Clinical trial NCT02265874
Conditions: Sarcoidosis
Sponsor: Ohio State University
Start date: 2015-10-21; Completion date: 2021-11-01
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine if nicotine treatment is beneficial for the treatment of sarcoidosis. Sarcoidosis is a disease of unknown cause that leads to inflammation. This disease affects your body's organs.

Detailed description:
Participants will be randomly divided into two groups. One group will receive a nicotine patch to use for approximately 7 months; the other group will receive placebo for nicotine patches to use for the same time period.

Both groups will be contacted weekly by phone for the first 3 weeks then monthly for the duration of the study to monitor for any side effects.

The following information and samples will be collected:

Questionnaires Medical History Spirometry CT Scans Physical Exam Blood Samples for nicotine and nicotine metabolites

Arms: arm 1: Habitrol Nicotine patch - 7,14,21 mg patches Qd arm 2: Placebo patch
Interventions: intervention 1: Habitrol intervention 2: Placebo to Habitrol
Intervention descriptions: intervention 1: Patch used daily for 28 weeks intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
IRB Protocol Number: 2014H0291 
 
 
1 
September 1, 2015 
 
 
 
The following Study Protocol and Statistical Analysis Plan pertains to:  
Protocol ID 2014H0291  
NCT02265874 
Document date: March 26, 2018 
Nicotine Treatment for Pulmonary Sarcoidosis: A Clinical Trial Pilot Study  
Study Type: Interventional  
Official Title: Nicotine Treatment for Pulmonary Sarcoidosis: A Clinical Trial Pilot Study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


IRB Protocol Number: 2014H0291 
 
 
2 
September 1, 2015 
 
Project Title: Nicotine Treatment for Pulmonary Sarcoidosis: A Clinical Trial Pilot Study 
Table of Contents 
A. Introduction………………………………………..………………………………… 
3 
 
B. Background…………………………………………………………………………. 
3-4 
 
C. Study Objectives………………………………………………………………………. 4 
 
D. Investigational Agent……………………………………………………………….. 4-5 
D1. Preclinical Data…………………………………………………………… 
4-5 
D2. Clinical Data to Date…………………………………………………… 
5 
D3. Dose Rationale and Risk/Benefit……………………………….. 
 
5 
E. Study Design……………………………………………………………………….. 
6-9 
E1. Design Summary…………………………………………………………. 
6 
E2. Subject Selection and Withdrawal………………………………. 
 
7-8 
E3. Study Drug………………………………………………………………….. 
9 
F. Study Procedures………………………………………………………………….. 
8-12 
F1. Screening Procedures…………………………………………………. 
8 
F2. Schedule of Measurements……………………………………….. 
 
9 
F3. Safety and Adverse Events…………………………………………..  
9-11 
F4. Study outcome Measures and Ascertainment…………….  
 
11-12 
G. Statistical Plan…………………………………………………………………….. 
12-14 
G1. Sample Size and Determination of Power………………….. 
 
12 
G2. Interim Monitoring and Early Stopping………………………. 
 
13 
G3. Analysis Plan……………………………………………………………….. 
13 
G4. Statistical Methods…………………………………………………….. 
13 
G5. Missing Outcome Data………………………………………………… 
14 
G6. Unblinding Procedures………………………………………………..  
14 


IRB Protocol Number: 2014H0291 
 
 
3 
September 1, 2015 
 
H. Data Handling and Security……………………………………………………….. 14-15 
H1. Confidentiality and Security……………………………………… 
 
14 
H2. Training…………………………………………………………………….. 
14 
H3. Case Report Forms and Source Documents……………… 
 
14 
H4. Records Retention and Disposal………………………….…… 
 
15 
H5. Performance Monitoring…………………………………………. 
 
15 
I. 
Study Monitoring, Auditing and Inspecting………………………………  
15-16 
 
J. Study Administration……………………………………………………………….. 16-17 
J1. Organization and Participating Centers…………………….. 
 
16 
J2. Committees………………………………………………………………. 
17 
J3. Subject Stipends……………………………………………………….. 
17 
J4. Study Timetable………………………………………………………… 
17 
K. Data Sharing and Publication Plan……………………………………………… 
17-18 
 
L. Tables…………………………………………………………………………….… 
19 
 
M. References…………………………………………………………………………… 
20-22 
 
 
 


IRB Protocol Number: 2014H0291 
 
 
4 
September 1, 2015 
 
A. Introduction 
Sarcoidosis is a systemic granulomatous disease of unknown cause, most commonly affecting the lungs, 
afflicting young to middle-aged adults in the prime of their lives, for which highly effective and well-tolerated 
therapies are lacking.  First-line therapies for sarcoidosis are often ineffective, poorly tolerated and promote 
long-term health complications.   Industry-sponsored clinical trials have tested proprietary, expensive and 
potentially toxic therapies that are reserved for refractory cases of sarcoidosis (1). Given that nicotine patches 
are FDA approved for other indications and readily available to the public without a prescription, it is unlikely 
that a multi-center placebo-controlled nicotine trial for sarcoidosis will ever be conducted without NIH-support.  
In keeping with the NIH’s goal to “repurpose” existing biologics, the proposed Clinical Trial Pilot Study will 
provide preliminary data required to design subsequent Phase II/III trials to evaluate nicotine as a novel low-
cost, highly-effective, and safe treatment option for patients with active pulmonary sarcoidosis.  
Nicotine may be beneficial for the treatment of pulmonary sarcoidosis.  At least three independent 
epidemiological studies indicate that smokers and chewing tobacco users, chronically exposed to nicotine, 
have a ~2-fold lower risk of developing sarcoidosis (2-4).   Nicotine reprograms inflammatory pathways through 
the actions of α7 nicotinic receptors (5), thereby inhibiting various pro-inflammatory immune responses (5,6), 
particularly prototypical Th1 immune responses (7,8), which are the hallmark of sarcoidosis and other 
granulomatous disorders.  Reprogramming of Th1 immunity could explain the benefits of nicotine treatment for 
Crohn’s disease (9) and hypersensitivity pneumonitis (10), granulomatous disorders of the intestines and 
lungs, respectively.   Our pilot study showed that nicotine is well-tolerated, and normalizes Th1 type immune 
responses in patients with active pulmonary sarcoidosis (11).   The specific objective of this project will 
determine if nicotine treatment is safe and efficacious for patients with active pulmonary disease despite 
conventional therapy. 
 
B. Background 
Sarcoidosis is characterized by the development of non-necrotizing granulomatous inflammation in the 
absence of identifiable infectious or environmental causes.  The disease typically involves the lungs, frequently 
leading to impaired exercise tolerance and associated dyspnea.  A majority of patients with active pulmonary 
sarcoidosis complain of overwhelming fatigue, which often persists despite administration of immune-
modulating drugs typically used to treat sarcoidosis (12,13).  Furthermore, conventional treatments are 
associated with a spectrum of serious untoward effects, including diabetes mellitus, osteoporosis, bone 
marrow suppression, severe infections, cirrhosis, etc. (14,15).  Indeed, the use of corticosteroids, the mainstay 
of pulmonary sarcoidosis treatment, is independently associated with a reduced quality-of-life (16).   Although 
potent anti-TNFα drugs can be effective alternatives to usual care (1,14,15) they are exceedingly expensive, 
many insurance agencies (e.g., Medicare) and the FDA do not approve their use for sarcoidosis, and they 
predispose to serious complications, including the reactivation of latent TB, serum sickness, and increased risk 
of malignancy (17).  As such, these agents are typically reserved for the treatment of refractory disease.  
Nicotine, through its actions on α7-nicotinic receptors, possesses potent immune-modulating actions.  At 
higher concentrations (µM), nicotine suppresses antigen-mediated TNFα production (5,6), induces regulatory T 
cells (18-20), suppresses Th1 type immune responses (7,8), particularly in the lung (21,22), and, as such, is 
expected to suppress Th1-dependent granuloma formation.  In support of a benefit in sarcoidosis, large 
epidemiological studies consistently show that chronic nicotine use (smoking or smokeless tobacco) reduces 
the risk of developing sarcoidosis (2-4).  Moreover, by stimulating the dopaminergic axis of the brain, nicotine 
significantly improves fatigue (23) and depression symptoms (24,25), which are common (prevalence >50%), 


IRB Protocol Number: 2014H0291 
 
 
5 
September 1, 2015 
 
quality-of-life-altering disease manifestations in sarcoidosis patients (16,26).  Based upon these observations, 
and our supportive preliminary data, we hypothesize that nicotine will be an effective therapy for sarcoidosis.  If 
shown to be effective, the contribution is significant because nicotine is already FDA approved for this 
application (established for our pilot study), is readily available to patients, is shown to be well-tolerated, and 
represents a low-cost, low-risk alternative to currently available treatments.  As such, this project represents an 
opportunity to “repurpose” nicotine for a new therapeutic application.   
C. Study Objectives 
Rationale for the proposed study aims:  It should first be emphasized that this Clinical Trial Pilot Study is 
designed to provide preliminary clinical efficacy and safety data for the purpose of planning a subsequent 
definitive multi-institutional clinical trial 
In terms of meaningful clinical endpoints, serial pulmonary function testing, particularly forced vital capacity 
(FVC) is the current objective standard for assessing disease status in patients with pulmonary sarcoidosis.  
Thus, changes in FVC will be considered as the primary clinical endpoint for this clinical trial.  However, serial 
FVC measurements can vary up to 10%, and expected changes in FVC with effective therapies is typically less 
than 5%, necessitating larger clinical trials to demonstrate efficacy.  In contrast, changes in radiographic 
pulmonary disease manifestations in the context of effective therapies for sarcoidosis are much greater in 
magnitude than FVC (27).  Furthermore, changes in pulmonary radiographic disease burden are an accepted 
surrogate for FVC and other clinical endpoints (28-31).  In this regard, we have developed an objective 
computerized CT image analysis tool that can detect the common manifestations of pulmonary sarcoidosis and 
correlates strongly with FVC (32).  Of note, our new unpublished data demonstrates strong correlations 
between the Lung Texture Score (LTS) derived from computerized CT image analysis and lung disease 
severity (as reflected by FVC, total lung capacity (TLC), and lung diffusing capacity) in other interstitial lung 
diseases (data not shown), which further validates this novel lung CT image analysis approach.  Other 
meaningful clinical endpoints relating to disease-specific symptoms will be considered in Aim 3.  For instance, 
fatigue is among the most common and disabling symptoms associated with sarcoidosis, which is often 
refractory to conventional sarcoidosis treatments (16, 26), and there is reason to believe that nicotine treatment 
will attenuate these symptoms (23-25).  Finally, and in the spirit of a Clinical Trial Pilot Study, Aim 4 will 
address drug safety and tolerance, for the purpose of planning a larger, more definitive clinical trial.  
Aim 1: Estimate study size for a definitive randomized control trial (RCT) based upon change in Forced 
Vital Capacity (FVC) in pulmonary sarcoidosis patients treated with transdermal nicotine for 24 weeks.    
Aim 2: Determine if nicotine treatment is associated with improvement in radiographic lung disease 
burden in patients with pulmonary sarcoidosis. 
Aim 3: Consider alternative clinical endpoints for future nicotine RCT based upon subjective clinical 
response to nicotine treatment in pulmonary sarcoidosis patients.    
Aim 4: Determine the safety and tolerance of nicotine treatment in patients with pulmonary sarcoidosis 
for the design of subsequent definitive double-blinded RCT.  
D. Investigational  Agent 


IRB Protocol Number: 2014H0291 
 
 
6 
September 1, 2015 
 
D1. Preclinical Data from the Pilot Study: “Nicotine for the Treatment of Pulmonary Sarcoidosis”:  Our 
pilot study sought to determine if nicotine was well-tolerated and would restore antigen-mediated immune 
responses in patients with active pulmonary sarcoidosis.  Nicotine was reviewed as an investigational new 
drug (IND) by FDA and by our local IRBs to treat sarcoidosis patients.  The findings of the study are detailed in 
our recent publication (11).  To summarize, there were no serious adverse events or signs of addiction or 
dependency.  In keeping with previous nicotine patch studies (33), minor side effects occurring at a frequency 
exceeding 10% were: headaches, abnormal dreams, agitation, insomnia, and local skin irritation, which 
improved or resolved within weeks of treatment.  There was a trend towards lower fatigue scores, but no 
statistically significant changes were observed in reported sarcoidosis symptoms (SHQ, FAS) or measured 
FVC following nicotine treatment. 
Nicotine treatment was associated with normalization of peripheral blood T cell subsets. In keeping with 
previous studies (34), active pulmonary sarcoidosis was associated with peripheral lymphopenia, including 
reduced FoxP3+ regulatory T cells (Tregs).  Nicotine was shown to reverse peripheral lymphopenia and 
restore Treg populations, particularly a CD25- subset that was recently shown to be a “pre-activated” Treg.  
The CD4+CD25-FoxP3+ Treg subtype is interesting in that it lacks suppressive actions on effector (CD4+) T 
cells, becoming regulatory upon stimulation (e.g., IL-2) (35).  Thus, these cells are believed to be in transit to 
diseased tissues whereupon they adopt suppressive activity (36). 
Nicotine treatment reverses peripheral anergy.  Peripheral anergy to certain antigens is a well-known 
feature of active pulmonary sarcoidosis, and correlates with disease severity (37).  In keeping with previous 
studies (38,39), our data shows that patients with active pulmonary sarcoidosis are specifically anergic to 
TLR2, TLR4 and TLR9 ligands.  Moreover, nicotine treatment restored immune responsiveness to these 
ligands.  This data is conforms to the hypothesis that sarcoidosis is associated with blunted antigen-mediated 
immune responses leading to impaired antigen clearance and sustained granulomatous inflammation (40).  
The proposed ancillary studies will determine the mechanisms by which nicotine, and more specifically α7-
nicotinic receptors, restores antigen-mediated T cell responses.   
Nicotine treatment did not promote tachyphylaxis.  It is interesting to note that α7-nicotinic receptor 
expression is dramatically increased in patients with active pulmonary sarcoidosis, which is predictive of 
response to nicotine (11).  One concern relating to the chronic effects of nicotine was the potential 
development of tachyphylaxis (e.g., reduced α7-nicotinic receptor expression).   No change in α7-nicotinic 
receptor expression on immune cells was observed in the nicotine treatment group (11).   
D2. Clinical Data to Date 
Our previous pilot study was not powered to assess clinical endpoints relating to efficacy.  However, nicotine 
was well-tolerated in patients with pulmonary sarcoidosis.  Common (>10%) minor side effects observed in our 
pilot study (11), and reported elsewhere (33), includes local skin irritation, headaches, nightmares, sleep 
disturbances, which tend to subside with ongoing therapy.  There were no serious adverse effects. 
D3. Dose Rationale and Risk/Benefits 
Cigarette smokers, and smokeless tobacco users, have ~2-fold reduction in risk of developing sarcoidosis (2-
4).  Transdermal nicotine patch delivery systems are designed to attain in vivo drug levels approximating that 
of regular cigarette smokers, which is in the 10-40 nM range (41,42).  Nicotine in this concentration, when 
achieved in animals, is shown to suppress T-cell mediated immune responses (43, 44).  The 21 mg/day 
nicotine patch achieves drug levels within this range humans (41,42), and is shown to be well tolerated in 
terms of serious adverse events in large clinical studies (45).  Furthermore, the transdermal nicotine delivery 


IRB Protocol Number: 2014H0291 
 
 
7 
September 1, 2015 
 
approach reduces the risk of developing dependency by providing steady nicotine levels in vivo (46).  To the 
extent that nicotine levels attained in smokers prevents the development and progression of sarcoidosis, the 
21 mg/day transdermal nicotine dose achieves our goal of attaining a biologically relevant dose of nicotine that 
will be well-tolerated in most subjects. 
 
 


IRB Protocol Number: 2014H0291 
 
 
8 
September 1, 2015 
 
E. Study Design 
E1. Overview of Design Summary 
This will be a prospective, randomized, parallel design with multiple measures, double-blinded, placebo-
controlled study conducted on adults with confirmed sarcoidosis (e.g., biopsy proven, or a clinical diagnosis 
made by sarcoidosis experts) sarcoidosis to determine the effects of transdermal nicotine treatment in patients 
with active pulmonary disease despite conventional therapies.  Patients will be enrolled sequentially and based 
solely on eligibility.  Patients will be randomized in a 1:1 ratio to receive transdermal nicotine 21 mg/daily or an 
identical-appearing placebo patch.  Baseline measurements will be made at the screening and baseline visits 
on all patients prior to receiving their randomized assigned treatment  to a nicotine treatment group (n = 25 
patients) and a control group (n = 25 patients) assigned to placebo patch treatment. Nicotine treatment will 
begin with a 2 week phase in during which the dose of nicotine will be increased weekly towards the highest 
tolerated dose, using the transdermal drug delivery approach (7 mg patch, 14 mg patch, 21 mg patch). 
Patients will be maintained on the highest tolerated dose (7-21 mg patch) for the duration of the 24 week 
treatment protocol.  Nicotine treatment will then be deescalated weekly (i.e., 14 mg, 7 mg, and then 
discontinued).   
E2. Subject Selection and Withdrawal 
 Inclusion and Exclusion Criteria:   
Adult male and female subjects ≥ 18 to ≤ 75 years of age will be screened for eligibility. Eligible adult patients 
will have: 
 
Strong clinical evidence of sarcoidosis confirmed by the expert pulmonologists (site PIs), diagnosed at 
least 2 months before screening, with evidence of parenchymal disease on a recent chest radiograph 


IRB Protocol Number: 2014H0291 
 
 
9 
September 1, 2015 
 
performed as part of routine clinical care or during initial screening for this study (for the purpose of 
research). 
 
 A Medical Research Council dyspnea score (47) of at least grade 1 
 
Patients must be on no treatment or on a stable treatment regimen for sarcoidosis for at least one 
month prior to enrollment in the study.  
Major exclusion criteria include: 
 
Recent (within 3 mos) treatment with an anti-TNFalpha therapy (infliximab, adalimumab, etanercept, 
etc).   
 
Active tobacco smoking or use of smokeless tobacco products containing nicotine  
 
Active cardiac or central nervous system disease  
 
History of adverse reaction to nicotine or nicotine-containing products  
 
Patients with extensive irreversible pulmonary fibrosis (based upon lung biopsy or high resolution CT 
scan criterion)  
 
Inability to provide consent.   
 
The subject will be excluded if they have recently smoked (within 6 months ) or have a diagnosis of 
other significant respiratory disorder other than sarcoidosis that in the opinion of the investigator would 
complicate the evaluation of response to treatment.  
 
History of substance abuse (drugs or alcohol) within 3 years prior to screening or other circumstances 
(e.g., psychiatric disease) that could interfere with the subject’s adherence to protocol requirements or 
increase their risk of drug (nicotine) dependence.   
 
Patients with a diagnosis of current or recently active cancer (within 1 year) will be excluded.  
 
Pregnant women will be excluded 
 
Ethical Considerations:  Enrollment will be restricted to adults who are capable of providing informed consent 
and will be unbiased to race, gender or economic status.  To avoid any risk of coercion, we will not recruit 
prisoners.   
Subject Recruitment Plans and Consent Process:  Patients will be enrolled sequentially and based solely on 
eligibility. Consent will be obtained by experienced research coordinators under the direct supervision of the 
site PI at each clinical site and only after obtaining written, informed consent.  Subjects who are successfully 
screened will be assigned a subject number. 
 
We will leverage existing CTSA (NIH) supported resources.  For instance, we will utilize OSU’s CTSA-
sponsored “Research Match” program, a secure volunteer registry for prospective study participants, to screen 


IRB Protocol Number: 2014H0291 
 
 
10 
September 1, 2015 
 
for potential study subjects and subjects will be able to actively seek the study using the “StudySearch” tool 
that lists research studies and clinical trials at The Ohio State University that are actively seeking participants.  
Additional advertising of the study will be available by entering the study into the ClinicalTrials.gov registry.   
If, during the screening phase, the subject has a clinically significant worsening of sarcoidosis requiring 
adjustment of baseline medications, the subject will be considered a screen failure and is not eligible for 
randomization at that time. In this case, the subject may be rescreened after appropriate treatment has been 
given, and the subject has been on a stable dose of the medication for at least 4 weeks.  
An informed consent form will be prepared according to the institutional requirements for informed 
consent and the applicable regulations.  A sample consent form from the related pilot study (11) is provided in 
the Appendix.  The appropriate IRB must approve the protocol and informed consent documents, agree to 
monitor the conduct of the study, and agree to review study progress periodically, at intervals not to exceed 1 
year.  To this end, the two Clinical and Translational Science Award (CTSA) institutions engaging in this study 
from Ohio (Ohio State University and Cleveland Clinic Foundation) have established a statewide collaborative 
agreement allowing a single IRB, in this case Ohio State University’s, to assume IRB responsibilities on behalf 
of multiple institutions when conducting multicenter studies.  This collaborative arrangement will serve to 
accelerate research by streamlining human subject protection processes. 
The consent form will be reviewed with the prospective study subject or his/her legal representative, 
and the investigator will be available to answer questions regarding procedures, risks, and alternatives. The 
principal investigator or his/her entitled designee (as defined on the Delegation List) will obtain written informed 
consent from each subject or from the subject’s legal representative or designee. Consent will be obtained 
before any protocol-specific procedures are performed. Documentation of the subject’s informed consent for 
and participation in this study will be noted in the subject’s medical record. If the subject is enrolled in the 
ancillary study relating to this protocol, a sub study-specific consent must also be used. The subject or his/her 
legal representative must be provided with a copy of the consent form for the main study and a copy of any 
separate consent form for the sub study (if applicable). 
 
Randomization Method and Blinding: Patients will be randomized to nicotine or placebo in a 1:1 ratio.  
Randomization will be within each site (balanced by site) and use permuted blocks of varying size (2,4,6).  The 
randomization scheme will be developed by the study statisticians and the scheme allocated through the 
blinded study subject number.  Study drug will be pre-packaged with an assigned study subject number, 
corresponding to the allocated randomized treatment. All baseline measurements will be obtained at the 
screening and baseline visit before allocation of the random assignment.  Identically labeled nicotine and 
placebo patches will be randomly designated treatments “A” or “B”, and will be distributed by each clinical 
center. 
Risks and Benefits:  Nicotine intolerance rates are very low, even at doses 2-fold greater than the maximum 
dose used in this study (48).  Common (>10%) minor side effects observed in our pilot study (11), and reported 
elsewhere (33), includes local skin irritation, headaches, nightmares, sleep disturbances.  We are aware of the 
potential for serious adverse events, particularly cardiac arrhythmias (49) and seizures (50) in patients with 
underlying heart or central nervous system disease, respectively, and will exclude patients with these risk 
factors from enrollment in this study. 
Early Withdrawal of Subjects:  Patients will be immediately withdrawn from the clinical trial for any of the 
following reasons: 1) at the request of the subject, 2) at the discretion of clinicians caring for the patient, 3) as 


IRB Protocol Number: 2014H0291 
 
 
11 
September 1, 2015 
 
advised by the DSMB, 4) if the subject is unable to comply with the study protocol.  The Research Manager will 
be notified within 48 hrs of the subject’s withdrawal and will record the reason for withdrawal. 
Data Collection and Follow-up for Withdrawn Subjects:  Withdrawn subjects will be encouraged to return for 
the post intervention study-related procedures, including image analyses, surveys, and PFTs, in order to 
include them in analysis, following the intention-to-treat principle. 
E3. Study Drug 
Description: Sustained release transdermal nicotine (7, 14 and 21 mg daily dose patches) and matching 
placebo patches will be provided. The nicotine patches and matching control patches will be administered daily 
according to the manufacturer’s recommendations and in compliance with a FDA approved dosing regimen. 
Treatment Regimen: To optimize patient compliance and minimize side-effects, nicotine (or matching placebo 
patch) treatment will be initiated at 7 mg/day and escalated at weekly intervals to 14 mg/day, then 21 mg/day, 
as tolerated.  If intolerance develops, the dose will be reduced to the highest tolerated dose.  The dose will be 
maintained at 21 mg/day (or the highest tolerated dose) for 24 weeks, at which time the dose will be 
deescalated to 14 mg/day, then 7 mg/day at weekly intervals, after which nicotine treatment will be 
discontinued.   
Method for Assigning Subjects to Treatment Groups:  Patients will be randomized to nicotine or placebo 
patches in a 1:1 ratio. The randomization scheme will be developed by the study statisticians and the scheme 
allocated through the blinded study subject number.  Study drug will be pre-packaged with an assigned study 
subject number, corresponding to the allocated randomized treatment. Treatment allocations will be blinded to 
study clinical staff, treating clinicians and patients. Nicotine and replica placebo patches will be randomly 
designated treatments “A” or “B”, and will be distributed by each clinical center.  All baseline measurements will 
be obtained at the screening and baseline visit before allocation of the random assignment  
Preparation and Administration of Study Drug:  Patients will be instructed to apply a new patch to their skin 
every day.  The site should be clean (e.g., with warm soapy water) and dry at the time of application and only 
one patch should be placed at a time (old patches must be removed before applying a new one).  The backing 
of the patch is removed to reveal the sticky surface, which is placed on the skin.  To avoid local skin irritation, a 
new site is recommended (e.g., on the upper arm) each day. 
Subject Compliance Monitoring:  Subject compliance with nicotine will be monitored by history and objectively 
at regular intervals, as reflected by measuring nicotine and cotinine, a stable nicotine metabolite, as per the 
Study Schedule of Events (Table 1), described below. 
Prior and Concomitant Therapy:  As described in the Inclusion Criteria, above, study subjects will remain on 
prior and concomitant medications (if applicable), as tolerated, for the duration of the study.  The addition of 
new medications or changes in current medication doses will be considered a violation of the study protocol.  
However, the patients will be retained in the study to consider trends in de-escalation or escalation of treatment 
in the treatment and placebo groups. 
Packaging and Blinding:  The packaging of the nicotine patches and placebo patches will be identical in 
appearance such that the patients and research staff remain blinded to treatment.  Identically labeled nicotine 
and placebo patches will be randomly designated treatments “A” or “B”, and will be distributed by each clinical 
center.   


IRB Protocol Number: 2014H0291 
 
 
12 
September 1, 2015 
 
F. Study Procedures 
F1. Screening Procedures 
This study will be conducted in accordance with current US FDA regulations and guidelines, ICH guidelines on 
GCP, the principles of the Declaration of Helsinki, as well as all other applicable national and local laws and 
regulations.  Patients will be screened by fully qualified research coordinators at each clinical center based 
upon the inclusion and exclusion criteria.  Verification of active pulmonary sarcoidosis will include review of 
pathology reports and/or tissue samples (if available), and review of radiographs (chest x-ray and/or lung CT 
scans) by a board-certified pulmonologists (i.e., the site PIs).   A chest x-ray will be performed if the patient has 
not had one done within the past year. A thorough history and physical exam will be conducted and an ECG 
will be routinely obtained (if not already available) to screen for cardiac disease and other exclusion criteria, as 
described above. 
F2. Schedule of Measurements 
The schedule for study visits including the assessments and procedures to be performed at each visit is 
presented in the Schedule of Events (see Table 1). The scheduled study visits should occur at the specified 
week post-randomization ± 7 days unless otherwise specified. It is encouraged that study visits be scheduled 
in the morning, at the same time for each visit, unless extenuating circumstances exist.  In addition to 
scheduled visits, monthly telephone interviews will be conducted by the study site research coordinators to 
establish/encourage compliance with nicotine (placebo) patches and to screen for adverse events. 
F3. Safety and Adverse Events 
Safety analyses will be based on treatment received. Safety data, including but not limited to, AEs, serious AEs 
(SAEs), infections, serious infections, mortality, changes in laboratory assessments, and changes in vital signs. 
Treatment-emergent AEs will be summarized by treatment group. 
All untoward events occurring between the time of obtaining informed consent through Week 34 must 
be reported as an AE.  In keeping with the standards of clinical trials research, the relationship of AEs to 
nicotine will be classified as “definitely related”, “possibly related” or “unrelated”, and we will further document 
the reason for subject dropout, report subjects with multiple adverse events, and track disease exacerbations 
(requiring escalation of corticosteroid dose or unscheduled healthcare visits).   
 
The severity of AEs will be made using the following general categorical descriptors: 
 
Mild: Awareness of symptoms that are easily tolerated causing minimal discomfort and not interfering 
with everyday activities. 
 
Moderate: Sufficient discomfort is present to cause interference with normal activity. 
 
Severe: Extreme distress causing significant impairment of functioning or incapacitation and preventing 
normal everyday activities. 
 
Based upon our pilot study (11) and previous published reports (33), we expect to see an increase in the 
frequency of mild side effects with no significant SAEs in the nicotine treatment group compared to placebo 
controls.  These minor side effects tend to abate with continued use of nicotine, and only one subject withdrew 
from the pilot study due to local skin irritation at the site of the patch.  For this reason, we will encourage the 
subjects to alter the site of the transdermal patch on a daily basis. 


IRB Protocol Number: 2014H0291 
 
 
13 
September 1, 2015 
 
There is a potential for a placebo effect with respect to the use of a patch in the nicotine treatment 
group compared to controls.  However, a placebo effect would be expected to influence subjective measures 
(e.g., dyspnea scores); whereas, objectives measures of lung function or radiographic findings would be 
effected very little, if at all. 
Subjects will be instructed to call the investigator if their symptoms of sarcoidosis worsen. Based upon 
the investigator’s assessment of the subject’s symptoms, functional parameters, and the subjects’ history, a 
clinic visit may be scheduled. If in the investigator’s opinion the symptoms of sarcoidosis have worsened 
sufficiently to require treatment, the investigator will assess the severity and initiate appropriate treatment 
depending upon the subject’s condition.  Despite escalation of treatment, the patient will remain enrolled in the 
study. 
 
Patients will be followed for an additional 4 weeks after nicotine treatment to determine if they required 
any change in medications, including escalation of therapy for sarcoidosis, and to screen for signs of nicotine 
dependency or withdrawal.  Although nicotine dependency did not occur in the pilot study and is documented 
to be rare in the setting of transdermal preparations (33), likely due to steady and sustained drug levels 
(45,46), it remains a potential concern.  As such, study subjects demonstrating nicotine dependency or 
addiction symptoms (e.g., nicotine craving or inability to discontinue nicotine-containing products) one month 
after discontinuation of the drug will be provided support to engage in a smoking cessation program, which has 
extensive experienced with nicotine dependency and addiction management (51). 
F4. Study Outcome Measurements and Ascertainment 
The primary endpoint of the study will be the change in FVC, measured before and after treatment with 
nicotine or placebo for a total of 24 weeks.  
The secondary clinical endpoint of major interest will be the change in total burden of lung disease, as 
reflected by the computer-generated CT image analysis or changes in lung function.  Data files will be de-
identified and thereby blinded to the investigative team.  Moreover, the computer-generated Lung Texture 
Score (LTS) ascertained from these analyses are objective, highly reproducible, and strongly correlate with 
standard physiological (PFT) measures (32).  
Other secondary endpoints will determine if changes in LTS correlate with changes in simultaneous 
PFT measures or measures of the rate of nicotine metabolism, as reflected by the ratio of 3-hydroxycotinine to 
cotinine in serum samples.  Finally, the effects of nicotine treatment on disease-related symptoms will be 
determined by comparing the results of surveys (SAT, SGRQ, FAS) conducted at regular intervals during the 
study protocol.  Again, these analyses will remain blinded to treatment allocation until the close and un-blinding 
of the study. 
PFT measurements: 
The post-bronchodilator FVC, forced expiratory volume in 1 second (FEV1), peak expiratory flow rate (PEFR), 
and forced expiratory flow at 25% to 75% of vital capacity (FEF25-75) will be measured according to the body 
temperature, pressure, and saturation (BTPS) standard convention. PFTs will be repeated up to 8 times to 
obtain 3 acceptable readings according to American Thoracic Society (ATS) guidelines. Acceptable 
repeatability is achieved when the difference between the largest and the next largest FVC is ≤ 0.150 L and the 
difference between the largest and the next largest FEV1 is ≤ 0.150 L. However, if a subject is too tired to meet 
this consistency requirement, the PFT values from the best effort can still be accepted as long as this best 
effort meets the other ATS criteria. Subjects should refrain from using short acting bronchodilators for at least 4 


IRB Protocol Number: 2014H0291 
 
 
14 
September 1, 2015 
 
hours and long-acting bronchodilators for at least 12 hours prior to the screening visit. Percent predicted FVC 
and FEV1 will be calculated according to the Crapo equation (52), with correction for race. 
CT scans and x-ray:  CT scans will be performed at the baseline assessment or within 3 months prior to 
enrollment so long as the following criteria are also met: 1) the CT scan was obtained for clinical reasons and 
on the same scanner used for the research study, 2) the patient’s sarcoidosis treatment regimen was 
unchanged within the past 3 months, and 3) respiratory symptoms (cough, dyspnea) were stable.  The imaging 
protocol will be standardized across the clinical centers: Non-contrast CT scans will be obtained by using a 
helical technique with a 16- or 64-detector row CT scanner. Images will be obtained from lung apices to the 
lung bases in a single breath hold with the following parameters: collimation, 1.25 or 0.625 mm; field of view, 
36 cm; beam pitch, 1.35 or 1.375; gantry speed, 0.5 or 0.6 sec/rotation; 120 kVp; 150–200 mA.  The image 
files will be sent from a proxy PACS server located at each clinical center and transferred via a Virtual Private 
Network (to assure data confidentiality) and processed by Dr. Erdal via a workstation located within the 
Department of Radiology at OSU.  The image data will be reformatted with a 5-mm section thickness using 
standard lung algorithms.  The lung image files are then segmented using Houndsfield units (-200 to -1000), 
and a two-point correlation function based approach to determine the presence of texture mismatches 
representing diseased lung is conducted within each volume of lung tissue using a proprietary plug-in program 
that can be operated on the publicly available NIH Image J Toolkit (http://rsbweb.nih.gov/ij/index.html ) to create a 
regional lung texture score (LTS).  The LTS for a given volume is integrated into an LTS for the entire lung, 
reflecting the overall burden of lung disease (32).   
A chest x-ray will be performed at screening if one has not been done within the past year.  
Prior to all radiation procedures, a urine pregnancy test will be done. If the result of the urine pregnancy test is 
positive, a serum pregnancy test will be done. P 
Blood draws: Study subjects will undergo scheduled venopuncture under sterile technique for the purpose of 
obtaining 10 ml of blood to measure nicotine and nicotine metabolites (at baseline, 10 and 28 weeks). The 
blood samples will be labelled with the same identifier used for the subject’s web-based data entry (REDCap), 
and will be stored on site at OSU and CCF at -80º F in a secure (password protected) laboratory until the final 
analysis for nicotine and related metabolites (cotinine).  The samples from CCF will be shipped by same-day 
delivery on dry ice (i.e., -80 º  F) as a single batched sample prior to analysis.   
Surveys:  Well-standardized surveys will be administered according to the Study Schedule of Events (Table 
1).  These will be conducted during scheduled study-related visits or by mail (self-addressed first class mail 
through the US postal service).    The following standardized surveys will be employed (examples of each are 
provided in the Appendix): 
The Fatigue Assessment Scale (FAS) is a 10-item patient self-report instrument with five items reflecting 
physical fatigue and five assessing mental fatigue. The response options range from never (1) to always (5) for 
a total score from 10 to 50. Psychometric qualities are reported as satisfactory by the authors, and the 
instrument has been able to differentiate healthy respondents from patients with sarcoidosis (53,54). 
The St George’s Respiratory Questionnaire (SGRQ) is a disease-specific survey instrument designed for 
use with adult subjects to assess the impact of respiratory disease and its treatment on the subject’s health 
outcomes (55). The SGRQ is self-administered and is usually completed within 10 to 20 minutes. The 
instrument contains 76 items in three domains: symptoms (frequency and severity), activity limitations, and 
impacts on social and psychological functioning.  The response categories use a Likert scale or dichotomous 


IRB Protocol Number: 2014H0291 
 
 
15 
September 1, 2015 
 
responses. The methods used for development of the instrument have not been published and criteria for item 
selection are unclear. The psychometric properties have been reported to be adequate. The instrument has 
been used extensively in research with asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, 
IPF, and interstitial lung disease.  
The Sarcoidosis Assessment Tool (SAT) is a self-administered health-related quality-of-life (HRQL) 
instrument that is validated against other standardized HRQL instruments for patients with active sarcoidosis 
and is further validated to specifically detect changes in the severity of lung involvement (56). 
 
G. Statistical Plan 
G1. Sample Size Determination and Power 
Depending on the clinical efficacy of nicotine compared to another immune modulating agent (infliximab), we 
expect to see up to 3% improvement in FVC in the nicotine treatment group based upon a comparable study 
design in patients with active pulmonary sarcoidosis (27).  With the expected 25 patients per group and average 
change variance at a minimum of 3% for FVC, the precision of a comparison of means is roughly adequate for 
planning, but is insufficient for achieving significance unless the nicotine effect on FVC is large (e.g., >5%) as 
compared to controls.  We will report p-values for these as secondary outcomes, and derive meaning only if our 
primary outcome (FVC) shows significance, i.e. we will use some of the logic of gatekeeping hypothesis testing 
(57).   Assuming 5-10% variance (standard deviation) between consecutive FVC measurements, and a 3% 
change in FVC with treatment the estimated study size would range from 44-178 in each arm of the subsequent 
Phase II trial.  
Our pilot study was not designed to detect radiographic changes after nicotine treatment (11).  However, based 
upon the results of a recent Phase II sarcoidosis clinical trial structured almost identically to the study proposed 
herein (total n = 40/group), wherein the radiologist-generated “radiology score” (R-score) change from 
baseline was >30% post-treatment with low dose (3 mg/kg) anti-TNFα drug (i.e., 3.11 to 2.07, on a scale from 
0-4 with “4” being most severe disease, p <0.001) and changed significantly relative to matching controls [i.e., 
net change -1.33 ( +0.29 ± 2.21 for controls and -1.04 ± 2.02 for treatment group, p < 0.001)] (27), we predict 
that 55 patients in each group (nicotine treatment and control) will be sufficient to detect a 15% difference in 
LTS score change before and after treatment with 90% power and type I error at 0.05 assuming a standard 
deviation of LTS score change at 20%. We consider the latter to be a conservative assumption based upon 
previous texture-based computerized volumetric CT analysis studies (as will be employed for this study) 
designed to detect changes in lung nodules of varying sizes over time wherein the standard deviation in the 
volumetric score was less than 10% across a broad range of nodule sizes and textures, including solid and 
ground glass densities (which are very common in sarcoidosis patients) (57). Of note, if the standard deviation 
of the LTS is closer to 10%, this study size will be sufficient to detect a 5-10% change in LTS with a power of 
~42-94%.   Thus, this pilot study may underpowered to detect a significant change in the LTS following nicotine 
treatment, but will be useful for estimating the study size required for a subsequent adequately powered Phase 
II trial. 
G2. Interim Monitoring and Early Stopping 
As above, we conservatively predict that nicotine treatment will result in a 3% and 10% reduction in FVC and 
LTS, respectively, relative to the control group.  In the spirit of a pilot study, we are unsure of the potency of 
nicotine in terms of preventing progression or promoting regression of disease, as reflected by the LTS.  


IRB Protocol Number: 2014H0291 
 
 
16 
September 1, 2015 
 
Moreover, there is a possibility that nicotine treatment could be ineffective or associated with serious side-
effects in too many patients.  As such, the DSMC will continuously monitor the progress of the study and will 
consider early discontinuation of the trial if nicotine treatment is associated with excess serious adverse events 
(SAE) (arrhythmias, seizures, syncope, new cancers, death).   
G3. Analysis Plan 
The research data for each Aim will be analyzed at the time of unblinding (year 03).  The exception being 
DSMC data analysis for study related AEs and SAEs, and for analyses relating to performance monitoring, as 
detailed below. 
G4. Statistical Methods 
The primary study endpoint will determine if nicotine treatment improves an objective measure of lung function 
that is commonly used in sarcoidosis clinical trials, and is considered to be the “gold standard” clinical endpoint 
for assessing clinical response in the setting of pulmonary disease activity (59).  We will use a longitudinal 
model, which has certain advantages over the usual ANCOVA (using baseline LTS as covariate) (60).  In this 
analysis both baseline and and post intervention LTS are dependent variables in the longitudinal model (60).  
Using SAS’s Proc Mixed (61), all patients will be included in analysis, whether they are missing either a 
baseline (unlikely to happen) or a post intervention measurement.  Included in the fixed effects model will be 
race and gender.  Interactions with either will only be explored in a sensitivity analysis.  With just two 
measures, we will use a saturated covariance structure (which allows the variances of the baseline and post 
measures to differ). 
For the LTS scores, a longitudinal model, as described in Aim 1, will be used to compare LTS results in each 
treatment group at baseline and at the completion of the 24 week treatment protocol.  Correlation between 
FVC and LTS: Bivariate plots will be used to describe the relationship between changes in FVC (Aim 1) and 
LTS (Aim 2). With 25 patients in the nicotine group, where substantial correlation of changes is expected, the 
standard error of the correlations will be ~0.15 for moderate values. 
G5. Missing Outcome Data 
Assuming a 10% dropout before follow-up, complete data will be obtained from ~22 subjects in each arm of the 
study. The missing at random (MAR) assumption will be our primary adjustment for potential missing data bias 
(62,63). Sensitivity analyses will confirm the main findings as recommended by the special NAS panel on 
missing data in clinical trials (63). 
G6. Unblinding Procedures 
Under normal circumstances, so as to not compromise the integrity of the study, the blind should be 
maintained. Otherwise, the blind should be broken only if specific emergency treatment would be dictated by 
knowing the treatment status of the subject. It is recommended that the investigator contact a designee of the 
DSMB to discuss the situation. Telephone contact with the DSMB representative will be available 7 days per 
week. However, if the investigator is unable to contact the DSMB, or emergency unblinding is considered 
medically necessary, the investigator may determine the identity of the treatment by contacting The Ohio State 
University’s Clinical Trials Office.  Subjects who have had their treatment assignment unblinded will still be 
expected to return for scheduled evaluations. The date, time, and reason for the unblinding must be 
documented in the source documents.  


IRB Protocol Number: 2014H0291 
 
 
17 
September 1, 2015 
 
H. Handling and Security 
H1. Confidentiality and Security 
Subject information collected in this study will comply with the standards for protection of privacy of individually 
identifiable health information as promulgated by applicable local/regional/national requirements for subject 
confidentiality (e.g., Health Insurance Portability and Accountability Act as mandated in Title 45 CFR, Parts 160 
and 164). All records will be kept confidential and the subject’s name will not be released at any time. 
Subject records will not be released to anyone other than the study personnel or its designee(s), and 
responsible government agencies, when requested. In all cases, caution will be exercised to assure the 
subject’s confidentiality. The developed REDCap database used for data collection will be stored on a 
password protected, firewall protected server maintained by OSU’s CTSA. 
H2. Training 
Initial training for core and study-specific elements will be conducted during week two following a review of the 
protocol by the DSMB. Core elements include 1) recruitment; 2) eligibility and screening; 3) informed consent; 
4) enrollment; 5) protocol implementation, 6) data collection, procedures and forms completion; 7) data entry 
and management and 8) adverse event monitoring and reporting. Follow-up training will occur during site visits 
and by conference calls as needed. Staff certification is based on full attendance at initial central training at 
OSU (week 1) and task observation during subsequent site visits. Site visits will occur four times per site during 
the study period.   
H3. Case Report Forms and Source Documents 
All subject data, including case report forms and source documents, will be uploaded to a password protected 
web-server maintained by The Ohio State University’s CTSA.   
H4. Records Retention 
OSU and CCF will maintain the records of drug disposition, worksheets, and all other study-specific 
documentation for at least 3 years after the completion of the study. 
H5. Performance Monitoring 
We will define a set of comprehensive data quality assurance and programmatic and/or project-specific 
tracking metrics.  Examples of such metrics include: data completion levels, timeliness of data entry, 
conformance of data with protocol-specified range and value checking logic, as well as the satisfaction of 
protocol-driven milestones such as participant and bio-specimen accrual rates.  We will use an instance of the 
Jasper Business Intelligence Suite (JBIS) to generate and visualize such metrics in both standard scheduled 
reports (delivered electronically via e-mail transmissions and a secure web portal interface) and a real-time 
dashboard, again delivered via a secure web portal.    All metrics will be reviewed on at least a quarterly basis 
by the program’s leadership to ensure their adequacy for data monitoring and project management/planning 
purposes.   
I. Study Monitoring, Auditing, and Inspection 
The first visit is mandated to occur after the 2nd and before the 5th enrolled study subjects to assure that 
adequate training has occurred and appropriate local documentation is in place including eligibility evaluation, 


IRB Protocol Number: 2014H0291 
 
 
18 
September 1, 2015 
 
informed consent, data collection, entry and management, and specimen collection and processing. Each site 
visit will also involve audits of a small random sample of participant records. The first site visit will also assure 
that the sites have adequate plans for recruitment. Site visit team will subsist of a designated OSU clinical 
coordinator and will include Dr. Crouser at least once a year. Prior to the visit, the OSU clinical coordinator will 
review performance reports to identify potential areas of concern.  OSU will work with the Cleveland Clinic to 
plan the visit agendas to best serve the projects’ needs for problem-solving, monitoring, and observation of 
tasks. The site visit team will also use the visit to obtain information regarding what additional database tools or 
resources are needed for efficient functioning at the sites. The site visit team will submit a report to the CC and 
provide a two week interval to respond. The report and response will then be submitted to the Steering 
Committee. If needed, performance improvement plans will be developed and OSU’s CTSA will assist clinic 
staff in implementing and monitoring subsequent performance. Data monitoring will be informed by quarterly 
review of JBIS generated metrics as previously described.   
A Data and Safety Monitoring Board (DSMB) will be appointed to oversee study design, 
implementation, patient recruitment, interim analyses, adverse events and data management.  The DSMB will 
be provided with routine reports on recruitment, timeliness and quality of data collection, adherence to protocol, 
and adverse effects for each of their regular meetings.  Serious adverse events will be reported to the DSMB 
within 48 hrs. Details of the DSMB structure and function are as follows:  
The specific responsibilities of DMSB will include the following: 
1. Review the research protocol, informed consent documents, and plans for data and safety monitoring;  
2. Evaluate the progress of the trial, including periodic assessments of data quality and timeliness, participant 
recruitment, accrual and retention, participant risk versus benefit, performance of the trial sites, and other 
factors that can affect study outcome;  
3. Consider factors external to the study that may be relevant, such as scientific or therapeutic developments 
which could have an impact on the safety of the participants or the ethics of the study;  
4. Review study coordinating center performance, make recommendations, and assist in the resolution of 
problems as reported by the PI;  
5. Protect the safety of the study participants and report on the safety and progress of the trial;  
6. Make recommendations to the research team and sponsor, as required, concerning continuation, 
termination or other modification(s) to the trial; 
7.  Ensure the confidentiality of the trial data and the results of monitoring;  
8. Assist on any problems with study conduct, enrollment, sample size and/or data collection. 
9. Review data for accuracy and quality 
The DSMB will be composed of pulmonologists experienced with clinical research [Marc Judson, MD-
Chairperson, and Kenneth Knox, MD] a pharmacologist and biomedical scientist [Daren Knoell, PhD], a 
biostatistician [Lai Wei, PhD], and a research subject advocate/ethicist [To be named]. All members are 
independent of the research team as well as have no financial, scientific or other conflict of interest with the 
project. The Chairperson will serve as the primary contact between the research team and DSMB. The DSMB 
in conjunction with the research team, shall meet before the initiation of the study, i.e. prior to subject 
enrollment, and at 12 month intervals throughout the duration of the project until after the final subject has 
completed all study-related assessments but no sooner than the time point at which study-related adverse 


IRB Protocol Number: 2014H0291 
 
 
19 
September 1, 2015 
 
events would likely present. All adverse events will be followed until resolution as is feasibly possible, inclusive 
of those events that result in premature withdrawal from the study.  
  
The DSMB meetings will include both an open and closed portion of review. An emergency meeting 
may be called at any time by the request to the Chairperson and/or the Principal Investigator. Beyond the 
interim analysis as described above no other formal stopping rules will be employed. Study progress reports 
will be prepared by the research team and distributed to the DSMB prior to the scheduled meeting(s). These 
reports will include updates on the protocol inclusive of revisions, enrollment progress and projections, 
retention, and safety data inclusive of description, severity, attribution, response, reporting and resolution of 
those events as well as if any events are unanticipated. Serious and/or unanticipated event(s) deemed to be 
related to the procedures of the study will be brought to the attention of the DSMB and then subsequently to 
the sponsor and IRB(s), as appropriate and as soon as possible. Moreover, in the event that any proposed 
change to the study may elevate the risk to benefit ratio such requested changes would be brought to the 
attention of the sponsor Program Officer, as per sponsor policy, prior to the implementation of such proposed 
change(s), e.g., the addition of a new study population that would be at higher risk for the existing study 
procedures, the addition of new procedures greater than minimal risk, any modifications to the existing study 
procedure(s) that may increase overall risk, and/or the addition of a new clinical study and/or study arm not 
originally proposed that is greater than minimal risk. 
A written summation of the DSMB’s review(s) of the study will be submitted to the PI. As appropriate, any 
such report will be forwarded to the Program Officer for the sponsor, and/or IRB(s). Continuation and/or 
revision of the study will be based upon the collective expertise of and guidance offered by the DSMB. 
 
J. Study Administration 
J1. Organization and Participating Centers 
Two clinical centers with extensive experience in sarcoidosis-related clinical trials, and representing diverse 
sarcoidosis populations will participate in the study.  Both centers are all supported through Clinical and 
Translational Science Awards (CTSA) and will coordinate their efforts through the CTSA-supported Center for 
Clinical and Translational Science (CCTS) at each facility.  The Ohio State University (OSU, Columbus, OH) 
will serve as the data coordinating center and will oversee subject recruitment and data quality assurance.  
Research subjects will also be recruited from a large sarcoidosis specialty clinic located at the Cleveland Clinic 
Foundation, Cleveland, Ohio.  The demographics of sarcoidosis in Cleveland and Columbus are distinct in that 
the latter is enriched with African Americans (AA).  The demographics of Columbus closely resemble that of 
the U.S. in general (64), and AAs in the U.S. share common ancestry (65). In total, these two centers actively 
manage ~ 2000 sarcoidosis patients, most of whom have pulmonary involvement (see Table 2).  And each 
center has successfully recruited to NIH-supported clinical trials relating specifically to lung diseases (Table 3). 
J2. Committees 
A Steering Committee (SC) comprised of the PIs from each clinical site, directors of administrative, protocol 
and clinical research will oversee patient recruitment, the implementation of the research protocols, and the 
generation of data towards the achievement of the proposed study aims.  A Data and Safety Monitoring Board 
(DSMB) will be appointed to oversee study design, implementation, patient recruitment, interim analyses, 
adverse events and data management. 


IRB Protocol Number: 2014H0291 
 
 
20 
September 1, 2015 
 
J3. Subject Stipends 
To cover travel-expenses and 
other costs relating to 
participation in this project, 
subjects will be provided a 
stipend of $50 for each of the 6 
scheduled protocol-related visits 
to cover parking/travel expenses. 
Additional reimbursement for 
travel will be available as 
needed.    
J4. Study Timetable 
See Study Timeline and Milestones Table. 
K. Data Sharing and Publication Plan 
In order to enable public access to all project-related data sets, we will use a multi-modal strategy, including: 1) 
regular submission of project-generated data sets to public repositories, including those associated with the 
National Library of Medicine’s National Center for Biotechnology Information (NCBI); 2) the deployment and 
configuration of one or more ProServer DAS (Distributed Annotation Service) servers to enable public access to 
all project-generated bimolecular data sets (his type of server complies with the standards established by the 
international bioinformatics community for open data access, and will be registered with a central DAS registry 
maintained by the Sanger Institute [http://www.dasregistry.org/]); and 3) the provision of an open-access section 
of the previously described (see Clinical Research Protocol) Confluence WIKI where project participants will be 
able to post and curate technical reports, publications, and other summary data/information concerning 
programmatic activities and research products.  Where appropriate, all data sets and documentation generated 
via this project and shared through any of the preceding mechanisms will be made to conform to applicable 
National Technical Information Service standards and guidelines.  
This study represents a joint effort of SC members (Drs. Crouser, Jackson and Culver), and as such, the 
parties agree that the recommendation of any party concerning abstracts, manuscripts or texts shall be taken 
into consideration in the preparation of final scientific documents for publication and presentation.  As such, 
decisions relating to the validity of the data, authorship (i.e., based upon relative intellectual contribution), and 
other publication plans will be at the discretion of the SC.  
OSU’s CTSA will support the preparation of manuscripts resulting from the study-wide protocols by providing 
data analysis, statistical consultation, and editorial support.  Manuscripts and presentations arising from the 
primary clinical trial will be submitted for review to the SC.  Following completion of a draft manuscript, the SC 
will conduct a thorough manuscript review for accuracy and clarity.  The SC, with assistance from OSU’s CTSA 
staff, will track all proposed and approved publications and coordinate the entire publication process from 
proposal through review, analysis, preparation, publication, and dissemination 
In accordance with national and local requirements, this study protocol will be listed in a publicly accessible 
clinical trials registry and given a unique identifier.  Additionally, the results of this clinical study will be 
Month
1
2
3
6
9
12
18
24
30
36
48
IRB approval
x
Site Visit
x
x
x
x
SC meeting
x
x
x
x
x
x
x
x
Subject 
Recruitment
x
25%
x
50%
75%
100%
DSMb
x
x
External 
Advisory
Board
x
x
x
x
Final Data 
Analysis
x
Publications
x
Study Timeline and Milestones


IRB Protocol Number: 2014H0291 
 
 
21 
September 1, 2015 
 
disclosed on a publically accessible clinical trials results database, regardless of the outcome.The OSU CCTS 
Research Informatics Services Core will be used as a central location for data processing and management. 
Vanderbilt University, with collaboration from a consortium of institutional partners (including OSU) and the NIH 
National Center for Research Resources, has developed a software toolset and workflow methodology for 
electronic collection and management of research and clinical trial data. REDCap (Research Electronic Data 
Capture) data collection projects rely on a thorough study-specific data dictionary defined in an iterative self-
documenting process by all members of the research team with planning assistance from the CCTS Research 
Informatics Services Core. As part of the data dictionary development process, individual fields can be denoted 
as “identifiers”.  When exporting a de-identified dataset, these variables are omitted.  Additionally, the data 
export tool also allows for the shifted of dates for a limited data set export. REDCap provides a secure, web-
based application that is flexible enough to be used for a variety of types of research, provides an intuitive 
interface for users to enter data and has real time validation rules (with automated data type and range checks) 
at the time of entry. It offers easy data manipulation with audit trails and ad hoc reporting functionality for 
reporting, monitoring and querying patient records, and an automated export mechanism to common statistical 
packages (SPSS, SAS, Stata, R/S-Plus).  REDCap is 21 CRF Part 11 capable.  Currently, REDCap 
installations support electronic signatures by positively identifying the user through a unique username and 
password combination.  The provisioning of accounts and user access to specific database(s) is integrated 
with the OSU Medical Center LDAP authentication service for studies containing protected health information 
(PHI), and the provisioning of access and specific user rights for all studies are managed by CCTS staff. 


IRB Protocol Number: 2014H0291 
 
 
22 
September 1, 2015 
 
Tables 
 
 
 
 
Ohio State 
University
Cleveland
Clinic 
Foundation
Total
Patient Visits 
(2012)
794
1198
1992
New Patient 
Visits
72
95
167
Female %
61
58
59
White/AA/other
(%)
50/45/5
60/26/14
56/34/10
Table 2.  Demographics of the sarcoidosis patient 
populations at participating clinical centers .
Site
Study
Sponsor/Description
Project 
Role
Recruitment 
Goal
# recruited
Timeframe
*OSU
NIH/LOTT Emphysema
Site PI
21/year
72
(24/yr)
3 yrs
OSU
NIH/HIV Emphysema
PI
264
264
4 yrs
OSU
ATS-FSR/Nicotine Tx for 
Sarcoid Pilot
PI
15/yr
19 
(15/yr)
15 months
CCF
NIH/IPFNet
Site PI
17
21
2 yrs
Table 3. Study Site Recruitment History
*Second highest recruitment among 17 participating centers


IRB Protocol Number: 2014H0291 
 
 
23 
September 1, 2015 
 
L. References Cited 
1. Denys BG, Bogaerts Y, Coenegrachts KL, De Vriese AS. Steroid-resistant sarcoidosis: is antagonism of 
TNF-alpha the answer? Clin Sci (Lond) 2007;112:281-9. 
2. Newman LS, Rose CS, Bresnitz EA, et al. A case control etiologic study of sarcoidosis: environmental and 
occupational risk factors. Am J Respir Crit Care Med 2004;170:1324-30.   
3. Valeyre D, Soler P, Clerici C, et al. Smoking and pulmonary sarcoidosis: effect of cigarette smoking on 
prevalence, clinical manifestations, alveolitis, and evolution of the disease. Thorax 1988;43:516-24. 
4. Carlens C, Hergens MP, Grunewald J, et al.  Smoking, use of moist snuff, and risk of chronic inflammatory 
diseases. Am J Respir Crit Care Med 2010; 181:1217-22. 
5. De Jonge WJ, Ulloa L. The alpha7 nicotinic acetylcholine receptor as a pharmacological target for 
inflammation. Br J Pharmacol 2007;151:915-29. 
6. Kox M, van Velzen JF, Pompe JC, et al. GTS-21 inhibits pro-inflammatory cytokine release independent of 
the Toll-like receptor stimulated via a transcriptional mechanism involving JAK2 activation. Biochem 
Pharmacol 2009;78:863-72. 
7. Yanagita M, Kobayashi R, Kojima Y, Mori K, Murakami S. Nicotine modulates the immunological function 
of dendritic cells through peroxisome proliferator-activated receptor-γ upregulation. Cell Immunol 
2012;274:26-33. 
8. Zhang S, Petro TM. The effect of nicotine on murine CD4 T cell responses. Int J Immunopharmac 1996; 
18:467-78. 
9. Ingram JR, Rhodes J, Evans BK, et al. Nicotine enemas for active Crohns Colitis: An open pilot study. 
Gastroenterol Res Pract 2008; 2008: 237185. 
10. Blanchet MR, Israel-Assayag E, Cormier Y.  Inhibitory effect of nicotine on experimental hypersensitivity 
pneumonitis in vivo and in vitro. Am J Respir Crit Care Med 2004;169:903-9. 
11. Julian MW, Shao G, Schlesinger LS, Huang Q, Cosmar D, Bhatt N, Culver DA, Baughman RP, Wood K, 
Crouser ED.  Nicotine treatment enhances TLR2 and TLR9 responses in pulmonary sarcoidosis.  Chest 
2012 (In Press: Published online August 1, 2012): doi: 10.1378/chest.12-0383. 
12. Hinz A, Fleischer M, Brahler E, et al. Fatigue in patients with sarcoidosis, compared with the general 
population. Gen Hosp Psychiatry 2011; 33:462-8.   
13. De Kleijn WPE, Elfferich MDP, De Vries J, et al. Fatigue in sarcoidosis American versus Dutch patients. 
Sarcoidosis Vasc Diffuse Lung Dis 2009;26:92-7. 
14. Chen ED, Moller DR. Sarcoidosis-scientific progress and clinical challenges. Nat Rev Rheumatol 
2011;7:457-67.   
15. Morgenthau AS, Iannuzzi MC. Recent advances in sarcoidosis. Chest 2011;139:174-82. 
16. Cox CE, Donohue JF, Brown CD, Kataria YP, Judson MA. Health-related quality of life of persons with 
sarcoidosis. Chest 2004; 125:997-1004. 
17. Vermine S, Van Assche G, Rutgeerts P. Serum sickness, encephalitis and other complications of anti-
cytokine therapy. Best Pract Res Clin Gastroenterol 2009;23:101-12. 
18. Wang DW, Zhou RB, Yao YM, et al. Stimulation of α7 nicotinic acetylcholine receptor by nicotine increases 
suppressive capacity of naturally occurring CD4+CD25+ regulatory T cells in mice in vitro. J Pharmacol 
Exp Ther 2010;335:553-61.   
19. Hao J, Simard AR, Turner GH, et al. Attenuation of CNS inflammatory responses by nicotine involves α7 
and non-α7 nicotinic receptors. Exp Neurol 2011;227:110-9. 
20. Bruchfeld A, Goldstein RS, Chavan S, et al. Whole blood cytokine attenuation by cholinergic agonists ex 
vivo and relationship to vagus nerve activity in rheumatoid arthritis. J Intern Med 2010;268:94-101. 
21. Nouri-Shirazi M, Guinet E. A possible mechanism linking cigarette smoke to higher incidence of respiratory 
infection and asthma. Immunol Lett 2006; 103:167-76. 
22. Matsunaga K, Klein TW, Friedman H, Yamamoto Y. Involvement of nicotine acetylcholine receptors in 
suppression of antimicrobial activity and cytokine responses of alveolar macrophages to Legionella 
pneumophila infection by nicotine. J Immunol 2001; 167: 6518-24. 


IRB Protocol Number: 2014H0291 
 
 
24 
September 1, 2015 
 
23. Poltavski DV, Petros T. Effects of transdermal nicotine on prose memory and attention in smokers and 
nonsmokers. Physiol Behav 2005;83:833-43. 
24. Picciotto MR, Brunzell DH, Caldarone BJ. Effect of nicotine and nicotinic receptors on anxiety and 
depression. Neuroreport 2002;13:1097-106. 
25. Salin-Pascual RJ, Rosas M, Jimenez-Genchi A, Rivera-Meza BL. Antidepressant effect of transdermal 
nicotine patches in nonsmoking patients with major depression. J Clin Psych 1996;57:387-9. 
26. Lower EE, Harman S, Baughman RP. Double-blind, randomized trial of dexmethylphenidate hydrochloride 
for the treatment of sarcoidosis-associated fatigue. Chest 2008;133:1189-95. 
27. Baughman RP, Drent M, Kavuru M, et al. Infliximab therapy in patients with chronic sarcoidosis and 
pulmonary involvement. Am J Respir Crit Care Med 2006; 174:795-802. 
28. Behr J. A small change in FVC but a big change for IPF. Defining the minimally important difference. Am J 
Respir Crit Care Med 2011; 184:1329-30. 
29. Baughman RP, Shipley R, Desai S, et al. Changes in chest roentgenograms of sarcoidosis patients during 
a clinical trial of infliximab therapy: comparison of different methods of evaluation.  Chest 2009;136:526-35. 
30. Bergin CJ, Bell DY, Coblentz CL, et al. Sarcoidosis: correlation of pulmonary parenchymal pattern at CT 
with results of pulmonary function tests. Radiology 1989; 171:619-24.   
31. Muller NL, Mawson JB, Mathieson JR, et al. Sarcoidosis: correlation of extent of disease at CT with clinical, 
functional, and radiographic findings. Radiology 1989; 171:613-8. 
32. Erdal BS, Crouser ED, Yildiz V, et al. Quantitative computerized two-point correlation analysis of lung CT 
scans correlates with pulmonary function in pulmonary sarcoidosis. Chest 2012 (Published online May 23, 
2012) doi: 10.1378/chest.11-2027. 
33. Hays JT, Ebbert JO. Adverse effects and tolerability of medications for the treatment of tobacco use and 
dependence. Drugs 2010;70:2357-2372. 
34. Sweiss NJ, Salloum R, Gandhi S, et al.  Significant CD4, CD8, and CD19 lymphopenia in peripheral blood 
of sarcoidosis patients correlates with severe disease manifestations. PLoS One 2010;5:e9088. 
35. Zelenay S, Lopes-Carvalho T, Caramalho I, Moraes-Fontes MF, Rebelo M, Demengeot J.  FoxP3+CD25- 
CD4 T cells constitute a reservoir of committed regulatory cells that regain CD25 expression upon 
homeostatic expansion. Proc Natl Acad Sci USA 2009;102:4091-4096. 
36. Zhang B, Zhang X, Tang FL, Zhu LP, Kiu Y, Lipsky PE. Clinical significance of increased CD4+CD25-
Foxp3+ T cells in patients with new-onset lupus erythematosus. Ann Rheum Dis 2008;67:1037-1040. 
37. Lee NS, Barber L, Kanchwala A, et al. Low levels of NF-kB/p65 mark angergic CD4+ T cells and correlate 
with disease severity in sarcoidosis. Clin Vaccine Immunol 2011;18:223-34. 
38. Gupta D, Chetty M, Kumar N, Aggarwal AN, Jindal SK. Anergy to tuberculin in sarcoidosis is not influenced 
by high prevalence of tuberculin sensitivity in the population. Sarcoidosis Vasc Diffuse Lung Dis 
2003;20:40-45.   
39. Veltkamp M, Van Moorsel CH, Rijkers GT, Ruven HJ, Van Den Bosch JM, Grutters JC. Toll-like receptor 
(TLR)-9 genetics and function in sarcoidosis. Clin Exp Immunol 2010;162:68-74. 
40. Mathew S, Saladino K, Fischoeder A, et al. The anergic state in sarcoidosis is associated with diminished 
dendritic cell function. J Immunol 2008; 181:746-55. 
41. Johnstone E, Benowitz N, Cargill A, et al. Determinants of the rate of nicotine metabolism and effects on 
smoking behavior. Clin Pharmacol Ther 2006; 80:319-30. 
42. Hukkanen J, Jacob P, Benowitz NL. Metabolism and disposition kinetics of nicotine. Pharmacol Rev 2005; 
57:79-115. 
43. Nizri E, Irony-Tur-Sinai M, Lory O, Orr-Urtreger A, Lavi E, Brenner T. Activation of the cholinergic anti-
inflammatory system by nicotine attenuates neuroinflammation via suppression of Th1 and Th17 
responses. J Immunol 2009;183:6681-88.   
44. Shi FD, Piao WH, Kuo YP, et al. Nicotine attenuation of central nervous system inflammation and 
autoimmunity.  J Immunol 2009;182:1730-9. 
45. Pickworth WB, Bunker EB, Henningfield JE. Transdermal nicotine: reduction of smoking with minimal 
abuse liability. Psychopharmacology (Berl) 1994;115:9-14. 


IRB Protocol Number: 2014H0291 
 
 
25 
September 1, 2015 
 
46. Henningfield JE, Shiffman S, Ferguson SG, Gritz ER. Tobacco dependence and withdrawal: science base, 
challenges and opportunities for pharmacotherapy. Pharmacol Ther 2009;123:1-16. 
47. Fletcher C. Standardized questionnaire on respiratory symptoms: a statement prepared and approved by 
the MRC Committee on the Aetiology of Chronic Bronchitis (MRC breathlessness score). BMJ 1960;2:1665 
48. Hughes JR, Lesmes GR, Hatsukami DK, et al. Are higher doses of nicotine replacement more effective for 
smoking cessation. Nicotine Tob Res 1999; 1:169-74. 
49. Miyauchi M, Qu Z, Miyauchi Y, et al. Chronic nicotine in hearts with healed ventricular myocardial infarction 
promotes atrial flutter that resembles typical human atrial flutter. Am J Physiol Heart Circ Physiol 2005; 
288:H2878-86. 
50. Dobelis P, Hutton S, Lu Y, Collins AC. GABAergic systems modulate nicotinic receptor-mediated seizures 
in mice. J Pharmacol Exp Ther 2003; 306:1159-66. 
51. Rahmanian SD, Diaz PT, Wewers ME. Tobacco use and cessation among women: Research and 
treatment-related issues. J Womens Health (Larchmt) 2011;20:349-57. 
52. Crapo RO, Morris AH, Gardner RM. Reference spirometric values using techniques and equipment that 
meet ATS recommendations. Am Rev Respir Dis 1981; 123:659-64. 
53. Drent M, Lower EE, De Vries J. Sarcoidosis associated fatigue. Eur Respir J 2012 May 22 [PMID: 
22441750].   
54. Michielsen HJ, De Vries J, Van Heck GL. Psychometric qualities of a brief self-rated fatigue measure: The 
Fatigue Assessment Scale. J Psychomosom Res 2003;54:345-52. 
55. Jones PW, Quirk FH, Baveystock CM, et al. A self-complete measure of health status for chronic airflow 
limitation. Am Rev Respir Dis 1992; 145:1321-7). 
56. Judson MA, Mack M, Beaumont JL, et al. Validation and important differences for the Sarcoidosis 
Assessment Tool. A new patient-reported outcome measure. Am J Respir Crit Care Med 2015; 191:786-
95. 
57. Dmitrienko A, Kordzakhia G, Tamhane AC. Multistage and mixture parallel gatekeeping procedures in 
clinical trials. J Biopharm Stat 2011; 21:726-47. 
58. Reeves AP, Chan AB, Yankelevitz DF, et al. On measuring the change in size of pulmonary nodules. IEEE 
Transactions on Medical Imaging 2006; 25:435-450. 
59. Baughman RP, Drent M, Culver DA, et al. Endpoints for clinical trials of sarcoidosis. Sarcoidosis Vasc 
Diffuse Lung Dis 2012; 29:90-8.).   
60. Liu, G.F., Lu, K., Mogg, R., Mallick, M., Mehrotra, D.V., 2009. Should baseline be a covariate or dependent 
variable in analyses of change from baseline in clinical trials? Stat Med 2009; 28: 2509-2530. 
61. SAS Proc Mixed, Version 9.0, Cary, North Carolina: SAS Institute 2009. 
62. Schafer J., 1997. Analysis of incomplete multivariate data. In: Chapman Hall, London.,  
63. NRCUSTR, Front Matter, National Academy of Sciences Panel." The Prevention and Treatment of Missing 
Data in Clinical Trials.” ; 2010. 
64. Erdal BS, Clymer BD, Yildiz VO, Julian MW, Crouser ED. Unexpectedly high prevalence of sarcoidosis in a 
representative U.S. metropolitan population. Resp Med 2012; 106:893-9. 
65. Zakharia F, Basu A, Absher D, et al. Characterizing the admix African ancestry of African Americans. 
Genome Biol 2009; 10:R141. 
 

ICF_001.pdf: 
CONSENT 
Biomedical/Cancer 
 
 
 
IRB Protocol Number:
2014H0291
IRB Approval date: 
02/25/2019
Version: 
02/07/2019 
 
 
Page 1 of 11 
Form date: 12/15/05
 
 
The Ohio State University Consent to Participate in Research 
 
 
Study Title:   
Nicotine Treatment for Pulmonary Sarcoidosis: A Clinical Trial 
Pilot Study 
Principal Investigator: 
Elliott Crouser MD 
Sponsor:  
National Heart Lung and Blood Institute 
 
 
This is a consent form for research participation.  It contains important information 
about this study and what to expect if you decide to participate.  Please consider the 
information carefully. Feel free to discuss the study with your friends and family and to 
ask questions before making your decision whether or not to participate. 
 
Your participation is voluntary.  You may refuse to participate in this study.  If you 
decide to take part in the study, you may leave the study at any time.  No matter what 
decision you make, there will be no penalty to you and you will not lose any of your usual 
benefits.  Your decision will not affect your future relationship with The Ohio State 
University.  If you are a student or employee at Ohio State, your decision will not affect 
your grades or employment status. 
 
You may or may not benefit as a result of participating in this study.  Also, as 
explained below, your participation may result in unintended or harmful effects for you 
that may be minor or may be serious depending on the nature of the research. 
 
You will be provided with any new information that develops during the study that 
may affect your decision whether or not to continue to participate.  If you decide to 
participate, you will be asked to sign this form and will receive a copy of the form.  You 
are being asked to consider participating in this study for the reasons explained below.   
 
Participation in a research study is not a substitute for medical care and does not 
provide free comprehensive doctor visits.  You should maintain (or establish) a 
relationship with your primary care physician. 
 
 
1.   Why is this study being done? 
The purpose of this study is to determine if nicotine treatment is beneficial for the treatment 
of sarcoidosis. Sarcoidosis is a disease of unknown cause that leads to inflammation and 
affects your body’s organs. 
 
2.   How many people will take part in this study? 
The Ohio State University Wexner Medical Center and the Cleveland Clinic are participating 
in this study. About 25 subjects will be enrolled at each site for a total of 50 participants will 
be enrolled in this study.  All participants will have evidence of sarcoidosis and active lung 
disease despite usual therapies for sarcoidosis.   
 
Participants will be randomized, like a flip of a coin, to receive daily treatments with a skin 
patch containing nicotine or a patch containing no nicotine (placebo). The nicotine patch is 


CONSENT 
Biomedical/Cancer 
 
 
 
IRB Protocol Number:
2014H0291
IRB Approval date: 
02/25/2019
Version: 
02/07/2019 
 
 
Page 2 of 11 
Form date: 12/15/05
 
approved by the U.S. Food and Drug Administration (FDA), but its use in this study is 
considered investigational. You will continue to receive study medication for about 28 weeks. 
 
Results of your medical testing will be collected to determine if nicotine treatment is helpful in 
terms of reducing signs or symptoms of the disease.  
 
3.   What will happen if I take part in this study? 
If you choose to participate in this study, you will continue to receive care for your sarcoidosis 
from your pulmonologist.  If you consent to take part in this research study, you will be asked to 
sign this consent form and will have the following tests and procedures.  Some of the 
procedures may be part of your standard medical care (you will be billed for these procedures), 
but others are being done solely for the purpose of this research study (you will not be billed for 
these procedures). 
 
There will be 5 visits to the clinic and 7 telephone calls as a part of this study. 
 
The study staff can answer any questions you have about individual study visits or about the 
evaluations that will occur.   The visits are outlined in the table below and then reviewed in 
detail.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONSENT 
Biomedical/Cancer 
 
 
 
IRB Protocol Number:
2014H0291
IRB Approval date: 
02/25/2019
Version: 
02/07/2019 
 
 
Page 3 of 11 
Form date: 12/15/05
 
 
Study 
Procedures
 
Screen 
 
Entry 
 
Week  
1*
 
Week 
2*
 
Week 
6*
 
Week 
10
 
Week 
14*
 
Week 
18
 
Week 
22*
 
Week 
26
 
Week 
27*
 
Week 
28*
 
Consent
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomize
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs
 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Urine 
Pregnancy Test
 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Blood Draw
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
Chest X-ray  
(if needed) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
(Electrocardiogram)
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
CT Scan
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Pulmonary 
Function Test
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Adverse Events
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Medication 
Review
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Questionnaires
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
*Visit weeks 1, 2, 6, 14, and 22 will be conducted by telephone.  Approximately 1 month after week 28 you will also receive a phone call to 
0 
see if you have had any nicotine dependency cravings. 
1 


CONSENT 
Biomedical/Cancer 
 
 
 
IRB Protocol Number:
2014H0291
IRB Approval date: 
02/25/2019
Version: 
02/07/2019 
 
 
Page 4 of 11 
Form date: 12/15/05
 
Screening Visit: 
2 
This visit will occur at the clinic and will take about 2 hours to complete.  At this visit, you will be 
3 
asked to: 
4 
 Have your vital signs (blood pressure, weight, and height measured) taken; 
5 
 Have an electrocardiogram (ECG).  An ECG is a non-invasive and painless  
6 
procedure that uses temporary adhesive patches on your chest and limbs to 
7 
measure the electrical activity of your heart; 
8 
 Have a chest x-ray if you have not had one done within the past year; 
9 
 Review your medications and medical history. 
10 
 
11 
You will not be eligible to participate in this study if you have significant coronary artery 
12 
disease. 
13 
 
14 
Study Entry Visit 
15 
This visit will occur at the clinic and will take about 2 hours to complete.  At this visit, you will be 
16 
asked to: 
17 
  Have your vital signs taken; 
18 
  Have a brief physical exam by the study doctor; 
19 
  Have blood drawn.  About 2 teaspoons (10mL) will be taken from a vein in your arm 
20 
prior to you starting study medication. Nicotine and nicotine metabolites will be 
21 
measured in the blood to determine if the rate of nicotine metabolism relates to the 
22 
measured results from the CT scans and pulmonary function tests; 
23 
  Have a Pulmonary Function Test (PFT), a group of tests that measure how   well 
24 
the lungs take in and release air.  Albuterol may be given after the spirometry, a 
25 
common office test used to assess how well your lungs work by measuring how 
26 
much air you inhale, how much you exhale and how quickly you exhale to dilate the 
27 
breathing passages;  
28 
 Have a CT scan of your chest.  This scan combines a series of X-ray views taken 
29 
from many different angles and computer processing to create cross-sectional 
30 
images of the bones and soft tissues inside your body; 
31 
 Complete questionnaires.  Each questionnaire measures a different aspect of your 
32 
quality of life, shortness of breath and level of stress. 
33 
 If you are a woman of childbearing age, you will be tested for pregnancy at no cost to 
34 
you. This will require a urine sample. Pregnant women cannot participate in this 
35 
study.  If you become pregnant while participating in this study, you must inform the 
36 
study doctor. If your urine pregnancy test is positive, blood will be drawn to perform a 
37 
serum pregnancy test.  
38 
 
39 
At this visit, you will be randomly divided into two groups.  One group will receive a nicotine 
40 
patch to use for approximately 7 months; the other group will receive placebo for nicotine 
41 
patches to use for the same time period.  You, the study doctor or the research staff will not 
42 
know if you are receiving study drug or not. 
43 
 
44 
You will be unable to tell if you have been assigned to receive nicotine or placebo patch 
45 
treatments because they are designed to look the same.  The treatment you are receiving will 
46 
be revealed to you at the end of the study.   
47 
 
48 


CONSENT 
Biomedical/Cancer 
 
 
 
IRB Protocol Number:
2014H0291
IRB Approval date: 
02/25/2019
Version: 
02/07/2019 
 
 
Page 5 of 11 
Form date: 12/15/05
 
You should only wear one patch at a time.  You may wear the patch from 16 to 24 hours.   
49 
Apply one new patch at least every 24 hours on skin that is dry, clean and hairless.   Remove 
50 
backing from patch and immediately press onto skin.  Hold for 10 seconds.  Wash hands after 
51 
applying or removing patch.  
52 
 
53 
Keep the empty boxes and pouches and return everything at your next study visit.   
54 
 
55 
Procedures and Evaluations While Receiving Study Medication 
56 
At regular time points during the study, you will be asked to have the following tests and 
57 
procedures.  
58 
 
59 
You will start your study medication at the minimum nicotine dose of 7mg.  In seven days 
60 
(week 1), we will call you to see how you are doing at this dose.  If you are doing well, we will 
61 
increase your dose to 14mg.  We will then call you seven days later (week 2) to see how you 
62 
are doing on the 14mg dose.  If you are doing well, we will increase the dose to 21 mg.  We will 
63 
not increase any of these doses if you are feeling side effects that make you uncomfortable.  
64 
We will also decrease the dose to the previous dose it you are feeling side effects that make 
65 
you uncomfortable. 
66 
 
67 
You will then be called  at visit weeks 6, 14, 22, 27 and 28 to see if you have had any nicotine 
68 
dependency cravings and  to monitor for any side effects such as insomnia (unable to sleep), 
69 
headaches, or feeling tired.. 
70 
 
71 
You will be asked to complete questionnaires week 10, week 18, and week 26, the final visit.  It 
72 
will take approximately 45 - 60 minutes at each visit to complete the questionnaires.   
73 
 
74 
You will be asked to have blood taken from a vein in your arm.  About 2 teaspoons of blood will 
75 
be drawn at weeks 10 and 26.   
76 
 
77 
If you are a woman of childbearing age, you will be tested for pregnancy by providing a urine 
78 
sample. Pregnant women cannot participate in this study.  If you become pregnant while 
79 
participating in this study, you must inform the study doctor. 
80 
 
81 
At week 26th of the study, you will start the “washout period.”  This is the process of taking 
82 
you off the nicotine patch at a slow pace.  We will decrease the drug on a weekly basis.  For 
83 
example, if you are on the 21mg patch during the study your dose will be reduced to 14 mg 
84 
for a week, then 7 mg, for a week, and then you will stop.  If you are on 7 mg at the 
85 
beginning of the washout period, you will just stop taking the drug.   
86 
 
87 
4.   How long will I be in the study? 
88 
You will be in the study for approximately 32 weeks. 
89 
 
90 
We anticipate that study visits will take approximately 1-2 hours.   
91 
 
92 
5. Can I stop being in the study? 
93 
You may leave the study at any time.  If you decide to stop participating in the study, there 
94 
will be no penalty to you, and you will not lose any benefits to which you are otherwise 
95 
entitled.  Your decision will not affect your future relationship or your medical care at The 
96 
Ohio State University Wexner Medical Center.  
97 


CONSENT 
Biomedical/Cancer 
 
 
 
IRB Protocol Number:
2014H0291
IRB Approval date: 
02/25/2019
Version: 
02/07/2019 
 
 
Page 6 of 11 
Form date: 12/15/05
 
 
98 
If you choose to withdraw from the study please return any/all nicotine patches to the study 
99 
research staff. 
100 
 
101 
6.   What risks, side effects or discomforts can I expect from being in the study? 
102 
 
103 
Nicotine patch 
104 
Common side effects include: 
105 
 
mild headache;  
106 
 
burning at the site of application (redness, itching, and/or burning which subsides 
107 
within 24 hours).   
108 
 
109 
To avoid skin irritation you should change the location of the patch each day.  Please 
110 
contact the study doctor if burning does not stop after 24 hours. You should not use 
111 
any type of tobacco product while using nicotine patches. 
112 
 
113 
Rare and less frequent side effects may include: change in sense of taste, increased 
114 
coughing, mild dizziness or lightheadedness; drowsiness, dryness of mouth, menstrual pain, 
115 
abdominal or stomach pain and/or gas, constipation, diarrhea, indigestion, mild loss of 
116 
appetite and nausea or vomiting, muscle or joint pain, increased sweating, trouble sleeping 
117 
or abnormal dreams, unusual irritability or nervousness.  If you experience abnormal dreams 
118 
or have trouble sleeping, you may take the patch off at night when you go to bed.  A new 
119 
patch must be used the next day, while the old one should be discarded. 
120 
 
121 
Risk of nicotine dependence: The risk of developing dependence to nicotine is very low.  
122 
Less than 1% of people that use nicotine to quit smoking develop dependency symptoms, 
123 
such as cravings. The slower release of nicotine and gradual decrease in dose will reduce 
124 
any craving for the drug.  If cravings or other signs of dependency continue at the end of the 
125 
washout period mentioned previously in this form, the study doctor will recommend tobacco 
126 
cessation programs and will pay for medications. 
127 
 
128 
There is little information known about nicotine patches being used on non-smokers and how 
129 
it will affects people, or if they may be more likely to become dependent, however the 
130 
nicotine patch has been used in a smaller study in patients with sarcoidosis.  In this smaller 
131 
study, the most common side effects found were skin irritation, headaches and changes in 
132 
sleep quality however, these symptoms improved after several days of using the patch.  
133 
None of these patients became addicted to the patch.   
134 
 
135 
Blood draw:  The risks of drawing blood include pain when the needle is inserted into the vein 
136 
in the arm, bruising and rarely infection or fainting.   
137 
 
138 
Spirometry: There is little risk from spirometry. Some people may have chest soreness or 
139 
light-headedness from the hard blowing. The chest soreness usually goes away by itself, but 
140 
can be relieved with non-prescription pain-relievers. 
141 
 
142 
Albuterol:   Albuterol is a medication that may be given after the spirometry to dilate the 
143 
breathing passages. On rare occasions (less than 10 out of 192 people) it may cause 
144 
nervousness, a rapid heartbeat or headache at the doses used in this study. If you 
145 


CONSENT 
Biomedical/Cancer 
 
 
 
IRB Protocol Number:
2014H0291
IRB Approval date: 
02/25/2019
Version: 
02/07/2019 
 
 
Page 7 of 11 
Form date: 12/15/05
 
develop any of these problems, we will monitor you closely until the problem goes away 
146 
(typically in 30 minutes). On rare occasions, albuterol may cause arrhythmias (the heart 
147 
beats in an abnormal way) . This side effect is usually related to taking high doses of the 
148 
medication and so are very unlikely to occur during this study.  
149 
 
150 
ECG: After you have an ECG, you may have mild irritation, slight redness, and itching at the 
151 
places on your skin where the recording patches are placed.    
152 
 
153 
Questionnaires:  You may be mentally tired or become stressed answering some of the 
154 
questions. 
155 
 
156 
CT Scan: If you take part in this research, you will have one or more medical imaging studies 
157 
which use radiation. The tests you will have include two lung CT scans. The radiation dose 
158 
from this research is about 11 millisievert. To give you an idea about how much radiation you 
159 
will get, we will make a comparison with an every-day situation. Everyone receives a small 
160 
amount of unavoidable radiation each year. Some of this radiation comes from space and 
161 
some from naturally-occurring radioactive forms of water and minerals. This research gives 
162 
your body the equivalent of about 4 extra year’s worth of this natural radiation. The radiation 
163 
dose we have discussed is what you will receive from this study only, and does not include 
164 
any exposure you may have received or will receive from other tests. 
165 
A possible health problem seen with radiation exposure is the development of cancer later in 
166 
life. 
167 
 
168 
This extra cancer risk is higher at younger ages and for girls and women. The extra lifetime 
169 
risk of dying of a fatal cancer due to the radiation exposure from this research may range 
170 
from about one in 3,000 to about one in 1,000. At such low radiation exposures, scientists 
171 
disagree about the amount of risk. These estimates are very uncertain, and there may be no 
172 
extra risk at all. We can compare this possible extra cancer risk to other risks (over a lifetime) 
173 
that everyone is subject to in everyday life. For example, the chances of a person dying of 
174 
cancer with no extra radiation exposure are about one in 4. The chances of dying in a car 
175 
crash are about one in 82, and the chances of being killed by a car while crossing the street 
176 
are about one in 730.  
177 
 
178 
X-Ray 
179 
A chest x-ray will be done if you have not had one in the past year. This involves a small 
180 
amount of radiation. The radiation exposure from this research is about 200 microsievert. To 
181 
give you an idea about how much radiation you will get, we will compare it to the amounts 
182 
that people encounter in daily life. There is radiation that naturally occurs from space and 
183 
from rocks in the soil. This natural radiation is greater at higher altitudes. This research gives 
184 
you about the same amount of radiation as you would get from living in a high altitude city 
185 
such as Denver for 12 days, or taking 4 airplane flights from New York to Los Angeles. The 
186 
radiation dose we have discussed is what you will receive from this study only, and does not 
187 
include any exposure you may have received or will receive from other tests. 
188 
 
189 
A possible health problem seen with radiation exposure is the development of a second 
190 
cancer later in life. This extra cancer risk is higher at younger ages and for girls and women. 
191 
The extra lifetime risk of dying of a fatal cancer due to the radiation exposure from this 
192 
research may range from about one in 200,000 to about one in 70,000. At such low radiation 
193 


CONSENT 
Biomedical/Cancer 
 
 
 
IRB Protocol Number:
2014H0291
IRB Approval date: 
02/25/2019
Version: 
02/07/2019 
 
 
Page 8 of 11 
Form date: 12/15/05
 
exposures, scientists disagree about the amount of risk. These estimates are very uncertain, 
194 
and there may be no extra risk at all. 
195 
 
196 
We can compare this possible extra cancer risk to other risks (over a lifetime) that everyone 
197 
is subject to in everyday life. For example, the chances of a person dying of cancer with no 
198 
extra radiation exposure are about one in 4. The chances of dying in a car crash are about 
199 
one in 82, and the chances of being killed by a car while crossing the street are about one in 
200 
730. 
201 
 
202 
Confidentiality: Every possible effort will be made to keep personal information confidential.  
203 
The researchers cannot guarantee absolute confidentiality. Personal information may be 
204 
disclosed if required by law.  In order to protect health information, data will be stored on a 
205 
password protected network server and only authorized study personnel will have access to 
206 
this confidential information.  Information that would allow you to be identified such as name, 
207 
medical record number, address, and phone number will be stored separately from the 
208 
research test results and will be linked by a randomly generated identifier (a unique number 
209 
assigned to the research participant). 
210 
 
211 
Risks to Women of Childbearing Age:  A urine pregnancy test will be repeated at each visit 
212 
if subject is a female and of childbearing potential. If you become pregnant you will be asked 
213 
to stop your study medication and you will be withdrawn from the study. If a urine pregnancy 
214 
test is positive, you will have blood drawn for a serum pregnancy test.  
215 
 
216 
7.   What benefits can I expect from being in the study? 
217 
There may be no direct benefit for participation in this study.  However, this study will benefit 
218 
society as researchers learn more about the mechanisms that cause sarcoidosis and possible 
219 
new treatments. 
220 
 
221 
8.   What other choices do I have if I do not take part in the study? 
222 
You may choose not to participate without penalty or loss of benefits to which you are 
223 
otherwise entitled. 
224 
 
225 
9.   Will my study-related information be kept confidential? 
226 
The NIH issues Certificates of Confidentiality for all NIH-funded studies, including this study. 
227 
This Certificate provides extra protection for you and your study information, documents, or 
228 
samples (blood, tissue, etc.). The Certificates are issued so that we cannot be required to 
229 
disclose any identifiable information collected about you as a part of this study in a lawsuit or 
230 
legal proceeding. This is a layer of protection over and above the already existing protections 
231 
in place for you and your information, documents, or samples. 
232 
 
233 
However, these protections do not apply in some situations. For example, we may have to 
234 
release your information if a law requires us to do so, if the NIH that is funding this study 
235 
requests the information, or if the FDA tells us to release this information. 
236 
 
237 
Please talk to your study team, or contact the Office of Responsible Research Practices at 
238 
614-688-8641, if you have questions. 
239 
 
240 
Please visit the NIH website at https://humansubjects.nih.gov/coc/faqs to learn more. 
241 
 
242 


CONSENT 
Biomedical/Cancer 
 
 
 
IRB Protocol Number:
2014H0291
IRB Approval date: 
02/25/2019
Version: 
02/07/2019 
 
 
Page 9 of 11 
Form date: 12/15/05
 
Efforts will be made to keep your study-related information confidential.  However, there may 
243 
be circumstances where this information must be released.  For example, personal 
244 
information regarding your participation in this study may be disclosed if required by state 
245 
law.  Also, your records may be reviewed by the following groups (as applicable to the 
246 
research): 
247 
 
Office for Human Research Protections or other federal, state, or international regulatory 
248 
agencies; 
249 
 
U.S. Food and Drug Administration; 
250 
 
The Ohio State University Institutional Review Board or Office of Responsible Research 
251 
Practices; 
252 
 
The sponsor supporting the study, their agents or study monitors; and 
253 
 
Your insurance company (if charges are billed to insurance). 
254 
 
255 
If a study procedure is related to your medical care (e.g., CT scan findings), your study-
256 
related information may be placed in your permanent hospital, clinic, or physician’s office 
257 
records. Authorized Ohio State University staff not involved in the study may be aware that 
258 
you are participating in a research study and have access to your information. 
259 
 
260 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
261 
by U.S. law.  This website will not include information that can identify you.  At most, the 
262 
website will include a summary of the results.  You can search the website at any time 
263 
 
264 
If the study involves the use of your protected health information, you may also be asked to 
265 
sign a separate Health Insurance Portability and Accountability Act (HIPAA) research 
266 
authorization form. 
267 
 
268 
10. What are the costs of taking part in this study? 
269 
Taking part in this study may lead to added cost to you or your insurance company if you need 
270 
additional medical treatment other than that given as part of the study. The additional medical 
271 
treatment is not covered by the study (for example, if you need to be hospitalized, then the 
272 
costs related to this hospitalization will not be paid for by the study).  You will need to check 
273 
with your insurance providers regarding any additional costs.   
274 
 
275 
11. Will I be paid for taking part in this study? 
276 
You will receive $50.00 for the completion of each of the five office visits (screening, entry, 
277 
study visit weeks 10, 18, and 26). If you complete all required study visits, you will receive a 
278 
total of $250.00. With appropriate documentation you may be reimbursed for travel costs (as 
279 
needed) such as parking, lodging, and bus fare. 
280 
 
281 
By law, payments to subjects are considered taxable income.   
282 
 
283 
12. What happens if I am injured because I took part in this study? 
284 
If you suffer an injury from participating in this study, you should notify the researcher or 
285 
study doctor immediately, who will determine if you should obtain medical treatment at The 
286 
Ohio State University Wexner Medical Center.   
287 
 
288 
The cost for this treatment will be billed to you or your medical or hospital insurance. The 
289 
Ohio State University has no funds set aside for the payment of health care expenses for this 
290 
study.  
291 


CONSENT 
Biomedical/Cancer 
 
 
 
IRB Protocol Number:
2014H0291
IRB Approval date: 
02/25/2019
Version: 
02/07/2019 
 
 
Page 10 of 11 
Form date: 12/15/05
 
 
292 
13. What are my rights if I take part in this study? 
293 
If you choose to participate in the study, you may discontinue participation at any time 
294 
without penalty or loss of benefits.  By signing this form, you do not give up any personal 
295 
legal rights you may have as a participant in this study. Follow-up is desired either in person 
296 
or via records review should the intervention be halted. Subjects are encouraged to continue 
297 
follow-up if withdrawn from interventions. 
298 
 
299 
You will be provided with any new information that develops during the course of the 
300 
research that may affect your decision whether or not to continue participation in the study. 
301 
 
302 
You may refuse to participate in this study without penalty or loss of benefits to which you are 
303 
otherwise entitled. 
304 
 
305 
An Institutional Review Board responsible for human subject research at The Ohio State 
306 
University reviewed this research project and found it to be acceptable, according to 
307 
applicable state and federal regulations and University policies designed to protect the rights 
308 
and welfare of participants in research. 
309 
 
310 
14. Who can answer my questions about the study? 
311 
For questions, concerns, or complaints about the study you may contact Elliott Crouser, M.D. 
312 
at 1-800-678-6495. 
313 
 
314 
For questions about your rights as a participant in this study or to discuss other study-related 
315 
concerns or complaints with someone who is not part of the research team, you may contact 
316 
Ms. Sandra Meadows in the Office of Responsible Research Practices at 1-800-678-6251. 
317 
 
318 
If you are injured as a result of participating in this study or for questions about a 
319 
study-related injury, you may contact Elliott Crouser M.D. at 1-800-678-6495. 
320 
 
321 
 
322 
 
323 
 
324 
 
325 
 
326 
 
327 
 
328 
 
329 
 
330 
 
331 
 
332 
 
333 
 
334 
 
335 
 
336 
 
337 
 
338 
 
339 
 
340 


CONSENT 
Biomedical/Cancer 
 
 
 
IRB Protocol Number:
2014H0291
IRB Approval date: 
02/25/2019
Version: 
02/07/2019 
 
 
Page 11 of 11 
Form date: 12/15/05
 
Signing the Consent Form 
341 
 
342 
I have read (or someone has read to me) this form and I am aware that I am being asked to 
343 
participate in a research study.  I have had the opportunity to ask questions and have had 
344 
them answered to my satisfaction.  I voluntarily agree to participate in this study.  
345 
 
346 
I am not giving up any legal rights by signing this form.  I will be given a copy of this form. 
347 
 
348 
 
349 
 
 
 
Printed name of subject
 
Signature of subject
 
 
 
 
 
AM/PM
 
 
Date and time
 
 
 
 
 
 
 
 
Printed name of person authorized to 
consent for subject (when applicable) 
 
Signature of person authorized to consent 
for subject  
(when applicable)
 
 
 
 
 
AM/PM
Relationship to the subject
 
Date and time
 
 
350 
 
351 
Investigator/Research Staff 
352 
I have explained the research to the participant or his/her representative before requesting 
353 
the signature(s) above.  There are no blanks in this document.  A copy of this form has been 
354 
given to the participant or his/her representative. 
355 
 
356 
 
 
 
 
Printed name of person obtaining consent
 
Signature of person obtaining consent
 
 
 
 
 
AM/PM
 
 
Date and time
 
 
357 
Witness(es) - May be left blank if not required by the IRB 
358 
 
359 
 
 
 
 
Printed name of witness
 
Signature of witness
 
 
 
 
 
AM/PM
 
 
Date and time
 
 
 
 
 
Printed name of witness
 
Signature of witness
 
 
 
 
 
 
AM/PM
 
 
Date and time
 
 
360