Clinical trial NCT02312934
Conditions: Chemo Brain Chemotherapy-related Cognitive Impairment Chemo Fog Breast Cancer Chemobrain
Keywords: Chemo brain Chemotherapy-related cognitive impairment CRCI Breast cancer Chemo fog Nicotine Transdermal nicotine
Sponsor: Vanderbilt University Medical Center
Start date: 2015-08-01; Completion date: 2018-05-01
Enrollment: 22 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the use of a nicotine patch as a treatment for problems with attention, learning and memory in breast cancer patients who are 1-5 years post chemotherapy.

Detailed description:
Studies have suggested that chemotherapy treatment for breast cancer may change the way the brain functions. As a result, patients who receive chemotherapy for breast cancer may experience problems with their attention, learning, and memory that they did not have before receiving chemotherapy. The investigators have found that nicotine treatment can help other types of patients with similar difficulties with attention, learning, and memory. Nicotine is a naturally occurring substance found in tobacco and is known to interact with nerve cells in the brain that are important for functions like learning and memory, and has been studied in a number of disorders. This study is designed to test whether nicotine treatment is helpful for learning and memory problems after chemotherapy for breast cancer.

This study will be a randomized, placebo-controlled pilot study to evaluate the effect of transdermal nicotine to 1) reduce subjective complaints and 2) enhance cognitive performance on laboratory measures of cognitive performance in breast cancer patients with persistent chemotherapy-related cognitive impairment (CRCI), a condition also known as "chemo brain." Participants will be randomized to either placebo or active compound (50/50) for the 6-week treatment portion of the study. Participants will be assessed before, during, and at the end of treatment. At the end of the 8-week study, participants will have the option to take part in the open-label portion of the study for an additional 6 weeks.

Arms: arm 1: Nicotine will be delivered by a transdermal patch delivery system for topical application. Each patch will contain approximately 1.75mg nicotine/cm2, and releases 7, and 14mg of nicotine, respectively, over 24 hours. Patches will be applied for 16 hours per day. Participants will be titrated over the course of the 6-week treatment period in order to avoid initial side effects as follows:

Week 1: ½ 7 mg patch per day, Week 2: 7 mg patch per day, Weeks 3-4: ¾ 14 mg patch per day, Weeks 5-6: 14 mg per day, Weeks 7-8: Treatment withdrawal arm 2: Matching transdermal placebo patches will be used. Participants will follow the same titration schedule as the transdermal nicotine arm.

Week 1: ½ 7 mg patch per day, Week 2: 7 mg patch per day, Weeks 3-4: ¾ 14 mg patch per day, Weeks 5-6: 14 mg per day, Weeks 7-8: Treatment withdrawal
Interventions: intervention 1: Transdermal nicotine intervention 2: Placebo Transdermal Patch
Intervention descriptions: intervention 1: Nicotine patches are currently FDA approved for smoking cessation. Nicotine has effects that have been well studied for many years. Studies have shown that nicotine by itself does not appear by itself to be cancer causing. The use of the nicotine patch is not expected to increase risk of breast cancer recurrence. intervention 2: Matching transdermal placebo patches will be used. Participants will follow the same titration schedule as the transdermal nicotine arm.

Protocol documents:
Prot_SAP_000.pdf: 
Principal Investigator: Paul A. Newhouse, M.D. 
 
                      Version Date: 27 November 2017 
Study Title: Nicotinic Treatment of Post-Chemotherapy Subjective Cognitive Impairment: A Pilot Study 
Institution/Hospital: Vanderbilt University Medical Center / VICC 
 
 
1 
 
Research Protocol for Vanderbilt University Institutional Review Board Application for 
Human Research Health Sciences 
Study Title:  Nicotinic Treatment of Post-Chemotherapy Subjective Cognitive Impairment: A 
Pilot Study 
 
Principal Investigator:  Paul A. Newhouse, M.D. 
      
 
 
 
 
 
 


Principal Investigator: Paul A. Newhouse, M.D. 
 
                      Version Date: 27 November 2017 
Study Title: Nicotinic Treatment of Post-Chemotherapy Subjective Cognitive Impairment: A Pilot Study 
Institution/Hospital: Vanderbilt University Medical Center / VICC 
 
 
2 
Table of Contents 
 
I. 
Project Summary, Specific Aims, Background, and Rationale  
 
3 
 
II. 
Inclusion/Exclusion Criteria 
 
 
 
 
 
 
6 
 
III. 
Study Design 
 
 
 
 
 
 
 
 
7 
 
IV. 
Double-Blind Study Visits  
 
 
 
 
 
 
7 
 
V. 
Open-Label Extension 
 
 
 
 
 
 
 
11 
 
VI. 
Potential Risks/Drug Safety:  Nicotine Transdermal Patch 
 
 
12 
 
VII. 
Adverse Event Reporting  
 
 
 
 
 
 
17 
 
VIII. 
Study Withdrawal/Discontinuation  
 
 
 
 
 
18 
 
IX. 
Statistical Considerations  
 
 
 
 
 
 
18 
 
X. 
Privacy/Confidentiality Issues 
 
 
 
 
 
 
19 
 
XI. 
References  
 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
 
 
 
 
 
 


Principal Investigator: Paul A. Newhouse, M.D. 
 
                      Version Date: 27 November 2017 
Study Title: Nicotinic Treatment of Post-Chemotherapy Subjective Cognitive Impairment: A Pilot Study 
Institution/Hospital: Vanderbilt University Medical Center / VICC 
 
 
3 
I. 
Project Summary, Specific Aims, Background, & Significance 
 
a. Project Summary 
 
This pilot study will obtain preliminary data regarding the use of transdermal nicotine 
treatment as a therapeutic strategy for persistent CRCI. This study will be a randomized, 
placebo-controlled pilot study to evaluate the effect of transdermal nicotine to 1) reduce 
subjective complaints and 2) enhance cognitive performance on laboratory measures of 
cognitive performance in breast cancer, colon cancer, lymphoma, or ovarian cancer patients 
with persistent CRCI. Participants will be randomized to either placebo or active compound 
(50/50) for the 6-week duration of the study. Participants will be assessed before, during, and 
at the end of treatment. At the end of the 8-week study, participants will have the option to 
take part in the open-label portion of the study for an additional 6 weeks. 
b. Specific Aims & Hypotheses 
 
Specific Aim 1: Assess if nicotine treatment will reduce subjective cognitive 
complaints in breast cancer, colon cancer, lymphoma, or ovarian cancer patients with 
persistent CRCI.  
Primary Hypothesis: Nicotine treatment will reduce subjective cognitive complaints in breast 
cancer, colon cancer, lymphoma, or ovarian cancer patients with persistent CRCI following 
6 weeks of treatment.   
Specific Aim 2: Assess if nicotine treatment will enhance performance on laboratory 
measures of cognitive performance in breast cancer, colon cancer, lymphoma, or ovarian 
cancer patients with persistent CRCI.  
Secondary Hypothesis: Nicotine treatment will enhance cognitive performance on measures 
of attention and/or processing speed in breast cancer, colon cancer, lymphoma, or ovarian 
cancer patients with persistent CRCI following 6 weeks of treatment. 
Exploratory Aims: As an exploratory analysis, a mixed-model ANOVA will be used to evaluate 
the effect of treatment group (nicotine, placebo) and APOE genotype (presence or absence 
of APOEε4 allele) on change scores (Visit 2 to Visit 4) for the PCI FACT-Cog and each 
objective measure of cognitive performance. Differences for rates of adverse events or other 
safety abnormalities between groups will be assessed using chi-square analysis. 
c. Background:  
 
Chemotherapy-related cognitive impairment (CRCI) is commonly reported following the 
administration of chemotherapy treatment in patients with cancer1. The American Cancer 
Society defines CRCI as: increased forgetfulness, trouble concentrating and remembering 
details, difficulty with multi-tasking word finding, and taking longer to finish tasks2. Although 
studies reporting cognitive impairments associated with chemotherapy have been reported 
since the 1980s3, the phenomenon commonly referred to as ‘chemo brain’ or ‘chemo fog’ is 
poorly understood4, and for some patients becomes the most distressful survivorship issue 
faced5. Advances in cancer treatment are producing a growing number of cancer survivors. 


Principal Investigator: Paul A. Newhouse, M.D. 
 
                      Version Date: 27 November 2017 
Study Title: Nicotinic Treatment of Post-Chemotherapy Subjective Cognitive Impairment: A Pilot Study 
Institution/Hospital: Vanderbilt University Medical Center / VICC 
 
 
4 
This is of particular importance for breast cancer survivors; the majority of women currently 
being diagnosed with breast cancer will be long-term survivors and will die of other, non-
breast cancer related illness. The 5-year relative survival rate for women diagnosed with 
localized breast cancer is 98%, with 84% survival if the breast cancer involves regional lymph 
nodes6. Therefore, as the number of breast cancer survivors who have to cope with CRCI 
increases dramatically, it is crucial that we understand the cognitive impairments, the impact 
on survivors' functioning, and develop treatments for CRCI. While acute cognitive 
impairments during chemotherapy are fairly common7–9, studies have shown that these 
impairments persist for months or years in up to 35% of cancer survivors1,10–15.To date, most 
treatment studies have centered on treating side effects of chemotherapy such as fatigue16–
19 and anemia20,21, and have largely not focused on improving or treating cognitive symptoms 
associated with chemotherapy.  
Investigators 
have 
proposed 
several models implicating that cancer 
treatment may modify the trajectory of 
normal cognitive aging 4,22,23 (Figure 1). 
The phase shift hypothesis postulates 
that 
cancer 
patients 
treated 
with 
chemotherapy will experience decline in 
cognitive function compared to non-
cancer/chemotherapy treated persons, 
and that the trajectory of decline will 
parallel normal aging and will remain constant over time4. Alternatively, the accelerated aging 
hypothesis proposes that treatment with chemotherapy is accelerating the normal aging 
process23. This model predicts that the slope of cognitive decline will be steeper for cancer 
patients treated with chemotherapy compared to non-cancer/chemotherapy treated persons. 
Recent studies have suggested that older patients are more vulnerable to cognitive decline 
associated with chemotherapy24 and tamoxifen25. Further, age appears to interact with 
predictors for future cognitive decline, such as cognitive reserve, to increase risk for cognitive 
decline following chemotherapy; older patients with low pretreatment cognitive reserve 
exposed to chemotherapy demonstrated reduced performance on measures of processing 
speed24. These models lead to the hypothesis that chemotherapy treatment should interact 
with factors that influence cognitive aging23. 
Although studies often find a lack of association between objective and subjective 
measures of cognitive function, there is increasing evidence that subjectively reported 
cognitive complaints, even with normal performance on cognitive tests, is associated with an 
increased risk for developing late-life cognitive decline and Alzheimer’s disease (AD)26. 
Interestingly, there is a large amount of overlap between the types of objective impairments 
observed/subjective cognitive complaints commonly reported in patients with CRCI and 
cholinergically modulation cognitive functions (Table 1). Cognitive abilities such as attention, 
executive control, and memory rely heavily on the cholinergic neurotransmitter system27. 
Although changes across various domains have been reported for CRCI, effects have been 
reported most prominently in the domains of attention, working memory, executive function, 
and processing speed7,8,10–15,28–35. Recently, a study has shown that smoking history 
moderated the detrimental effect of the CRCI risk allele APOEε436 on cognitive performance 


Principal Investigator: Paul A. Newhouse, M.D. 
 
                      Version Date: 27 November 2017 
Study Title: Nicotinic Treatment of Post-Chemotherapy Subjective Cognitive Impairment: A Pilot Study 
Institution/Hospital: Vanderbilt University Medical Center / VICC 
 
 
5 
in breast cancer patients treated with chemotherapy, suggesting a link between nicotinic 
cholinergic system functioning and CRCI37. Given the potential link between the nicotinic 
cholinergic system and CRCI and the overlap between domains affected in CRCI and 
cholinergically modulated cognitive functions, the nicotinic cholinergic system represents a 
potential therapeutic target for improving cognitive functioning in breast cancer patients with 
CRCI.  
 
The cholinergic system has been studied extensively in relation to cognitive aging and is 
the primary neurotransmitter system responsible for cognitive changes in both normal aging 
and dementia38. Given that cholinergic system integrity influences cognitive aging, it may 
interact with chemotherapy treatment. Cognitive abilities such as attention, executive control, 
and memory rely heavily on the cholinergic neurotransmitter system integrity, which 
modulates other neurotransmitter systems and overall cognition via nicotinic (and 
muscarinic) acetylcholinergic receptors27. The importance of the nicotinic cholinergic system 
was first understood using temporary blockade studies; antagonist drugs such as 
mecamylamine result in performance deficits across several cognitive domains, such as 
learning, memory, psychomotor speed, and attention39,40. Drugs that stimulate the nicotinic 
cholinergic system have the opposite effect, acting as cognitive enhancers41. A recent meta-
analysis of over 41 double-blind placebo-controlled laboratory studies by Heishman and 
colleagues concluded that there are significant positive effects of nicotinic stimulation with 
nicotine on motor abilities, attention, and memory41.  
Nicotinic agonists have been shown to improve cognitive performance in several 
clinical populations with cognitive impairment, including AD42–46, mild cognitive impairment 
(MCI)47, and attention deficit hyperactivity disorder (ADHD)48. However, nicotine has not 
been explored as a potential treatment for CRCI in the breast cancer population. Studies 
have shown that nicotinic agonists may exert differential effects on domains of cognition; 
certain cognitive domains tend to see more benefit than others48,49. The pattern of response 
to nicotine may follow an inverted ‘U’ shape model50, where nicotinic treatment tends to 
improve performance only in those with some level of baseline impairment, and can actually 
decrease performance in otherwise healthy individuals. Therefore, breast cancer patients 
with persistent CRCI (continued impairment 1-5 years post chemotherapy) may derive 
therapeutic benefit from nicotine treatment compared to those without cognitive impairment. 
d. Significance:  
 
This proposed study has broad clinical and scientific significance. If the hypotheses were 
validated, these findings would support a novel, broadly available, and inexpensive 
intervention for persistent CRCI and would encourage early treatment intervention to improve 
subjective cognitive complaints and/or cognitive performance and could have significant 
benefits for large numbers of cancer survivors. This would be the first trial of nicotine or 
nicotinic agonists to date in CRCI.   
 
 
 
II. 
Inclusion/Exclusion Criteria 


Principal Investigator: Paul A. Newhouse, M.D. 
 
                      Version Date: 27 November 2017 
Study Title: Nicotinic Treatment of Post-Chemotherapy Subjective Cognitive Impairment: A Pilot Study 
Institution/Hospital: Vanderbilt University Medical Center / VICC 
 
 
6 
a. Sample Size  
We used average pre-chemotherapy and post-chemotherapy FACT-Cog scores 
(provided by Dr. Lynne Wagner) to estimate an expected effect size (Pre-chemotherapy 
mean= 64.57, SD=12.16; Post-chemotherapy mean= 58.51, SD=14.55; Effect size 
d=0.44 or f=0.23). Based on the data provided, we would need 32 participants to see and 
effect size of f=0.23. Based on previous nicotine treatment studies conducted by the lab 
we anticipate a dropout rate of 10-20%47; therefore we will target recruitment at 40 
participants.  
 
b. Inclusion Criteria:  
All participants will:  
1. Be between 35 and 80 years of age,  
2. Have been diagnosed with noninvasive or invasive (Stage 1, 2, or 3A) breast cancer, 
colon cancer, lymphoma, or ovarian cancer 
3. Have undergone treatment with systemic chemotherapy within the last 1-5 years,  
4. Endorse persistent CRCI subjective complaints (as defined below),  
5. Be non-smokers (no nicotine use within the last 5 years),  
6. Have no active cardiac, neurologic, or psychiatric illness, and  
7. Fluent in and able to read English.  
 
c. Exclusion Criteria:  
Participants will be excluded for:  
1. Any active neurologic psychiatric disease, clinically significant cognitive impairment or 
dementia, history of significant head trauma followed by persistent neurologic deficits, 
or known structural brain abnormalities,  
2. Current major depression or another major psychiatric disorder as described in DSM-
5 (use of CNS active medications (e.g. antidepressants) will be permitted, provided 
dosing has been stable for at least 3 months),  
3. Any history of alcohol or substance abuse or dependence within the past 2 years 
(DSM-5 criteria),  
4. Any significant systemic illness or unstable medical condition which could lead to 
difficulty complying with the protocol including:  
4a. History of myocardial infarction in the past year or unstable, severe 
cardiovascular disease including angina or CHF with symptoms at rest, or 
clinically significant abnormalities on the ECG 
4b. Active vascular disease or medical conditions that per Investigator opinion can 
interfere with participant’s safety and treatment  
4c. Clinically significant and/or unstable pulmonary, gastrointestinal, hepatic, or 
renal disease  
4d. Insulin-requiring diabetes or uncontrolled diabetes mellitus,  
4e. Uncontrolled hypertension (systolic BP> 170 or diastolic BP> 100),  
5. Use of any investigational drugs within 30 days or 5 half-lives, whichever is longer, 
prior to screening, and  
6. Use of any drugs with pro-cholinergic properties (e.g. donepezil). Use of 
anticholinergic agents will be discouraged, but will be reviewed on a case-by-case 
basis by the PI.  


Principal Investigator: Paul A. Newhouse, M.D. 
 
                      Version Date: 27 November 2017 
Study Title: Nicotinic Treatment of Post-Chemotherapy Subjective Cognitive Impairment: A Pilot Study 
Institution/Hospital: Vanderbilt University Medical Center / VICC 
 
 
7 
7. Females who are pregnant or nursing 
 
III. 
Study Design 
 
This study will be a randomized, placebo-controlled pilot study to evaluate the effect of 
transdermal nicotine to 1) produce positive effects on subjective complaints and 2) enhance 
cognitive performance on laboratory measures of cognitive performance in breast cancer, 
colon cancer, lymphoma, or ovarian cancer patients with persistent CRCI. Participants will 
be randomized to either placebo or active compound (50/50) for 6-weeks, followed by 2 
weeks of treatment withdrawal (for a total of 8 weeks). Participants will be assessed both 
pre-, during, and post- treatment. At the end of the 8-week study, participants will have the 
option to take part in the open-label portion of the study for an additional 6 weeks (explained 
below). 
Table 2. Summary of Study Visits 
Visit 1 
Visit 2 
Randomization 
(nicotine/placebo) 
3 Weeks 
of 
Treatment 
Visit 3 
3 Weeks 
of 
Treatment 
Visit 4 
2 Weeks 
NO 
Treatment 
Visit 5 
Screening 
Baseline 
Assessment 
Repeat 
Assessment 
Repeat 
Assessment 
Repeat 
Assessment 
 
Pre-Screening 
 
Prior to consent, participants will be pre-screened to determine the participant’s preliminary 
eligibility for the study. Participants will be emailed a link to a RedCap form that asks the 
participant to provide the following information: demographics, contact information, SSN (SSN 
is required if the participant has not been previously seen at Vanderbilt University to create a 
medical record in Star Panel so Visit 1 can be scheduled at the Clinical Research Center), social 
and medical history, cancer history, concurrent medication, use of tobacco, alcohol, drug, head 
trauma, and behavioral concerns. Once the pre-screening form is filled out, it will be reviewed 
by Jennifer Vega, Study Coordinator and Paul Newhouse, MD to determine preliminary eligibility 
for the study.  
 
IV. 
Double-Blind Study Visits 
 
1. Screening (Visit 1) 
Participant Screening: Initial screening of recruited participants will be performed by the 
study coordinator (JNV). Following initial screening, a review of medical records will be 
conducted to ensure good general health. Review of cancer medical records will be done to 
confirm that the participant meets the criteria for breast, colon cancer, lymphoma, or ovarian 
cancer and systemic chemotherapy.  Information on allergies, all current medications, and 
present and past use of tobacco, alcohol, and illicit drugs will be collected. Participants will 
be cognitively and behaviorally screened to rule out dementia. Electrocardiogram (ECG) and 
blood draw for laboratory tests (FSH and DNA) screening will take place at the Vanderbilt 
Clinical Research Center (CRC) or the Center for Cognitive Medicine (CCM).  The screening 
packet including medical history, cancer medical records, ECG, cognitive testing, behavioral 
screening, and consent form will be reviewed by the study physician for approval prior to 
study entry.  


Principal Investigator: Paul A. Newhouse, M.D. 
 
                      Version Date: 27 November 2017 
Study Title: Nicotinic Treatment of Post-Chemotherapy Subjective Cognitive Impairment: A Pilot Study 
Institution/Hospital: Vanderbilt University Medical Center / VICC 
 
 
8 
 
Cognitive Screening Measures: All participants will be screened to exclude individuals with 
evidence of clinically significant cognitive impairment or dementia. Participants will be 
evaluated using the Wechsler Abbreviated Scale of Intelligence (WASI), Mini Mental State 
Exam (MMSE; score ≥ 26), Brief Cognitive Rating Scale (score ≤ 2) and the Mattis Dementia 
Rating Scale (minimum score 125) to establish a Global Deterioration Scale score (GDS; 
score ≤ 1) which rates the degree of cognitive impairment. To rule out the presence of current 
mood disorders, all participants will be psychiatrically assessed using a portion of the 
Structured Clinical Interview (SCID) for DSM disorders, the Beck Depression Rating Scale 
(BDI), and the Beck Anxiety Inventory (BAI). Information obtained from the BDI and/or BAI 
may be used as potential covariates in data analysis.  The Short Form-36 Health Survey (SF-
36)51 will be used to evaluate health and somatic complaints. The Adult Self-Report (ASR; 
for participants ≤ 59 years of age) or the Older Adult Self-Report (OSAR; for participants ≥ 
60 years of age)52 will be used to rule out presence of other psychopathology and to assess 
difficulty or impairment in instrumental, occupational, or social functioning. Participants will 
also fill out a Menopause Symptom Checklist to assess menopausal status. REDCap will be 
used to collect the SF-36, Menopause Symptom Checklist, BDI and BAI.  
 
Defining persistent CRCI: We recognize that the definition for CRCI is evolving, but for the 
purposes of the current study we will define persistent CRCI as follows: 1) endorsed change 
in cognitive functioning (self-report) the participant directly links to chemotherapy treatment 
received in the last 1-5 years, 2) evidence of subjective impairment on the Cognitive 
Complaint Index (see below), and 3) subjective complaints not better accounted for by 
presence of depression and/or another psychiatric or neurologic condition.  
 
The Cognitive Complaint Index (CCI; Visit 1)26 will be used to operationalize breast, colon 
cancer, lymphoma, or ovarian cancer cancer patients as having subjective complaints as 
follows: All participants will complete the multiple inventories that comprise the CCI on 
REDCap, including the Memory Functioning Questionnaire54, Memory Self-Rating 
Questionnaire55, the Neurobehavioral Function and Activities of Daily Living Rating Scale 
(ADL-self)56 , the Informant Questionnaire on Cognitive Decline in the Elderly (IQCDE)57, the 
30 items from the Geriatric Depression Scale (GDS)58, 12 items from a telephone-based 
screening for mild cognitive impairment (MCI), and 20 items from the Memory Assessment 
Questionnaire adapted in part from the Functional Activities Questionnaire59. A CCI score 
will be calculated as the percentage of all items endorsed. Participants must show a CCI that 
includes endorsement of at least 20% of all items to be considered as having chemotherapy-
related subjective complaints.26 
 
DNA Sample Collection for APOE Genotyping: From each participant, a nurse at the CRC 
or CCM will perform a blood draw and will obtain a whole blood sample of 7mL total volume 
from a trained phlebotomist using one 7mL Vacutainer tubes with K3EDTA.  This purple-top 
tube will be sent to the Vanderbilt DNA Resources Core and will be processed for DNA 
extraction, quantification, and banking.  DNA extractions will be performed on one of the 
Gentra Systems AutoPure automated DNA extraction system in the Vanderbilt DNA 
Resources Core. The genetics core will request a re-sampling if the sample condition is 
compromised or if there is poor sample yield.  


Principal Investigator: Paul A. Newhouse, M.D. 
 
                      Version Date: 27 November 2017 
Study Title: Nicotinic Treatment of Post-Chemotherapy Subjective Cognitive Impairment: A Pilot Study 
Institution/Hospital: Vanderbilt University Medical Center / VICC 
 
 
9 
 
Once approved for the study, participants will be asked to come in for 4 additional study visits, 
which will each last 2-3 hours each. Participants will also be randomized to receive either 
nicotine or placebo patch after, which they will begin after completing their baseline 
assessment.  
 
 
2. Baseline Assessment (Visit 2) 
a. Subjective Measure: The Functional Assessment of Cancer Therapy-Cognitive Function 
(FACT-Cog)59 (either the written form or the REDCap version) scale will be used to 
monitor change in CRCI subjective complaints. This instrument has been used to monitor 
change in CRCI subjective complaints in previous studies and demonstrates good internal 
consistency, test-retest reliability, and discriminant and convergent validity60–62. This 37-
item questionnaire is a self-report measure of cognitive function that aims to evaluate the 
“real world” impact of CRCI. It consists of four subscales (PCI: Perceived Cognitive 
Impairments, PCA: Perceived Cognitive Abilities, QOL: Impact on quality of life, and Oth: 
Comments from Others) and evaluates memory, concentration, mental acuity, verbal 
fluency, functional interference, and multitasking ability. Higher scores indicate better 
cognitive functioning.  
 
b. Objective Performance Measures: To characterize the effects of nicotine on cognitive 
functioning in breast cancer, colon cancer, lymphoma, or ovarian cancer patients with 
persistent CRCI, we will utilize measures that meet one or more of the following criteria: 
1) target domains most likely to be endorsed by patients with persistent CRCI (i.e. 
attention, working memory, executive function, and processing speed) and/or 2) prior 
demonstration of response to nicotinic stimulation or blockade in nicotine studies. Our 
cognitive performance battery (Table 3) will consist of subtests from the CogState battery 
and other computerized and verbal tests. The CogState battery (CogState Ltd., 
Melbourne, Australia) is comprised of a subset of tasks that includes measures of various 
cognitive domains63 (see Table 3). The tasks in the CogState battery have been 
specifically designed to assist with decisions about the presence or absence of cognitive 
change. The tests chosen in this battery were selected to specifically target the domains 
most likely to be endorsed by breast cancer patients with persistent CRCI and because 
they are brief and can be given repeatedly without eliciting practice effects over time64,65. 
Other computerized tasks such as the Critical Flicker Fusion (CFF) task,66 the Choice 
Reaction Time (CRT) task67, and the Conners Continuous Performance Test (CPT) will 
also be given.68,69 We have previously found the CPT to be sensitive to nicotine-induced 
attentional improvements in people with ADHD, AD70, healthy young adults71, and in 
nicotine-treated MCI patients47; improvements in performance on this task have been 
shown to correlate with clinical improvement. The Buschke Selective Reminding Task 
(SRT) will be used to assess immediate and delayed memory recall. The battery is 
expected to take 2-3 hours. 
 
 


Principal Investigator: Paul A. Newhouse, M.D. 
 
                      Version Date: 27 November 2017 
Study Title: Nicotinic Treatment of Post-Chemotherapy Subjective Cognitive Impairment: A Pilot Study 
Institution/Hospital: Vanderbilt University Medical Center / VICC 
 
 
10 
 
 
 
 
 
 
 
 
 
 
 
 
 
If a participant is pre-menopausal and of childbearing age, they will be required to take a 
urine pregnancy test prior to randomization (Visit 2) and at each subsequent visit throughout 
the study (Visits 3, 4, 5, 6, 7).  Post-menopausal participants are not required to take a 
pregnancy test. If at any point the participant believes they may be pregnant, they will be 
advised to discontinue use of the study medication and inform the study coordinator 
immediately. 
 
3. 6-Week Treatment Period 
Nicotine will be delivered by a transdermal patch delivery system for topical application, 
available in sizes of 10, 20cm2. . Each patch will contain approximately 1.75mg nicotine/cm2, 
and releases 7, and 14mg of nicotine, respectively, over 24 hours. Participants will be 
randomized (50/50) to receive either blinded nicotine or placebo skin patches. A random 
number generator will be used to assign participants to either the treatment or placebo group. 
The titration administration pattern will be as indicated in Table 4 to help to avoid initial side 
effects.  
 
 
 
 
 
 
 
 
 
 
Table 3. Summary of Subjective and Objective Cognitive Performance Measures 
Subjective Measure 
Administration 
 
Functional Assessment of Cancer 
Therapy-Cognitive Function 
(FACT-Cog) 
Self-Report 
Consists of four subscales (PCI: Perceived Cognitive 
Impairments, PCA: Perceived Cognitive Abilities, 
QOL: Impact on quality of life, and Oth: Comments 
from Others)  
Objective Measures 
Administration 
Cognitive Domain/Function 
Groton Maze 
Learning Test 
CogState Battery 
(Computerized) 
Executive Function/ 
Spatial Problem Solving 
Set-Shifting Task 
Executive Function 
Detection Task 
Psychomotor Function/ 
Speed of Processing 
Identification Task 
Visual Attention/Vigilance 
One Back Task 
Attention/Working Memory 
Two Back Task 
Attention/Working Memory 
CPT 
Computerized 
Sustained Attention/Vigilance 
CRT 
Attention /Psychomotor Speed 
CFF 
Attention/Vigilance 
 Buschke SRT 
Verbal 
Immediate/Delayed Memory Recall 
Table 4.  Drug Titration Schedule 
Week(s) 
Dose 
Week 1 
½ 7 mg patch per day (for 16 hours per day) 
Week 2 
7 mg patch per day (for 16 hours per day) 
Weeks 3-4 
¾ 14 mg patch per day (for 16 hours) 
Weeks 5-6 
14 mg per day (for 16 hours) 
Weeks 7-8 
Treatment withdrawal 


Principal Investigator: Paul A. Newhouse, M.D. 
 
                      Version Date: 27 November 2017 
Study Title: Nicotinic Treatment of Post-Chemotherapy Subjective Cognitive Impairment: A Pilot Study 
Institution/Hospital: Vanderbilt University Medical Center / VICC 
 
 
11 
 
Patches will be applied for 16 hours per day. Participants will be contacted by phone weekly 
to assess tolerability and answer questions. If a participant appears to be suffering persistent 
side effects at any dose, they will not be titrated to the next highest dose until they are free 
of side effects. Participants will be followed-up with 2-weeks after withdrawal of treatment at 
the end of the study to evaluate any residual effects of the nicotine or nicotine withdrawal 
symptoms. At the end of the study, if a participant would like to continue utilizing transdermal 
nicotine because of perceived cognitive benefits, the participant will be referred to their 
primary physician or another appropriate physician for management. 
 
4. Visits During Treatment (Visits 3 and 4) 
Visits 3 will take place after 3 weeks of treatment and Visit 4 will take place after 6 weeks of 
treatment. The battery in Table 3 will be repeated for Visits 3 and 4. After Visit 4 will be asked 
to stop using the nicotine or placebo patches for 2 weeks.  
 
5. Visit after 2 weeks of treatment withdrawal (Visit 5) 
Visit 5 will take place after 2 weeks of treatment withdrawal and will involve a repeat of the 
battery in Table 3 completed during previous visits.  
 
V. 
Open-Label Extension  
 
At the end of the double blind, placebo controlled 8-week study participants will have the 
option to take part in the open-label portion of the study for an additional 6 weeks. Since we 
will not know which condition (nicotine or placebo) the participant was randomized to during 
the blinded portion of the study, all participants will be treated as though they received 
placebo and will follow the titration administration pattern will be as indicated in Table 4 to 
help to avoid initial side effects. Patches will be applied for 16 hours per day. Participants will 
be contacted by phone weekly to assess tolerability and answer questions. If a participant 
appears to be suffering persistent side effects at any dose, they will not be titrated to the next 
highest dose until they are free of side effects. During this time, participants will come in for 
2 additional study visits, during which we will collect safety data (heart rate, respiration, blood 
pressure, and temperature) and FACT-Cog scores (see figure below). Each visit will take 
approximately 30 minutes. At the end of the open label portion of the study, if a participant 
would like to continue utilizing transdermal nicotine because of perceived cognitive benefits, 
the participant will be referred to their primary physician or another appropriate physician for 
management. Participants that are pre-menopausal and of childbearing age will be required 
to take a urine pregnancy test prior to beginning the Open-Label portion of the study (Visit 5) 
and throughout the duration of the Open-Label portion of the study (Visits 6 and 7). If you are 
post-menopausal, a pregnancy test will not be required. If at any point you believe that you 
are pregnant, you should discontinue use of the study medication and inform us immediately. 
 
 


Principal Investigator: Paul A. Newhouse, M.D. 
 
                      Version Date: 27 November 2017 
Study Title: Nicotinic Treatment of Post-Chemotherapy Subjective Cognitive Impairment: A Pilot Study 
Institution/Hospital: Vanderbilt University Medical Center / VICC 
 
 
12 
Table 5. Summary of Open-Label Extension Visits 
3 Weeks of Treatment 
Visit 6 
3 Weeks of Treatment 
Visit 7 
Safety Data & FACT-Cog 
 
Safety Data & FACT-Cog 
 
VI. 
Potential Risks/Drug Safety:  Nicotine Transdermal Patch 
 
Side Effects of Nicotine: At the nicotine doses proposed in this study, the major peripheral 
action of nicotine is facilitation of impulses through all autonomic ganglia, stimulation of the 
adrenal medulla and stimulation of sensory receptors including chemoreceptors in the carotid 
body.  Ganglionic depression occurs at higher nicotine levels.  In cardiovascular systems, 
mild increases in heart rate and blood pressure from sympathetic ganglion stimulation, 
catecholamine release from adrenal medulla, and aortic and carotid body chemoreceptor 
stimulation may occur.  A mild parasympathetic response may be seen in the gastrointestinal 
tract and bladder (increased tone and motor activity), with increased secretion of exocrine 
glands.  Nausea and vomiting can occur from peripheral (bowel activity and vagal efferent 
nerve stimulation) and central (medullary emetic chemoreceptor trigger zone stimulation) 
causes.  Low dose stimulation of the CNS could in theory produce tremors and respiratory 
stimulation, although this is rarely seen except in patients with tremor disorders.  Toxic 
nicotinic doses result in CNS depression. With use, tolerance develops to virtually all acute 
adverse effects. 
General Safety Experience with the Nicotine Transdermal Patch: A large meta-analysis 
was conducted examining data from 35 clinical trials utilizing the transdermal nicotine patch 
in over 5500 individuals72. Few adverse cardiovascular outcomes were reported and no 
excess of these outcomes was detected among patients assigned to nicotine patch use 
compared to placebo patch users.  Minor adverse effects such as sleep disturbances, 
nausea, localized skin irritation, and respiratory symptoms were elevated in patch users 
compared to placebo users.   
Adverse events from our recently published MCI trial (conducted in non-smoking 
individuals) are presented in Figure 2.  Total adverse events (AEs) for the double-blind 
treatment period were 82 for nicotine versus 52 for placebo (p < 0.05). However, the 
majority of AEs were mild (nicotine 57.3 %; placebo 54.9%) and there was no 
statistically significant difference in the proportion of adverse events within the 
different severity classifications between treatments (Mann-Whitney test p = 0.97). No 
severe AEs were classified as related to drug treatment in either treatment group.  
Adverse event rates by body systems reported in more than 10% of subjects were 


Principal Investigator: Paul A. Newhouse, M.D. 
 
                      Version Date: 27 November 2017 
Study Title: Nicotinic Treatment of Post-Chemotherapy Subjective Cognitive Impairment: A Pilot Study 
Institution/Hospital: Vanderbilt University Medical Center / VICC 
 
 
13 
comparable with the exception of 
“gastrointestinal” (virtually all mild 
nausea within the first week) and 
neurological 
(virtually 
all 
mild 
headache or dizziness in the first 2 
weeks) for which there were more AEs 
reported in the nicotine-treated group.  
Approximately 75% of AEs in both 
placebo and nicotine groups were 
judged not related or doubtfully 
related to treatment. Four nicotine-
treated 
subjects 
discontinued 
treatment for adverse events vs 0 
placebo-treated subjects (p=0.05).  No 
withdrawal symptoms were reported by 
subjects or informants nor were any 
subjects reported to be continuing to 
use nicotine after the study was 
completed. 
Dermatologic Safety: The most common adverse side effect of the nicotine transdermal 
patch is skin irritation and accounted for approximately 25 percent of adverse event reports 
regarding the nicotine transdermal patch to the FDA73.  These effects consist of erythema, 
pruritus, edema, and rash.  Mild skin irritation is common and generally occurs after three 
weeks of continuous use.  Mild to moderate reddening of the skin is seen in 25% of subjects 
and transient itching in 29%. More severe reactions requiring modification of treatment have 
been reported in up to 12% of users (DrugDex Drug Evaluation Monograph). Management 
of the symptoms is usually straightforward and is accomplished by patch rotation, local 
treatments, and instructing the patient to remove the patch prior to going to bed.  
Cardiovascular Safety: There are a number of mechanisms whereby nicotine could 
potentially cause or aggravate cardiovascular disease73.  Nicotine stimulates CNS 
sympathetic systems and increases release of catecholamines from both the adrenal and 
vascular nerve endings.  While tolerance appears to develop to these cardiac stimulatory 
effects, the tolerance developed is only partial73.  While there may be a small chronic cardio-
stimulatory effect (approximately seven beats per minute), the dose response curve appears 
to be flat73.  
However, studies have not demonstrated that nicotine replacement therapies are associated 
with increased cardiovascular risk or increased incidence of cardiovascular adverse events 
(DrugDex Drug Evaluation Monograph).  The largest and longest such study was the Lung 
Health Study that enrolled almost 6000 individuals in a study over 5 years involving nicotine 
replacement therapies for smoking cessation.  In this group with chronic lung disease, 
nicotine use was found to be marginally protective of cardiovascular health compared to non-
use of nicotine73.  This protective effect persisted even when adjusted for smoking status.  
Even within the ex-smoking sub-group in the same study, nicotine users had substantially 
lower rates of hospitalization then non-users.  Nicotine also showed a marginally protective 
Figure 2.  Adverse event numbers from MCI pilot trial. Vertical 
axis is total AE reports for each system/category 


Principal Investigator: Paul A. Newhouse, M.D. 
 
                      Version Date: 27 November 2017 
Study Title: Nicotinic Treatment of Post-Chemotherapy Subjective Cognitive Impairment: A Pilot Study 
Institution/Hospital: Vanderbilt University Medical Center / VICC 
 
 
14 
effect against peptic ulcer disease in the same subjects.  In a long-term maintenance study 
of non-smoking patients with ulcerative colitis, there were no increased cardiovascular events 
and markers of cardiovascular risk either did not change or actually decreased (e.g. 
fibrinogen)73. A recent investigation of the effects of 26 weeks of chronic oral nicotine showed 
improved cardiovascular risk parameters (e.g. capillary flow, fibrinogen) after smoking 
cessation with no negative effects of nicotine74. Nicotine does not appear to promote 
thrombosis or platelet aggregation nor does nicotine replacement therapy increase the risk 
of acute myocardial infarction (DrugDex Drug Evaluation Monograph).  
Studies of patients with known cardiovascular disease have similarly not shown an increase 
in cardiovascular events or toxicity secondary to nicotine therapy.  Two large studies of men 
with documented coronary artery disease with up to 10 weeks of nicotine therapy showed 
lower rates of cardiovascular endpoints and events in the nicotine-treated group73.  A study 
of myocardial perfusion in men with coronary artery disease showed that cigarette smoking 
was associated with significantly greater myocardial perfusion deficits than nicotine therapy 
alone, suggesting that such a perfusion defect is due to factors from tobacco other than 
nicotine.  In reviewing the available clinical trial literature and data reported to the FDA as of 
1998, Rennard and colleagues concluded: "the available clinical trial and the clinical 
experience reported to date are consistent with the relative safety of transdermal nicotine in 
stable patients with cardiac disease." 
MCI Pilot Study47:  Data from 
our recently published MCI 
trial 
(conducted 
in 
non-
smoking 
individuals) 
are 
presented in Figure 3. An 
examination of the change in 
systolic 
blood 
pressure 
revealed 
a 
significant 
reduction in systolic blood 
pressure compared to placebo 
treatment. By day 182, the 
placebo group showed an 
average increase of 9.6 mmHg 
in 
SBP 
compared 
to 
a 
reduction of 4 mmHg in the 
nicotine-treated group. There 
was a small reduction in diastolic blood pressure by day 182 in the nicotine-treated 
group.  An examination of the change in pulse showed no overall treatment effect (p 
= 0.51). 
Cerebrovascular Safety: Smoking is a preventable risk factor for ischemic stroke and some 
preclinical studies have suggested potential mechanisms by which smoking and/or nicotine 
might increase the risk of ischemic stroke75–77. However, a large meta-analysis of 35 smoking 
cessation trials did not find any increased incidence of stroke in nicotine replacement therapy 
users72.  
Systolic Blood Pressure
-15
-10
-5
0
5
10
15
0
50
100
150
200
Day
Change from baseline 
(mm Hg)
Nicotine
Placebo
Figure 3.  Systolic blood pressure change from the MCI pilot 
trial.  


Principal Investigator: Paul A. Newhouse, M.D. 
 
                      Version Date: 27 November 2017 
Study Title: Nicotinic Treatment of Post-Chemotherapy Subjective Cognitive Impairment: A Pilot Study 
Institution/Hospital: Vanderbilt University Medical Center / VICC 
 
 
15 
Conclusion regarding cardio- and cerebrovascular safety: As the subjects to be enrolled 
in this study will be nonsmokers selected for the absence of significant cardiovascular, 
cerebrovascular disease, or diabetes, we believe that the cardiovascular and 
cerebrovascular risk profile of transdermal nicotine in such patients is excellent. 
Insulin Sensitivity: There have been some epidemiologic studies suggesting a positive 
relationship between smoking and insulin resistance78 although some studies are 
contradictory79. Some investigations have suggested that changes in insulin sensitivity may 
be restricted to smokers who are also diabetic80.  One study that did examine long-term 
nicotine use without cigarette smoking showed that nicotine gum users had higher circulating 
leptin levels that were negatively correlated with the degree of insulin sensitivity81.  However, 
the subjects were also recent ex-smokers, complicating interpretation of these results and 
acute administration of nicotine during the study did not change circulating leptin levels.  
Contradictory results were also seen in studies of smokeless tobacco use on cardiovascular 
risk factors and insulin levels with one study of heavy users finding impaired measures of 
glucose tolerance82 while another study did not83. At this point, it is not conclusive that 
nicotine use alone in nonsmokers is associated with changes in insulin sensitivity.  
Fetal Development: The FDA does not recommend the use of transdermal nicotine patches 
during pregnancy. At present the risks and effects of transdermal nicotine patches to a 
developing human fetus are not fully known. Therefore, if participants are of childbearing age 
we will strongly recommend the use of effective contraception during this study. Participants 
that are pre-menopausal and of childbearing age will be required to take a urine pregnancy 
test prior to randomization (Visit 2) and at each subsequent visit throughout the study (Visits 
3, 4, 5, 6, 7).  Participants that are post-menopausal will not be required to take a pregnancy 
test. If at any point the participant believes they may be pregnant, they will be advised to 
discontinue use of the study medication and inform the study coordinator immediately. 
Carcinogenesis: Long-term epidemiologic studies of oral tobacco use suggest that the 
nitrosamine content of tobacco is critical to determining the cancer risk from non- smoke 
related tobacco use, rather than nicotine73.  Whether nicotine can act as a permissive agent 
to encourage the development of cancer is unclear, but it does not seem to have any effect 
unless co-administered with tobacco73. Nicotine by itself does not appear to be 
carcinogenic84, and is therefore not expected to increase risk of breast, colon cancer, 
lymphoma, or ovarian cancer recurrence. 
Abuse Potential: We believe that the probability that the subjects in this study might be 
prompted by their participation to begin to use nicotine containing products or tobacco is 
extremely low.  There have been no cases reported in the medical literature of primary abuse 
by never smokers of nicotine replacement therapies.  Furthermore, there are no cases 
reported of ex-smokers taking up nicotine replacement therapy and becoming addicted or 
dependent.  Additional reasons for our belief that the risk of abuse of transdermal nicotine in 
this population include: 
1. Nicotine replacement therapies have an extremely low abuse liability85; nicotine 
patches have some unpleasant side effects and therefore are unlikely to be 
reinforcing.   


Principal Investigator: Paul A. Newhouse, M.D. 
 
                      Version Date: 27 November 2017 
Study Title: Nicotinic Treatment of Post-Chemotherapy Subjective Cognitive Impairment: A Pilot Study 
Institution/Hospital: Vanderbilt University Medical Center / VICC 
 
 
16 
 
2. A study showed that experimental administration of tobacco did not induce ex-
smokers to relapse into smoking86.  In another study85, when non-smokers and ex-
smokers were followed after participating in a study of nicotine gum administration, no 
subjects were found to be smoking or using other nicotine products three months 
following completion of the study.  
 
3. An important characteristic of all drugs that produce dependency is the 
pharmacokinetic parameters associated with the route and form of administration87. 
With respect to nicotine, researchers of the NIDA Addiction Research Center88, as 
well as others in the field89–92, have reported that the slower absorption of nicotine 
offered by the transdermal patch relative to tobacco products substantially reduces 
the likelihood of nicotine dependence in users of the patch.  This was supported by a 
study describing a double-blind placebo-controlled study investigating the therapeutic 
potential of the transdermal nicotine patch for patients suffering from ulcerative 
colitis73. Although all of the subjects were adults and many former tobacco users, 
despite 26 weeks of daily applications of 15 mg nicotine patches, no withdrawal 
symptoms were reported from these patients following discontinuation of the patch.  
In addition, a crossover trial evaluating the "liking" rating for the patch (22mg or 44 
mg/24hr) in adults found no difference in scores between the active and placebo 
systems93.  
 
4. We have administered intravenous and/or transdermal nicotine and structurally 
related nicotinic agonists over the past 17 years to several hundred non-smoking 
subjects including young and elderly normal volunteers, patients with Alzheimer's 
disease, and patients with Parkinson's disease.  Perhaps most importantly, in our 
recently completed MCI trial47, no withdrawal symptoms were reported by subjects or 
informants nor were any subjects reported to be continuing to use nicotine after the 
study was completed. We have not had a single subject take up tobacco use as a 
consequence of study participation.  
The safeguards that we have instituted that are described above taken in conjunction with 
data documenting that the administration of nicotine via non-tobacco routes is not associated 
with abuse liability, suggests that the incremental additional risk to subjects for tobacco use 
over and above their background use rate is likely to be very small. 
Minimization of risks associated with psychological and cognitive testing: 
psychological and cognitive testing will take place over the period of 1 day for each study 
visit. Participants will be free to take as many breaks as needed to avoid exhaustion. The 
PI/study physician (Dr. Newhouse) will review the results of all behavioral tests and will 
handle any clinically significant results in a clinically appropriate manner.  
Minimization of risks associated with venipuncture to obtain DNA for genetic testing: 
the risks of blood draw include pain from the needle, bruising or infection at the site of 
venipuncture, or fainting as a response to blood draw.  


Principal Investigator: Paul A. Newhouse, M.D. 
 
                      Version Date: 27 November 2017 
Study Title: Nicotinic Treatment of Post-Chemotherapy Subjective Cognitive Impairment: A Pilot Study 
Institution/Hospital: Vanderbilt University Medical Center / VICC 
 
 
17 
Tolerability & Safety of Nicotine Treatment: At each visit we will collect vital signs (blood 
pressure, pulse, respirations, etc) and weight. Tolerability and safety will be determined by 
counting specific adverse events, counting dropouts due to adverse events, and by 
determining how often there is a need to reduce the dose of nicotine as determined by the 
participant and the study physician. Adverse events will be recorded and categorized by body 
system, event type, attribution, frequency, severity, and course.  
Potential Problems/Alternative Approaches: Medication intolerance may occur for some 
subjects.  We have designed the medication titration schedules such that subjects who are 
intolerant of the full dose may still continue on the study at lower dose.  Data analysis will 
consider dose as a covariate in the efficacy analysis and/or will be modified to utilize 
maximum tolerated dose as the independent variable. 
Risk/Benefit Ratio: When the safety record outlined above is considered, the risks of 
participation in this study are low.  The risks mainly consist of temporary side-effects from 
the nicotine and/or the transdermal patch that do not constitute a serious danger.  Long-term 
cardiovascular, cerebrovascular, and neurological safety of transdermal nicotine appears to 
be very favorable. Subjects may benefit from cognitive improvement associated with 
persistent CRCI. The benefits to society of greater knowledge about the treatment of the 
cognitive changes associated with chemotherapy in breast cancer patients and their possible 
amelioration, considering the human and economic costs of this disorder, would appear 
significant.  Overall the risk/benefit ratio appears to be in favor of conducting this study. 
VII. 
Adverse Event Reporting 
Adverse events associated with the study are communicated to the Principal Investigator on 
a weekly basis, as they occur. Weekly review occurs of all participants involved in the study 
for any evidence of adverse events or difficulties with study medication or procedures. 
 
The Vanderbilt University Institutional Review Board adverse event reporting system will be 
used. These reports will be forwarded to the office of the IRB within 5 days of the. This will 
be the responsibility of the Principal Investigator. The IRB will make a determination as to 
whether additional reporting requirements are indicated.   
  
All adverse event reports will be reviewed on their presentation for severity and frequency 
and examined within the overall context of protocol specific adverse events. Reviews of 
protocol specific adverse events will be performed no less than annually.  
 
VIII. 
Study Withdrawal/Discontinuation 
All participants will be free to withdraw from the study at any point without repercussions. 
Participation in this study will not change current cancer care.  
 


Principal Investigator: Paul A. Newhouse, M.D. 
 
                      Version Date: 27 November 2017 
Study Title: Nicotinic Treatment of Post-Chemotherapy Subjective Cognitive Impairment: A Pilot Study 
Institution/Hospital: Vanderbilt University Medical Center / VICC 
 
 
18 
IX. 
Statistical Considerations 
Sample Size Justification: We used 
average pre-chemotherapy and post-
chemotherapy 
FACT-Cog 
scores 
(provided by Dr. Lynne Wagner) to 
estimate an expected effect size (Pre-
chemotherapy mean= 64.57, SD=12.16; 
Post-chemotherapy 
mean= 
58.51, 
SD=14.55; Effect size d=0.44 or f=0.23). 
Based on the data provided, we would 
need 32 participants to see and effect 
size of f=0.23. Based on previous 
nicotine treatment studies conducted by 
the lab we anticipate a dropout rate of 
10-20%47; therefore we will target 
recruitment at 40 participants.  
 
Statistical Analysis Plan: All outcome 
variables of interests are shown in Table 
6. For Specific Aim 1, mixed-models repeated measures ANOVA will be used to assess the 
interaction of treatment group (nicotine, placebo) with PCI FACT-Cog score over time (Visit 
2, Visit 3, and Visit 4). In addition, unpaired t-tests will be used to conduct a pre-
treatment/baseline (Visit 2) and post-treatment (Visit 4) comparison, as well as a loss of effect 
comparison for the FACT-Cog PCI component.  We hypothesize that nicotine treatment will 
improve FACT-Cog scores in breast cancer, colon cancer, lymphoma, or ovarian cancer 
patients with persistent CRCI over 6 weeks of treatment compared to placebo. 
 
For Specific Aim 2, mixed-models repeated measures ANOVA will be used to assess the 
interaction of treatment group (nicotine, placebo) with CPT reaction time standard error 
divided by interstimulus interval (a measure of variability of reaction time) over time (Visit 2, 
Visit 3, and Visit 4). In addition, unpaired t-tests will be used to conduct a pre-
treatment/baseline (Visit 2) and post-treatment (Visit 4) comparison, as well as a loss of effect 
comparison for the CPT reaction time standard error divided by interstimulus interval. We 
hypothesize that nicotine treatment will improve performance (reduce reaction time 
variability) the CPT in breast cancer, colon cancer, lymphoma, or ovarian cancer patients 
with persistent CRCI over 6 weeks of treatment compared to the placebo group. Differences 
for rates of adverse events or other safety abnormalities between groups will be assessed 
using chi-square analysis. 
 
X. 
Privacy/confidentiality Issues 
All departments and laboratories involved in this study will follow procedures to ensure that 
no reasonable chance of the participant’s data can be linked to her/his identity. Confidentiality 
will be sincerely attempted, but cannot be guaranteed. All research data will be kept 
confidential and will be identified by ID number rather than name.  Only research personnel 
will have access to participants’ files.  Data will not be released to any source without written 


Principal Investigator: Paul A. Newhouse, M.D. 
 
                      Version Date: 27 November 2017 
Study Title: Nicotinic Treatment of Post-Chemotherapy Subjective Cognitive Impairment: A Pilot Study 
Institution/Hospital: Vanderbilt University Medical Center / VICC 
 
 
19 
consent from the participant or the participant’s caregivers. Participants and their caregivers 
will be informed that they may withdraw from the study at any time without negative 
consequences. 
 
Cognitive and Psychological Test Data: Electronic databases containing identifiable 
participant information will be password protected. Written information containing participant 
identifiers (informed consent, lab results, participant payment, etc.) will be stored in locked 
file cabinets in offices within the Center for Cognitive Medicine separate from other data.  
Only the PI and authorized key study personnel will have access to this information.  
Participants will be assigned an alphanumeric code that will be used to label all research 
data. Information will not be entered directly into a participant’s medical record or shared with 
their insurance company.   
 
After the study ends, the PI will continue to maintain (for future analysis, quality control 
checks, etc.) the original forms and questionnaires in locked file cabinets, and the DNA 
samples will continue to be stored in the Vanderbilt University DNA Resources Core. 
 
Genetic Research and Storage of Genetic Material: The de-linking of the sample from the 
participant occurs at the time the blood is sent to the Vanderbilt University DNA Resources 
Core. Samples are labeled with barcodes, which are linked to the participant’s ID number, 
not name, in the Core’s Oracle database.  Bar code labels affixed to each sample vial will 
contain the following information: sample ID# (to preserve confidentiality), date of collection 
and processing, total initial volume collected, volume, aliquot number, freezer, shelf, rack, 
box, location in the box. A bar code label will be used on the sample tracking form. Vanderbilt 
University DNA Resources Core will not have information regarding the participant’s name 
and thus will be unable to link the DNA analysis results to the person.  
 
XI. 
References 
1. 
Janelsins, M. C. et al. An update on cancer- and chemotherapy-related cognitive 
dysfunction: current status. Semin. Oncol. 38, 431–8 (2011). 
2. 
Craig, C. D., Monk, B. J., Farley, J. H. & Chase, D. M. Cognitive impairment in 
gynecologic cancers: a systematic review of current approaches to diagnosis and 
treatment. Support. Care Cancer 22, 279–87 (2014). 
3. 
Silberfarb, P. M. Chemotherapy and cognitive defects in cancer patients. Annu. Rev. 
Med. 34, 35–46 (1983). 
4. 
Ahles, T. A. Brain vulnerability to chemotherapy toxicities. Psychooncology. 21, 1141–8 
(2012). 
5. 
Boykoff, N., Moieni, M. & Subramanian, S. K. Confronting chemobrain: an in-depth look 
at survivors’ reports of impact on work, social networks, and health care response. J. 
Cancer Surviv. 3, 223–32 (2009). 


Principal Investigator: Paul A. Newhouse, M.D. 
 
                      Version Date: 27 November 2017 
Study Title: Nicotinic Treatment of Post-Chemotherapy Subjective Cognitive Impairment: A Pilot Study 
Institution/Hospital: Vanderbilt University Medical Center / VICC 
 
 
20 
6. 
American Cancer Society. Cancer Facts & Figures. (2013). 
7. 
Ahles, T. A. & Saykin, A. J. Breast cancer chemotherapy-related cognitive dysfunction. 
Clin. Breast Cancer 3 Suppl 3, S84–90 (2002). 
8. 
Ferguson, R. J. & Ahles, T. A. Low neuropsychologic performance among adult cancer 
survivors treated with chemotherapy. Curr. Neurol. Neurosci. Rep. 3, 215–22 (2003). 
9. 
Hess, L. M. et al. Pilot study of the prospective identification of changes in cognitive 
function during chemotherapy treatment for advanced ovarian cancer. J. Support. Oncol. 
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10. 
Ahles, T. A. et al. Neuropsychologic impact of standard-dose systemic chemotherapy in 
long-term survivors of breast cancer and lymphoma. J. Clin. Oncol. 20, 485–93 (2002). 
11. 
Brezden, C. B., Phillips, K. A., Abdolell, M., Bunston, T. & Tannock, I. F. Cognitive 
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Van Dam, F. S. et al. Impairment of cognitive function in women receiving adjuvant 
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13. 
Wefel, J. S., Lenzi, R., Theriault, R. L., Davis, R. N. & Meyers, C. A. The cognitive 
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14. 
Yamada, T. H., Denburg, N. L., Beglinger, L. J. & Schultz, S. K. Neuropsychological 
outcomes of older breast cancer survivors: cognitive features ten or more years after 
chemotherapy. J. Neuropsychiatry Clin. Neurosci. 22, 48–54 (2010). 
15. 
Wefel, J. S., Vardy, J., Ahles, T. & Schagen, S. B. International Cognition and Cancer 
Task Force recommendations to harmonise studies of cognitive function in patients with 
cancer. Lancet Oncol. 12, 703–8 (2011). 
16. 
Lower, E. E. et al. Efficacy of dexmethylphenidate for the treatment of fatigue after 
cancer chemotherapy: a randomized clinical trial. J. Pain Symptom Manage. 38, 650–62 
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Mar Fan, H. G. et al. A randomised, placebo-controlled, double-blind trial of the effects of 
d-methylphenidate on fatigue and cognitive dysfunction in women undergoing adjuvant 
chemotherapy for breast cancer. Support. Care Cancer 16, 577–83 (2008). 
18. 
Kohli, S. et al. The effect of modafinil on cognitive function in breast cancer survivors. 
Cancer 115, 2605–16 (2009). 


Principal Investigator: Paul A. Newhouse, M.D. 
 
                      Version Date: 27 November 2017 
Study Title: Nicotinic Treatment of Post-Chemotherapy Subjective Cognitive Impairment: A Pilot Study 
Institution/Hospital: Vanderbilt University Medical Center / VICC 
 
 
21 
19. 
Lundorff, L. E., Jønsson, B. H. & Sjøgren, P. Modafinil for attentional and psychomotor 
dysfunction in advanced cancer: a double-blind, randomised, cross-over trial. Palliat. 
Med. 23, 731–8 (2009). 
20. 
O’Shaughnessy, J. A. Effects of epoetin alfa on cognitive function, mood, asthenia, and 
quality of life in women with breast cancer undergoing adjuvant chemotherapy. Clin. 
Breast Cancer 3 Suppl 3, S116–20 (2002). 
21. 
Fan, H. G. M. et al. The influence of erythropoietin on cognitive function in women 
following chemotherapy for breast cancer. Psychooncology. 18, 156–61 (2009). 
22. 
Ahles, T. A., Root, J. C. & Ryan, E. L. Cancer- and cancer treatment-associated 
cognitive change: an update on the state of the science. J. Clin. Oncol. 30, 3675–86 
(2012). 
23. 
Maccormick, R. E. Possible acceleration of aging by adjuvant chemotherapy: a cause of 
early onset frailty? Med. Hypotheses 67, 212–5 (2006). 
24. 
Ahles, T. A. et al. Longitudinal assessment of cognitive changes associated with 
adjuvant treatment for breast cancer: impact of age and cognitive reserve. J. Clin. Oncol. 
28, 4434–40 (2010). 
25. 
Schilder, C. M. et al. Effects of tamoxifen and exemestane on cognitive functioning of 
postmenopausal patients with breast cancer: results from the neuropsychological side 
study of the tamoxifen and exemestane adjuvant multinational trial. J. Clin. Oncol. 28, 
1294–300 (2010). 
26. 
Saykin, A. J. et al. Older adults with cognitive complaints show brain atrophy similar to 
that of amnestic MCI. Neurology 67, 834–42 (2006). 
27. 
Ellis, J. R. et al. Muscarinic and nicotinic receptors synergistically modulate working 
memory and attention in humans. Int. J. Neuropsychopharmacol. 9, 175–89 (2006). 
28. 
Tannock, I. F., Ahles, T. A., Ganz, P. A. & Van Dam, F. S. Cognitive impairment 
associated with chemotherapy for cancer: report of a workshop. J. Clin. Oncol. 22, 
2233–9 (2004). 
29. 
Anderson-Hanley, C., Sherman, M. L., Riggs, R., Agocha, V. B. & Compas, B. E. 
Neuropsychological effects of treatments for adults with cancer: a meta-analysis and 
review of the literature. J. Int. Neuropsychol. Soc. 9, 967–82 (2003). 
30. 
Downie, F. P., Mar Fan, H. G., Houédé-Tchen, N., Yi, Q. & Tannock, I. F. Cognitive 
function, fatigue, and menopausal symptoms in breast cancer patients receiving 
adjuvant chemotherapy: evaluation with patient interview after formal assessment. 
Psychooncology. 15, 921–30 (2006). 


Principal Investigator: Paul A. Newhouse, M.D. 
 
                      Version Date: 27 November 2017 
Study Title: Nicotinic Treatment of Post-Chemotherapy Subjective Cognitive Impairment: A Pilot Study 
Institution/Hospital: Vanderbilt University Medical Center / VICC 
 
 
22 
31. 
Jansen, C. E., Dodd, M. J., Miaskowski, C. A., Dowling, G. A. & Kramer, J. Preliminary 
results of a longitudinal study of changes in cognitive function in breast cancer patients 
undergoing chemotherapy with doxorubicin and cyclophosphamide. Psychooncology. 
17, 1189–95 (2008). 
32. 
Schagen, S. B. et al. Cognitive deficits after postoperative adjuvant chemotherapy for 
breast carcinoma. Cancer 85, 640–50 (1999). 
33. 
Castellon, S. A. et al. Neurocognitive performance in breast cancer survivors exposed to 
adjuvant chemotherapy and tamoxifen. J. Clin. Exp. Neuropsychol. 26, 955–69 (2004). 
34. 
Donovan, K. A. et al. Cognitive functioning after adjuvant chemotherapy and/or 
radiotherapy for early-stage breast carcinoma. Cancer 104, 2499–507 (2005). 
35. 
McDonald, B. C., Conroy, S. K., Ahles, T. A., West, J. D. & Saykin, A. J. Gray matter 
reduction associated with systemic chemotherapy for breast cancer: a prospective MRI 
study. Breast Cancer Res. Treat. 123, 819–28 (2010). 
36. 
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Study Title: Nicotinic Treatment of Post-Chemotherapy Subjective Cognitive Impairment: A Pilot Study 
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Principal Investigator: Paul A. Newhouse, M.D. 
 
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Study Title: Nicotinic Treatment of Post-Chemotherapy Subjective Cognitive Impairment: A Pilot Study 
Institution/Hospital: Vanderbilt University Medical Center / VICC 
 
 
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Principal Investigator: Paul A. Newhouse, M.D. 
 
                      Version Date: 27 November 2017 
Study Title: Nicotinic Treatment of Post-Chemotherapy Subjective Cognitive Impairment: A Pilot Study 
Institution/Hospital: Vanderbilt University Medical Center / VICC 
 
 
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Principal Investigator: Paul A. Newhouse, M.D. 
 
                      Version Date: 27 November 2017 
Study Title: Nicotinic Treatment of Post-Chemotherapy Subjective Cognitive Impairment: A Pilot Study 
Institution/Hospital: Vanderbilt University Medical Center / VICC 
 
 
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