer cognitive functioning among breast cancer 
survivors who were ε4 carriers and who received either chemotherapy with or without anti-estrogen 
hormonal therapies40. In an exploratory analysis, we propose to examine whether APOE genotype is 
associated with greater cognitive impairment following chemotherapy.  
 
‘Cognitive reserve’ (CR) refers to acquired compensatory strategies that enhance a person’s cognitive 
and behavioral capacities41, 42.  Individuals with higher CR should have less cognitive impairment because 
of their greater adaptive capacity.  Common proxies for CR are literacy and educational and occupational 
attainment.  Higher levels of CR have been associated with lower incident rates for age-associated 
cognitive impairment and longer delayed onset of dementia.  CR will be examined as a susceptibility 
factor for CRCD (low CR individuals will have greater cognitive impairment at baseline than high CR 
individuals).   
 
There are other potential markers of susceptibility and treatment modifiers including telomere length and 
other genotypes (e.g., catechol-O-methyltransferase). We propose to collect and store blood for analyses 
of genetic and non-genetic factors of interest in the future pending outcome of this study.  
 
In summary, CRCD is a common problem following chemotherapy. It can affect various cognitive 
functions (especially memory, executive function and processing speed) and can last for or develop years 
following treatment. Little is known about the underlying biological mechanisms, but it appears that 
chemotherapeutic agents adversely impact the hippocampus, a part of the brain that is heavily involved in 
learning and memory as well as mood.  Treatments that enhance hippocampal-dependent functions, 
therefore, may have particular benefit for patients who receive chemotherapy.  At the WF NCORP 
Research Base we have completed two phase 2 and one phase 3 studies examining whether donepezil, an 
acetylcholine esterase inhibitor that affects hippocampal function, reduces CRCD in diverse cancer 
populations. Encouraging treatment effects and our demonstrated ability to conduct these studies strongly 
support this larger phase 3 RCT.  
 
3. 
SUMMARY OF STUDY PLAN 
 
3.1 
Study Design 
 
Randomized, double-blind, placebo-controlled study with 24 weeks of exposure to drug or placebo 
followed by a 12 week wash-out period. A total of 276 patients will be enrolled (138 per arm).  We expect 


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an accrual rate of 7-10 participants per month based on our prior feasibility study. We expect the study to 
be complete within 40 months. 
 
Study population. Participants will be women ≥18 years old with history of invasive breast cancer treated 
with ≥4 cycles of cytotoxic adjuvant/neo-adjuvant chemotherapy between 1 and 5 years prior to 
enrollment; who have no clinical evidence of recurrent disease; who have a complaint of 
memory/cognitive problems since chemotherapy started; and who have a demonstrated memory deficit on 
a standardized memory test (score ≤7 on single learning trial of Hopkins Verbal Learning Test-Revised 
Form 3) 
 
3.2 
Intervention Plan  
 
Participants will be asked to take one 5mg tablet of donepezil or one tablet of matching placebo orally 
once a day for 6 weeks followed by two 5mg tablets (10mg total) of donepezil or two placebo tablets 
orally once a day for 18 weeks.  After 24 weeks, participants will begin a 12 week wash-out period.  
 
Time points for performing study assessments. Participants will be administered the cognitive battery of 
tests and questionnaires at baseline, week 12, week 24 and week 36. In addition, a single vial of blood 
will be drawn at baseline for APOE genotyping and subsequent bioassays (pending supplemental 
funding).  Additional monitoring visits are described in Section 7. 
 
3.3 
Measurements taken to meet study objectives.   
 
Neurocognitive Performance - Tests have been selected to represent a range of functions reported to be 
affected by cancer and chemotherapy including attention, memory, working memory, executive function 
and verbal fluency. All cognitive testing will be performed by a trained and certified research assistant 
blinded to treatment assignment.  Proposed neurocognitive measures are: Hopkins Verbal Learning Test-
Revised (HVLT; 10 min)43, 44(Aim 1); Digit Span-Backwards (DST-B; 2 min) and Digit Symbol Coding 
(DSC; 3 min) subtests from the Wechsler Adult Intelligence Scale-Revised45; Trail Making Test A & B 
(TMT; 8 min max)46; and the Controlled Oral Word Association test (3 letters; 4 min)47 that has been used 
with cancer patients49 and has non-cancer norms50 (Aim 2).  Each cognitive measure proposed has 
adequate psychometric properties and has been used in cancer research including large national and 
international clinical trials 51-53.  An alternate version of the HVLT-R word list will be used for screening 
to reduce practice effects.  
 
Patient Reported Outcomes - Patient-reported outcomes will complement the neurocognitive battery.   
We will assess cognitive symptoms (Functional Assessment of Cancer Therapy-Cognition (Version 3; 
FACT-Cog; 5 min)(Aim 3) 54, 55; fatigue (PROMIS 7-item scale; 1 min), sleep disturbance (PROMIS 8-
item sleep scale; 1 min); and depression (Patient Health Questionnaire-9; 2 min) 56, 57. This entire battery 
of neurocognitive tests and questionnaires will take approximately 40 minutes to complete.  We have used 
a similar battery successfully in two phase 2 studies and one phase 3 study involving breast and brain 
tumor cancer survivors. Data completeness in those studies was over 95%.  
 
Other variables to be measured - Additional variables to be assessed only at baseline include age, 
education, occupation, race/ethnicity, marital status, menopausal status, cancer treatment received 
(chemotherapeutic agent, anti-estrogen hormonal agent), and time since end of chemotherapy.  Comorbid 
medical conditions, anti-estrogen status, use of psychotropic medications will be assessed at each 
assessment point. Cognitive reserve will be measured with the Shipley Institute of Living-Version 2 
Vocabulary test with educational (years in school) and occupational attainment (standardized 8-level 
classification) used as additional proxies for CR.  
 


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Biomarker -  APOE genotype will be derived from whole blood samples taken at baseline at each 
NCORP site of study enrollment. Prepared shipping kits will be sent to participating NCORP sites from 
the Wake Forest Biotech Laboratory following procedures used previously in Research Base studies. The 
lab will provide sample handling, storage, tracking, and logistics.  DNA will be isolated from whole 
blood, collected in yellow-top Vacutainer tubes (with citrate as the preservative). Blood samples will be 
brought to the Wake Forest Center for Genomics and Personalized Medicine Research laboratories, where 
they will be entered into a database and the DNA isolated.  DNA from whole blood will be isolated using 
the AutoPure LS instrument (Qiagen, Inc.).  SNP genotyping of the APOE haplotype will be performed in 
the Center for Genomics and Personalized Medicine Research at Wake Forest using the iPlex SNP 
genotyping system (Sequenom, Inc.), which has been successfully tested and fully integrated into our 
laboratory. The APOE haplotype will be determined by genotyping the two individual SNPs that make up 
the haplotype, rs429358 and rs7412, in each individual. Genotypes will be scored using the SpectroTyper 
software (Sequenom, Inc.), and quality control parameters (e.g., CEPH DNA samples, negative controls) 
will be determined. Problem samples or SNPs will be reviewed and repeated if necessary. 
 
3.4 
Procedures to Monitor Effects of Study Agent 
 
Procedures to monitor effects of study agent on human safety and to minimize risks are described in 
Section 5.  
 
4. 
PARTICIPANT SELECTION 
 
 
4.1 
Inclusion Criteria 
 
4.1.1 
Women ≥18 years old with history of invasive breast cancer  
 
4.1.2 
Must have completed at least 4 cycles of adjuvant/neo-adjuvant cytotoxic chemotherapy between 
1 and 5 years prior to enrollment (Ongoing herceptin or other chronic HER 2 directed therapies 
are allowed). 
 
4.1.3 
Patients receiving ongoing hormonal therapy for breast cancer must be on the same hormonal 
agent for at least 3 months prior to study enrollment and plan to continue for the duration of the 
study (9 months). 
 
4.1.4 
Use of psychotropic medications (anti-depressants, anxiolytics, sleeping aids, narcotics) is 
permitted if the patient whose eligibility is being assessed has been on the medication for at least 
12 weeks. The dose of this medication must be stable for at least 4 weeks prior to enrollment.  
 
4.1.4.1 Patients who were previously on one of these psychotropic medications and have 
subsequently discontinued the drug must have been off the medication for at least 4 
weeks prior to enrollment.  
 
 
 
4.1.4.2 Patients who have been on a psychotropic medication for at least 12 weeks but have 
recently switched to a medicine in the same class (for example, switching from one 
SSRI antidepressant to a different SSRI antidepressant) need to be on a stable dose of 
the new medication for at least 4 weeks prior to enrollment to be eligible.   
 
4.1.5 
Self-reported cognitive problem plus a measured memory deficit (score ≤ 7 on single trial of 
Eligibility Pre-screen HVLT-R Form 3). 
 
4.1.6 
ECOG performance status 0-2   


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4.1.7 
Able to understand and willing to sign a written informed consent document.  
 
4.1.8 
Must be able to speak English. 
 
4.1.9 
Patients currently taking a moderate risk QTc prolongation medication (see Appendix A) are 
allowed if one of the following criteria are met: 
 
4.1.9.1 The moderate risk QTc prolongation medication is stopped. The patient should be off 
the moderate risk QTc prolongation medication for at least 5 half-lives before starting 
study drug. 
 
4.1.9.2 Patients that continue using a moderate risk QTc prolongation medication must have a 
normal QTc interval (≤ 460 milliseconds) on a screening ECG following informed 
consent and prior to study enrollment. These patients will also be monitored at 
designated study follow-up visits per Section  7.5 (monitored 3-7 days after initiating 
study drug, at week 3, and 3-7 days after the study drug dose increase with ECG’s to 
assess the QTc interval; the QTc level must be ≤ 500 milliseconds at these time points in 
order to continue on the study drug). 
 
4.1.9.3 Moderate risk QTc prolongation medications that are only taken occasionally may be 
stopped at the discretion of the treating site physician. Patients must be off medication 
for at least 5 half-lives prior to starting study drug to be eligible. 
 
4.1.10 Patients currently taking a moderate risk bradycardia-causing agent (see Appendix B) are allowed 
if one of the following criteria are met: 
 
 
 
4.1.10.1 The moderate risk bradycardia-causing agent is stopped.  The patient should be off the 
moderate risk bradycardia-causing agent for at least 5 half-lives before starting study 
drug. 
 
4.1.10.2 Patients that continue using a moderate risk bradycardia-causing agent must have a 
resting heart rate ≥ 55 beats per minute at screening following informed consent.  These 
patients’ resting heart rate will be monitored 3-7 days after initiating study drug, at week 
3, and 3-7 days after the study drug dose increase per Section 7.5. 
 
4.1.10.3 Moderate risk bradycardia-causing agents that are only taken occasionally may be 
stopped at the discretion of the treating site physician. Patients must be off medication 
for at least 5 half-lives prior to starting study drug to be eligible. 
 
 
4.2 
Exclusion Criteria 
 
 
 
4.2.1 
Evidence of or suspected recurrent or metastatic disease.  
 
4.2.2 
Prior brain irradiation. 
 
4.2.3 
Planned therapy (surgery, radiation, chemotherapy, or immunotherapy) while on the study for 
brain and/or extracranial primary/metastatic disease. 
 
4.2.4 
Hypersensitivity to donepezil or piperidine derivatives 
 


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4.2.5 
Current use of ceritinib  
 
4.2.6 
Current use of Succinylcholine/Acetylcholinesterase Inhibitors as listed in Appendix C. For 
patients who have used these medications, they must not have used them within 4 weeks prior to 
enrollment. 
 
4.2.7 
Current use of high-risk QTc prolonging medication(s). See Appendix D. 
 
4.2.8 
Current use of quinidine or systemic ketoconazole (topical ketoconazole is acceptable to use 
while on study). 
 
4.2.9 
History of dementia, Alzheimer’s disease, multi-infarct dementia or clinically significant 
Cerebrovascular Accident (history of transient ischemic attack (TIA) is allowed). 
 
4.2.10 Current use of donepezil, galantamine, rivastigmine, tacrine, memantine, methylphenidate, 
dextroamphetamine, or any other specific cognition enhancing drug(s). For patients who have 
used these medications, they must not have used them within 4 weeks prior to pre-screening. 
Patients who plan to start taking a cognition enhancing drug while on this study are also 
excluded. 
 
4.2.11 History of allergic reactions attributed to compounds of similar chemical or biologic composition 
to donepezil. Hypersensitivity to donepezil. 
 
4.2.12 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, recent myocardial infarction, or 
cardiac arrhythmia.  
 
4.2.13 Major medical conditions that affect cognition, traumatic brain injury, multiple sclerosis, acute 
severe fatigue, chronic fatigue syndrome or fibromyalgia. 
 
4.2.14 Psychiatric illness/social situations that would limit compliance with study requirements 
including but not limited to a history of schizophrenia, psychosis or substance abuse. 
 
4.2.15 Untreated current severe depression. Currently treated depression is permitted if treatment is 
stable.  
 
4.2.16 Patients with a resting heart rate less than 55 beats per minute, seizure disorder or peptic ulcer 
disease (PUD). 
 
4.2.17 Screening QTc of > 460 milliseconds will make the patient ineligible. 
 
4.2.18 History of congenital long QT syndrome or torsades de pointes. 
 
4.2.19 Pregnant women are excluded from this study.  Following informed consent, women of child-
bearing potential will be screened with a serum or urine pregnancy test within 10 days of 
enrollment.  The effects of donepezil on the developing human fetus at the recommended 
therapeutic dose are unknown.  For this reason and because donepezil is known to be teratogenic, 
women of child-bearing potential must agree to use adequate contraception (hormonal or barrier 
method of birth control; abstinence) prior to study entry and for the duration of study 
participation.  Should a woman become pregnant or suspect she is pregnant while participating in 
this study, she should inform her study physician immediately.  


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4.2.20 It is unknown whether donepezil is excreted in breast milk, for this reason women who are 
currently breast-feeding are not eligible for this study. 
 
4.2.21 On another intervention study involving medication at the time of enrollment or during 
participation in this study. (Exception: Patients will remain eligible for this study if they are also 
enrolled on the Alliance for Clinical Trials in Oncology study (NCT02927249): Aspirin in 
Preventing Recurrence of Cancer in Patients with HER2 Negative Stage II-III Breast Cancer 
After Chemotherapy, Surgery, and/or Radiation Therapy.  Studies that involve only blood draws 
or questionnaires are also permitted.) 
 
4.2.22 Use of investigational drugs likely to affect cognition within 30 days prior to pre-screening visit. 
 
4.3 
Inclusion of Women and Minorities  
 
Women who are members of all races and ethnic groups are eligible for this trial.  
 
 
Race/Ethnicity 
 
Gender 
White, not 
of Hispanic 
Origin 
Black, not 
of Hispanic 
Origin 
 
Hispanic 
Asian or 
Pacific 
Islander 
 
Unknown 
 
Total 
Male 
 
 
 
 
 
 
 
 
Female 
 
226 
41 
6 
3 
0 
276 
Total 
 
226 
41 
6 
3 
0 
276 
 
4.4 
Recruitment and Retention Plan 
 
We will recruit patients from all participating sites within the WF NCORP Research Base network.  Sites 
will be required to have a centrally trained and certified examiner.  We recently completed a phase II, 
placebo-controlled, double-blind feasibility study comparing the proposed treatment regimen (donepezil 
5mg for 6 weeks followed by 10mg daily for 18 weeks versus placebo) in breast cancer survivors who 
had completed adjuvant chemotherapy 1-5 years prior to enrollment and who reported cognitive 
dysfunction (WF NCORP Research Base study #97211).  The study was open at 16 sites within the WF 
NCORP Research Base.  We enrolled 62 women between 7/24/11 and 1/24/12 for an excellent accrual 
rate of 10.2 patients per month.  Of the women who completed study (76% of those enrolled), self-
reported adherence to study drug was 98% and completion of all assessments was 98%.  Thus, we have 
demonstrated that a Phase III clinical trial testing the efficacy of donepezil in comparison to placebo is 
feasible and that we are well positioned to conduct such a trial. There are no other WF NCORP Research 
Base studies currently open or planned that will compete with this study.   
 
Females with a history of breast cancer and who have received prior chemotherapy will be identified by 
their physicians, resident, research nurse or study staff at each participating Research Base NCORP site. 
They may review cancer registry and medical chart information to identify patients eligible for this 
protocol. Patients identified will be asked about their interest in participating in a study of the cognitive 
effects of chemotherapy in clinic or by a letter from their physician informing them about the study, and 
indicating that a research nurse/study staff will be calling to tell them more about the study.  Pre-


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screening and screening activities will proceed as described in protocol section 7. Each patient will be 
followed for 36 weeks. After the 36 week study visit, the patient is no longer followed and data is no 
longer collected from the patient. Accrual is expected to be 7-10 patients per month. A maximum of 276 
patients will be enrolled on this trial. A total N of 276 (138 in each arm) is likely to be enrolled after 
approximately 40 months.   
 
To ensure adequate minority participation, we will identify Minority Base NCORP sites for recruitment, 
and provide recruitment information to minority community leaders. 
 
5. 
AGENT ADMINISTRATION 
 
Intervention will be administered on an outpatient basis.  Reported adverse events and potential risks are 
described in Section 6.2.   
 
5.1 
Dose Regimen and Dose Groups 
 
 
Donepezil or placebo will be taken once daily by mouth. 
 
Weeks 1- 6 titration from one 5mg tablet of donepezil or one matching placebo tablet orally 
once a day to two 5mg tablets of donepezil (10mg total) or 2 tablets of matching placebo 
orally once a day x 7-24.weeks. 
 
5.2 
Study Agent Administration  
 
 
Drug will be self-administered orally on an outpatient basis. 
 
It will be recommended that patients take tablets (donepezil or placebo) at the same time 
every day. This may be in the morning or evening; with or without food. 
 
Donepezil is provided as a non-dispersible tablet, therefore the study medication (donepezil 
and placebo tablets) are over encapsulated and should be swallowed whole. 
 
Patients may be asked to return completed medication diaries via mail or in-person study 
visits. 
 
For the first 6 weeks of the study patients will be instructed to take one 5mg tablet of 
donepezil or one matching placebo tablet orally once per day.   
 
At the 6 week study time point, the patient will be contacted and assessed for toxicities.  At 
this time the dose may be modified per Section 5.6. 
 
5.3 
Wash Out Procedure 
 
There will be a 12-week wash-out period between end of treatment (24 weeks) and the end of follow-up 
(36 weeks).  The patient will be evaluated for toxicities and will complete study assessments at Week 24 
and Week 36 study time points per Sections 7.4 and 7.5, respectively.  The wash-out period will help us 
to determine if there is a worsening of cognitive symptoms and test performance following withdrawal of 
treatment.  
 
5.4 
Contraindications 
 
 
Hypersensitivity to donepezil or piperidine derivatives. 
 
Due to possible metabolism changes when used concomitantly with donepezil, systemic 
Ketoconazole and quinidine are prohibited.  
 
Patient must not have any planned therapy (surgery, radiation, chemotherapy, or 
immunotherapy) while on study for brain and/or extracranial primary/metastatic disease. 


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5.5 
Concomitant Medications 
 
All prescription medications and over the counter medications taken by the patient will be documented on 
the Concomitant Medication form (brand or generic name) at study time points designated in Section 7.1. 
 
Refer to Section 7.5 for study visits and study medication criteria specific to patients taking a moderate 
risk QTc prolongation medication that met inclusion criteria 4.1.9 and/or patients taking a moderate risk 
bradycardia causing agent that met inclusion criteria 4.1.10.  
 
Some medications are known to have neurocognitive effects.  Women currently taking donepezil, 
galantamine, rivastigmine, tacrine, memantine, methylphenidate, dextroamphetamine or any other 
specific cognition enhancing drugs will be excluded from participation in the study.  If cognition 
enhancing drugs have been used in the past, they must not have been used in the 4 weeks prior to pre-
screening. 
 
Use of stable doses of psychotropic medications (anti-depressants, anxiolytics, sleeping aids, narcotics) 
are allowed if the patient whose eligibility is being assessed has been on the medication for at least 12 
weeks.  The dose of this medication must be stable for at least 4 weeks prior to enrollment (per section 
4.1.4).   
 
Patients should not begin taking a cognition enhancing and/or psychotropic medication while on study.  
However, patients who do begin taking a cognition enhancing and/or psychotropic medication while on 
study must immediately stop taking the study agent and should continue study follow-up.  The Patient 
Status Form should be completed. 
 
5.6 
Dose Modification 
 
Study patients will take a single oral 5mg tablet of donepezil or one oral tablet of placebo once per day for 
6 weeks.  At the 6 Week study time point, the patient will be contacted by research personnel to assess 
toxicities and any changes in medications.   Patients will be evaluated using an AE Report Form.  If the 
patient is tolerating donepezil/placebo and does not present with any unacceptable toxicities (grade 3 or 
greater related to study medication), the donepezil/placebo dose will be increased to two tablets of 
donepezil (10mg total) or two tablets of placebo orally once per day starting on Week 7 and continuing 
through Week 24. Patients taking a moderate risk QTc prolongation medication and/or moderate risk 
bradycardia causing medication will have a study visit 3-7 days after increasing dose. Refer to Section 7.5 
for follow-up assessment instructions. Patients will have in-person study visits that will include toxicity 
assessments at weeks 12, 24 and 36. 
 
Patients that do not tolerate one oral tablet (5mg of donepezil or placebo) will discontinue study drug, but 
will continue to be followed on study.  The Patient Status Form should be completed if the patient 
discontinues study drug. 
If donepezil two tablets (10 mg total) or placebo 2 tablets is not tolerated after escalation, the treating 
physician should decrease dose to donepezil one 5 mg tablet or one placebo tablet orally once a day for 
the remaining study period.  Any unacceptable drug-related (Grade 3 or greater) toxicities while patient is 
taking one 5 mg tablet or one placebo tablet per day will require patient to have donepezil/placebo 
discontinued.  
 
5.7 
Adherence/Compliance 
 
5.7.1 
To be considered compliant with study medication a patient must take at least 75% of scheduled 
doses. 


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5.7.2  Compliance is monitored by daily diaries completed by the patient which are systematically 
collected at weeks 6, 12 and 24.  In addition, compliance is monitored when appointments are 
made and when medication tolerance is assessed by the research nurse/study staff over the phone 
at week 3 and again at week 6 when dose escalation occurs. During the week 6 phone contact, 
patients are requested to return study diaries via mail to the research staff. These data are entered 
into the study data base for analyses by our biostatistician every 6 months when the study is 
reviewed by our DSMB. 
 
6. 
PHARMACEUTICAL INFORMATION 
 
6.1 
Study Agent  
 
Donepezil hydrochloride is a reversible inhibitor of the enzyme acetylcholinesterase available only by 
prescription.  It is currently FDA approved for use in the treatment of mild to moderate dementia of the 
Alzheimer’s type.  Donepezil hydrochloride is available for oral administration in 5 or 10mg film-coated 
tablets.  It is to be stored at room temperature (15C to 30C).   Donepezil is postulated to exert its 
therapeutic effect by enhancing cholinergic function.  The concentration of acetylcholine is increased by 
reversible inhibition of its hydrolysis by acetylcholinesterase.   Donepezil has a relative oral bioavailability 
of 100%.  It reaches peak plasma concentrations in 3 to 4 hours.  The elimination half-life is about 70 
hours and steady state is reached within 15 days.  Donepezil is metabolized by CYP 450 isozymes 
2D6and 3A4 and undergoes glucuronidation.  In a small study of patients with cirrhosis, the clearance of 
donepezil was decreased by 20% compared to healthy controls.  In a few patients with severe renal 
impairment, the clearance was unchanged compared to healthy controls.  There have been no interactions 
of donepezil with furosemide, digoxin, warfarin, theophylline, or cimetidine.  Inducers of CYP 2D6 and 
CYP 3A4 could increase the rate of elimination of donepezil but this has not been demonstrated 
clinically.  These drugs include phenytoin, carbamazepine, dexamethasone, rifampin, and phenobarbital.  
Ketoconazole and quinidine inhibit donepezil metabolism in vitro but it is not known whether there is a 
clinical effect.     
 
6.2 
Reported Adverse Events and Potential Risks 
 
The most frequent adverse clinical events are due to donepezil’s cholinomimetic effect.  These include 
anorexia, nausea, vomiting, diarrhea, fatigue, insomnia, and muscle cramps.  These are often mild and 
transient, resolving with continuation of the drug.  There are a few more side effects noted when the drug 
is titrated from 5mg to 10mg in one week vs. six weeks.   
 
Common, Some May Be Serious (>20% Chance) 
 
Diarrhea 5-15 % dose related 
 
Loss of Appetite 2-8 % dose related 
 
Muscle Cramps 3-8 % 
 
Nausea 3-19 % dose related 
 
Trouble in sleeping 2-14%  
 
Unusual tiredness or weakness 1-8 % 
 
Vomiting 3-9 % dose related 
 
Occasional, Some May Be Serious (<20% Chance) 
 
Headache 3-10 % 
 
Dizziness 2-8 % 
 
Weight loss 3-5 % dose related 


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Rare, Some May Be Serious 
 
High blood pressure 3%  
 
Risk of seizures < 1 % 
 
Slow heart beat  > 1 % 
 
Neuroleptic malignant syndrome (NMS) (fever, severe muscle cramps, confusion, unusual 
heartbeat) < 1 % 
 
Irregular heartbeat or palpitations (due to torsades de pointes) 
 
6.3  
Availability 
 
Donepezil (Aricept®) was initially manufactured and marketed by Eisai Inc., Teaneck NJ and distributed 
by Roerig Division of Pfizer Inc, New York, NY. For this study generic donepezil will be purchased from 
Vensun Pharmaceuticals. Drug and matching placebo will be purchased in bulk in packages containing 
tablets and provided at no cost for patients participating in this study.  
 
6.4  
Agent Ordering and Distribution 
 
Donepezil /placebo will be distributed by RxCrossroads by McKesson, Inc. Irving, Texas (1-800-693-
4906; fax: 1-919-256-0794). RxCrossroads by McKesson, Inc. will distribute study drug/placebo directly 
to participating sites following randomization of study patients. The study medication (donepezil/placebo) 
will be provided to patients at no cost.  
 
6.5  
Agent Accountability 
 
The Investigator, or a responsible party designated by the Investigator, will maintain a careful record of 
the inventory and disposition of all agents received using the NCI Drug Accountability Record Form 
(DARF).  The Investigator will maintain adequate records of receipt, dispensing and final disposition of 
study agent. On dispensing record, note quantities and dates study agent was dispensed to and returned by 
each patient.  
 
Institutions should document drug accountability using the NCI DARF. 
 
6.6  
Packaging and Labels 
 
When a patient is enrolled and randomized to the study, WF NCORP Research Base sends RxCrossroads 
by McKesson, Inc. notification via email. 
 
Upon receipt of an email, RxCrossroads by McKesson will place a call to the study site confirming the 
order was received, gather patient specific data and arrange day and time of arrival for the study drug.  
They will require the following information from the site: 
 
 
Patient Full Name or Initials 
 
Site Shipping Address and phone number 
 
Doctor’s name 
 
RxCrossroads by McKesson will pull a total of 294 tablets of the study drug for the patient to complete 
the entire 24 week treatment. Drug will be packaged in 2 bottles and mailed in one shipment to the site: 
 
 
‘Bottle A, Weeks 1-6’ containing 42 tablets of study drug to complete weeks 1-6 at a dose of 
‘one tablet by mouth daily’. 


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 
‘Bottle B, Weeks 7-24’ containing 252 tablets of study drug to complete weeks 7-24 at a dose 
of ‘two tablets by mouth daily’. 
 
Study drug is patient specific and each patient specific label will include at least the following 
information: 
 
 
Study Number 
 
Patient Name 
 
Patient Study ID Number 
 
Drug identification 
 
Lot number and expiration 
 
Storage conditions 
 
Dosing instructions (Take as Directed per Protocol) 
 
Date dispensed 
 
The number of capsules 
 
IND caution statement and/or local regulatory statements 
 
Emergency contact instructions 
 
For all drug shipments from RxCrossroads by McKesson, Inc. a packing slip will be enclosed that 
includes the date and quantity of drug provided patient name/initials, study ID number, drug identification 
including lot number and expiration date. 
 
RxCrossroads by McKesson, Inc. will process and ship “same day” of patient randomization if received 
before 2:00 p.m. E.T Monday through Friday.   Orders received after 2:00 pm E.T. Monday through 
Friday will be processed and shipped the next business morning. 
 
All drug orders are shipped via FedEx for Priority Overnight delivery. Study Drug is shipped in a 
RxCrossroads by McKesson, Inc. branded box designed to maintain temperature stability. 
 
Once study drug is received at the clinical trial site, the designated site coordinator validates contents of 
package matches information provided on packing slip with study medication received. The inventory and 
disposition of donepezil or placebo pills must be recorded using the NCI Drug Accountability Record 
Form (DARF). See section 6.5 Agent Accountability.    
 
6.7 
Storage 
 
Study medication should be stored at room temperature.  (15°C to 30°C /59°F to 86°F)  
 
6.8 
Emergency Unblinding Methods 
 
In the event a patient on this study develops a toxicity (adverse event or severe adverse event) for which 
the patient’s physician or other health care professional feels that it is in the patient’s best interest to know 
what drug they are taking (active study drug(s) or placebo), the following procedure should be followed: 
 
 
Step 1: During regular business hours (8:00am – 5:00pm EST), the site should contact the 
WF NCORP Research Base Site Coordinator at (336) 713-6519 or (336) 713-6907.  If after 
hours or on the weekend, the patient’s physician or a designated health care professional 
should call the Wake Forest University Baptist Medical Center Physician Access Line (336-
716-7654) and ask that Dr. Glenn Lesser, Principal Investigator of the WF NCORP Research 
Base, be contacted immediately. In the event Dr. Lesser cannot be reached, the PAL operator 


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should contact Kate Weaver, PhD.  Site staff may also try contacting Dr. Lesser, 
glesser@wakehealth.edu, or Dr. Weaver, keweaver@wakehealth.edu, by email if the PAL 
line is unsuccessful in reaching them. 
 
 
Step 2: Once contact has been made; the patient’s physician or health care professional 
should explain the reason for the request to unblind the treatment arm that the patient is on. If 
the Research Base representative feels that the toxicity (AE/SAE) is possibly, probably or 
definitely related to the study drug, then the next step will be followed. 
 
 
Step 3: The responsible Research Base representative will call the pharmacist @ 
RxCrossroads by McKesson, Inc.(phone: 1-800-850-4306). There is an “on-call” service 
provided 24 hours a day, seven days a week for the Chemical Drug Trials unblinding service. 
The RxCrossroads by McKesson pharmacist may contact the patients’ physician and/or 
health care professional directly with the unblinding information. Written documentations of 
the unblinding process will be sent to the Research Base Principal Investigator by 
RxCrossroads by McKesson, Inc. 
 
 
Step 4: In the event that the patient’s treatment is unblinded, that patient will be taken off 
study with no further study follow-up. Appropriate procedures for grading toxicities, 
assigning causality, and reporting severe adverse events (if applicable), should be followed 
for each protocol for all Phase II and Phase III Clinical Trials. The event will be reviewed by 
the WF NCORP Clinical Research Oversight Committee and reviewed by the NCORP 
Research Base Data Safety and Monitoring Board. 
 
6.9 
Unblinding Study Patients at Study Completion 
 
Study patients may be unblinded at the conclusion of the study if all patient specific data for the 
requesting site are completed and submitted to the DMC.  Site members can obtain unblinding 
information by sending an email request to the NCORP Research Base Administrator or Site Coordinator 
with a list of PID #s.  After confirming with the DMC that patient specific data for the patient at the 
requesting site have been received, completed and entered into the RB database, RxCrossroads by 
McKesson Inc will be notified. An email from RxCrossroads by McKesson containing the unblinding 
information will be sent directly to the requesting site. 
 
6.10 
Agent Destruction/Disposal 
 
Unused drug should be destroyed on site following site institutional policies and procedures. 
 
7.  
CLINICAL EVALUATIONS AND PROCEDURES 
 
7.1  
Schedule of Events 
 
Pre-screening and screening are to be conducted within 30 days prior to enrollment/randomization. 
Baseline procedures may be obtained within 7 days post enrollment/randomization. 
 
Protocol therapy must begin within 7 days post baseline evaluation. 
 


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Assessment 
Pre-Screen 
Screen 
Enrollment 
Baseline 
Baseline + 3-
7 DaysA 
3 Week 
6 WeekF 
6 Week +  
3-7 DaysK 
12 Week 
24 Week 
36 Week 
Memory Question 
X 
 
 
 
 
 
 
 
 
 
 
HVLT-R Form 3 Trial 1 
X 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
 
XB,L 
 
 
 
 
 
 
 
 
 
Serum or Urine Pregnancy Test 
 
XC 
 
 
 
 
 
 
 
 
 
Height 
 
 
 
X 
 
 
 
 
 
 
 
Weight 
 
 
 
X 
 
 
 
 
 
 
 
Heart Rate 
 
X 
 
 
XD 
XD 
  
XD 
 
 
 
ECG 
 
X 
 
 
XE 
XE 
  
XE 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
ECOG Performance Status 
 
X 
 
 
 
 
 
 
X 
X 
X 
APOE Genotyping 
 
 
 
X 
 
 
 
 
 
 
 
Flow Sheet 
 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
Adverse Event Report Form 
 
 
 
 
X 
X 
X 
 
X 
X 
X 
Concomitant Medication Form 
 
 
 
X 
 
 
X 
 
X 
X 
X 
Donepezil Medication Diary 
(Pill Count) 
 
 
 
 
 
 
X 
 
X 
X 
 
Telephone Contact Form 
 
 
 
 
 
XF 
XF 
 
 
 
 
Baseline Assessment Booklet 
 
 
 
XH 
 
 
 
 
 
 
 
12 Week Assessment Booklet 
 
 
 
 
 
 
 
 
XH 
 
 
24 Week Assessment Booklet 
 
 
 
 
 
 
 
 
 
XH 
 
36 Week Assessment Booklet 
 
 
 
 
 
 
 
 
 
 
XH 
Patient Status Form 
 
 
XJ 
A 
Post study agent initiation. 
B 
Consent must be obtained prior to screening activities. 
C       Negative serum or urine pregnancy test is required within 10 days prior to enrollment for women of child-bearing potential. 
D 
For patients on moderate risk bradycardia-causing agents (Appendix B) only, resting heart rate will be obtained by a 
trained individual.  See Section 7.5. 
E 
For patients on moderate QTc prolonging agents (Appendix A) only.  See Section 7.5. 
F 
Refer to Section 5 for dose modification information. 
G 
Pre-screen consists of 2 parts and will be completed on the Pre-Screen form. 1) Memory question – must answer “mildly 
worse”, “moderately worse” or “much worse” to proceed.  2) HVLT-R Form 3 single trial score must be ≤ 7 to meet 
eligibility requirements.  
H 
Booklet instruments are provided in Section 7.8.  
I 
Request completed medication diaries be returned at 6, 12 and 24 week assessment, may be collected via mail.  
J 
Complete the Patient Status Form if the patient stops taking study medication for any reason, withdraws from the study, or 
completes study intervention and study follow-up. 
K 
Post study agent dose increase.  
L 
Reconsent all patients, as of amendment 3. See Appendix E. 
 


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7.2 
Pre-study Evaluation and Consent 
 
All pre-screening and screening evaluations must be done in person.  The Decline Form is to be 
completed by all potential participants if they decline to participate.  Submit all Decline Forms at the end 
of each month per section 11.1. 
 
7.2.1 
Pre-Screening 
 
Prospective participants will be identified by research personnel, a review of cancer registry, 
medical chart information or by patient’s response to advertisements or flyers posted in the 
clinics. All potential participants will first be verbally consented by asking “May we ask you a 
few questions to determine if your activities meet the requirements to take part in the study?” The 
verbal consent process will be documented by study staff administering the verbal consent.   If a 
“no” response is given the prospective participant will be thanked for her time and no longer be 
considered possibly eligible.  If a “yes” response is given, the potential participant will be asked 
the self-reported cognitive problem question “How would you rate the change in your ability to 
think including remembering, organizing your thoughts and speaking since you were first 
diagnosed with cancer?”  Response choices will be ‘No change or better’, ‘mildly worse’, 
‘moderately worse’, ‘much worse’.  Only if a potential participant responds with “mildly worse”, 
“moderately worse” or “much worse” will she proceed to the HVLT-R Form 3 Trial 1.  Study 
staff will administer and score the HVLT- R Form 3 Trial 1.  An entry level score of ≤ 7 words 
recalled is required.  Potential participants who score > 7 are not eligible to participate.  All pre-
screening data collected on ineligible and eligible patients who choose to not participate will be 
submitted to the WF NCORP Research Base per Section 11.1.  Use the site CTEP ID and 
patients’ initials on pre-screening forms. 
 
Pre-screened patients who meet study criteria after completing the Memory Question and HVLT-
R Form 3 Trial 1 will be provided additional study information and offered participation in the 
study. If the patient agrees to participate a protocol specific consent form will be signed with a 
copy provided to the patient.  
 
7.2.2 
Screening 
 
Screening activities will occur after eligible patients have completed pre-screening and signed 
consent.  Screened patients will be identified using the site CTEP ID and patients’ initials on 
completed forms.   
 
Patients will have a screening ECG performed to measure their QTc.  Patients with a screening 
QTc interval > 460 milliseconds will no longer be eligible and will be excluded from study 
participation.  The screening ECG QTc interval should be recorded on the Cardiac Monitoring 
Form. 
 
Patients who are on Bradycardia-causing agents will have their resting heart rate taken by trained 
individuals at screening.  Patients who present with a pulse less than 55 beats per minute  will no 
longer be eligible and will be excluded from study participation. The resting heart rate taken at 
screening should be recorded on the Cardiac Monitoring Form. 
 
Patients who are of child-bearing potential and have not had a negative serum or urine pregnancy 
test clinically performed within 10 days of enrollment will be screened with a serum or urine 
pregnancy test.  Patients who test positive for pregnancy will no longer be eligible and will be 


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excluded from study participation.  Record date performed and results of the serum or urine 
pregnancy test on the Flow Sheet. 
 
Patients who meet pre-screening eligibility criteria, sign informed consent, and meet screening 
eligibility criteria will be enrolled to the study as described in Section 7.3. 
 
Patients who screen fail will no longer be eligible, will not be enrolled, and will be excluded from 
further study participation.  The Pre-Screen form, Eligibility Checklist and Flow Sheet must be 
submitted to the WF NCORP DMC on all patients who screen fail. 
 
7.3 
 Patient Enrollment and Randomization 
 
Electronic enrollment must be completed after eligibility has been determined, consent has been signed, 
and no later than 30 days after pre-screening began.  Refer to Section 7.1 and 7.2 for pre-screening and 
screening study assessments to be completed prior to enrollment.  At the time of electronic enrollment, 
patients will be electronically randomized and study drug (donepezil or placebo) will be provided to the 
enrolling site per Section 6.6. 
 
NCORP site staff will electronically enroll their study patients in the Wake Forest NCORP Research Base 
website, CCRBIS, at https://ccrbis.phs.wakehealth.edu. 
 
 
Log in to the database website using your CCRBIS username and password. 
 
In the drop-down menu next to Enroll Patient/Patient Info select 97116, then click Enroll 
Patient/Patient Info. 
 
Click on Enroll New Patient. 
 
Complete the Eligibility Checklist/Enrollment Form then click submit. 
 
Following successful submission, a confirmation page will appear with the assigned PID, 
print this page for your records. 
 
If you have questions related to the patient enrollment process or require assistance with enrollment, 
please contact the Wake Forest NCORP Research Base between 8:00am and 5:00pm EST, Monday 
through Friday at (336) 716-0891 or by email at NCORP@wakehealth.edu.  
 
7.4 
Baseline Evaluations 
 
Baseline evaluations should be obtained within 7 days post enrollment and before the patient takes the 
first dose of donepezil/placebo.  Baseline evaluations will include: study assessment including pt. and 
family history, concomitant medications, Baseline Assessment Booklet and toxicity assessment.  
 
APOE Genotyping - A blood sample of approximately 8ml will be taken from a vein in the arm/central 
line for lab analysis. Blood samples will be stored with a unique identifier and will not include any 
information protected by HIPAA regulations. Blood samples will be stored at Wake Forest.  Refer to 
Section 9.0 for specimen management. 
 
7.5 
Evaluations During Study Intervention 
 
Patients taking a moderate risk QTc prolonging medication who met eligibility criteria 4.1.9 will have a 
study visit 3-7 days after initiation of the study agent.  An ECG will be performed and results will be 
recorded on the Cardiac Monitoring Form and toxicities will be assessed.  If the patient’s QTc interval is 


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> 500ms they should stop taking the study agent and continue study follow-up visits.  If the participant 
stops taking the study agent, complete a Patient Status Form. 
 
Patients taking a moderate risk bradycardia causing agent will have a study visit 3-7 days after initiating 
the study agent.  Resting heart rate will be recorded on the Cardiac Monitoring Form and toxicities will be 
assessed.  If the patient’s resting heart rate is < 55 beats per minute, the participant should stop taking the 
study agent and continue study follow-up visits.   If the participant stops taking the study agent, complete 
a Patient Status Form. 
 
At Week 3 the patient will be evaluated for any toxicities associated with the study agent, this may be 
done by phone.  Patients taking a moderate risk QTc prolonging medication who met eligibility criteria 
4.1.9 will have a Week 3 in person study visit and an ECG will be performed in addition to evaluation of 
any toxicities.  If the patient’s QTc interval is > 500ms they should stop taking the study agent and 
continue study follow-up visits.  Patients taking a moderate risk bradycardia causing agent will have a 
Week 3 in person study visit and their resting heart rate will be recorded in addition to evaluation of any 
toxicities.  If the patient’s resting heart rate is < 55 beats per minute, the participant should stop taking 
study agent and continue study follow-up visits.   
 
At week 6 the patient will be evaluated for any toxicities associated with the study agent, this may be 
done by phone.  If patient is tolerating donepezil/placebo without any unacceptable toxicities at week 6, 
donepezil/placebo dose will be modified per Section 5.6 and continued through Week 24. Patients will be 
asked to return completed medication diaries via mail. 
 
Patients taking a moderate risk QTc prolonging medication, who had a normal ECG assessment at the 3-7 
day and 3 week visits will be permitted to modify the study agent dose per Section 5.6. These patients 
will have a study visit 3-7 days after the dose increase. An ECG will be performed and recorded on the 
Cardiac Monitoring Form. If the patient’s QTc interval is > 500ms they should reduce study agent dose to 
5mg and continue through Week 24. 
 
Patients taking a moderate risk bradycardia causing agent, who had a normal resting heart rate at the 3-7 
day and 3 week visits will be permitted to modify the study agent dose per Section 5.6. These patients 
will have a study visit 3-7 days after the dose increase. The patient’s resting heart rate will be recorded on 
the Cardiac Monitoring Form. If the patient’s resting heart rate is <55 beats per minute, the patient should 
reduce the study agent dose to 5mg and continue through Week 24.  
 
At Week 12 the patient will return to the clinic to complete a study assessment, the 12 Week Assessment 
Booklet and toxicity assessment.  Concomitant medications will be reviewed in addition to the study 
medication.  Medication diaries will be collected to verify compliance of study medication. 
 
The Cardiac Monitoring Form should be used to record heart rate and ECG at all applicable study time 
points. The Flow Sheet should be used to record ECOG performance status at specified study time points.  
Toxicities must be reported using the Adverse Event Report Form and per Section 10.  The Patient Status 
Form must be completed if the patient stops taking the study agent and per Section 8. 
 
7.6  
Evaluations at Completion of Study Intervention 
 
Study agent will be discontinued at week 24 prior to a 12-week wash-out phase per Section 5.3. The 
patient will return to the clinic to complete a study assessment, the 24 Week Assessment Booklet and 
toxicity assessment. Concomitant medications will be reviewed in addition to the study medication. 
Medication diaries will be collected to verify compliance of study medication.  Record ECOG 
performance status on the Flow Sheet.  Toxicities must be reported using the Adverse Event Report Form 


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and per Section 10.  The Patient Status Form must be completed if the patient stops taking the study agent 
and per Section 8. 
 
7.7  
Post-intervention Follow-up Period 
 
The 12-week wash-out phase of the study will begin at Week 24 and continue through Week 36 following 
which the patient will return to the clinic for a study assessment, 34 Week Assessment Booklet, toxicity 
assessment and review of concomitant medications.  
 
7.8  
Methods for Neurocognitive and Patient Related Outcomes Tests 
 
This entire battery of neurocognitive tests and questionnaires will take approximately 30 - 45 minutes to 
complete, which is equivalent to the time needed in our WF NCORP Research Base studies of donepezil 
among brain tumor survivors and breast cancer survivors.  Retention in these studies exceeded 90% and 
data completeness was over 95%.   
 
7.8.1 
Specific Training and Certification Procedures 
 
Each participating site will be required to have at least one examiner who is trained and certified 
in the administration and scoring of the cognitive battery (neurocognitive tests and 
questionnaires). Training will follow the procedures developed in prior WF NCORP 
neurocognitive studies such as our recently completed Phase II feasibility study trial of donepezil 
in breast cancer survivors previously exposed to chemotherapy. We will train using didactic 
presentations (describing the purpose and instructions for each test and questionnaire), live and 
video demonstrations of a complete battery administration, live practice sessions supervised by a 
certified examiner and trainer with specific feedback, and a review by certified trainers of an 
audio-recorded administration. If needed, remediation will occur with review of subsequent 
recorded administrations with corrective feedback. Once the examiner has met study criteria s/he 
will be certified to administer and score the battery at his/her site.  Periodic re-certifications will 
be required. This procedure has been successfully used in our studies of cognitive effects of 
cancer and its treatments as well as by Dr. Rapp and his team in large scale, multi-site clinical 
trials and observational studies (e.g., WHIMS, CoSTAR, SPRINT, Look AHEAD, LIFE, 
MESA). 
 
7.8.2 
Neurocognitive Function Assessments 
 
Neurocognitive tests have been selected to represent a range of cognitive abilities which have 
been reported in the literature to be affected by chemotherapy including attention, verbal 
memory, working memory, executive function, speed of mental processing, and verbal fluency. 
All cognitive testing will be performed by a trained and certified research assistant blinded to 
treatment assignment. The WF NCORP Research Base has conducted training workshops for 
administering this cognitive test battery for our on-going trials of donepezil among irradiated 
brain patients, and maintains a stringent certification process.  Each cognitive test has adequate 
psychometric properties and has been used in cancer research including large national and 
international clinical trials.  
 
Hopkins Verbal Learning Test-Revised (HVLT-R):  The HVLT-R  measures verbal learning and 
memory.  It consists of a 12-item word list which is read to patients on three successive learning 
trials. Free recall scores are recorded for each learning trial.  After a 20-minute interval during 
which patients complete other non-interfering tasks and questionnaires they are asked to recall the 
target words. Lastly, a yes/no recognition task is then presented in which patients are asked to 


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identify all target words by responding “yes,” and to reject 12 non-target words by responding 
“no”.  Test-retest reliability of the HVLT-R is quite good.  The test is brief, taking only 10 
minutes to administer, and it is well-tolerated by compromised (geriatric and dementia) 
populations. Scores for immediate recall (total of three trials), delayed recall (total number of 
words recalled after 20 minutes), and recognition (total number of words correctly identified) will 
be the variables derived from the HVLT-R.  There are 6 alternate forms of the HVLT-R. Forms 
A, B, D, and E will be used for assessments at baseline and weeks 12, 24 and 36.  A single trial 
with Form 3 will be used to screen patients for the study.  
 
Trail Making Test, Parts A & B (TMT-A, TMT-B):  Part A of the TMT measures attention and 
visual motor skills and processing speed and requires patients to connect 25 numbered circles in 
the proper sequence (1-2-3-…) as quickly as possible. TMT-B is similar except patients are 
required to connect dots in an alternating numerical and alphabetical sequence (1-A-2-B-…). 
TMT-B with its added complexity and set shifting requirements is a widely used measure of 
executive function. The score for TMT-A and TMT-B is the total time in seconds required to 
complete the task. Scores can also be generated for number of errors and number of circles 
correctly connected. 
 
Controlled Oral Word Association Test (COWA):  The COWA measures speed of mental 
processing, verbal fluency, and executive function. Patients are asked to name as many words as 
possible all beginning with a specified letter.  A total of three trials are administered, each with a 
different letter (F-A-S).  The score on the COWA is the total number of words named across the 
three trials minus repetitions. 
 
Digit Span Test-Backwards (DST-B):  The DST-B assesses attention and working memory.  It 
requires respondents to repeat back in reverse order spans of numbers.  Seven pairs of spans of 
increasing lengths are presented and repeated.  A total score is the number of correctly repeated 
spans. 
 
Digit Symbol Coding:  The DSC test measures processing speed. It requires respondents to 
transcribe symbols (e.g., >) associated with a number (0-9) into empty boxes beneath a series of 
randomly ordered numbers. Total score is number of correctly transcribed symbols in 2 minutes. 
Scores range from 0-133. 
 
7.8.3 
Cognitive Reserve 
 
Shipley Institute of Living Scale-Version 2 Vocabulary:  This vocabulary test requires 
respondents to read a target word and select one of four words that most closely means the same 
thing. Score it total correct of 40 items. This provides an assessment of premorbid intellectual 
functioning comparable to a verbal IQ and thus is a proxy for cognitive reserve. It will be 
administered only at baseline. 
 
7.8.4 
Patient Reported Outcomes (PRO) Assessment 
 
Functional Assessment of Cancer Therapy-Cognition (Version 3):  The FACT-Cog is a validated 
self-report questionnaire that assesses patients’ perceptions of their cognitive function and the 
impact of cognitive problems on overall quality of life over the prior 7 days. The FACT-Cog 
(Version 3) has 37 items grouped into four subscales—Perceived Cognitive Impairments (PI; 20 
items, 18 scored), Comments from Others (CO; 4 items), Perceived Cognitive Abilities (PA; 9 
items) and Impact on Quality of Life (IQOL; 4 items). For each subscale items are scored on a 
Likert scale ranging from 0 (Never) to 4 (Several times a day). Negatively worded items are 


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reverse coded and summed for each subscale.  Higher scores reflect better cognitive functioning 
and less impairment.  
 
Personal Health Questionnaire-9 Depression scale:  The PHQ-9 is a widely used self-report scale 
for assessing depression severity. It has 9 items assessing cardinal features of major depression 
which are rated from zero (“Not at all”) to 5 (“nearly every day”).    
 
PROMIS 7-item Fatigue Scale:  This self-report scale assesses fatigue. 
 
PROMIS 8-item Sleep Disturbance Scale:  Self-reported sleep disturbance will be measured with 
the PROMIS Sleep Disturbance scale. 
 
8 
Off-Agent/Off-Study 
 
8.1 
Off Agent Criteria  
 
Patients may stop taking study agent for one or more of the following reasons: completed the 
protocol-prescribed intervention, adverse event (AE) or serious adverse event (SAE), inadequate 
agent supply, refusal to continue with study procedures, the need for contraindicated concomitant 
medications, medical contraindication, disease progression, death or treating physician decision. 
Date and reason off agent should be documented on the Patient Status Form.  Reasons that are not 
specified on the form should be coded as ‘Other’ and a brief description provided.  Patients who 
go off-agent must be followed for adverse events (AEs) for up to 30 days from their last 
treatment. 
Note that patients who go off-agent should be encouraged to stay in the study and provide data at 
the regularly scheduled visits. 
8.2 
Off Study Criteria 
 
Patients may go ‘off-study’ for one or more of the following reasons: the protocol intervention 
and any protocol-required follow-up period is completed, AE/SAE, lost to follow-up, refusal to 
continue with study procedures, the need for contraindicated concomitant medication, medical 
contraindication, disease progression, withdraw consent, death, determination of ineligibility 
(including screen failure), pregnancy, or treating physician decision. 
 
Any patient with a cancer recurrence must be evaluated by the treating physician and followed by 
a discussion with the Wake Forest NCORP Research Base Study PI or their representative to 
determine if the patient meets the off-study criteria.  
 
Note that a patient is not automatically taken off-study if they refuse further treatment.  In fact, 
these patients should be encouraged to remain in the study and provide data at their regularly 
scheduled visits.  Date and reason off-study should be documented on the Patient Status Form.  
Reasons that are not specified on the form should be coded as ‘Other’ and a brief description 
provided. 
 
A final evaluation of the patient may be performed if/when they withdraw from the study.  If a 
patient decides to discontinue participation in study (withdraw) at any time prior to study 
completion, the patient should be asked to complete the entire battery of neurocognitive tests and 
forms prior to withdrawing from the study.  This should be completed using the next 


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Neurocognitive and PRO tests they would have received as well as all other items in the Schedule 
of Events (section 7.1) for the visit. 
 
Patients who go off study will not be replaced. 
 
9. 
SPECIMEN MANAGEMENT  
 
A single blood draw will be made at the baseline visit. Samples will be sent to the Wake Forest School of 
Medicine Center for Genomics and Personalized Medicine Research Lab for storage and processing.  
APOE genotype will be derived from the whole blood samples 
 
 
9.1 
Storage of Blood for Future Research Testing (if applicable)  
 
  
All blood samples will receive a unique identifier and stored at the Wake Forest School of Medicine 
Center for Genomics and Personalized Medicine Research Lab located in Winston-Salem, NC. Only 
researchers approved by Dr. Stephen Rapp, the principal investigator at Wake Forest School of Medicine 
will receive the sample.  
 
9.2 
Laboratories 
 
DNA will be isolated from whole blood, collected in one (8 ml max) yellow-top Vacutainer tubes (with 
citrate as the preservative). Blood samples received from all sites will be brought to the Wake Forest 
School of Medicine Center for Genomics and Personalized Medicine Research laboratories, where they 
will be entered into a database and the DNA isolated.  DNA from whole blood will be isolated using the 
AutoPure LS instrument (Qiagen, Inc.).   
 
SNP genotyping of the APOE haplotype will be performed in the Center for Genomics and Personalized 
Medicine Research at Wake Forest School of Medicine using the iPlex SNP genotyping system 
(Sequenom, Inc.), which has been successfully tested and fully integrated into our laboratory. The APOE 
haplotype will be determined by genotyping the two individual SNPs that make up the haplotype, 
rs429358 and rs7412, in each individual. Genotypes will be scored using the SpectroTyper software 
(Sequenom, Inc.), and quality control parameters (e.g., CEPH DNA samples, negative controls) will be 
determined. Problem samples or SNPs will be reviewed and repeated if necessary. 
 
9.3 
Collection and Handling Procedures 
 
Prepared shipping kits will be sent to participating NCORP sites from the Wake Forest Biotech 
Laboratory following procedures used previously in Research Base studies. The lab will provide sample 
handling, storage, tracking, and logistics.  
 
9.4 
Shipping instructions 
 
Sites should request shipping kits at the time of study approval in advance of putting patients on study.  The 
Wake Forest NCORP Research Base will provide shipping kit request forms and shipping instructions to 
participating sites. 
 
10. 
REPORTING ADVERSE EVENTS 
 
Adverse event (AE) any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign, 


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symptom, or disease temporally associated with participation in a study, whether or not related to that 
participation. This includes all deaths that occur while a patient is on a study. 
 
Please note that all abnormal clinical laboratory values that are determined to be of clinical significance 
based on a physician’s assessment are to be reported as AEs. Those labs determined to be of no clinical 
significance or of unknown clinical significance (per the physician’s assessment) should not be reported 
as AEs. Any lab value of unknown clinical significance should continue to be investigated/followed-up 
further for a final determination, if possible. 
 
A list of AEs that have occurred or might occur can be found in Section 6.2 Reported Adverse Events and 
Potential Risks, as well as the package insert. 
 
10.1 
 Adverse Events 
 
10.1.1  Reportable AEs 
 
All AEs that fit reporting criteria after the informed consent is signed and baseline assessments 
are completed must be recorded on the AE Report Form whether or not related to study agent as 
detailed below. 
 
The prompt reporting of adverse events is the responsibility of each investigator engaged in 
clinical research, as required by Federal Regulations. 
 
10.1.2 AE Data Elements: 
 
The following data elements are required for AE reporting. 
 
AE verbatim term 
 
NCI Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) AE term 
(MedDRA lowest level term) 
 
CTCAE (MedDRA) System Organ Class (SOC) 
 
Event onset date and event ended date 
 
Treatment assignment code (TAC) at time of AE onset 
 
Severity grade 
 
Attribution to study agent (relatedness) 
 
Whether or not the event was reported as a SAE 
 
Whether or not the subject dropped due to the event 
 
Outcome of the event 
 
10.1.3   CTCAE term (AE description) and Grade 
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. All appropriate treatment 
areas should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 
can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
Identify the AE using the CTCAE version 5.0. The CTCAE provides descriptive terminology 
(MedDRA lowest level term) and a grading scale for each AE listed. AEs that do not have a 
corresponding CTCAE term will be assessed according to the general guidelines for grading used 
in the CTCAE v5.0 as stated below.  


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CTCAE v5.0 general severity guidelines:  
 
Grade 
Severity 
Description  
1 
Mild 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
2 
Moderate 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living 
(ADL)*. 
3 
Severe 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL**. 
4 
Life-
threatening 
Life-threatening consequences; urgent intervention indicated. 
5 
Fatal 
Death related to AE. 
   
ADL 
 
*Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
 
**Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
 
10.1.4 Assessment of relationship of AE to treatment 
 
 
The possibility that the AE is related to study agent will be classified as one of the following 
attribution: Unrelated, unlikely, possible, probable, definite. 
 
Attribution: An assessment of the relationship between the adverse event and study 
agent/intervention, using the following categories.  
 
ATTRIBUTION 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to the study agent (or 
product)/intervention 
Unlikely 
The AE is doubtfully related to study agent 
/intervention 
Possible 
The AE may be related to study agent/intervention 
Probable 
The AE is likely related to study agent/intervention 
Definite 
The AE is clearly related to study agent/intervention 
 
10.1.5 Follow-up of AEs 
 
All AEs, including lab abnormalities that in the opinion of the investigator are clinically 
significant, will be followed according to good medical practices and documented as such.  
 
 
 
 
 


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10.2 
Serious Adverse Events  
 
Serious Adverse Event (SAE): A serious adverse event is defined by regulation 21 CFR §312.32 as any 
adverse medical event (experience) that results in at least one of the outcomes listed below: 
 
 
Death 
 
A life-threatening 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
A persistent or significant incapacity or substantial disruption of the ability to perform normal 
life functions 
 
A congenital anomaly or birth defect 
 
Important medical events that may not be immediately life-threatening or result in 
death or hospitalization should also be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient and may require 
intervention to prevent one of the other outcomes. 
 
Hospitalization (or prolongation of hospitalization): For AE reporting purposes, a hospitalization is 
defined as an inpatient hospital stay equal to or greater than 24 hours.   
 
10.3 
Reporting for Adverse Events (AEs) 
 
All adverse events, whether observed by study staff or investigator, elicited from or volunteered by the 
patient, should be documented. Each adverse event will include the date of onset, date of resolution, 
severity, and the relationship to the study agent or intervention, and any action taken with respect to the 
study agent or intervention. 
 
 
Donepezil (Aricept®) is a widely used medication taken routinely on an outpatient basis. An 
identical regimen was used in Wake Forest phase 2 and phase 3 studies. In both studies 
tolerance of donepezil was quite good. Side effects are well documented, therefore Grade 1 
and 2 adverse events (AEs) will not be collected.  
 
All expected adverse events (AEs) grade 3 and unexpected that are unrelated or unlikely 
adverse events (AEs) grade 3 will also not be collected. 
 
All expected adverse events (AEs) grade 4 will also not be collected. 
 
All other adverse events will be reported to the Wake Forest NCORP Research Base using 
the AE Report Form. Serious adverse events requiring expedited reporting via CTEP-AERS 
are described below.  Serious adverse events not requiring expedited reporting through 
CTEP-AERS should be entered into AE Report Form within 10 calendar days of learning of 
the event and sent to the Wake Forest NCORP Research Base. 
 
Site staff and/or Principal Investigators will also notify WF NCORP Research Base via AE 
Report Form and report to CTEP-AERS within 24 hours of discovering the details of all 
unexpected severe, life-threatening (grade 4) that are possible, probably or definitely 
related to the drug and/or all fatal adverse events (grade 5). 
 
All recorded adverse events reported to the Wake Forest NCORP Research Base will be 
reported to the Data Safety Monitoring Committee 
 
 
 
 
 


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Adverse Events 
 
Grade 1 & 2 
Grade 3 
Grade 4 
Grade 5 
 
Expected Unexpected Expected 
Unexpected 
Expected 
Unexpected 
Expected 
Unexpected 
Unrelated 
 
 
 
 
 
AE Report 
Form 
AE Report 
Form & 
CTEP-AERS 
AE Report 
Form & 
CTEP-AERS 
Unlikely 
 
 
 
 
 
AE Report 
Form 
AE Report 
Form & 
CTEP-AERS 
AE Report 
Form & 
CTEP-AERS 
Possible 
 
 
 
AE Report 
Form 
 
AE Report 
Form & 
CTEP-AERS 
AE Report 
Form & 
CTEP-AERS 
AE Report 
Form & 
CTEP-AERS 
Probable 
 
 
 
AE Report 
Form 
 
AE Report 
Form & 
CTEP-AERS 
AE Report 
Form & 
CTEP-AERS 
AE Report 
Form & 
CTEP-AERS 
Definite 
 
 
 
AE Report 
Form 
 
AE Report 
Form & 
CTEP-AERS 
AE Report 
Form & 
CTEP-AERS 
AE Report 
Form & 
CTEP-AERS 
 
The Research Base Grant PI, DSMB and/or Study Chair will take appropriate action to inform the 
membership and statistical personnel of any protocol modifications and/or precautionary measures, if this 
is warranted. 
 
Institutions must comply with their individual Institutional Review Board (IRB) policy regarding 
submission of documentation of adverse events. All CTEP-AERS reports should be sent to the local IRB 
in accordance with the local IRB policies. 
 
10.4 
Responsibilities for Expedited Reporting (CTEP-AERS) 
 
Wake Forest NCORP affiliates (local sites) are required to notify the WF NCORP Research Base if a 
patient has an adverse event requiring expedited reporting.  All SAEs that meet expedited reporting 
criteria defined in the reporting table below will be reported via CTEP-AERS, the Adverse Event 
Expedited Reporting System, accessed via the CTEP web site, https://eapps-
ctep.nci.nih.gov/ctepaers/pages/task  
 
IMPORTANT: When reporting in CTEP-AERS please ensure a copy of the report is sent to WF NCORP 
RB by adding NCORP@wakehealth.edu to the distribution list within the reporting system. Any 
correspondence between CTEP-AERS and/or the FDA about a reportable SAE should be forwarded to 
NCORP@wakehealth.edu also. 
 
Commercial reporting requirements are provided in the table below.  The commercial agent used in this 
study is Donepezil (Aricept®).  
 
Expedited reporting requirements for adverse events experienced by patients who are receiving 
study agent/intervention (including within 30 days of the last administration of commercial study 
agent/intervention) should be reported as follows: 
 


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Attribution 
Grade 4 
Grade 5 
Expected 
Unexpected 
Expected 
Unexpected 
Unrelated or Unlikely 
 
 
CTEP-AERS 
CTEP-AERS 
Possible, Probable, Definite 
 
CTEP-AERS 
CTEP-AERS 
CTEP-AERS 
 
1) 
This includes all deaths within 30 days of the last dose of study agent with a commercial agent/intervention, 
regardless of attribution.  Any death that occurs more than 30 days after the last dose of study commercial 
agent/intervention and is attributed (possibly, probably or definitely) to the agent/intervention and is not due 
to cancer recurrence must be reported according to the instructions above. 
 
2) 
Submission of the on-line CTEP-AERS report plus any necessary amendments generally completes the 
reporting requirements.  You may, however, be asked to submit supporting clinical data to the CTEP-AERS, 
cIRB or WF NCORP RB in order to complete the evaluation of the event.   
 
For more information see: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
 
Contact Information for NCI Safety Reporting: 
 
Website for submitting expedited reports 
http://eapps-ctep.nci.nih.gov/ctepaers  
AEMD Help Desk (for CTEP)* 
301-897-7497 Monday through Friday, 7:00 AM 
to 7:00 PM (US Eastern Time) 
Fax for expedited report supporting 
Medical Documentation for 
CTEP Trials 
301-230-0159  
(Back-up FAX: 301-897-7404) 
AEMD Help Email: 
aemd@tech-res.com 
Technical (E.G., IT or computer issues 
ONLY) Help Phone * 
1-888-283-7457 or 301-840-8202 
CTEP-AERS Technical Help Email 
ncictephelp@ctep.nci.nih.gov 
CTCAE v 4 Help/Questions Email 
ncicctcaehelp@mail.nih.gov  
CTEP-AERS FAQs link 
https://eapps-
ctep.nci.nih.gov.ctepaers/help/webhelp/CTEP-
AERS%20FAQ.htm 
CTEP-AERS Computer based training  
https://ctep.cancer.gov/protocolDevelopment/ 
electronic_applications/adverse_events.htm  
Office phone and fax are accessible 24 hours per day 7 days a week.The AEMD phone line is staffed 
from Monday through Friday, 7:00 AM to 7:00 PM ET. Any phone call after these hours will go to 
voicemail. Please leave contact information and the phone call will be returned the following business 
day. 
 
11. 
STUDY MONITORING 
 
11.1 
Data Management Schedule 
 
Data forms must be submitted to the Wake Forest NCORP Research Base within 14 days of the study 
visit and Decline Forms and screening logs must be submitted at the end of each month by email, 
NCORP@wakehealth.edu, or fax, (336) 713-6476. 


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11.2 
Case Report Forms 
 
Participant data will be collected using protocol-specific case report forms (CRF).  
 
11.3 
Source Documents 
 
Source documents are the original signed and dated records of participant information (e.g., the medical 
record, shadow chart) which may include electronic documents containing all the information related to a 
participant’s protocol participation. Source documents are used to verify the integrity of the study data, to 
verify participant eligibility, and to verify that mandatory protocol procedures were followed. An 
investigator and other designated staff are required to prepare and maintain adequate and accurate 
documentation that records all observations and other data pertinent to the investigation for each 
individual participating in the study. All data recorded in the research record (including data recorded on 
CRFs) must originate in the participant’s medical record, study record, or other official document sources. 
 
Source documents substantiate CRF information. All participant case records (e.g., flow sheets, clinical 
records, physician notes, correspondence) must adhere to the following standards: 
 
 
Clearly labeled in accordance with HIPAA practices so that they can be associated with a 
particular participant or PID; 
 
Legibly written in ink; 
 
Signed and dated in a real time basis by health care practitioner evaluating or treating the 
participant; and 
 
Correction liquid or tape must not be used in source documents or on CRFs. 
 
Corrections are made by drawing a single line through the error. Do not obliterate the original 
entry. Insert the correct information, initial, and date the entry. 
 
All laboratory reports, pathology reports, x-rays, imaging study and scans must have: 
 
 
Complete identifying information (name and address of the organization performing, 
analyzing, and/or reporting the results of the test); and 
 
Range of normal values for each result listed. 
 
11.4 
Data and Safety Monitoring Board 
 
The Data Safety Monitoring Board meets every six months to review all phase II and phase III protocols.  
The Board includes members demonstrating experience and expertise in oncology, biological sciences, 
biostatistics and ethics. The DSMB report is generated by the Research Base statistician. Areas of review 
may include the following: Study Objectives; Patient Accrual; Patient Status and Retention; Study Status; 
Last Contact Status; Patient Compliance; Number of Biopsies/Labs as needed; Patient Characteristics; 
Summary of Observed Toxicities; Adverse Events; Date, Event briefly described, Relationship to Drug, 
Arm assigned; Summary of Primary and Secondary Measures. 
 
11.5 
Record retention 
 
Clinical records for all participants, including CRFs, all source documentation (containing evidence to 
study eligibility, history and physical findings, laboratory data, results of consultations, etc.), as well as 
IRB records and other regulatory documentation will be retained by the Investigator for 5 years in a 


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secure storage facility in compliance with HIPAA, OHRP, FDA regulations and guidance, and NCI/DCP 
requirements unless the standard at the site is more stringent. 
 
11.6 
CDUS Reporting 
 
The WF NCORP Research Base Data Management Center will submit quarterly reports to DCP/CTEP by 
electronic means using the Clinical Data Update System (CDUS). 
 
12. 
STATISTICAL CONSIDERATIONS 
 
12.1 
Study Design/Endpoints 
A randomized, placebo controlled, double-blind, parallel group Phase 3 design will be used to assess the 
effect of 24 weeks of donepezil on cognitive function (memory) in breast cancer survivors who report 
having cognitive dysfunction and demonstrate memory impairment 1-5 year post chemotherapy.  Patients 
who meet the eligibility criteria will be stratified by age (<50, 50-59, 60-69, ≥70) and randomized to 
donepezil or placebo with equal probability.  The primary objective of this trial is to assess the effect of 
donepezil on memory as quantified by the HVLT-R Immediate Recall score.  Secondary objectives will 
be to assess the impact of donepezil on i) executive functions: Trail Making Test B/A; working memory: 
Digit Span Backward; processing speed: Digit Symbol Coding; verbal fluency: COWA); and self-
reported cognitive problems (FACT Cog) and iii) toxicities and adverse events. For exploratory aims 5 
and 6, we will assess the treatment interaction effects for  APOE genotype and cognitive reserve.   
 
The measures used to quantify these outcomes are described above.  Estimates of treatment efficacy will 
be obtained using the ‘intent to treat’ approach. That is, all randomized participants will be used in the 
analyses, regardless of whether or not the participants were treated according to protocol. 
 
12.2 
Sample Size 
 
For design purposes, we will base our sample size on data collected in our recently completed phase 2 
pilot (feasibility) study.  Baseline means and adjusted post-randomization standard deviations (obtained 
from ANCOVA models using the baseline and 24 week data) are shown below in Table 1, along with the 
estimates of the treatment effects.  These are provided for the overall sample and for those participants 
who had lower memory scores at baseline. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 1.  Estimates of the means, adjusted standard deviations, and treatment effects for some of the 
proposed outcomes – overall and [within the subgroup with poor initial memory scores]*  
 
Outcome 
Baseline 
Mean 
Adjusted SD 
Raw Treatment 
Effect (SE)** 
Standardized 
Effect Size*** 
HVLT_IR 
24.2 [21.8] 
4.33 [4.26] 
  2.61 (1.32) [ 4.88 (1.57)] 
 0.60 [ 1.15] 
HVLT_DR 
  8.5 [  7.7] 
1.81 [1.75] 
  0.28 (0.55) [ 0.70 (0.64)] 
 0.15 [ 0.40] 
HVLT_Recog 
11.1 [10.8] 
1.02 [1.19] 
  0.30 (0.32) [ 0.21 (0.44)] 
 0.29 [ 0.18] 
HVLT_sav 
86.2 [83.5] 
16.8 [19.4] 
  0.25 (5.08) [-2.78 (7.08)] 
 0.01 [-0.14] 
HVLT_discrim 
10.5 [10.1] 
1.37 [1.48] 
  1.05 (0.42) [ 1.23 (0.54)] 
 0.77 [ 0.83] 
COWA 
35.0 [33.8] 
7.53 [6.93] 
  2.41 (2.30) [ 0.65 (2.62)] 
 0.32 [ 0.09] 
TMT_A 
33.7 [33.8] 
8.12 [8.57] 
-1.09 (2.46)  [ 1.66 (3.18)] 
-0.13 [ 0.19] 
TMT_B 
86.7 [90.7] 
24.4 [26.9] 
  6.29 (7.37) [ 11.1 (9.92)] 
 0.26 [ 0.41] 
DST_F 
10.3 [10.2] 
1.40 [1.39] 
  0.29 (0.43) [ 0.14 (0.55)] 
 0.21 [ 0.10] 
DST_B 
  6.1 [  5.6] 
1.45 [1.47] 
-0.19 (0.44) [-0.41 (0.54)] 
-0.13 [-0.28] 
DST_T 
16.3 [15.8] 
2.41 [2.50] 
  0.11 (0.73) [-0.27 (0.96)] 
 0.04 [-0.11] 
 
Notes: HVLT-R = Hopkins Verbal Learning Test-Revised; COWA = Controlled Oral Word Association 
test; TMT = Trail Making Test; DST = Digit Span Test (F = Forward, B = Backward, T = Total). 
* 
 Estimates obtained from the pilot study discussed above in Section 2.3. 
**  Donepezil minus Placebo (positive effects favor donepezil except for TMT) 
*** Treatment difference between group means divided by adjusted standard deviation  (positive 
 
effects favor donepezil except for TMT) 
 
Our primary outcome variable will be a memory score as quantified by the HVLT-R Immediate Recall 
(total of 3 trials).  In our pilot study, the adjusted post-randomization standard deviation was 4.33 (SD of 
the outcome at 24 weeks, adjusted for its correlation with the baseline level) and the difference (SE) was 
2.61 (1.32) (p=.03).  In the subgroup of participants with poor initial memory scores, the adjusted post-
randomization standard deviation was 4.26 and the difference (SE) was 4.88 (1.57) (p<.01).   Assuming 
that standard deviations will be similar in the proposed study and equal in the two groups, the sample 
sizes required to detect mean differences between groups of 1 to 3 words with 80% and 90% power are 
shown in Table 2, assuming a 5% two-sided level of significance.  These calculations use data from the 
subgroup of participants with poor initial memory scores and assume a single stage design will be 
implemented, an ANCOVA model will be used to compare the treatment arms, and that 73% of the 
participants will have 24 week data (25% drop-out and 2% missing data, based on our pilot #97211). 
 
 
 
 
 
 
 
 
 


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Table 2. Total sample size needed to ensure sufficient power for detecting clinically meaningful 
differences in HVLT-R immediate recall at the 5% two-sided level of significance 
Absolute Difference 
80% power 
90% power 
1.0 
784 
1050 
1.5 
351 
469 
2.0 
200 
266 
2.5 
129 
170 
3.0 
91 
121 
 
We see that 266 participants are required to detect a treatment difference of 2 words with 90% power at 
the 5% two-sided level of significance.  We observed a larger treatment effect in the pilot study so that 
targeted difference is attainable.  Table 3 shows the differences that are detectable in the secondary 
outcomes with 90% power (using a Bonferroni corrected significance level of .005 for each test).  We see 
that we will have sufficient power for detecting relative differences between groups of less than 20% in 
all outcomes and relative differences of less than 15% for most outcomes.  
 
Table 3.  Differences detectable in secondary outcomes with 90% power*   
Outcome 
Absolute Difference 
Relative Difference (%)** 
HVLT_DR 
1.04 
13.5 
HVLT_Recog 
0.71 
  6.5 
HVLT_sav 
11.5 
13.8 
HVLT_discrim 
0.88 
  8.7 
COWA 
4.11 
12.2 
TMT_A 
5.08 
15.0 
TMT_B 
16.0 
17.6 
DST_F 
0.82 
  8.1 
DST_B 
0.87 
15.6 
DST_T 
1.48 
  9.4 
* Using a Bonferroni corrected significance level of .005 for each test. 
** Assuming post-treatment means remain at baseline levels in the control group. 
 
12.3 
Randomization and Stratification  
 
Participants will be stratified by age (<50, 50-59, 60-69, ≥70) and assigned with equal probability to 
donepezil or placebo using variably sized permuted block randomization. Block sizes will be chosen 
randomly to ensure that future assignments cannot be inferred from previous assignments.  Treatment 
assignments will be generated using nQuery Advisor 7.0 and incorporated into the randomization table in 
our enrollment facility which is accessible to the site via the internet 24/7. Participants, investigators, 
research staff, and statisticians will all be blinded to treatment assignment. Only RxCrossroads by 


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McKesson, the company that distributes the drugs and placebo, will be unblinded. If requested by the 
DSMB, RxCrossroads by McKesson can unblind the study statistician. 
 
12.4 
Primary Endpoint(s) 
The primary outcome, HVLT_IR is a continuous variable that will be measured at baseline, 12, 24 (end of 
treatment) and 36 weeks. This outcome will be analyzed using a mixed effects repeated measures analysis 
of covariance (RMANCOVA) model which includes treatment arm, time, the time*treatment interaction, 
the baseline levels of the outcomes, and the stratification factors as covariates, the latter included to 
ensure that the analysis matches the design. An unstructured covariance matrix will be used to account for 
the within participant correlation over time.  The major hypothesis will be assessed using a linear contrast 
to test the significance of the group effect at 24 weeks.  Least squares means and 95% confidence 
intervals will be provided for each outcome, stratified by treatment arm and time, and for the difference 
between treatment arms at each time.  
 
Subsequent RMANCOVA models that include several additional pre-specified, baseline covariates will be 
performed as a sensitivity analysis to the primary analysis. These additional covariates have been selected 
as those that are highly prognostic of cognitive outcomes and include education, race/ethnicity, fatigue, 
depressive symptom severity, and sleep quality (and APOE genotype and cognitive reserve for exploratory 
aims).Through inclusion of these additional covariates, we will correct for chance imbalances in pre-
specified important prognostic variables and account for that part of the variability in the outcome measure 
that is due to the covariates, thus improving the precision of the treatment effect.  Additionally, to address 
our tertiary exploratory objectives, we will include covariate by treatment interactions for APOE status and 
cognitive reserve in these models, thus allowing the determination of whether the effect of donepezil differs 
based on the level of the covariates.  One model will be fit that includes all the covariates and their 
interactions with treatment. Non-significant interactions will be removed from the model. Regression 
diagnostics, residual plots, and exploratory analyses will be done to identify appropriate transformations 
for the variables in these analyses. Order of priority in choosing a transformation will be to satisfy the 1) 
linearity assumption, 2) homogeneity of variances assumption, and 3) normality assumption.  Interim 
analyses will be undertaken after 1/2 of the participants have been accrued and followed for 24 weeks.  
Results of the interim analysis will be compared to the stopping rules detailed below and will be presented 
to the Cancer Center DSMB. 
 
12.5 
Secondary Endpoint(s) 
The secondary outcomes include additional neurocognitive measures as well as patient reported outcomes 
such as self-report cognitive function, fatigue, sleep disturbance, and depression (see Section 7.2).  These 
outcomes are primarily continuous variables that will be measured at baseline, 12, 24 (end of treatment) 
and 36 weeks.  They will be analyzed as described in Section 12.4 for the primary outcome. 
 
12.6 
Retention and Compliance 
Drop-outs are a difficult problem and one that is best handled proactively rather than retrospectively. We 
will make a concerted effort to minimize the number of drop-outs, beginning with the participants who 
are accrued. If a participant seems unwilling to participate or indicates that she may not be able to be 
compliant, we will not press her to participate. In addition, participants who refuse treatment at some 
point during the course of therapy will be encouraged to stay in the study and provide outcome data.  
Despite our best efforts, some data will be missing due to missed visits or participants refusing further 
participation. We propose to analyze the data using SAS Proc Mixed, a program that provides several 
computational methods for obtaining maximum likelihood estimates for repeated measures problems, 
allows for unbalanced designs, missing data at some times, structured or unstructured covariance 
matrices, and growth curve parameterizations of time effects.  Additionally, we will employ multiple 
imputation methods to assess the treatment effect on the outcomes using the SAS multiple imputation 
procedures. Both the mixed models and imputation analyses assume participants are missing at random, 


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that is, the missingness can depend on covariates and observed outcomes but not the missing outcomes. 
This assumption that the missingness does not depend on the missing data cannot be tested completely 
since the data needed to test the assumption are missing.  However, we will use logistic regression to see 
if we can determine which covariates, if any, are related to missingness, and these covariates will be used 
to create a propensity-to-be-missing score which will used to generate a stratified analysis as described by 
Baker et al58.  Additionally, exploratory analyses using multiple imputations will assess the treatment 
effect over a range of assumptions regarding the missingness, allowing us to assess the sensitivity of our 
assumptions. 
 
Compliance is defined as the number of pills consumed over the course of the trial divided by the ideal 
number that should have been consumed over that period.  It will be calculated based on the patient’s self-
reported pill diaries. The primary analyses estimating treatment efficacy will include all randomized 
participants, regardless of compliance.  Additional exploratory analyses will assess the treatment effect in 
those patients who were at least 75% compliant. 
 
12.7 
Reporting and Exclusions 
 
Descriptive reports will consist of summary statistics (means, standard deviations, proportions, etc.) for 
participant characteristics and outcome measures by treatment arm, actual versus projected accrual, 
participation by the various NCORP sites, quality control information (retention, missing data, etc.), and a 
summary of toxicities and adverse events. Tables, graphs, and charts will be used to illustrate the data 
when appropriate. These reports will be prepared and presented to the WF DSMB committee every six 
months.  All life threatening or greater toxicities (using CTCAE version 4 criteria) and severe adverse 
events will also be reported to the IRB and the WF Cancer Center Toxicity Review Committee for further 
action.  
 
12.8 
Evaluation of Toxicity 
 
All participants will be evaluable for toxicity from the time of their first dose of donepezil. Toxicities will 
be determined using the CTCAE v4.0 for Toxicity and Adverse Event Reporting, and participants will be 
evaluable for toxicity from the time of their first dose of donepezil or placebo. Fisher exact tests will be 
used to assess treatment differences in the incidence of individual toxicities, and logistic regression will 
be used to assess treatment differences in the incidence of any grade 3 or higher toxicity adjusting for 
baseline participant characteristics. 
 
12.9 
Evaluation of Response 
 
Tumor response will not be evaluated in this trial.  
 
12.10 Interim Analysis 
 
For ethical considerations, we will incorporate a single interim analysis into the design that allows 
stopping for rejection of the null hypothesis. We will not allow early stopping for acceptance of the null 
hypothesis as the effect of donepezil on the secondary outcomes would still be of interest.  The rejection 
boundaries were determined by the S-Plus software module SeqTrial (using an alternative boundary shape 
parameter of .75).  This two-stage design will require a maximum sample size that is approximately 3.5% 
greater than the fixed sample design; a maximum of 276 participants will be randomized, approximately 
138 to each arm. The interim analysis will occur after 138 participants have been accrued and followed 
for 24 weeks. If the two-sided p-value of the test statistic comparing the two treatment arms is less than 
0.0154 during the interim analysis, the study will be stopped and the null hypothesis rejected. Otherwise 
the trial will continue until 276 participants have been accrued, at which point the null hypothesis will be 


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rejected if the two-sided p-value < .0416. Although the two-stage design has a larger maximum sample 
size (276 vs 266), it does have a smaller expected sample size compared to that of a single stage design 
under the alternative hypothesis.  Under the null hypothesis, the probability of stopping at the first stage is 
2%, and the expected sample size is approximately 273.  Under the alternative hypothesis, the probability 
of stopping early is 46%, and the expected sample size is approximately 213. 
 
13. SITE REGISTRATION 
 
CTEP Investigator Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy require all 
individuals contributing to NCI-sponsored trials to register and to renew their registration annually.  To 
register, all individuals must obtain a Cancer Therapy Evaluation Program (CTEP) Identity and Access 
Management (IAM) account at https://ctepcore.nci.nih.gov/iam.  In addition, persons with a registration 
type of Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site 
staff requiring write access to OPEN, RAVE, or TRIAD or acting as a primary site contact) must 
complete their annual registration using CTEP’s web-based Registration and Credential Repository 
(RCR) at https://ctepcore.nci.nih.gov/rcr.   
RCR utilized 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 (e.g., 
Roster Update Management System (RUMS), OPEN, Rave,); 
 
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 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 
HSP/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 


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all clinical practice sites and Institutional Review Boards (IRBs) covering their practice sites on the FDA 
Form 1572 in RCR to allow the following: 
 
Added to a site roster 
 
Act as the site-protocol Principal Investigator (PI) on the IRB approval 
 
Additional information can be found on the CTEP website at  
https://ctep.cancer.gov/investigatorResources/default.htm.  For questions, please contact the RCR Help 
Desk by email at < RCRHelpDesk@nih.gov >. 
 
Protocol documents are found on the CTSU website, but supplemental documents may be available on the 
Wake Forest NCORP Research Base website. 
 
Permission to view and download the neurocognitive test packet are restricted and is based on person 
specific training and is housed on the Wake Forest NCORP Research Base website.  
 
CTSU Registration Procedures 
 
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 CTSURegPref@ctsu.coccg.org 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 emailing the email address above or calling 1-888-651-CTSU (2878). 
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory Office using the 
Regulatory Submission Portal located in the Regulatory section of the CTSU website. Acceptable 
documentation of local IRB/REB approval includes: 
 
Local IRB documentation; 
 
IRB-signed CTSU IRB Certification Form; and/or 
 
Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of Exemption 
Form. 
 
 
 
In addition, the site-protocol Principal Investigator (PI) (i.e. the investigator on the IRB/REB approval) 
must meet the following criteria to complete processing of the IRB/REB approval record: 


WF-97116 
Amendment 4, Protocol Version Date 06/07/2019 
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 
Holds an Active CTEP status; 
 
Rostered at the site on the IRB/REB approval and on at least on participating roster; 
 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
 
Included the IRB number of the IRB  providing approval in the Form FDA 1572 in the RCR 
profile; and 
 
Holds the appropriate CTEP registration type for the protocol. 
 
Additional Requirements: 
Additional 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); and 
 
Compliance with all protocol-specific requirements (PSRs). 
 
Protocol Specific Requirements for WF-97116 Site Registration: 
 
 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, an IRB-signed 
CTSU IRB Certification Form, Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form, or combination is accepted ) 
 
Neurocognitive training and certification through the Wake Forest NCORP Research Base is required 
prior to patients being enrolled. 
 
Submitting Regulatory Documents:  
 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory Submission 
Portal on the CTSU website. 
 
To access the Regulatory Submission Portal log onto the CTSU members’ website  Regulatory  
Regulatory Submission. 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU Regulatory 
Office immediately at 1-866-651-2878 in order to receive further instruction and support. 
 
Checking Your Site’s Registration Status: 
 
You can verify your site registration status on the members’ side of the CTSU website.   
 
 Go to https://www.ctsu.org and log in to the members’ website using your CTEP-IAM username 
and password; 
 Click on Regulatory at the top of your screen; 
 Click on the Site Registration; 
 Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status shown only reflects institutional compliance with site registration requirements as 
outlined above. It does not reflect compliance with protocol requirements for individuals participating on 
the protocol or the enrolling investigator’s status with the NCI or their affiliated networks. 
 
 
 


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in Alzheimer disease. Clin Neuropharmacol 2004;27(4):166-170. 
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patients: effect on cognitive function, mood, and quality of life. J Clin Oncol 2006;24(9):1415-
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Randomized Placebo-Controlled Clinical Trial. J Clin Oncol 2015;33(15):1653-1659. 
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dementia. Dement Geriatr Cogn Disord 2006;22(1):15-19. 
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analysis. Dement Geriatr Cogn Disord 1999;10(3):199-209. 
 39.  Ahles TA, Saykin AJ, Noll WW et al. The relationship of APOE genotype to neuropsychological 
performance in long-term cancer survivors treated with standard dose chemotherapy. 
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 40.  Ahles TA, Li Y, McDonald BC et al. Longitudinal assessment of cognitive changes associated with 
adjuvant treatment for breast cancer: the impact of APOE and smoking. Psychooncology 2014. 
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 42.  Stern Y, Gurland B, Tatemichi TK, Tang MX, Wilder D, Mayeux R. Influence of education and 
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 43.  Benedict RH, Schretlen D, Groninger L, Brandt J. Hopkins Verbal Learning Test-Revised: 
Normative data and analysis of inter-form and test-retest reliability. Clinical Neuropsychologist 
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 44.  Shapiro AM, Benedict RH, Schretlen D, Brandt J. Construct and concurrent validity of the Hopkins 
Verbal Learning Test-revised. Clin Neuropsychol 1999;13(3):348-358. 
 45.  Wechsler D. Manual for the Wechsler Adult Intelligence Scale-Revised (WAIS-R). New York: 
Psychological Corporation; 1981. 
 46.  Reitan R. Validity of the Trail Making Test as an indicator of organic brain damage. Perceptual and 
Motor Skills 1958;8:271-276. 
 47.  Benton AL, Hamsher K. Multilingual Aphasia Examination. Iowa City, IA: Univ of Iowa Press; 
1976. 
 48.  Nasreddine ZS, Phillips NA, Bedirian V et al. The Montreal Cognitive Assessment, MoCA: a brief 
screening tool for mild cognitive impairment. J Am Geriatr Soc 2005;53(4):695-699. 
 49.  Olson RA, Chhanabhai T, McKenzie M. Feasibility study of the Montreal Cognitive Assessment 
(MoCA) in patients with brain metastases. Support Care Cancer 2008;16(11):1273-1278. 
 50.  Rossetti HC, Lacritz LH, Cullum CM, Weiner MF. Normative data for the Montreal Cognitive 
Assessment (MoCA) in a population-based sample. Neurology 2011;77(13):1272-1275. 
 51.  Ahles TA, Saykin AJ. Breast cancer chemotherapy-related cognitive dysfunction. Clin Breast 
Cancer 2002;3 Suppl 3:S84-S90. 
 52.  Mehta MP, Shapiro WR, Glantz MJ et al. Lead-in phase to randomized trial of motexafin 
gadolinium and whole-brain radiation for patients with brain metastases: centralized assessment of 
magnetic resonance imaging, neurocognitive, and neurologic end points. J Clin Oncol 
2002;20(16):3445-3453. 
 53.  Meyers CA, Smith JA, Bezjak A et al. Neurocognitive function and progression in patients with 
brain metastases treated with whole-brain radiation and motexafin gadolinium: results of a 
randomized phase III trial. J Clin Oncol 2004;22(1):157-165. 
 54.  Vardy J, Wong K, Yi QL et al. Assessing cognitive function in cancer patients. Support Care 
Cancer 2006;14(11):1111-1118. 
 55.  Jacobs SR, Jacobsen PB, Booth-Jones M, Wagner LI, Anasetti C. Evaluation of the functional 
assessment of cancer therapy cognitive scale with hematopoietic stem cell transplant patients. J 
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 56.  Spitzer RL, Kroenke K, Linzer M et al. Health-related quality of life in primary care patients with 
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 57.  Gilbody S, Richards D, Brealey S, Hewitt C. Screening for depression in medical settings with the 
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59.  Lawrence JA, Griffin L, Balcueva EP, Groteluschen DL, Samuel TA, Lesser GJ, et al. A study of 
donepezil in female breast cancer survivors with self-reported cognitive dysfunction 1 to 5 years 
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0463-x. PubMed PMID: 26130292. 
 
60.  Rapp SR, Case D, Peiffer A, Naughton MJ, Stieber VW, Bayer GK, et al. Phase III randomized, 
double-blind, placebo-controlled trial of donepezil in irradiated brain tumor survivors. Journal of 
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61.   Shaw EG, Rosdhal R, D'Agostino RB, Jr., Lovato J, Naughton MJ, Robbins ME, et al. Phase II 
study of donepezil in irradiated brain tumor patients: effect on cognitive function, mood, and 
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16549835. 
 
 
 


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Appendix A – Moderate Risk QTc Prolonging Medications 
 
A 
 Albuterol 
 Alfuzosin 
 Amantadine 
 Amisulpride 
 Amitriptyline 
 Amoxapine 
 Apomorphine 
 Arformoterol 
 ARIPiprazole 
 ARIPiprazole Lauroxil 
 Atazanavir 
 AtoMOXetine 
 
B 
 Bortezomib 
 Bosutinib 
 Buserelin 
 
C 
 Capecitabine 
 Chloral Hydrate 
 ClomiPRAMINE 
 
D 
 Dabrafenib 
 Dasatinib 
 Degarelix 
 Desflurane 
 Desipramine 
 DiphenhydrAMINE 
(systemic) 
 Doxepin (systemic) 
 Doxepin (topical) 
 
E 
 Ebastine 
 Eperisone 
 EriBULin 
 Ezogabine 
 
F 
 Famotidine 
 Felbamate 
 Fingolimod 
 Fluconazole 
 Fluroruracil (systemic) 
 Formoterol 
 Foscarnet 
 Fosphenytoin 
 
G 
 Gadofosveset 
 Galantamine 
 
H 
 Halothane 
 Histrelin 
 HydrOXYzine 
 
I 
 Ibandronate 
 Imipramine 
 Indacaterol 
 Indapamide 
 Isoflurane 
 Isoproterenol 
 Isradipine 
 Itraconazole 
 Ivabradine 
 
L 
 Lacidipine 
 Lapatinib 
 Levalbuterol 
 Levosimendan 
 Levosulpiride 
 Lithium 
 Loperamide 
 Loperamide Oxide 
 
M 
 Maprotiline 
 Mefloquine 
 Methotrimeprazine 
 Metoclopramide 
 MetroNIDAZOLE 
(systemic) 
 Mianserin 
 Mirabegron 
 Mirtazapine 
 Moexipril 
 
N 
 Nelfinavir 
 NIcarDIPINE 
 Norfloxacin 
 Nortriptyline 
 
O 
 Octreotide 
 OLANZapine 
 Olodaterol 
 Oteracil 
 Oxaliplatin 
 Oxytocin 
 
P 
 PARoxetine 
 Pasireotide 
 Pentamidine (Oral 
Inhalation) 
 Periciazine 
 Posaconazole 
 Promethazine 
 Propofol 
 Protriptyline 
 
R 
 Ranolazine 
 Rilpivirine 
 RisperiDONE 
 Ritonavir 
 RomiDEPsin 
 
S 
 Sameterol 
 Sertraline 
 Sevoflurane 
 Solifenacin 
 SORAfenib 
 Sulfamethoxazole 
 SUNItinib 
 
T 
 Tacroliumus (Systemic) 
 Tamoxifen 
 Tegafur 
 Terbutaline 
 Thiothixene 
 TiZANidine 
 Tolerodine 
 TraZODone 
 Treprostinil 
 Trifluridine 
 Tipiracil 
 Trimethoprim 
 Trimipramine 
 Triptorelin 
 Tropisetron 
 
V 
 Vardenafil 
 Venlafaxine 
 Vilanterol 
 Vorconazole 
 Vorinostat 
See up to date link: https://www.uptodate.com/drug-
interactions/?search=donepezil&usage_type=default&source=responsive_results&display_rank=3#di-
analyze  
 


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Appendix B – Moderate Risk Bradycardia-Causing Agents 
 
A 
 Acebutolol 
 Ajmaline 
 Alectinib 
 Amiodarone 
 Arotinolol 
 Atenolol 
 
B 
 Beractant 
 Betaxolol (Systemic) 
 Bisoprolol 
 Bovine Lipid Extract Surfactant 
 Bovine Lung Extract 
 
C 
 Calfactant 
 Carteolol (Ophthalmic) 
 Carvedilol 
 CloNIDine 
 Crizotinib 
 
D 
 Dexmedetomidine 
 Digitoxin 
 Digoxin 
 DiltiaZEM 
 Dronedarone 
 
E 
 Esmolol 
 
F 
 Fingolimod 
 
G 
 Galantamine 
 GuanFACINE 
 
I 
 Ivabradine 
 
L 
 Labetalol 
 Lanreotide 
 Levobunolol 
 Lofexidine 
 Lucinactant 
 
M 
 Methyldopa 
 Metiprandolol 
 Metoprolol 
 
N 
 Nadolol 
 Nebivolol 
 
O 
 Octreotide 
 Oxprenolol 
 
P 
 Pasireotide 
 Penbutolol 
 Pilsicainide 
 Pindolol 
 Poractant Alfa 
 Propanfenone 
 Propranolol 
 
R 
 Rivastigmine 
 
S 
 Sotalol 
 SUFentanil 
 
T 
 Timolol (Ophthalmic) 
 Timolol (Systemic) 
 TiZANidine 
 
V 
 Verapamil 
See up to date link: https://www.uptodate.com/drug-
interactions/?search=donepezil&usage_type=default&source=responsive_results&display_rank=3#di-
analyze  
 
 


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Appendix C – Succinylcholine/Acetylcholinesterase Inhibitors 
 
 Distigmine 
 Edrophonium 
 Neostigmine 
 Physostigmine 
 Pyridostigmine 
 
See up to date link: https://www.uptodate.com/drug-
interactions/?search=donepezil&usage_type=default&source=responsive_results&display_rank=3#di-
analyze  
 
 
 


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Page 52 of 54 
 
 
Appendix D – High Risk QTc Prolonging Medications 
 
A 
 Ajmaline 
 Amiodarone 
 Anagrelide 
 Arsenic Trioxide 
 Artemether 
 Asenapine 
 Astemizole 
 
B 
 Bepridil 
 Buprenorphine 
 
C 
 Cisapride 
 Citalopram 
 
D 
 Disopyramide 
 Dofetilide 
 Domperidone 
 Dosulepin 
 Dronedarone 
 
E 
 Eliglustat 
 Escitalopram 
 
F 
 FLUoxetine 
 Flupentixol 
 
H 
 Halofantrine 
 
I 
 Ibutilide 
Iloperidone  
 
L 
 Lopinavir 
 Lumefantrine 
M 
 MiFEPRIStone 
 
N 
 Nilotinib 
 
P 
 Paliperidone 
 Pimavansrin 
 Pimozide  
 Pipamperone [INT] 
 Procainamide 
 
Q 
 QUEtiapine 
 QuiNIDine 
 QuiNINE 
 
S 
 Sotalol 
 Sparfloxacin 
 Sulpiride 
 
T 
 Terfenadine 
 Tetrabenazine 
 Thioridazine 
 Toremifene 
 
V 
 Vandetanib 
 Vemurafenib 
 Vernakalant 
 
Z 
 Ziprasidone 
 Zuclopenthixol 
 
See up to date link: https://www.uptodate.com/drug-
interactions/?search=donepezil&usage_type=default&source=responsive_results&display_rank=3#di-
analyze  


WF-97116 
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Appendix E – Guidelines for Reconsenting Patients 
(A Result of Changes per Amendment 3, Released 5/16/2019) 
 
1) All Patients: 
 
a. All patients currently on study should be reconsented to make them aware of 
potential interactions of study drug and certain concurrently taken medications 
 
b. All patients still receiving study drug will require an ECG to rule out unrecognized 
QTc prolongation or bradycardia 
 
2) Patients currently taking the study drug and a moderate risk QTc prolongation medication 
(reference Appendix A): 
 
a. Patients taking the study drug and a moderate risk QTc prolongation medication 
(reference Appendix A) should be notified of the new amendment requirements and 
reconsented immediately. These patients will receive an ECG and heart rate 
assessment at the time of reconsent as per 1b above. 
 
i. Reconsented patients who have an acceptable QTc interval (< 500ms) on 
their ECG and who are within the first 6 weeks of study drug (Baseline – 6 
Week) should refer to section 7.5 in the protocol for timing of additional 
ECG monitoring required in the amended protocol.  
ii. Reconsented patients who have an acceptable QTc interval (< 500ms) on 
their ECG and who are beyond the study drug dose increase time point (6 
Week) will not require any further cardiac monitoring 
iii. Reconsented patients who have an unacceptable QTc interval (≥ 500ms) on 
their ECG and who are within the first 6 weeks of study drug (Baseline – 6 
Week) should stop study drug and be followed as per protocol guidelines 
iv. Reconsented patients who have an unacceptable QTc interval (≥ 500ms) on 
their ECG and who are beyond the study drug dose increase time point (6 
Week) may have the dose of study drug reduced by half (i.e. back to initial 
dose level of study drug). Such a patient would then require repeat ECG 
testing in 3-7 days at which time they would be allowed to continue on 
reduced dose of study drug (if QTc is < 500ms) or be taken off the study 
drug and followed per protocol guidelines (if QTc ≥ 500ms). 
 
3) Patients currently taking the study drug and a moderate risk bradycardia-causing agent 
(reference Appendix B):  
 
a. Patients taking the study drug and a moderate risk bradycardia-causing agent 
(reference Appendix B) should be notified of the new amendment requirements and 
reconsented immediately. These patients should receive a heart rate assessment at the 
time of reconsent (use the ECG required as per 1b above).  
 
i. Reconsented patients who have an acceptable heart rate (≥ 55) and who are 
within the first 6 weeks of study drug (Baseline – 6 Week) should refer to 
section 7.5 in the protocol for timing of additional heart rate monitoring 
required in the amended protocol.  


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ii. Reconsented patients who have an acceptable heart rate (≥ 55) and who are 
beyond the study drug dose increase time point (6 Week) will not require 
any further heart rate monitoring. 
iii. Reconsented patients who have an unacceptable heart rate (< 55) and who 
are within the first 6 weeks of study drug (Baseline – 6 Week) should stop 
study drug and be followed as per protocol guidelines. 
iv. Reconsented patients who have an unacceptable heart rate (< 55) and who 
are beyond the study drug dose increase time point (6 Week) may have 
the dose of study drug reduced by half (i.e. back to initial dose level of study 
drug). Such a patient would then require repeat heart rate testing in 3-7 days 
at which time they would be allowed to continue on reduced dose of study 
drug (heart rate ≥55) or be taken off the study drug and followed per protocol 
guidelines (if heart rate < 55). 
 
The results of these ECG and heart rate assessments, along with the date of the assessment, should be 
recorded on the Cardiac Monitoring Form under Other Assessment and should be submitted to the WF 
NCORP RB. 
 

ICF_000.pdf: 
Official Title:  A Phase 3 Randomized Placebo Controlled Clinical Trial of Donepezil in 
Chemotherapy Exposed Breast Cancer Survivors With Cognitive Impairment  
NCT02822573
IRB-Approved Date:  11/29/2017


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Adult Consent Form 
Study Title for Study Participants: DONEPEZIL FOR COGNITIVE 
IMPAIRMENT 
OFFICIAL STUDY TITLE FOR INTERNET SEARCH ON 
HTTP://WWW.CLINICALTRIALS.GOV: WFU 97116 – A PHASE 3 PLACEBO 
CONTROLLED CLINICAL TRIAL OF DONEPEZIL IN CHEMOTHERAPY 
EXPOSED BREAST CANCER SURVIVORS WITH COGNITIVE IMPAIRMENT  
Informed Consent Form to Participate in Research 
Stephen Rapp, PhD, Principal Investigator 
What is the usual approach to my memory function as related to my breast 
cancer treatment? 
You are being asked to take part in this research study because you have memory problems 
following chemotherapy for breast cancer. There is no standard of care for memory loss 
associated with breast cancer and chemotherapy.  Many patients may undergo formal memory 
testing.  Patients are encouraged to "stay mentally active" by reading, using word games, puzzles 
and other brain stimulating activities.  Other interventions may include memory training 
programs, or use of other medications that may help memory loss.    
What are my other choices if I do not take part in this study? 
If you decide not to take part in this study, you have other choices.  For example: 
•
you may choose to have the usual approach described above,
•
you may choose to take part in a different study, if one is available,
•
or you may choose to do nothing.
WHY IS THIS STUDY BEING DONE? 
Donepezil is currently FDA approved for the treatment of mild to moderate dementia of the 
Alzheimer’s type, but not for its use in this study evaluating cancer-related cognitive dysfunction 
in breast cancer survivors. There will be about 276 people taking part in this study. 
The purpose of this study is to compare the safety and effects of donepezil (Aricept) or placebo 
on people and their risk of memory problems after receiving chemotherapy for breast cancer. 


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WHAT ARE THE STUDY GROUPS? 
This study has two study groups. Group 1 will receive the study drug donepezil and Group 2 will 
receive a placebo, a pill that looks like the study drug but contains no medication.  
A computer will by chance assign you to one of the treatment groups in the study. This is done 
because no one knows if one study group is better, the same, or worse than the other group. Once 
you are put in a group, you cannot switch to the other group. Neither you nor your doctor will 
know if you are receiving the study drug or placebo. Your doctor cannot choose which group 
you will be in. 
If you are randomized to the: 
•
Donepezil Group: You will be asked to take one 5 mg donepezil tablet by mouth each
day for 6 weeks. Then, you will be asked to take two 5 mg donepezil tablets by mouth
each day until the end of the study (18 weeks). This will be a total of 24 weeks.
If you are randomized to the: 
•
Placebo Group: You will be asked to take one placebo tablet by mouth each day for 6
weeks. Then, you will be asked to take two placebo tablets by mouth each day until the
end of the study (18 weeks). This will be a total of 24 weeks.
Both Groups will fill in a drug diary and mail it back to the study nurse at 6 weeks. You will be 
asked to bring your completed drug diaries to the 12 and 24 week study visits.  
 Three and six weeks after starting your pills the study nurse will call to ask you about any side 
effects you may be having while taking the donepezil or placebo.  
During weeks 24 – 36 you will not take study pills.  This is called a “Wash-Out” period.  At the 
end of this wash-out period, you will have a nurse visit to complete study questionnaires. 
Donepezil Tablets x 24 weeks 
Weeks 1-6: one 5 mg tablet per day 
Weeks 7-24: two 5mg tablets per day 
Weeks 24-36: Wash-out 
Placebo Tablets x 24 weeks 
Weeks 1-6: one placebo tablet per day 
Weeks 7-24:  two placebo tablets per 
day 
Randomize (The 
computer will randomly 
put you in a study 
group.) 
You agree to 
take part in the 
study. 


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HOW LONG WILL I BE IN THE STUDY? 
You will be in this study for 36 weeks. You will receive the study medication for 24 weeks. Even 
if you do not finish the study, your doctor will continue to watch you for side effects and follow 
your condition for 24 - 36 weeks. 
WHAT EXTRA TESTS AND PROCEDURES WILL I HAVE IF I TAKE 
PART IN THIS STUDY? 
Most of the exams, tests, and procedures you will have are part of the usual approach for your 
condition. However, there are some extra lab tests and questionnaires that you will need to have 
if you take part in this study. 
Before you begin the study: 
You will need to have the following extra tests to find out if you can be in the study: 
•
Pregnancy test if you are able to have children
•
Memory Questions:
If the Memory Questions show that you can take part in the study, and you choose to take
part, then you will need the following extra lab tests, memory tests and Quality of Life
questions. These tests and questions are not part of the usual approach for your condition.
At the beginning of the study, you will have the following: 
•
Blood draw for APOE genotyping:
APOE genotyping is an important part of the study. This blood sample is required for you
to take part in this study and you must be willing to allow this sample to be stored for
future research.  This sample may be used to learn more about other diseases.
•
Nurse assessment to evaluate current medications, family history or problems you may be
experiencing, additional memory questions and complete questionnaires about things like
your mood and well-being, language, and how you organize your thoughts.
•
Study drug or placebo will be given at your baseline visit.
•
You will be given one 5 mg tablet of donepezil to take by mouth once a day or one
placebo tablet to take by mouth once a day at weeks 1-6. These tablets should be
swallowed whole. You should take the tablets at the same time every day. This may be in the
morning or evening; with or without food.
•
You will be given a drug diary to complete and send to the study team by mail at six
weeks.


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You will have approximately two teaspoons of blood withdrawn from a vein or currently placed 
central line (port-a-cath) at the beginning of the study. If you are a woman of child-bearing 
potential, you will have an additional 1teaspoon of blood withdrawn to verify your pregnancy 
status for study eligibility. The total amount of blood withdrawn during the study will be about 
2- 3 teaspoons. 
 
Your privacy is very important and the researchers will make every effort to protect it. Your test 
results will be identified by a unique code and the list that links the code to your name will be 
kept separate from your sample and health information.  However, study results will not be made 
available to you or your study doctor. 
 
Neither you nor your health care plan/insurance carrier will be billed for the collection of the 
blood sample that will be used for this study. 
 
During the study: 
 
• At 3 weeks and 6 weeks after starting your study medication, the nurse will call you to 
make sure you are not having problems taking your study medication. If you are not 
having any problems at 6 weeks, the drug dose will increase to two 5 mg tablets of 
donepezil once a day or two placebo tablets once a day starting at week 7.  
 
• You will come for a visit with the study nurse at12 weeks and 24 weeks. The study nurse 
will ask what medications you are taking, problems you may be experiencing, ask 
memory questions and complete questionnaires about things like your mood and well-
being memory, language, and how you organize your thoughts. You will be asked to 
bring your completed drug diaries when coming for these visits. At 24 weeks you will 
stop taking your study medication. 
 
• At 36 weeks, you will return for a visit with the study nurse. You will be asked about 
medications you are taking, problems you may be experiencing, asked memory questions 
and complete questionnaires about things like your mood and well-being memory, 
language, and how you organize your thoughts. This is called the wash-out period. This 
will help us to determine if there is a worsening of cognitive symptoms and test 
performance following withdrawal of treatment 
 
The memory questions will be given to you by a trained study staff who will explain how to do 
them. It will take about 30-45 minutes to complete during each nurse visit. 
 
BLOOD COLLECTION FOR DNA APOE GENOTYPING 
As part of this study, a blood sample will be obtained so that DNA from your blood sample will 
be purified. DNA, or deoxyribonucleic acid, stores and transmits inherited traits, such as eye 
color or blood type. APOE  genotyping works with DNA to help express these traits. As part of 
this research project, your DNA and APOE genotyping will be studied in an effort to find out if 
there are genes that contribute to medical conditions that are part of this study. Because we do not 
know how the results of this DNA/APOE genotyping study relate to your individual health, the 


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results of the research will not be given to you or your doctor. These results will also not be 
placed in your medical records. 
Your blood sample will be stored with a unique identifier. The unique identifier will be a 
randomly assigned number and only the principal investigator or select study personnel identified 
by him will have access to the code that links the unique identifier to you. Your name, address, 
social security number, etc., will never be disclosed to future researchers and neither will the code 
that links your identifiers to the sample. 
Your sample will be processed in the Center for Genomics and Personalized Medicine Research 
(CGPMR) at Wake Forest University Baptist Medical Center. The sample will be stored in the 
CGPMR and it will be given only to researchers approved by Dr. Rapp. An Institutional Review 
Board (IRB) must also approve any future research study using your blood sample.  
WHAT POSSIBLE RISKS CAN I EXPECT FROM TAKING PART IN THIS 
STUDY? 
If you choose to take part in this study, there is a risk that: 
•
You may lose time at work or home and spend more time in the hospital or doctor’s
office than usual.
•
You may be asked sensitive or private questions which you normally do not discuss.
There is a risk someone could get access to the personal information in your medical
records or other information researchers have kept about you. Someone might be able to
trace this information back to you.  The researchers believe the chance that someone will
identify you is very small, but the risk may change in the future as people come up with
new ways of tracing information.  In some cases, this information could be used to make
it harder for you to get or keep a job. There are laws against misuse of genetic
information, but they may not give full protection.  The researchers believe the chance
these things will happen is very small, but cannot promise that they will not occur.
•
There can also be a risk in finding out new genetic information about you.  New health
information about inherited traits that might affect you or your blood relatives could be
found during a study.
•
Risks associated with blood draws: You may experience discomfort, bruising and/or
bleeding where the needle is inserted for the blood test. Occasionally some people
become dizzy lightheaded or feel faint. Infection may occur on rare occasions.
There is also a risk that you could have side effects from donepezil. 
Here are important points about side effects: 
•
The study doctors do not know who will or will not have side effects.
•
Some side effects may go away soon, some may last a long time, or some may never go
away.
•
Some side effects may interfere with your ability to have children.
•
Some side effects may be serious and may even result in death.


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Here are important points about how you and the study doctor can make side effects less of a 
problem: 
•
Tell the study doctor if you notice or feel anything different so they can see if you are
having a side effect.
•
The study doctor may be able to treat some side effects.
•
The study doctor may adjust the study drugs to try to reduce side effects.
The bullets below show the most common and the most serious side effects that researchers 
know about. There might be other side effects that researchers do not yet know about. If 
important new side effects are found, the study doctor will discuss these with you. 
COMMON, SOME MAY BE SERIOUS (>20% CHANCE) 
•
Diarrhea 5-15 % dose related
•
Loss of Appetite 2-8 % dose related
•
Muscle Cramps 3-8 %
•
Nausea  3-19 % dose related
•
Trouble in sleeping 2-14%
•
Unusual tiredness or weakness  1-8 %
•
Vomiting 3-9 % dose related
OCCASIONAL, SOME MAY BE SERIOUS (<20% CHANCE) 
•
Headache 3-10 %
•
Dizziness 2-8 %
•
Weight loss 3-5 % dose related
RARE, SOME MAY BE SERIOUS 
• High blood pressure 3%
• Risk of seizures <1%
• Slow heart beat > 1%
• Neuroleptic malignant syndrome (NMS) (fever, severe muscle cramps, confusion,
unusual heartbeat) <1%
Let your study doctor know of any questions you have about possible side effects. You can ask 
the study doctor questions about side effects at any time. 
Reproductive risks: 
You should not get pregnant, breastfeed, while in this study. The donepezil used in this study 
could be very damaging to an unborn baby. Check with the study doctor about what types of 
birth control, or pregnancy prevention, to use while in this study. 
WHAT POSSIBLE BENEFITS CAN I EXPECT FROM TAKING PART IN 
THIS STUDY? 
This study may or may not help you because we do not know how the study drugs will compare 
to the usual approach for your condition. This study may help us learn things that could help 
people in the future. 


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The research that may be performed with your blood sample is not designed to help you 
specifically. There is no personal benefit to you from taking part in this aspect of the research 
study. It might help people who have diseases at some point in the future, but it is not known if 
this will happen. The results of the research performed with your blood will not be given to you 
or your doctor. The results will not be put in your medical record. The research using your blood 
sample will not affect your care. 
 
 
CAN I STOP TAKING PART IN THIS STUDY? 
Yes. You can decide to stop at any time. If you decide to stop for any reason, it is important to let 
the research staff  know as soon as possible. If you stop, you can decide whether or not to talk to 
the investigators or study staff to provide your medical information to the organization running 
the study. 
 
The study doctor will tell you about new information or changes in the study that may affect 
your health or your willingness to continue in the study. 
 
The study doctor may take you out of the study: 
 
• If your health changes  
• If the study is no longer in your best interest. 
• If new information becomes available. 
• If you do not follow the study rules. 
• If the study is stopped by the sponsor, IRB, or FDA. 
 
 
WHAT ARE MY RIGHTS IN THIS STUDY? 
Taking part in this study is your choice. No matter what decision you make, and even if your 
decision changes, there will be no penalty to you. You will not lose medical care or any legal 
rights. 
 
For questions about your rights while in this study, call the (insert name of institution) 
Institutional Review Board at (insert phone number) 
 
 
WHAT ARE THE COSTS OF TAKING PART IN THIS STUDY? 
 
The donepezil will be supplied at no charge while you take part in this study. The cost of getting 
the donepezil ready and giving it to you is also provided at no charge. The memory questions, 
pregnancy testing, and DNA/genotype testing will also be performed at no charge.  It is possible 
that the donepezil may not continue to be supplied while you are on the study. Although not 
likely, if this occurs, your study doctor will talk to you about your options. 
 
You and/or your health plan/insurance company will need to pay for all of the other costs of your 
cancer while in this study, including the cost of tests, procedures, or medicines to manage any 


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side effects, unless you are told that certain tests are supplied at no charge. Before you decide to 
be in the study, you should check with your health plan or insurance company to find out exactly 
what they will pay for. 
 
You will not be paid for taking part in this study. 
 
 
WHAT HAPPENS IF I AM INJURED OR HURT BECAUSE I TOOK PART IN 
THIS STUDY? 
If you feel you have been injured or hurt as a result of taking part in the study, it is important that 
you tell the study doctor immediately. You will get medical treatment if you are injured or hurt 
as a result of taking part in this study.  
 
The study sponsors will not offer to pay for medical treatment for injury. Your insurance 
company may not be willing to pay for study-related injury. If you have no insurance coverage, 
you would be responsible for any costs. Even though you are in a study, you keep all of your 
legal rights to receive payment for injury caused by medical errors. 
 
If you feel this injury was a result of medical error, you keep all your legal rights to receive 
payment for this even though you are in a study. 
 
 
WHO WILL SEE MY MEDICAL INFORMATION? 
Your privacy is very important to us and the researchers will make every effort to protect it. 
Your information may be given out if required by law. For example, certain states require 
doctors to report to health boards if they find a disease like tuberculosis. However, the 
researchers will do their best to make sure that any information that is released will not identify 
you. Some of your health information, and/or information about your specimen, from this study 
will be kept in a central database for research. Your name or contact information will not be put 
in the database. 
 
There are organizations that may inspect your records. These organizations are required to make 
sure your information is kept private, unless required by law to provide information. Some of 
these organizations are: 
 
• Wake Forest Center for Genomics. 
• Personalized Medicine Research Lab. 
• The study investigator and his/her staff.  
• The Institutional Review Board, IRB, is a group of people who review the research with 
the goal of protecting the people who take part in the study. 
• The Food and Drug Administration and the National Cancer Institute in the U.S., and 
similar ones if other countries are involved in the study. 
 


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WHERE CAN I GET MORE INFORMATION? 
You may visit the NCI Web site at http://cancer.gov/ for more information about studies or 
general information about cancer. You may also call the NCI Cancer Information Service to get 
the same information at: 1-800-4-CANCER (1-800-422-6237). 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
 
WHO CAN ANSWER MY QUESTIONS ABOUT THIS STUDY? 
You can talk to the study doctor about any questions or concerns you have about this study or to 
report side effects or injuries. Contact the study investigator, (insert name of study doctor at 
_______________ (insert telephone number. 
 
 
 
MY SIGNATURE AGREEING TO TAKE PART IN THE STUDY 
I have read this consent form or had it read to me. I have discussed it with the research staff and 
my questions have been answered. I will be given a signed copy of this form. I agree to take part 
in this study. 
 
 
 
Participant’s Signature (Printed):_____________________________ 
 
Participant’s Signature: _______________________ Date: _______Time:_____ am pm  
  
 
Signature of person(s) conducting Informed Consent Discussion:  
 
_________________________________             Date:_________ Time:_______ am pm