Conditions: Neuropathy Peripheral Neuropathy Neuropathic Pain Chemotherapy-induced Peripheral Neuropathy
Keywords: Nicotine Peripheral Neuropathy
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 4
Healthy volunteers: no

Brief summary:
Assess the efficacy of short-term nicotine transdermal patch administration for the treatment of chemotherapy-induced peripheral neuropathy (CIPN) in cancer stable patients or patients in remission.

Detailed description:
This phase 2 study will test the efficacy of short-term transdermal nicotine transdermal patch administration in patients who have been diagnosed with CIPN. The study will follow an open-label, crossover within-subjects clinical trial design with nicotine transdermal patch.

Arms:
arm 1: Each patient will complete two 14-day treatment conditions, for 7 mg nicotine transdermal patch administration with a washout period in between (≥ 14 days and up to 21 days), then 14 mg nicotine transdermal patch administration (14 days).

Interventions: intervention 1: Nicotine Transdermal Patch
Intervention descriptions: intervention 1: Nicotine Treatment Condition

Protocol document:
Prot_SAP_000.pdf: 
MCC-16-12518
NCT04468230
Phase 2 Study of Nicotine for the Treatment of Pain Associated with Chemotherapy-
Induced Peripheral Neuropathy
10/21/2022


,r 
Mb.$Nx Virginia Commonwealth University Massey Cancer Center
@VCU 
MCC Protocol#: MCC-16-12518 
Phase 2 Study of Nicotine for the Treatment of Pain Associated with Chemotherapy-Induced 
Peripheral Neuropathy. 
Principal Investigator: 
Renato Martins, MD 
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MCC Protocol#: MCC-16-12518 
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SCHEMA 
  
 
 
 
 
 
 
 
 
Patients with Chemotherapy-induced Peripheral 
Neuropathy (CIPN)  
(current non-smoker, non-pregnant, non-lactating, ≥ 18years) 
Eligibility and Screening  
Nicotine Treatment Condition 1 
7 mg Nicotine Transdermal Patch 
(14-day treatment) 
Wash-out Period 
 (≥ 14 days and up to 21 
days, no treatment)  
Nicotine Treatment Condition 2 
14 mg Nicotine Transdermal Patch 
 (14-day treatment) 
INITIATE STUDY 
30-Day Follow-up Period 
 
Study Closure 
If toxicities 
exceed stopping 
rule, no additional 
patients will be 
enrolled 
90-Day Follow-up Period 
 


 
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TABLE OF CONTENTS 
SCHEMA ...................................................................................................................................... 2 
 ...................................................................................................................................................... 2 
REVISION HISTORY .................................................................................................................... 3 
TABLE OF CONTENTS ............................................................................................................... 4 
LIST OF FIGURES ....................................................................................................................... 6 
LIST OF TABLES ......................................................................................................................... 6 
LIST OF ABBREVIATIONS ......................................................................................................... 7 
1 
BACKGROUND ............................................................................................................. 8 
1.1 
INTRODUCTION ................................................................................................................. 8 
1.2 
RATIONALE AND PREVIOUS WORK .................................................................................... 8 
1.3 
STUDY DESIGN ............................................................................................................... 10 
1.4 
POTENTIAL RISKS AND BENEFITS OF THE INVESTIGATIONAL TREATMENT .......................... 11 
2 
OBJECTIVES .............................................................................................................. 12 
2.1 
PRIMARY OBJECTIVE ...................................................................................................... 12 
2.2 
SECONDARY OBJECTIVES ............................................................................................... 12 
2.3 
EXPLORATORY OBJECTIVES ........................................................................................... 12 
3 
STUDY DESIGN .......................................................................................................... 12 
3.1 
GENERAL DESCRIPTION .................................................................................................. 12 
3.2 
PRIMARY ENDPOINT ....................................................................................................... 13 
3.3 
SECONDARY ENDPOINTS ................................................................................................ 13 
3.4 
EXPLORATORY ENDPOINTS ............................................................................................. 13 
4 
PATIENT SELECTION ................................................................................................ 14 
4.1 
INCLUSION CRITERIA ...................................................................................................... 14 
4.2 
EXCLUSION CRITERIA ..................................................................................................... 15 
5 
STUDY ENTRY AND WITHDRAWAL PROCEDURES ............................................... 16 
5.1 
STUDY ENTRY PROCEDURES .......................................................................................... 16 
5.2 
STUDY WITHDRAWAL ...................................................................................................... 17 
6 
STUDY TREATMENT .................................................................................................. 17 
6.1 
BASELINE TESTS AND PROCEDURES ............................................................................... 17 
6.2 
INVESTIGATIONAL AGENT ADMINISTRATION ..................................................................... 17 
6.3 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES .................... 18 
6.4 
DURATION OF THERAPY .................................................................................................. 18 
6.5 
FOLLOW-UP PERIOD....................................................................................................... 18 
6.6 
EXTENDED (90-DAY) FOLLOW-UP PERIOD ....................................................................... 19 
6.7 
MONITORING PATIENT COMPLIANCE ................................................................................ 19 
7 
MISSED DOSES .......................................................................................................... 19 
7.1 
RECORDING MISSED DOSES ........................................................................................... 19 
7.2 
GENERAL INSTRUCTIONS AND GUIDELINES ...................................................................... 19 
8 
ADVERSE EVENTS: DEFINITIONS AND REPORTING REQUIREMENTS .............. 20 


 
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8.1 
DEFINITIONS................................................................................................................... 20 
8.2 
KNOWN AES LIST ........................................................................................................... 22 
8.3 
TIME PERIOD AND GRADE OF AE CAPTURE ..................................................................... 22 
8.4 
PROCEDURES FOR RECORDING EVENTS ......................................................................... 23 
8.5 
EXPEDITED REPORTING PROCEDURES FOR SAES, SSARS, UPS, AND QUALIFYING 
TOXICITIES ..................................................................................................................... 23 
9 
PHARMACEUTICAL INFORMATION ......................................................................... 24 
9.1 
NICODERM CQ NICOTINE TRANSDERMAL PATCH, 7MG AND 14MG ................................... 24 
10 
MEASUREMENT OF EFFECT .................................................................................... 26 
10.1 
EVALUATION OF TRANSDERMAL NICOTINE PATCH EFFICACY ............................................ 26 
11 
SERUM NICOTINE ANALYSIS ................................................................................... 27 
11.1 
PARTICIPATION IN SERUM NICOTINE ANALYSIS ................................................................ 27 
11.2 
COLLECTION, PROCESSING, AND DISTRIBUTION OF SAMPLES .......................................... 27 
12 
STUDY CALENDAR .................................................................................................... 28 
13 
STATISTICAL CONSIDERATIONS ............................................................................ 30 
13.1 
STUDY DESIGN ............................................................................................................... 30 
13.1 
SAMPLE SIZE AND ACCRUAL ........................................................................................... 30 
13.2 
STATISTICAL ANALYSIS ................................................................................................... 30 
13.3 
QUALIFYING TOXICITIES FOR EARLY STOPPING RULE ...................................................... 31 
13.4 
EVALUABILITY FOR QUALIFYING TOXICITY AND EFFICACY ................................................. 32 
14 
DATA AND SAFETY MONITORING PLAN (DSMP) .................................................. 33 
14.1 
STUDY TEAM .................................................................................................................. 33 
14.2 
MONITORING AND AUDITING ............................................................................................ 33 
15 
REGULATORY COMPLIANCE AND ETHICS ............................................................ 33 
15.1 
ETHICAL STANDARD ....................................................................................................... 33 
15.2 
REGULATORY COMPLIANCE ............................................................................................ 33 
15.3 
INSTITUTIONAL REVIEW BOARD ....................................................................................... 33 
15.4 
INFORMED CONSENT PROCESS ...................................................................................... 34 
15.5 
PATIENT CONFIDENTIALITY AND ACCESS TO SOURCE DOCUMENTS/DATA ......................... 34 
16 
DATA COLLECTION AND MANAGEMENT ............................................................... 34 
16.1 
DATA MANAGEMENT RESPONSIBILITIES ........................................................................... 34 
16.2 
CASE REPORT FORMS AND DATA COLLECTION ................................................................ 35 
16.1 
ONCORE DATA ENTRY ................................................................................................... 35 
16.2 
STUDY RECORD RETENTION ........................................................................................... 35 
17 
REFERENCES ............................................................................................................. 36 
18 
APPENDIX 1. PERFORMANCE STATUS CRITERIA ................................................ 39 
19 
APPENDIX 2. NEW YORK HEART ASSOCIATION CLASSIFICATION .................... 40 


 
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LIST OF FIGURES 
Figure 1. Nicotine reverses paclitaxel-induced mechanical allodynia in mice. ............................. 9 
 
LIST OF TABLES 
Table 1. Expedited Reporting Requirements (Events, Report Recipients, and Time Frames)... 23 
Table 2. Reported/Suggested Numerical Relationship Between CTCAE v4.0/v5.0 and EORTC 
QLQ-CIPN-20 Scores. ................................................................................................................ 26 
Table 3. Study Caledar – Eligibility/Screening Through Washout Period ................................... 28 
Table 4. Study Calendar – Treatment Condition 2 Through the 90-Day Follow-up Period ......... 29 
Table 5. Number of Subjects With Observed Toxic Events Needed to Stop Trial Given Accrued 
Sample Size. ............................................................................................................................... 32 
 


 
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LIST OF ABBREVIATIONS  
AE 
adverse event 
BPI-SF 
Brief Pain Inventory – Short Form 
CIPN 
Chemotherapy-induced peripheral neuropathy 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTRL 
Clinical and Translational Research Lab 
DLT 
dose-limiting toxicity 
DSMC 
Data and Safety Monitoring Committee 
EORTC QLQ-CIPN20 
European Organization for Research and Treatment of Cancer 
Quality of Life-CIPN20 Questionnaire 
FDA 
Food and Drug Administration 
HIV 
Human immunodeficiency virus 
IIT 
Investigator Initial Trial  
IMPACT 
Initiative on Methods, Measurement, and Pain Assessment in 
Clinical Trials 
IRB 
Institutional Review Board 
MCC 
Massey Cancer Center 
nAChR(s) 
nicotinic acetylcholine receptor(s) 
NYHA 
New York Heart Association 
OHRP 
Office for Human Research Protections 
PGIC 
Patient Global Impression of Change 
PRO 
patient-reported outcome 
PRMC 
Protocol Review and Monitoring Committee 
SAE 
serious adverse event 
SAR 
suspected adverse reaction 
UP 
unanticipated problem 
VCU 
Virginia Commonwealth University 
 


 
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1 BACKGROUND 
1.1 Introduction 
Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect associated 
with the taxanes and platinum-based compounds, drugs commonly used for the treatment 
of breast, lung, and ovarian cancer. CIPN results from damage to, or dysfunction of, the 
peripheral motor, sensory, and autonomic nerves and manifests with a variety of 
symptoms including mechanical and cold allodynia, numbness and tingling, loss of 
proprioception, and long-lasting burning pain (1-4). CIPN affects quality of life, and can 
often result in chemotherapy dose reductions and early treatment discontinuation (5).  
Depending on the specific chemotherapy regimen used, the duration of exposure, and 
method of CIPN assessment, approximately 30% to 70% of multiple-agent, chemotherapy-
treated cancer patients are diagnosed with CIPN (6-8). Current CIPN treatment options 
include duloxetine, tricyclic antidepressants, gabapentin, and topical applications (eg, 
baclofen and ketamine) (5). However, treatment options to manage CIPN are not 
consistently effective for the majority of patients. Thus, there is a critical need to identify 
new agents that can manage the pain associated with CIPN.  
This clinical trial is designed to determine if nicotine transdermal patch use can suppress 
the pain associated with CIPN. Demonstrating that nicotine can suppress such pain would 
be highly significant on 3 fronts. First, by relieving CIPN-associated pain, suboptimal 
chemotherapeutic dosing schemes might be adjusted upwards, increasing the probability 
of effective treatment of the cancer. Second, the use of an FDA-approved, over-the-
counter drug with a relatively safe short-term use profile would greatly accelerate the 
clinical development of this pain management strategy. Third, a demonstration that 
nicotine can manage the pain associated with CIPN would stimulate the development of 
targeted agents that interact with subtypes of nicotinic acetylcholine receptors (nAChRs) 
and which might act with fewer side effects.  
1.2 Rationale and Previous Work 
This clinical trial will focus on nicotine, the prototype agonist of nAChRs, as a possible 
agent for symptom suppression of CIPN. The analgesic properties of nicotine and nicotinic 
agonists have been established in many animal (9) and human studies (10) including 
neuropathic pain in humans (11, 12). Animal models have been developed that reiterate 
many of the neuropathological changes and electro-physiological abnormalities observed 
in patients with CIPN (13). Nicotine has analgesic properties and has been shown to 
reduce pain in both animal and human studies ((9-12). Nicotine has the advantage of 
having a well-established risk profile and is relatively safe for short-term use (16).  It is also 
available over-the-counter as a transdermal patch which greatly simplifies drug delivery. 
These qualities of nicotine provide a strong rationale for using it to treat CIPN-associated 
pain. Thus, the primary objective of this trial is to test, in  cancer stable/remission patients 
with diagnosed CIPN, the efficacy of acute nicotine transdermal patch administration in 
assessing clinically subjective improvements in measures of neuropathic pain, as well as 
improvements in quality of life CIPN patient-reported outcomes (PROs). This study will 
serve as a proof-of-principle study that could lead to future studies employing more 
selective nAChR-targeted drugs that are currently in development by our group. 




 
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1.3 Study Design 
This study will test the efficacy of acute nicotine transdermal patch administration using an 
open-label, within-subjects clinical trial design with nicotine transdermal patch 
concentrations of 7 mg and 14 mg. Patients will be recruited via clinician referral and must 
not have used any nicotine or tobacco products (eg, cigarettes, electronic cigarettes, 
smokeless tobacco, or other nicotine replacement therapies) within the last 14 days prior to 
study treatment start date. Each treatment condition will have a duration of 14 days, with a 
washout period of at least 14 days in between conditions. Patients will be evaluated by the 
study team once per week during the treatment cycles (2 study visits per treatment cycle). 
Patients will be evaluated by the study team once during the washout period (1 study visit). 
Patients will also be evaluated at least once during the 30-day follow-up period (1 study 
visit). During study visits, patients will be evaluated by the study team for CIPN PROS, 
pain scale, and Adverse Events (AE). This evaluation schedule will provide complete 
clinical and research assessments related to pain and neuropathy at baseline, during 
treatment conditions, and post-treatment.  
The primary outcome measure is the change in CIPN-related PRO as measured by the 
total sensory score of the European Organization for Research and Treatment of Cancer 
quality of life questionnaire (EORTC QLQ-CIPN-20). EORTC QLQ-CIPN-20 is a well-
developed 20-item questionnaire, that provides valuable information on CIPN- related 
symptoms and functional limitations of patients exposed to potentially neurotoxic 
chemotherapeutic and/or neuroprotective agents (17). It has also been validated clinically 
by showing very significant association between QLQ-CIPN20 scores and the NIH 
Common Terminology Criteria for Adverse Events (CTCAE) grades for AEs associated 
with CIPN symptoms (p<0.0001), whereby patients with higher CTCAE grade had worse 
QLQ-CIPN20 scores (18).  
The secondary outcome measures include the following items: 1) the change in average 
pain based on the well-validated Brief Pain Inventory-Short Form (BPI-SF) average pain 
severity item; and 2) evaluation of the safety and toxicity of nicotine transdermal patch 
administration in a population of non-smokers experiencing CIPN.  
The BPI-SF contains 4 items assessing average, worst, least, and immediate pain severity 
in the last 24 hours. Pain severity items are scored using an 11-point numeric rating scale 
(0, no pain; 10, pain as bad as you can imagine). Seven BPI-SF items will be used to 
quantify the degree to which pain interferes with daily activities or function (0, does not 
interfere; 10, completely interferes). The 7 items are summed to obtain a total interference 
score. The BPI-SF worst pain severity item has been shown to be reliable and valid for use 
as a single item. We chose average pain severity as an outcome measure based on 
recommendations from the initiative on Methods, Measurement, and Pain Assessment in 
Clinical Trials (IMPACT) and other CIPN studies (19).  
Patients will be monitored for nicotine-associated toxicity utilizing CTCAE v5.0. AE 
assessments will occur at least once per week during treatment conditions.  
Exploratory outcome measures include the patient’s assessment of the efficacy of a 
transdermal nicotine transdermal patch for the treatment of CIPN utilizing the Patient 
Global Impression of Change and Patient Preference Questionnaire (PGIC) for neuropathy 
(upper and lower extremity questionnaires). The PGIC is used to assess patients' own 
impressions of change (20). The questionnaire uses a global scale from “much better” 


 
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through “no change” to “much worse” (21, 22). This study will use a version of the PGIC 
adapted to patients with CIPN that focuses on patients’ self-assessment of their upper and 
lower extremities. Additional exploratory investigations include: 1) the correlation between 
serum nicotine levels and efficacy of nicotine transdermal patch administration for the 
treatment of CIPN in patients whose cancer is stable or in remission; 2) the differences in 
CIPN PROs and BPI-SF measures between patients that received previous platinum-
based chemotherapy versus patients that received previous taxane-based chemotherapy; 
and 3) the differences in CIPN PROs and BPI-SF measures between never-smokers 
(nicotine-naïve) and current non-smokers.  
The clinical trial will yield several important results. First, using an acute nicotine 
transdermal patch administration will determine both the potential efficacy and feasibility of 
using nicotine as a potential treatment for neuropathic pain associated with CIPN. 
Additionally, if nicotine appears to have a positive treatment effect, as defined by a ≥ 2.7 
point decrease in patient’s total sensory score (baseline compared to treatment and post-
treatment scores) of the QLQ-CIPN-20 questionnaire (eg, an improvement in the patients 
quality of life by one grade), future randomized clinical trials comparing nicotine to other 
commonly prescribed treatments, such as duloxetine, may be warranted. In addition, 
further studies of subtype receptor selective agents or of patient population subgroups 
(based on smoking history, gender, chemotherapeutic agents, or receptor expression 
level) can be designed. 
1.4 Potential Risks and Benefits of the Investigational Treatment 
1.4.1 Potential Benefits 
The analgesic properties of nicotine and nicotinic agonists have been established in 
many animal and human studies. Acute nicotine transdermal patch administration 
could improve patient’s CIPN-associated pain, and thus their quality of life. Further, 
successful management of patients’ CIPN could circumvent chemotherapy dose 
reduction and early treatment discontinuation. The use of an FDA-approved, over-
the-counter drug with a relatively safe short-term use profile would greatly 
accelerate the clinical development of this as a pain management strategy. Finally, if 
successful, this study would stimulate the development of targeted agents that 
interact with subtypes of nAChRs, which might act with fewer side effects. 
1.4.2 Potential Risks 
One of the challenges with the use of nicotine as a therapeutic agent relates to the 
potential side effects of nicotine on nicotine-naïve patients (ie, patients with no 
nicotine use history). Related symptoms experienced by non-smokers being treated 
with a nicotine transdermal system include nausea, dizziness, vomiting, minor skin 
irritations, and palpitations (23). There is also a risk for the development of nicotine 
dependence for current non-smokers and a recurrence of nicotine dependence for 
previous smokers. Overall, the published side effects for a 15mg or less nicotine 
transdermal patch were reported as mild and tolerable (24-27). Nonetheless, we will 
evaluate the safety and toxicity of nicotine transdermal patch administration in a 
population of non-smokers experiencing CIPN as described in our secondary 
outcome measures. 


 
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2 OBJECTIVES 
2.1 Primary Objective 
Assess the efficacy of short-term nicotine transdermal patch administration for the 
treatment of CIPN in cancer stable patients or patients in remission. 
2.2 Secondary Objectives 
Secondary objectives include: 
2.2.1 Assess pain-related functional interference associated with nicotine transdermal 
patch administration for the treatment of CIPN in patients whose cancer is stable or 
in remission. 
2.2.2 Assess the AEs profile of nicotine transdermal patch administration for the treatment 
of CIPN in patients whose cancer is stable or in remission.  
3 STUDY DESIGN 
3.1 General Description 
This phase 2 study will test the efficacy of short-term transdermal nicotine transdermal 
patch administration in patients who have been diagnosed with CIPN. The study will follow 
an open-label, crossover within-subjects clinical trial design with nicotine transdermal patch 
concentrations of 7 mg and 14 mg.  


 
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3.2 Primary Endpoint 
Efficacy of short-term nicotine transdermal patch administration in the treatment of CIPN in 
patients whose cancer is stable or in remission as defined by a ≥ 2.7 point decrease in the 
total sensory score of the EORTC QLQ-CIPN-20 (eg, an improvement in the patients 
quality of life by one grade). 
3.3 Secondary Endpoints 
Secondary endpoints include:  
3.3.1 Efficacy of short-term nicotine transdermal patch administration in the treatment of 
CIPN in patients whose cancer is stable or in remission by assessing changes in the 
degree of pain-related functional interference measured by the BPI-SF interference 
score. 
3.3.2 Nicotine transdermal patch safety and tolerability in non-smokers by assessing AEs 
characterized and graded according to CTCAE v5.0 and PROs related to nausea, 
dizziness, vomiting, minor skin irritations, and palpitations.    


 
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4 PATIENT SELECTION 
4.1 Inclusion Criteria 
A patient must meet all of the following inclusion criteria to be eligible to participate in the 
study. 
4.1.1 Age ≥ 18 
4.1.2 CIPN characteristics 
4.1.2.1 Clinically diagnosed peripheral sensory neuropathy defined as:  
4.1.2.1.1 Greater than Grade 1 peripheral sensory neuropathy using the 
CTCAE v5.0 grading scale 
• Grade 1 Asymptomatic  
• Grade 2 Moderate symptoms; limiting instrumental activities 
of daily living (ADL) 
• Grade 3 Severe symptoms; limiting self-care ADL 
 
• Grade 4 Life-threatening consequences; urgent intervention 
indicated 
AND 
4.1.2.2 Have a baseline CIPN PRO total sensory score ≥ 24.3 on a 19 to 76 scale 
using the EORTC QLQ-CIPN-20 questionnaire  
AND 
4.1.2.3 Have a CIPN-related neuropathic pain score ≥ 4 on a 0 to 10 scale using 
the Brief Pain Inventory-Short Form (BPI-SF) item 5 
Note: Patients currently being treated for CIPN will not be excluded and are allowed 
to continue their treatment and current treatment dose while on study. 
4.1.3 Will not have used any nicotine or tobacco products (eg, cigarettes, electronic 
cigarettes, smokeless tobacco, or other nicotine replacement therapies) within 14 
days prior to study treatment start date 
4.1.4 Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 (see 
Appendix 1) 
4.1.5 Not currently receiving any chemotherapy 
4.1.6 Have previously received platinum- and/or taxane-based chemotherapy treatments 
and have persistent pain at least 3 months after completion of treatments. 


 
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4.1.7 Willing and able to comply with study procedures and visit schedule.  
4.1.8 Willing to abstain from all tobacco/nicotine product use during study treatment and 
30-day follow-up period.  
4.1.9 Ability to self-apply or have the patch applied at home daily. 
4.1.10 Ability to understand and the willingness to sign a written informed consent 
document 
4.2 Exclusion Criteria 
A patient who meets any of the following exclusion criteria is ineligible to participate in the 
study.  
4.2.1 History of pre-existing peripheral sensory neuropathies related to the following:  
• 
Autoimmune disease 
• 
B12/folate deficiency  
• 
Diabetes Mellitus 
• 
Human immunodeficiency virus (HIV) 
• 
Hyper/hypothyroidism 
• 
Monoclonal gammopathy of undetermined significance or multiple myeloma  
4.2.2 History of receiving other types of neurotoxic chemotherapy drugs (eg, vinca 
alkaloids, bortezomib, thalidomide) 
4.2.3 Current or prior pheochromocytoma 
4.2.4 History of or active or clinically significant cardiac disease including any of the 
following: 
• 
Unstable angina (eg, anginal symptoms at rest) or onset of angina within  
3 months prior to initiating study treatment 
• 
Myocardial infarction diagnosed within 6 months prior to initiating study 
treatment 
• 
Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers 
4.2.5 New York Heart Association (NYHA) class III or IV congestive heart failure  
(see Appendix 2) 
4.2.6 Poorly controlled high or low blood pressure defined as: 
• 
SBP ≥ 140; DBP ≥ 90 


 
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• 
SBP ≤ 90; DBP ≤ 60 
4.2.7 Regular use of the following medications: 
• 
Varenicline 
• 
Bupropion (ie, bupropion hydrochloride sustained release) 
4.2.8 Women will be excluded if they are breastfeeding or are pregnant (by urinalysis) 
within 14 days prior to the start of nicotine transdermal patch administration. 
4.2.9 Medical, psychological, or social condition that, in the opinion of the investigator, 
may increase the patient’s risk or limit the patient’s adherence with study 
requirements 
5 STUDY ENTRY AND WITHDRAWAL PROCEDURES 
5.1 Study Entry Procedures 
5.1.1 Required Pre-Registration Screening Tests and Procedures 
Refer to the study calendar in Section 12 for the screening tests and procedures 
that are required prior to registration. 
5.1.2 Study Enrollment 
The following documents are required for patient registration: 
• 
Completed registration cover sheet 
• 
Completed, signed, and dated eligibility checklist 
• 
Signed and dated consent form 
The registrar will complete the registration process by assigning a study 
identification (ID) number and forwarding the “Confirmation of Registration” form to 
the registering study team. 
No patient may begin study treatment until the Confirmation of Registration 
assigning a study ID number has been received from the registrar. The registering 
study team will enter the patient’s initial enrollment data (eg, demographics, 
consent, eligibility, on study) into the OnCore database within 24 hours following 
study registration (before treatment begins). 


 
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5.2 Study Withdrawal 
A patient may decide to withdraw from study participation at any time. Patients must be 
withdrawn from the study when any of the following occurs: 
• 
The patient has withdrawn consent for study treatment and study procedures. 
• 
If, in the investigator's opinion, continuation of the study requirements would be harmful 
to the patient's well-being. 
• 
The patient is lost to follow-up. 
The reason for and date associated with study withdrawal or removal from the study must 
be documented in the source documents and OnCore database. 
6 STUDY TREATMENT 
6.1 Baseline Tests and Procedures 
Refer to the study calendar in Section 12 for requirements prior to initiation of treatment 
administration. Initiation of study treatment should begin as soon as possible following 
study registration. Patients who are eligible and enrolled in the study but do not 
immediately initiate study treatment are expected to meet eligibility criteria until the time 
when treatment is initiated.  
6.2 Investigational Agent Administration 
6.2.1 Nicotine Transdermal Patch Administration and Treatment Schedule: 
• 
Each patient will complete two 14-day treatment conditions, one each for 7 mg 
and 14 mg nicotine transdermal patch administration with a washout period in 
between (≥ 14 days and up to 21 days). 
• 
Nicotine transdermal patch administration will begin on Cycle 1, Day 1 (7mg) 
and Cycle 2, Day 1 (14mg). 
• 
Nicotine transdermal patches will be applied once daily for 14 consecutive days. 
• 
Nicotine transdermal patches will be removed for at least 14 days and up to 21 
days at the end of Cycle 1, Day 14. 
• 
Patients will be instructed as follows: 
− 
Apply the nicotine transdermal patch to dry, clean, hairless skin 
− 
Patients should apply and remove the nicotine transdermal patch at the same 
time everyday 
− 
Patients should wear the nicotine transdermal patch for at least 16 hours per 
day. 


 
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6.2.2  Missed Doses 
Patients will be instructed to apply the nicotine transdermal patch on the same day, 
as soon as they remember, with the following considerations: 
• 
Patients should still remove the missed nicotine transdermal patch at the 
planned daily removal time. 
• 
Patients should not apply more than one nicotine transdermal patch per day. 
6.3 General Concomitant Medication and Supportive Care Guidelines 
Nicotine transdermal patch-related symptoms experienced by non-smokers include 
nausea, dizziness, vomiting, minor skin irritations, and palpitations (23). These common 
side effects associated with nicotine administration can occur more commonly in patients 
with no nicotine use history (ie, never-smokers, nicotine naive patients). The published 
side effects for a 15mg or less nicotine transdermal patch have been reported as mild and 
tolerable (24-27). 
6.3.1 Nausea/Vomiting 
Management of nausea and vomiting will include anti-nausea medication to reduce 
the risk of grade 3 nausea or nicotine transdermal patch discontinuation. Anti-
emetics should be prescribed as clinically indicated. 
6.4 Duration of Therapy 
Treatment will continue until any of the following occurs (also see information regarding 
study withdrawal in Section 5.2): 
• 
AE that requires discontinuation of study treatment (See Section 7.2.2) 
• 
Pregnancy 
• 
Patient decision to discontinue study treatment or withdraw from the study 
• 
Investigator determination that discontinuation is in the patient’s best medical interest 
• 
Patient non-compliance with the required study treatment visits such that the patient 
has not been present for more than 60% of the  visits (≥ 3 out of 5 visits) 
• 
Inability to initiate Cycle 2 within 21 days after completion of Cycle 1 
6.5  Follow-Up Period 
During the 30-day follow-up period, patients will be evaluated by the study team at least 
once. They will be assessed for nicotine serum levels, pain (BPI-SF), global impression of 
change, CIPN PROs, and AEs. 


 
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6.6 Extended (90-day) Follow-Up Period 
The extended (90-day) follow-up period will begin at the end of Cycle 2, Day 14 after the 
last nicotine transdermal patch is removed. The 90-day follow-up will consist of a phone 
call to patients once at the end of the 90-day follow-up period. Patients will be asked if they 
have continued to use the nicotine transdermal patch to lessen their CIPN symptoms and  
if they have developed a dependence to nicotine in any form (eg, cigarettes, electronic 
cigarettes, smokeless tobacco, or other nicotine-containing products). 
6.7 Monitoring Patient Compliance 
Patients will be instructed to record the time of their daily self-administration and removal 
of the nicotine transdermal patch in the study drug diary that will be provided. This record 
will also document the number of nicotine transdermal patches used during each treatment 
cycle. Patients will be instructed to bring their diary and any unused drug supply to each 
visit with the study team. 
Patient reports of self-administration and review of the study drug diary will be used to 
assess the patient’s compliance with the nicotine transdermal patch study treatment 
regimen.  
7 MISSED DOSES  
Dose reductions or dose omissions will not occur. 
7.1 Recording Missed Doses  
All missed doses will be recorded in the source documents and captured in the OnCore 
database. 
7.2 General Instructions and Guidelines  
7.2.1 Missed Doses 
• 
If a nicotine transdermal patch is missed for an entire 24-hour period, the 
transdermal patch is omitted, not made up. 
• 
If a nicotine transdermal patch is missed for less than a 24-hour period, the 
transdermal patch is applied for the remaining hours of the 24-hour period, if 
possible. 
7.2.2 Required Discontinuation of Study Treatment 
Nicotine transdermal patch administration will be discontinued if clinically significant 
toxicities or qualifying toxicities that are related to nicotine transdermal patch 
therapy occur (See Section 8.1.6 for Qualifying Toxicities).  


 
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8 ADVERSE EVENTS: DEFINITIONS AND REPORTING 
REQUIREMENTS 
8.1 Definitions 
8.1.1 Adverse Event (AE) 
AE means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
8.1.2 Suspected Adverse Reaction (SAR) 
Any AE for which there is a reasonable possibility that the drug caused the AE. 
“Reasonable possibility” means that there is evidence to suggest a causal 
relationship between the drug and the AE. 
An AE with an attribution of possible, probable, or definite (see Section 8.1.9 below) 
is a SAR. 
8.1.3 Serious AE (SAE) or Serious SAR (SSAR) 
An AE or SAR is considered “serious” if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes: 
• 
death, 
• 
a life-threatening AE (An AE or SAR is considered “life-threatening” if, in the 
view of either the investigator or sponsor, its occurrence places the patient or 
subject at immediate risk of death. It does not include an AE or SAR that, had it 
occurred in a more severe form, might have caused death.), 
• 
inpatient hospitalization or prolongation of existing hospitalization, 
Planned inpatient hospitalizations are exempt from SAE reporting. Events 
that prolong hospitalization beyond the expected period of time and otherwise 
meet reporting criteria are, however, subject to SAE reporting requirements. 
• 
a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or 
• 
a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
8.1.4 Unexpected SAR 
A SAR is considered “unexpected” if 


 
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• 
it is not listed in the investigator brochure or is not listed at the specificity or 
severity that has been observed; 
• 
or, if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan or elsewhere in 
the current application, as amended. 
“Unexpected” as used in this definition, also refers to SARs that are mentioned 
in the investigator brochure as occurring with a class of drugs or as anticipated 
from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation. 
8.1.5 Unanticipated Problem (UP) 
UPs include any incident, experience, or outcome that meets all of the following 
criteria: 
• 
unexpected (in terms of nature, severity, frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
• 
related or possibly related to participation in the research (possibly related 
means there is a reasonable possibility that the incident, experience, or outcome 
may have been caused by the procedures involved in the research); and 
• 
suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
8.1.6 Qualifying Toxicities  
The following nicotine-related toxicities listed below are considered qualifying 
toxicities and will be used to ensure patient safety and tolerability. The following 
toxic event as defined per CTCAE v5.0 will be counted toward the stopping rules 
(See Section 13.3). 
• 
Grade 3 nausea 
• 
Grade 3 vomiting 
• 
Grade 3 dizziness 
• 
Grade 3 pruritus 
• 
Grade 3 headache 
• 
Grade 2 heart palpitations 


 
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8.1.7 AE Description and Grade 
The descriptions and grading scales found in the revised Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. 
8.1.8 AE Expectedness 
AEs can be ‘Unexpected’ or ‘Expected’. 
Expected AEs are listed in Section 8.2 below. 
Unexpected AEs are those AEs occurring in one or more subjects participating in 
the research protocol, the nature, severity, or frequency of which is not consistent 
with either: 
• 
The known or foreseeable risk of AEs associated with the procedures involved 
in the research that are described in (a) the protocol-related document, such as 
the IRB-approved research protocol, any applicable investigator brochure, and 
the current IRB-approved informed consent document, and other relevant 
sources of information, such as product labeling and package inserts; or 
• 
The expected natural progression of any underlying disease, disorder, or 
condition of the subject(s) experiencing the AE and the subject’s predisposing 
risk factor profile for the AE. 
8.1.9 AE Attribution 
• 
Definite – The AE is clearly related to the study treatment. 
• 
Probable – The AE is likely related to the study treatment. 
• 
Possible – The AE may be related to the study treatment. 
• 
Unlikely – The AE is doubtfully related to the study treatment. 
• 
Unrelated – The AE is clearly NOT related to the study treatment. 
8.2 Known AEs List 
The expected AEs for a  nicotine transdermal patch can be found in Section 9.1.9 
8.3 Time Period and Grade of AE Capture 
All AE’s regardless of grade or attribution will be recorded from the beginning of study 
treatment (Cycle 1, Day 1 of nicotine transdermal patch administration) through the 30-day 
follow-up period. AE assessment may be shortened if the patient goes off study. 
Qualifying toxicities will be captured and recorded from the beginning of study treatment 
(Cycle 1, Day 1 of nicotine transdermal patch administration) through the 30-day follow-up 
Day 8 - Day 15 study visit. Qualifying toxicity assessment may be shortened if the patient 
goes off study. 




 


 
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9.1.9 Adverse Events 
Nicotine transdermal patches can cause the following side effects: 
9.1.9.1 Common side effects: 
• 
Dizziness 
• 
Headache 
• 
Itching 
• 
Nausea 
• 
Rapid heartbeat 
• 
Skin irritation 




 
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11 SERUM NICOTINE ANALYSIS 
11.1 Participation in Serum Nicotine Analysis 
A blood sample collected for the analysis of serum nicotine levels will be used to confirm 
that patients meet eligibility and screening criteria. Blood samples will also be collected 
once during Cycle 1, once at the beginning of Cycle 2 before nicotine transdermal patch 
administration, once during Cycle 2,  and once during the 30-day follow-up period to 
measure serum nicotine levels throughout the study (a total of 5 blood samples). 
Participation in serum nicotine studies using blood samples is mandatory. 
11.2 Collection, Processing, and Distribution of Samples 
The study team will coordinate collection and de-identification of all blood samples. 
11.2.1 Collection Time Points 
Blood samples will be collected at the following time points: 
• 
Eligibility/Baseline (during eligibility screening) 
• 
Cycle 1, Treatment Condition 1, Day 8 or within 5 days 
• 
Cycle 2, Treatment Condition 2, before nicotine transdermal patch 
administration  
• 
Cycle 2, Treatment Condition 2, Day 8 or within 5 days 
• 
30-day follow-up period, Day 8-15 or within 7 days 
11.2.2 Blood Sample Collection Instructions 
At least 2.0 mL of blood will be collected at each of the time points listed in Section 
11.2.1. Blood collection will follow VCU Toxicology Laboratory specimen 
specifications. 
11.2.3 Labeling for all Blood Samples 
• 
Study number 
• 
Patient study identification number 
• 
Date of sample collection 
• 
Time of sample collection 
• 
Study time point 
11.2.4 Tracking for all Blood Samples 
Collection and distribution of all blood samples will be logged by the study team in 
OnCore. 






 
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13 STATISTICAL CONSIDERATIONS 
13.1 Study Design  
This is a phase 2 study that will test the efficacy of acute nicotine transdermal patch 
administration using an open-label, crossover within-subjects clinical trial design with 
nicotine transdermal patch concentrations of 7 mg and 14 mg. Patients will be evaluated 
for nicotine-associated toxicity and undergo assessments of pain and neuropathy 
administered by the study team, which will provide subjective and clinical measurements at 
baseline, during treatment conditions, and post-treatment. The primary endpoint is to 
assess the efficacy of short-term nicotine transdermal patch administration in the treatment 
of CIPN in patients whose cancer is stable or in remission by assessing decreases in 
neuropathic pain symptoms measured by the total sensory score of the EORTC QLQ-
CIPN-20.  
13.1 Sample Size and Accrual 
Using the 19-76 numerical scale for QLQ-CIPN220, a minimum decrease of 2.7 points 
(range of 2.7 – 5.6 points) would be required to improve the patient’s quality of life by one 
grade (grade 2 to grade 1).  A sample size of 47 would provide a power of at least 95% to 
detect a minimum change of 2.7 EORTC QLQ-CIPN20 scale points, assuming a 
moderately sized effect (ie, effect size 0.54) and 5% level of significance. Assuming 10% 
dropout or non-compliance, this will bring the total size to 52 patients. Recruitment ends 
when the required number of evaluable patients to complete the study is reached. A 
patient is evaluable if pain scores are available for the patient with each dose level. This 
still might have missing values due to non-compliance.  All of the patients will be included 
in the final analysis and subjects with missing values will be included based on imputation-
based method provided the amount of missing values is not excessive. If final data 
contains patients with more than 50% missing observations, we will use a pattern mixture 
model for imputation of missing data followed by longitudinal data. 
13.2 Statistical Analysis 
13.2.1  Analysis of Primary Endpoint 
The primary endpoint of the study is the decrease in neuropathic pain symptoms for 
CIPN patients using a short-term nicotine transdermal patch. CIPN PROs will be 
measured using the EORTC QLQ-CIPN20 sensory subscale score. The QLQ-
CIPN20 numerical score has a range of 19-76, in which lower scores indicate less 
symptoms and a better quality of life. Patient QLQ-CIPN20 scores at baseline, 
during treatments, and post- treatment will be analyzed by a one-sided test of the 
hypothesis using a matched paired t-test using 5% level of significance. Data will be 
tested for compliance with normality assumption and simple transformations would 
be used if required to restore normality of the data.  


 
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13.2.2 Analysis of Secondary Endpoints  
The secondary endpoints include the following: 
13.2.2.1 Changes in the degree of pain-related functional interference measured by 
the BPI-SF interference score. 
13.2.2.2 This trial will use change in average pain severity as an outcome measure 
based on recommendations from the initiative on Methods, Measurement, 
and Pain Assessment in Clinical Trials (IMPACT) and other CIPN or pain 
studies (16). Specifically, a previously published study investigating the 
effects of transdermal nicotine transdermal patches on post-operative pain 
observed an average of 1 point reduction in numerical pain scores in the 
nicotine group (28). Patient BPI-SF scores at baseline, during treatments, 
and post- treatment will be analyzed by a one-sided test of the hypothesis 
using a matched paired t-test. Nicotine transdermal patch safety and 
tolerability in non-smokers will be assessed using CTCAE v5.0 and PROs 
related to nausea, dizziness, vomiting, minor skin irritations, and 
palpitations.  
Incidence and severity of AEs will be listed and summary descriptive 
statistics will be calculated. 
13.3 Qualifying Toxicities for Early Stopping Rule 
Early stopping criteria based on nicotine-related toxicities listed below will be used to 
ensure patient safety and tolerability. The stopping rule is based on a 30% maximum rate 
of toxic events. For all the toxic events the assumed null proportion of subjects with any 
dose-limiting toxicity is 30% for each of the 6 toxicities listed below. 
The following toxic event as defined per CTCAE v5.0 will be counted toward the stopping 
rules in Table 5. 
• 
Grade 3 nausea 
• 
Grade 3 vomiting 
• 
Grade 3 dizziness 
• 
Grade 3 pruritus 
• 
Grade 3 headache 
• 
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14 DATA AND SAFETY MONITORING PLAN (DSMP) 
14.1 Study Team 
While patients are on treatment, the principal investigator, the study team members 
(research nurses, and clinical research associates) will meet at least monthly to review 
study status. The biostatistician will review data with the principal investigator and study 
team members at least quarterly. This review will include, but not be limited to, reportable 
events and an update of the ongoing study summary that describes study progress in 
terms of the study schema. All meetings, including attendance, are documented. 
14.2 Monitoring and Auditing 
14.2.1 MCC Compliance Office 
Compliance specialists in the MCC Compliance Office will provide monitoring and 
auditing for this study. 
14.2.2 Data Safety and Monitoring Committee (DSMC) 
The study will be reviewed by the MCC DSMC initially according to the risk level 
specified by the MCC Protocol Review and Monitoring Committee (PRMC) and then 
according to a schedule based on study status and quality indicators. The DSMC 
will review reports provided by the principal investigator/study team and the MCC 
Compliance Office focusing on data integrity and patient safety. 
15 REGULATORY COMPLIANCE AND ETHICS 
15.1 Ethical Standard 
This study will be conducted in conformance with the principles set forth in The Belmont 
Report: Ethical Principles and Guidelines for the Protection of Human Subjects of 
Research (US National Commission for the Protection of Human Subjects of Biomedical 
and Behavioral Research, April 18, 1979). 
15.2 Regulatory Compliance 
This study will be conducted in compliance with the clinical trial protocol and with federal 
regulations, as applicable, including: 21 CFR 50 (Protection of Human Patients/Informed 
Consent); 21 CFR 56 (Institutional Review Boards); 21 CFR 312 (IND Application); and 45 
CFR 46 Subparts A (Common Rule), B (Pregnant Women, Human Fetuses and 
Neonates), C (Prisoners), and D (Children). 
15.3 Institutional Review Board 
The VCU IRB, which is registered with the Office for Human Research Protections 
(OHRP), must review and approve the protocol, the associated informed consent 
document, and recruitment material (if any). Any amendments to the protocol or consent 
form must also be approved. 


 
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15.4 Informed Consent Process 
Informed consent is a process that is initiated prior to the individual’s agreeing to 
participate in the study and continues throughout the individual’s study participation. 
Discussion of risks and possible benefits of this therapy will be provided to patients and 
their families. Consent forms describing the study interventions, study procedures, and 
risks are given to the patient and written documentation of informed consent is required 
prior to starting intervention/administering study product. 
Consent forms will be IRB-approved and the patient will be asked to read and review the 
document. Upon reviewing the document, the investigator will explain the research study to 
the patient and answer any questions that may arise. The patient will sign the informed 
consent document prior to any procedures being done specifically for the study. Patients 
should have the opportunity to discuss the study with their surrogates or think about it prior 
to agreeing to participate. Patients may withdraw consent at any time throughout the 
course of the trial. A copy of the informed consent document will be given to patients for 
their records; the original consent form will be maintained in the research records. The 
rights and welfare of patients will be protected by emphasizing to them that the quality of 
their medical care will not be adversely affected if they decline to participate in this study. 
15.5 Patient Confidentiality and Access to Source Documents/Data 
Patient confidentiality is strictly held in trust by the principal investigator, participating 
investigators, and any staff. This confidentiality includes the clinical information relating to 
participating patients, as well as any genetic or biological testing. The study protocol, 
documentation, data, and all other information generated will be held in strict confidence. 
No information concerning the study or the data will be released to any unauthorized third 
party without prior written approval of principal investigator  
The principal investigator will allow access to all source data and documents for the 
purposes of monitoring, audits, IRB review, and regulatory inspections.  
The study monitor or other authorized representatives of the principal investigator may 
inspect all documents and records required to be maintained by the investigator, including 
but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the 
patients in this study. The clinical study site will permit access to such records. 
16 DATA COLLECTION AND MANAGEMENT 
16.1 Data Management Responsibilities 
The principal investigator is responsible for: (i) the overall conduct of the investigation; (ii) 
ongoing review of trial data including all safety reports; and (iii) apprising participating sites 
of any UPs. 


 
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16.2 Case Report Forms and Data Collection 
MCC will provide standard electronic case report forms (eCRFs) and create study-specific 
eCRFs to be able to capture all information required by the protocol. The eCRFs will be 
approved by the study team to ensure the most effective data acquisition. 
The investigator(s) and study coordinator(s) must maintain source documents for each 
patient in the study. All information on eCRFs will be traceable to the source documents 
which are generally maintained in the patient’s file.  
All eCRFs should be completed and available for collection within a timely manner, 
preferably no more than 14 days after the patient’s visit. 
16.1 OnCore Data Entry 
Data will be entered into MCC’s OnCore database on an ongoing basis by the study team. 
The study team is responsible for updating data to allow for data compilation and review. 
The electronic data submissions will be reviewed periodically for data timeliness and 
accuracy. 
16.2 Study Record Retention 
As applicable, study records will be maintained a minimum of 5 years beyond: (i) the 
publication of any abstract or manuscript reporting the results of the protocol; (2) the 
submission of any sponsored research final report; or (iii) submission of a final report to 
clinicaltrials.gov. 


 
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23. 
Barr RS, Culhane MA, Jubelt LE, Mufti RS, Dyer MA, Weiss AP, Deckersbach T, Kelly 
JF, Freudenreich O, Goff DC, Evins AE. The Effects of Transdermal Nicotine on 
Cognition in Nonsmokers with Schizophrenia and Nonpsychiatric Controls. 
Neuropsychopharmacology. 2008; 33(3):480-490. PMID: 17443126. 
24. 
Mishriky BM, Habib AS. Nicotine for Postoperative Analgesia: A Systematic Review and 
Meta-Analysis. Anesth Analg. 2014; 119(2):268-275. PMID: 24384863. 
25. 
Srivastava ED, Russell MA, Feyerabend C, Masterson JG, Rhodes J. Sensitivity and 
Tolerance to Nicotine in Smokers and Nonsmokers. Psychopharmacology (Berl). 1991; 
105(1):63-68. PMID: 1745713. 
26. 
Levin ED, Conners CK, Sparrow E, Hinton SC, Erhardt D, Meck WH, Rose JE, March J. 
Nicotine Effects on Adults with Attention-Deficit/Hyperactivity Disorder. 
Psychopharmacology (Berl). 1996; 123(1):55-63. PMID: 8741955. 
27. 
Barr RS, Pizzagalli DA, Culhane MA, Goff DC, Evins AE. A Single Dose of Nicotine 
Enhances Reward Responsiveness in Nonsmokers: Implications for Development of 
Dependence. Biol Psychiatry. 2008; 63(11):1061-1065. PMID: 17976537. 
28. 
Hong D, Conell-Price J, Cheng S, Flood P. Transdermal Nicotine Patch for 
Postoperative Pain Management: A Pilot Dose-Ranging Study. Anesth Analg. 2008; 
107(3):1005-1010. PMID: 18713921. 





ICF_001.pdf: 
MCC-16-12518
NCT04468230
Phase 2 Study of Nicotine for the Treatment of Pain Associated with Chemotherapy-
Induced Peripheral Neuropathy
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RESEARCH PARTICIPANT CONSENT FORM
TITLE: 
Phase 2 Study of Nicotine for the Treatment of Pain Associated with 
Chemotherapy-Induced Peripheral Neuropathy
PROTOCOL #:
MCC-16-12518
VCU IRB #:
HM20019616  
SPONSOR:
VCU Massey Cancer Center
INVESTIGATOR:
Renato Martins, MD
VCU Massey Cancer Center
1201 East Marshall Street
Box 980070
Richmond, VA 23298
804-628-3121
INTRODUCTION
This consent form will tell you about this research study, which is also called a clinical trial. Your 
study doctor or study team will explain the research study to you. Research studies only include 
people who choose to take part. You have the option to not participate. You may take home an 
unsigned copy of this consent form so that you can discuss the study with your family or friends 
before making your decision. You may also discuss it with your health care team. If you have any 
questions, ask your study doctor or study team for more explanation. Please take your time to 
make your decision about taking part in this study.
OVERVIEW AND KEY INFORMATION
Taking part in this study is your choice
You can choose to take part or you can choose not to take part in this study. You also can 
change your mind at any time. Whatever choice you make, you will not lose access to your 
medical care or give up any legal rights or benefits.
Why is this study being done?
Some of the chemotherapy and other drugs used to treat cancer can damage nerves that are 
around the body and outside of the brain and spinal cord (i.e., peripheral nerves). Peripheral 
nerves carry sensations (feelings) to the brain and control the movement of our arms and legs. 
They also control the bladder and bowel. When this happens, it is called chemotherapy-induced 
peripheral neuropathy (CIPN), a set of symptoms that include pain, burning, tingling, weakness, 
and loss of feeling or numbness. These symptoms may start in the hands and feet and may 
move to other parts of the body. CIPN can cause severe pain and can make it difficult to do 
things like walk, write, or button your shirt. If it gets very bad, it can cause more serious 
problems like changes in your heart rate and blood pressure, dangerous falls, trouble breathing, 
or loss of muscle function. 
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The purpose of this study is to test whether nicotine, in the form of a nicotine patch that is 
placed on the skin, can lessen the symptoms of CIPN. Another purpose of this study is to test 2 
different doses of the nicotine patch and if see one dose works better than the other. 
Up to 52 people will take part in this study.
What is the usual approach to treating my CIPN
You are being asked to take part in this study because you have been diagnosed with CIPN. 
People who are not in a research study may be treated with other drugs or other treatments 
available for CIPN.
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 duloxetine, tricyclic antidepressants, gabapentin, and topical 
applications (e.g., baclofen and ketamine) or another type of treatment, if any are 
available

You may choose to take part in a different study, if one is available

Or you may choose not to be treated for CIPN
How will my CIPN be treated if I take part in this study?
This study will not change how your cancer is treated. 
During the first treatment part of the study, you will place a nicotine patch that has a dose of 
7 mg of nicotine on your arm every day for 14 days. You will need to keep your patch on for at 
least 16 hours per day. After 14 days, you will have a washout period of at least 14 days and 
possibly up to 21 days, which means you will not wear a nicotine patch during this time. Next, 
you will place a nicotine patch that has a dose of 14 mg of nicotine on your arm every day for 
14 days for at least 16 hours per day. 
During the 14 days that you are wearing the 7 mg and the 14 mg nicotine patch, you will be 
asked to visit the clinic about once a week. You will also be asked to visit the clinic at least once 
after you have finished using the nicotine patches.
You will be given a study drug diary and will be asked to write down when you put your nicotine 
patch on and when you take the nicotine patch off every day.
How long will I be in this study?
If you do not have any serious side effects, you will be in this study for about 18 weeks or a little 
over 4 months.
After your last day of placing the 14 mg nicotine patch on your arm, your study doctor will 
continue to watch you for side effects and follow your condition for about 1 month or 30 days. 
About 3 months after your last day of placing the 14 mg nicotine patch on your arm, your study 
doctor or research nurse will call you to see if you have continued using the nicotine patch to 
lessen your CIPN symptoms, and to ask you if you have developed a dependence or addiction 
to nicotine or products containing nicotine.
What test and procedures will I have if I take part in this study?
If you decide to take part in this study, some of the exams, tests, and procedures you will have 
are part of the usual approach when treating your CIPN. Your study doctor or study team will tell 
you about these. The results of the usual exams, tests, and procedures may also be used for 
the research purposes of this study.
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In addition to the regular exams, tests, and procedures, you will need to have blood tests to find 
out if you can take part in the study. 
You will be asked to fill out some surveys with questions about your CIPN symptoms and how 
you feel. Researchers will use this information to learn more about how the nicotine patch 
affects CIPN symptoms. Each survey should take about 2 to 5 minutes. You don’t have to 
answer any question that makes you feel uncomfortable. 
You will also be asked to give one blood sample at each visit (about half of 1 teaspoon) that will 
be used to measure the amount of nicotine in your blood. This study will not use your samples 
to sequence all or part of your DNA. Blood samples remaining after the tests are completed will 
be destroyed.
You will be asked to fill out the surveys and give a blood sample during clinic visits at the 
following times during the study:

Before beginning the study 

Week 2 of your 7 mg nicotine patch treatment

Week 1 of your 14 mg nicotine patch treatment

Week 2 of your 14 mg nicotine patch treatment

During your 30-day follow-up period
Individual results of the research using your samples will not be provided to you, and there will 
be no benefit to you. The samples are collected only for this research study. If any inventions or 
discoveries result from the use of your samples, there are no plans to share any money or 
profits with you.
What are the risks and benefits of taking part in this study?
Risks
We want you to know about a few key risks right now. We give you more information in the 
“WHAT POSSIBLE RISKS CAN I EXPECT FROM TAKING PART IN THIS STUDY” section of 
this consent form.  
Some of the most common side effects that the study doctors know about are:

Dizziness

Nausea

Headache

Mild itching or redness near the area that your nicotine patch is placed
There is a small risk that you could become addicted to or dependent on nicotine while using 
nicotine patches.
Participation in research might involve some loss of privacy.
Benefits
There is no guarantee that you will receive any medical benefits from being in this study. The 
study drugs may or may not be make your CIPN symptoms better. Patients in the future may 
benefit from the knowledge gained through your participation in the study.
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WHAT POSSIBLE RISKS CAN I EXPECT FROM TAKING PART IN THIS STUDY?
You will be receiving nicotine through a patch that will be placed on your skin if you choose to 
take part in this study. There is a risk that the nicotine patch may not be as good as other drugs 
at treating your CIPN. There is also a risk that you could have side effects from the nicotine 
patch. These side effects may be worse and may be different than you would get with the usual  
approach for your CIPN.
The lists below are the most common and the most serious side effects that we know about.  If 
important new side effects are found, your study doctor will discuss these with you. Here are 
important points about side effects:

Your study doctor does 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 be serious and may even result in death
Here are important points about how you and your study doctor can make side effects less of a 
problem:

Tell your study doctor if you notice or feel anything different so they can see if you are 
having a side effect

Your study doctor may be able to treat some side effects

Your study doctor may adjust the study drugs to try to reduce side effects

Let your study doctor know of any questions you have about possible side effects. You 
can ask your study doctor questions about side effects at any time.
Common side effects associated with nicotine include:

Dizziness

Headache

Nausea

Skin Irritation

Rapid heartbeat
Some less common side effects associated with nicotine include:

Constipation

Drowsiness

Stomach cramps
Some rare side effects of nicotine include:

Hives 

Seizures

Irregular heart beat or palpitations

Trouble breathing
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We will watch you and other patients in this study very closely for any serious problems that 
could happen with a nicotine overdose and will mean that you need to stop using the nicotine 
patch:

Severe headache

Chest pain

Irregular heartbeat or palpitations

Swelling in the hands, ankles, and/or feet
The nicotine will be given to you in the form of a skin patch. Side effects that may occur near the 
area that your nicotine patch is placed include:

Mild itching

Redness

Burning

Stinging
Risk of Developing Nicotine Dependence 
There is a small risk that you could become addicted to or dependent on nicotine while using 
nicotine patches. There is a small risk that you will experience nicotine withdrawal side effects 
during the weeks that you are not using a nicotine patch (washout period) and after you remove 
the 14 mg nicotine patch on the last day of study treatment. Nicotine withdrawal side effects 
may occur within 4 to 24 hours after the removal of the nicotine patch and may last up to 3 days.
Common side effects associated with nicotine withdrawal include:

Feelings of sadness or depression

Headache

Increased appetite

Irritability

Nausea

Trouble sleeping 
Risks Associated with Collection of Blood Samples
Common side effects of blood sample collection are brief pain and bleeding or bruising at the 
puncture site used to collect the blood sample. There is also a small risk of infection, 
light-headedness, and fainting.
Reproductive Risks
You should not get pregnant or breastfeed while taking part in this study. The effects of nicotine 
to an unborn child or breastfeeding child are not fully known.
If you are able to become pregnant, you will need to have a pregnancy test to find out if you can 
be in the study. If you participate in this study, you must agree to use a reliable method to 
prevent pregnancy during the study treatment. Check with the study doctor about what methods 
of preventing pregnancy are acceptable for you.
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Interactions with Other Medications, Supplements, and Food 
There are numerous medications, herbal products, vitamins, and dietary products that can 
interact with the study drugs. Interactions with medications and supplements may cause more 
side effects or decrease the effectiveness of the study drugs or other medications. Your study 
team will review your current medications and supplements to be sure that there are no 
concerns before you start taking the study drugs. You should not start taking any new over-the-
counter or prescription medications or supplements without first checking with your study team 
about possible interactions. 
You will be given a pocket card that identifies this research study. Carry this with you at all 
times. You should show it to your health care providers so that they can check with your study 
doctor or study team member about possible interactions that may occur with new medications 
added while you are participating in this study.
Risk of Loss of Confidentiality 
Participation in research might involve some loss of privacy. Researchers will make every effort 
to protect your privacy, but there is a small risk that someone outside the research study could 
see and misuse information about you.
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 study doctor know as soon as possible so you can stop safely. If you stop, you can 
decide whether or not to let the study doctor continue to provide your medical information for the 
purpose of 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 and the study is no longer in your best interest

If you have serious side effects that require you to stop according to the rules of the 
study

If new information becomes available

If you do not follow the study rules; or

If the study is stopped by the sponsor, the Food and Drug Administration (FDA), or the 
institutional review board (IRB), which is a group of people who review the research with 
the goal of protecting the people who take part in the study
If you withdraw from the study, data that has already been collected about you will remain part 
of the study database and may not be removed.
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 cannot lose medical care or any legal 
rights by agreeing to participate in this study.
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WHAT ARE THE COSTS OF TAKING PART IN THIS STUDY?
The nicotine patches will be supplied at no charge while you take part in this study. 
You will not be charged for any costs related to the collection and testing of your blood for 
nicotine levels or surveys that are for research purposes. The blood samples and surveys are 
not used for testing that affects your care.
You and/or your health plan/insurance company will be billed for all standard costs of treating 
your CIPN, including the cost of tests, procedures, medicines, or hospital admissions to manage 
any side effects.
WILL I BE PAID TO PARTICIPATE IN THE STUDY? 
You will not be paid to take part in this study. 
WHAT HAPPENS IF I AM INJURED OR BECOME SICK BECAUSE I TOOK PART IN THIS 
STUDY?
If you are injured by, or become ill, from participating in this study, please contact your study 
doctor immediately. Medical treatment is available at the Virginia Commonwealth University 
Health System (VCU Health System). Your study doctor will arrange for short-term emergency 
care at the VCU Health System or for a referral if it is needed. 
Fees for such treatment may be billed to you or to appropriate third party insurance. Your health 
insurance company may or may not pay for treatment of injuries or illness as a result of your 
participation in this study. To help avoid research-related injury or illness, it is very important to 
follow all study directions.
WHO WILL SEE MY MEDICAL INFORMATION?
Your privacy is very important to us. The researchers will make every effort to protect it, but your 
information may be given out if required by law. However, the researchers will do their best to 
make sure that any information that is released will not identify you.
Your research information and your personal identifying information will be kept private through 
the use of password-protected electronic files, locked research areas, and study identification 
numbers. Blood samples obtained for research purposes will be stored with the same 
safeguards. The results of this research may be presented at meetings or in publications, but 
you will not be identified by name.
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:

Virginia Commonwealth University (VCU)

VCU Institutional Review Board (IRB)

Food and Drug Administration (FDA)

National Cancer Institute (NCI)
In the future, the identifiers (like your name and birthday) could be removed from the information 
you provide for this study. After that removal, your information could be used for new studies 
without asking for your consent again. Those possible new studies could be done by this study 
team or other researchers. 
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USE AND DISCLOSURE OF PROTECTED HEALTH INFORMATION
The Health Insurance Portability & Accountability Act (HIPAA) of 1996 provides for the 
protection of your health information from unauthorized use and disclosure. This section tells 
you what health information about you may be used and given out in the study and who may 
give and receive the information. By signing the consent form for this study, you agree that 
health information that identifies you may be used and disclosed as needed for this research.  
Authority to Request Protected Health Information
The following people and/or groups may request your protected health information:

Principal investigator and research staff

Study sponsor    

Research collaborators 

VCU IRB  

Data and Safety Monitoring Committee   

Government/health agencies  

Others as required by law
Authority to Release Protected Health Information 
The VCU Health System (VCUHS) may release the information identified in this authorization 
from your medical records and provide this information to:  

Health care providers at the VCUHS   

Principal investigator and research staff  

Study sponsor     

Research collaborators     

Data coordinators  

VCU IRB  

Data and Safety Monitoring Committee     

Government/health agencies     

Others as required by law
Once your health information has been disclosed to anyone outside of this study, the 
information may no longer be protected under this authorization.
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Type of Information that may be Released 
The following types of information may be used for the conduct of this research: 
Complete health record
Diagnosis and treatment codes
Discharge summary
History and physical exam
Consultation reports
Progress notes
Laboratory test results
Information about HIV tests
Information about psychiatric care
Expiration of This Authorization  
This authorization will expire (end) when the research study is closed, or when there is no need 
to review, analyze, and consider the data generated by the research study, whichever is later.
Right to Revoke Authorization and Re-disclosure
You may change your mind and revoke (take back) the right to use your protected health 
information at any time. Even if you revoke this authorization, the researchers may still use or 
disclose health information they have already collected about you for this study. If you revoke 
this authorization you may no longer be allowed to participate in the research study. To revoke 
this authorization, you must write to the investigator.
WHERE CAN I GET MORE INFORMATION?
You may visit the NCI website 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 website will not include information that can identify you. At most, the website will 
include a summary of the results. You can search this website at any time.
WHO CAN ANSWER MY QUESTIONS ABOUT THIS STUDY?
The investigator and study staff named below are the best persons to contact if you have any 
questions or concerns about this study or to report side effects or injuries. 
Renato Martins, MD
VCU Massey Cancer Center
1201 East Marshall Street
Box 980070
Richmond, VA 23298
804-628-3121
You can also contact a study team member at masseycpc@vcu.edu or the Evening/Weekend 
Doctor on Call at 804-828-0951; ask for the doctor carrying pager 9898.
The Office of Research can answer your general questions or concerns about your rights as a 
participant in this or any other research. Also, if you would like to speak to a person who does 
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not work directly with your study doctor and the study team or if you cannot reach your study 
doctor or a member of the study team, you may contact:
Virginia Commonwealth University Office of Research
800 East Leigh Street, Suite 3000
Box 980568
Richmond, VA 23298
804-827-2157
https://research.vcu.edu/human_research/volunteers.htm
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MY SIGNATURE AGREEING TO TAKE PART IN THIS STUDY
I have been given the opportunity to carefully read this consent form. All of the questions that I 
wish to raise concerning this study have been answered.
By signing this consent form, I have not given up any of my legal rights or benefits. My signature 
indicates that I freely consent to participate in this research study. 
________________________________________________
Participant Name (Printed) 
________________________________________________
________________
Participant Name (Signature) 
Date
________________________________________________
Person Conducting Informed Consent Discussion (Printed Name) 
________________________________________________
________________
Person Conducting Informed Consent Discussion (Signature) 
Date
________________________________________________
________________
Signature of Investigator (If different than above) 
Date
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