Treatment Alternatives in Adult Rare Disease; Assessment of Options in Idiopathic Subglottic Stenosis North American Airway Collaborative PR-02 Study (NoAAC PR-02 Study)
Conditions: Idiopathic Subglottic Stenosis (iSGS)
Sponsor: Vanderbilt University Medical Center

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Treatment Alternatives in Adult Rare Disease;  
Assessment of Options in Idiopathic Subglottic Stenosis  
 
North American Airway Collaborative PR-02 Study (NoAAC PR-02 Study) 
 
 
NoAAC Protocol Number: PR-02 
PCORI Grant Number:  1409-22214 
Principal Investigator:  Alexander Gelbard M.D. 
Draft or Version Number:  7 
12 July 2018 
 
 
 
Alexander Gelbard M.D.  
Principal Investigator 
Assistant Professor of Otolaryngology  
Vanderbilt University Bill Wilkerson Center 
Vanderbilt University Medical Center 
 
Nashville, TN  37232 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents: 
 
Study Schema 
1.0 
Background 
2.0 
Rationale and Specific Aims 
3.0 
Inclusion/Exclusion Criteria 
4.0 
Enrollment/Randomization 
5.0 
Study Procedures 
6.0 
Data Entry, Collection and Quality Control 
7.0 
Patient Reimbursement 
8.0 
Risks to Patients 
9.0 
Study Benefits to Patients 
10.0 
Reporting of Adverse Events Involving Risk to Participants or Others 
11.0 
Study Withdrawal/Discontinuation 
12.0 
Statistical Considerations 
13.0 
Ethics / Protection of Human Subjects 
14.0 
Data Handling and Record Keeping 
15.0 
Participant Confidentiality 
16.0 
Publication/Data Sharing Policy 
17.0 
References 
 
 
 
 
 

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STATEMENT OF COMPLIANCE 
The study will be conducted in accordance with the International Conference on Harmonisation guidelines 
for Good Clinical Practice (ICH E6), the Code of Federal Regulations on the Protection of Human Subjects 
(45 CFR Part 46), and the PCORI Clinical Terms of Award.  All personnel involved in the conduct of this 
study have completed human subjects protection training.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Title: 
Treatment Alternatives in Adult Rare Disease; Assessment of Options 
in Idiopathic Subglottic Stenosis 
Précis: 
The proposed study intends to create an international, multi-institutional 
prospective cohort of iSGS patients. It will enable rigorous treatment 
strategy comparisons to determine how well the most commonly used 
treatments in iSGS “work”; and what quality of life trade-offs are 
associated with each approach.  
Objectives: 
Prospective rigorous treatment comparisons to provide the critical 
information to patients to allow them to answer the questions,  
1) “given my personal characteristics, conditions and preferences, what 
should I expect will happen to me?” and  
2) “what are my options and what are the potential benefits and harms of 
these options?”  
 
Primary Endpoint: Treatment effectiveness: time to recurrent procedure 
and need for tracheostomy.  
 
Secondary Endpoint:  Health and quality of life tradeoffs: patient reported 
outcome measures in voice, swallowing, breathing, and global quality of 
life  
Population: 
All clinically confirmed iSGS patients at the participating institutions are 
eligible for enrolment. 
Number of Sites: 
45 Sites  
Study Duration: 
60 months 
Subject 
Participation 
Duration: 
>6months 
Estimated Time to 
Complete 
Enrollment: 
 24 months 

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Schematic of Study Design: 

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Key Personnel and Study Responsibilities: 
 
 
 
 
 
 
 
 
 
 

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Principal Investigator:   
Dr. Alexander Gelbard M.D. 
 
PCORI Program Official:   
Dr. Layla Lavasani Ph.D. 
 
Institutions: 
 
Vanderbilt University 
University of Virginia  
University of Utah 
 
 
Mayo Clinic  
 
 
 
Cleveland Clinic 
Johns Hopkins 
Massachusetts Eye & Ear Infirmary  
 
Oregon Health Science University 
Emory University 
 
University of Washington 
 
University of California San Francisco 
University of Colorado 
Baylor College of Medicine  
Louisiana State University 
 
Imperial College Health Care, Charring Cross 
 
University of Alabama Birmingham 
University of Wisconsin 
University of Michigan 
 
University of Nebraska 
 
University of Minnesota 
 
 
University of California San Diego  
 
University of Iowa 
 
University of Texas Southwestern 
 
Duke University 
University of North Carolina 
Augusta University 
University of California, Los Angeles 
University of Sydney 
University of California, Irvine 
University of Pittsburgh 
Loma Linda University 
Stanford University 
Emory University 
Ohio State University 
University of Southern California 

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Temple University 
Medical College of Wisconsin 
Landspitali University Hospital 
Bastian Voice Institute 
New York University  
University of Cincinnati 
Columbia University 
University of Miami 

Assess me nt of O pti o ns i n I di o pat hic S u b gl ottic Ste n osis  
V ersi o n 7  
Pr ot o c ol P R 0 2  
1 2 J ul y 2 0 1 8  
 
P a g e 9  of 2 8  
 
1. 0  
B ac k gr o u n d  
I di o pat hic s u b gl ottic ste n osis (i S G S) is a rare disease i n w hic h t he trac hea 
narr o ws f or n o k n o w n reas o n. Alt h o u g h u nc o m m o n  ( wit h a n esti mate d i nci de nce of 
1: 4 0 0, 0 0 0 pers o ns per year 1), it is life-t hreate ni n g a n d life-alteri n g w he n s ur vi ve d.  
B ot h t he disease a n d its t hera pies pr of o u n dl y affect patie nts’ a bilit y t o breat he 2, 
c o m m u nicate3 a n d s w all o w 4. Breat hi n g diffic ulties (i.e. d ys p nea) is t he hall mar k 
s y m pt o m a n d t he pri mar y ca us e of deat h a n d disa bilit y 5. H o we v er, p atie nts ca n als o 
e x perie nce d e bilitati n g v oice c h a n ges 3, 6, 7 a n d s wall o wi n g pr o ble ms 8 d ue t o t h e 
c o n diti o n ( Fi g ure 1) or its treat me nt.  
 
Pe o ple wit h t his disease ofte n re q uire se veral s ur geries p er year 9. A vari et y of 
treat me nts ha ve b ee n a d va nce d t o 
ma na ge t his c o n diti o n1, 2, 9 b ut are ge nerall y 
cate g orize d i nt o: 1) e n d osc o pic dilati o n  of t he trac heal ste n osis (acc o m plis he d wit h 
ri gi d i nstr u me nts or i nfl ata ble ball o o ns); 2) e n d os c o pic resecti o n  of t he ste n osis ( wit h 
pr ol o n ge d me dical t hera p y after s ur ger y); or 3) o pe n nec k s ur ger y  wit h resecti o n of 
t he affecte d tr ac heal se g me nt wit h e n d-t o-e n d a nast o m osis ( Fi g ure 2). Eac h patie nt 
ca n re q uire re peate d s ur geries t o kee p t heir tr ac hea o pe n, w hic h i ncreas es o d ds of 
treat me nt si de effects a n d c o m plicati o ns. All a p pr oac hes ha v e u ni q ue a n d ofte n 
disa bli n g ass o ciate d si de effects, w hic h ca n si g n ifi ca ntl y affect t h e patie nt’s q ualit y of 
life. 
H o we v er, c o m parati ve data o n tra d e-offs ha ve n e ver bee n s yste maticall y 
e val uate d.  
 
Beca use t he disease is rare, it is diffic ult f or patie nts t o fi n d g o o d i nf or mati o n s o t hat t he y ca n 
u n dersta n d t he s pectr u m of treat me nt o pti o ns 1 0. T his is partic ularl y diffic ult beca use m ost patie nts prese nt 
wit h se vere breat hi n g tr o u ble a n d n ee d treat me nt q uic kl y, li miti n g t heir a bilit y t o e x pl ore o pti o ns (as w o ul d 
be t h e case wit h less life -t hreate ni n g s y m pt o ms). A d diti o nall y, t h ere is a ge n eral lac k of hi g h-q ualit y, 
relia ble, a n d accessi ble d ata t o i nf or m i n di vi d ual p atie nt decisi o n-ma ki n g.  I m perfect i nf or mati o n a n d li mite d 
e vi de nce o n tr eat me nt o utc o mes c o m plicate p ati e nt decisi o n -ma ki n g as t he y tr y t o bala nce s ur vi val, 
s y m pt o ms, a n d q ualit y of life c o nsi derati o ns. I n 
esse nce, patie nts wit h a ne w dia g n osis of i S G S face 
m yria d t hera pe utic o pti o ns, b ut are u na ble t o e x pl ore 
t he m beca use it is ur ge nt t hat t he y q uic kl y relie ve 
t heir breat hi n g diffi c ult y.  
 
T he pr o p ose d pr os pecti ve st u d y ( N o A A C P R -
0 2) is desi g ne d t o fill t his v oi d, a n d le vera ges a n d 
e x pa n ds u p o n o ur pre vi o us retr os pecti ve 
m ulti -
i nstit uti o nal i n vesti gati o n, t he 
N ort h 
A merica n 
Air wa y C olla b orati ve R P -0 1 ( N o A A C R P -0 1). I n t hat 
st u d y nearl y 5 0 0 i S G S patie nts were i de ntifie d a n d 
st u die d fr o m te n 
e x pert tertiar y 
care 
ce nters. 
S pecificall y, t he nee d f or re peat s ur ger y, fre q u e nc y of 
disease rec urre n ce, a n d nee d f or trac h e ost o m y were 
i de ntifie d as pri mar y o ut c o me meas ures.  
Fi g ur e 2 . Tr e at m e nt a p pr o a c h e s f or i S G S: 1) e n d o s c o pi c 
dil ati o n of t h e tr a c h e al st e n o si s ( a c c o m pli s h e d wit h ri gi d 
i n str u m e nt s or i nfl at a bl e b all o o n s); 2) e n d o s c o pi c r e s e cti o n of 
t h e st e n o si s ( wit h pr ol o n g e d m e di c al t h er a p y aft er s ur g er y); 
or 3) o p e n n e c k s ur g er y 
wit h r e s e cti o n of t h e aff e ct e d 
tr a c h e al s e g m e nt wit h e n d-t o-e n d a n a st o m o si s.  
1. 
E n d os c opi c 
Di latio n
A.
B.
C.
2. 
E n d os c opi c 
R es ecti o n
A.
B.
C.
R es ecti o n
A na st om o sis
A.
B.
C.
Di ag n osis
3. 
O p e n A nt eri o r N ec k S urg er y
 
Fi g ur e 1 . Di a gr a m of 
n or m al t r a c h e a ( A.), 
H e alt h y tr a c h e a ( B.), 
& i S G S p ati e nt wit h 
o b str u cti v e 
tr a c h e al 
s c ar ( C.).
V oc al C or ds
Tr ac h e a
( wi n d pi p e)
A. Di a gr a m
B. H e alt h y
C. i S G S
 

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Collaboration of experienced high volume centers in both the 
United States and the United Kingdom provided us with the largest and 
most representative signature of this disease’s epidemiology, natural 
history, and current management. Inclusion of patients across regions 
and national borders ensured a racially/ethnically representative cohort 
spanning a range that includes socioeconomic disadvantaged and 
medically underserved patients.  Interestingly, this condition was shown 
to be quite similar at the separate centers; as it nearly universally affects 
40 – 60 year old women (median age 50.3, 95% CI 49.1 – 51.5) who 
undergo a median 1.75 surgeries per year (95% CI 0.8 – 2.6) (Figure 3).9 
The NoAAC RP-01 study also found variation in the standard of care for 
iSGS at expert centers. Three basic treatment approaches were used (i.e. 
endoscopic dilation, endoscopic resection with adjuvant medical 
therapy, and open anterior neck surgery) despite an absence of 
randomized controlled trials (RCTs) or other rigorous comparative 
studies to assess their differential effectiveness at avoiding disease 
recurrence or tracheostomy. 
 
In contrast to the retrospective nature of RP-01, our proposed PR-02 prospective study design will 
directly compare effectiveness of contemporary treatments and assess their associated quality of life 
tradeoffs in iSGS patients. While evaluating treatment effectiveness is important, it is equally critical that 
the patient experience with the disease itself and its treatment be systematically characterized. This is 
imperative since patient and physician perspectives are often significantly discordant11. To this end, NoAAC 
PR-02 will collect patient-reported outcomes (PROs) in the cohort at initial presentation and at a priori 
determined intervals thereafter, (e.g. immediately pre-intervention, as well as 3, 6, and 12 months post-
intervention) and conduct patient interviews and focus groups (labeled “engagement studios”) to better 
understand the patient experience with this condition.  
 
Beyond the gaps in understanding of the relative effectiveness of clinical outcomes, no studies have 
explored health-related quality of life (HRQOL) or functional outcomes in iSGS. These endpoints are 
important to patients and are arguably a primary determinant in decision-making. For example, results show 
that endoscopic dilation is associated with a higher rate of disease recurrence and thus need for repeated 
surgery.  Meanwhile, open cricotracheal resection is a major surgery with significant immediate 
perioperative risks and has been associated with alterations in voice3,6 and swallowing4.  Open surgery 
appears to reduce the risk of disease recurrence, but the degree of benefit, and the trade-offs associated with 
this invasive surgery are questions that demand prospective study. 
 
 
 
 
 
 
 
 
 
0
0
0
0
0
0
250
200
150
100
50
0
Time between interventions (m)
Operative Procedure number
0  2  4  6  8  10  12  14  16  18
Figure 
3. 
Recurrent 
nature 
of 
interventions in iSGS.  Operative 
procedure number vs. recurrence 
interval. 
 
Each 
line 
represents 
individual patient. 

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2.0 
Rationale and Specific Aims 
Data from our prior retrospective multi-center study highlighted potential differential treatment 
effects based on reduced need for repeated surgery, while also providing insight into the typical 
disease course for iSGS patients.  However, the need to systematically validate and expand upon 
these findings to provide patient-centered outcomes data requires longer-term prospective study. The 
proposed 5-year study will evaluate clinical outcomes data and generate novel information for iSGS 
patients beyond the currently available center-specific treatment outcome estimates to better guide 
clinicians and patients and they discuss treatment options.  
 
In summary, the proposed study will address the questions outlined above through 3 specific aims:  
 
AIM I:  We will build an international, multi-center prospective cohort of iSGS patients  
 
AIM II:  We will prospectively compare treatments in iSGS at multiple national and international 
centers to determine what “works” with respect to treatment outcomes of disease 
recurrence and tracheostomy. 
 
AIM III:  We will define the trade-offs in breathing, voice, swallowing and global quality of life 
between each treatment approach  
 
 
3.0 
Inclusion/Exclusion Criteria 
Inclusion Criteria: 
 
>18 years of age. 
 
The lesion must involve the subglottis.  
 
Exclusion Criteria 
 
<18years of age 
 
Patients without capacity to consent for themselves 
 
History of significant laryngotracheal traumatic injury.  
 
History of endotracheal intubation or tracheotomy within 2 years of presentation.  
 
Major anterior neck surgery.  
 
History of neck irradiation.  
 
History of caustic or thermal injuries to the laryngotracheal complex.  
 
History of a clinically diagnosed vasculitis or collage vascular disease. 
 
Positive antinuclear cytoplasmic antibody titers.  
 
 
4.0 
Randomization 
There is no randomization as part of this study.  This is a prospective observational multicenter study 
consisting of approximately 30 centers (Appendix 1). Each center enrolling patients will utilize a 
common diagnostic algorithm (Appendix 2), and then apply their explicitly defined standard of care.  
The patients will be prospectively tracked for outcomes with respect to disease recurrence, need for 

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additional surgery, trachesotomy, as well as subjective patient reported outcomes in breathing, voice, 
and swallowing.   
 
 
5.0 
Study Procedures 
Recruitment and Enrollment: We anticipate a sample size of 800-1100 patients recruited across 
the participating centers.  The target goal for Vanderbilt recruitment is 750-800 patients.  There are 
currently 40 confirmed participating sites that will contribute patients (additional centers may be 
added in protocol amendments provided they meet defined study site selection criteria).   
Participating centers include those across all regions of the U.S. and international sites in the UK. 
Many are academic centers that are tertiary referral centers for adult laryngotracheal stenosis (LTS) 
and thus have significant experience treating this rare condition1,9,12-15. Nearly all LTS patients are 
ultimately referred for care and cluster at such high-volume centers, and thus we anticipate enrolling 
a representative patient cohort. Each research site has appropriate technological infrastructure for 
data collection and pathologic specimen tracking.  
 
Study participants will be recruited via several mechanisms.  Direct recruitment by participating 
clinician providers that diagnose and treat these patients will occur at each of the participating 
centers. It is expected that the majority of patients will be recruited through this approach. Patients 
will be identified by PI, Sub-I or Key study personnel and approached by a member of the research 
team at each institution regarding the study, or contacted by phone or email about the study.  
Participants may also be seen due to referrals in to participating sites/providers. 
 
Additionally interested stakeholders can identify this study directly through its registration with 
ClinicalTrials.gov, the National Organization for Rare Disorders (NORD) website and rare disease 
database.  Once recruited patients will undergo detailed discussion regarding risks and benefits of 
the trial, and informed consent will be obtained.   
 
Consent: Informed consent is a process that is initiated prior to the individual agreeing to participate 
in the study and continues throughout study participation.  Extensive discussion of risks and possible 
benefits of study participation will be provided to participants and their families, if applicable.  A 
consent form describing in detail the study procedures and risks will be given to the participant, or 
reviewed with the patient by phone or email (i.e., econsent).  Consent forms will be IRB-approved, 
and the participant will read and review the document or have the document read to him or her.  The 
participant will sign the informed consent document prior to any study-related assessments or 
procedures, or agree to participation if consent is done by phone or email (i.e., econsent).  
Participants will be given the opportunity to discuss the study or think about it prior to agreeing to 
participate.  They may withdraw consent at any time throughout the course of the study.  A copy of 
the signed informed consent document will be given to participants for their records, i.e. by mail, 
email, electronic link or in person.  The rights and welfare of the participants will be protected by 
emphasizing to them that the quality of their clinical care will not be adversely affected if they 
decline to participate in this study. The consent process will be documented in the clinical or 
research record.  
 

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Given the observational nature of the study and the minimal risk involved to patients, we will utilize 
established methodology for electronic consent and phone consent as alternative options to consents 
obtained in providers offices.  Electronic consenting of patients requires an alteration of the 
traditional consent model to fit within electronic delivery through email or for electronic capture of 
consent in a face to face encounter with participants.  Retention of many elements of the traditional 
consent procedure to ensure participant protections are in place, and we will abide by the 
institutional guidelines regarding these alternative consent methods. (Appendix 4).  
 
The investigator or designee will also be available to explain the research study to the participant and 
answer any additional questions that may arise. After informed consent, the patient will be 
considered to be a participant in the study.   
 
Protocol. Once enrolled and consented, patients will receive standard of care treatment at the 
respective center (Appendix 1) and will be followed longitudinally for symptom changes, need for 
further treatment, complications, and will have PROs (Appendix 2) administered at a priori 
determined intervals. 
 
Data collection: Data collection for the proposed clinical cohort study will include the following 
case report forms (CRFs) (Appendix 3), implemented in an electronic data capture (EDC) system 
(please see further details, below, regarding EDC development and implementation). 
 
 
Baseline. Baseline data will include such things as demographics, medical and surgical history, 
physical exam findings, and relevant diagnostics 
 
 
Procedure. Details of initial surgical procedure will be captured (e.g. site and degree of 
narrowing within the trachea). This information along with other procedure related information 
will be abstracted from the operative procedure note and clinical record into the EDC. 
 
 
Recurrence. At patient recurrence, information regarding the date of recurrence will be 
captured as for the initial procedure.  
 
 
Patient-reported outcomes (PROs). Validated PRO instruments will be utilized to assess patient 
quality of life. These relate to voice (VHI-10), dysphagia (EAT-10), breathing (COPD 
dyspnea), and general quality of life (SF-12). Additionally 4 “Non-traditional” PROs focused 
on 1) social support16, participatory decision-making style17, disease anxiety and burden18 and 
fear of disease recurrence19 will also be administered at the initial visit. Patients will be asked 
to complete “traditional” and “non-traditional PROs at baseline.  The “traditional” PROs will 
be repeated at recurrence, and at routine intervals post-procedure (e.g., at 3, 6, and 12 months). 
For patients with Internet access and email connectivity, interval PRO completion may be done 
directly by the patient into the web-based data capture instrument, with automated email 
reminders to patients at each PRO interval. For patients without Internet/email access, 
completion of PROs will be via mailed or in person paper forms, or over the phone with a 
member of the research team; the research staff will then will transfer PRO data from paper to 
the EDC.  
 

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 
Patient Generated Health Data (PGHD). Patient reported health data will be captured, an 
example of this is home peak flow measurements (obtained with a handheld asthma peak flow 
monitoring device supplied by the study) or number of steps taken during the week. 
 
 
Specimen. Biospecimens collected during routine standard of care from each patient (such as 
tracheal biopsies obtained during surgery, or surgical specimens generated thru open 
reconstructive surgeries), will be annotated in the EDC system with a minimum dataset to 
include date of specimen collection, specimen type (e.g., frozen biopsy tissue; FFPE block), 
and storage location.  Additionally if blood is collected during standard of care, we may ask the 
participants to consent to providing a one-time blood specimen for research.  We plan to obtain 
30 mL of blood at a time when other medically indicated labs, operative or office-based 
procedures occur. A member of the research team will be present at the scheduled blood draw 
to obtain the necessary research blood and transport to a research lab for storage and analysis.  
We may examine excess tissue obtained at standard of care surgical biopsy for bacterial 
pathogens, inflammatory molecular markers, and protein alterations. Techniques will include 
immunohistochemistry, DNA isolation, PCR, Microarray. We will analyze blood samples for 
functional immunologic assays, Elispot for IFN-gamma secretion in response to peptide 
stimulation, flow cytometry for cellular subset abundance, and molecular studies for evidence 
of t-cell exhaustion and singe nucleotide polymorphisms. 
 
 
6.0 
Data entry, collection, and quality control 
Data collection and management for the proposed project will be performed via a custom web-based 
electronic data capture system (EDC), implementing each of the CRFs described above in electronic 
format (eCRFs), and built using the Ruby on Rails (RoR) platform.  
 
This system is currently in place and actively functioning as the digital infrastructure for BetrNET, 
the NIH funded nationwide Barrett’s disease monitoring network.  The established HIPAA 
compliant technology has been actively in use for more than 5 years, as has a demonstrated track 
record of data privacy and fidelity.  The system is based on the Ruby on Rails (RoR) platform.  RoR 
is an open-source web application development framework for creating rich Internet applications 
that model complex data and reinforce data integrity through custom validations. The RoR 
framework for web-based data entry will be linked to a MySQL database for the data storage 
component. All data entry interfaces will utilize dropdown menus, radio buttons/checkboxes, and 
other structured variable formats whenever feasible, to enforce consistency of variable values in data 
entry. Also to support data quality control, extensive validations will be developed; these validations 
check records for internal consistency, conformity to any pre-specified data ranges, as well as 
compliance with any known inter-variable relationships. Support for longitudinal data will be 
provided through the use of a relational database architecture that models one-to-many relationships.  
 
In addition to the use of structured variables and validations to prevent data entry errors, other 
mechanisms for data quality control include: 
 
 
Testing. The EDC will be tested extensively in both the development/staging and production 
environments. Automated testing is performed via scripted tests, to verify that observed 

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behavior of the system conforms to expected behavior. Manual testing of all system features 
will also be employed via the user interface and performed by dedicated testing personnel. 
 
 
Access controls. Access to the EDC will be restricted to authorized personnel. Data entry 
personnel and other users are provided secure access to the web-based application via standard 
Internet technologies (i.e., HTTPS), with tiered access permissions appropriate to their study 
role; such access is granted only when the following criteria are met: 1) request for access is 
authorized by a study principal investigator or other designated key study personnel and is 
accompanied by a designation of the user’s role, to ensure appropriate level of access; and 2) 
the user completes training on system use, which may include a live training provided by our 
group and/or documented completion of a pre-recorded video training. 
 
Patient Surveys: 
A critical component to understanding the patient experience with their disease is their own 
subjective input.  This will be accomplished with established surveys of metrics for patient related 
health outcomes.  The Vanderbilt University Office of Research will be used as a central location for 
data processing and management for these surveys. Vanderbilt University, with collaboration from a 
consortium of institutional partners, has developed a software toolset and workflow methodology for 
electronic collection and management of research and clinical trial data. Two of those technologies 
are REDCap (Research Electronic Data Capture), a secure, web-based application that is flexible 
enough to be used for a variety of types of research and the BetrNet Ruby on Rails (ROR) platform. 
Both provide an intuitive user interface that streamlines project development and improves data entry 
through real-time validation rules (with automated data type and range checks). They also provide 
easy data manipulation (with audit trails for reporting, monitoring and querying patient records) and 
an automated export mechanism to common statistical packages (SPSS, SAS, Stata, R/S-Plus). In 
addition to traditional data capture functionality; REDCap and ROR survey capabilities are a 
powerful tool for building and managing online surveys. The research team can create and design 
surveys in a web browser and engage potential respondents using a variety of notification methods. 
All data collection projects rely on a thorough, study-specific data dictionary, defined by all members 
of the research team in an iterative, self-documenting process. This iterative development and testing 
process results in a well-planned and individualized data collection strategy. Surveys will either be 
completed via REDCap, the Ruby on Rails (RoR) platform or a combination. 
 
Patient Generated Health Data: 
One important element of research is an understanding of the experiences of individual patients, and 
one of the ways to learn about those experiences is by collecting patient-generated data. Such 
information can be obtained in a variety of ways, including during medical visits, through use of 
smartphones and other electronic devices, and as part of research studies.  These techniques will be 
employed during our study to capture patient self-reported peak-flow measurements.  An established 
REDCap-based platform will be used to allow patients to input their data and provide the ability to 
track these measurements longitudinally over time. This technology utilizes smartphone reminders 
and automated voice algorithms for patient phone call, as well as having options for secure encrypted 
HTTPS data transfer over the web to the servers in the Data monitoring center. 
 

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The survey REDCap servers are housed in a local data center at Vanderbilt, and all web-based 
information transmission is encrypted. REDCap was developed specifically around HIPAA-Security 
guidelines and is recommended to Vanderbilt researchers by both our Privacy Office and Institutional 
Review Board. REDCap has been disseminated for local use at more than 940 other academic/non-
profit consortium partners in 75 countries. Vanderbilt leads the REDCap Consortium, which currently 
supports more than 99,000 projects and 128,000 users. More information about the consortium and 
system security can be found at http://www.projectredcap.org/.  
 
 
7.0 
Patient Reimbursement: 
None 
 
 
8.0 
Risks 
Minimal risk is anticipated. There are no investigational treatments under study in this project. Study 
patients will be asked to answer questions on self-administered hard copy electronic, mailed, or 
telephone surveys, and self-reported health data (i.e. peak flow breathing measurements).  
Additionally, limited information from their routine medical care will be obtained. Patients will be 
informed that they can refuse to answer any of the questions. They will also be told that refusal to 
participate in the study will not in any way change or alter the care they will receive.  Patients will 
be told that survey data are to be obtained for research purposes only and that no individual results 
will be reported. The data will be kept strictly confidential. No data of any sort will be released to 
anyone outside the study for any reason. Individual patients are never identified in publications. 
Risks to the participants will be minimized by proper screening of potential candidates and strict 
adherence to confidentiality rules.  In addition, access to the Electronic Data Capture (EDC) system 
will be strictly restricted to authorized personnel. Data entry personnel and other users are provided 
secure access to the web-based application via standard Internet technologies (i.e., HTTPS), with 
tiered access permissions appropriate to their study role; such access is granted only when the 
following criteria are met: 1) request for access is authorized by a study principal investigator or 
other designated key study personnel and is accompanied by a designation of the user’s role, to 
ensure appropriate level of access; and 2) the user completes training on system use, which may 
include a live training provided by our group and/or documented completion of a pre-recorded video 
training. 3) The user has appropriate training for protection of human subjects. 
All requests for user access, with documentation of fulfillment of the above criteria, are recorded in 
the permanent system documentation.   
 
 
 
 
9.0 
Benefits 
The risks for this study are minimal given the potential benefits to patients and society of any 
insights gained regarding the comparative effectiveness of idiopathic subglottic stenosis. Patients 
will be offered remuneration for study participation, as the various surveys will include roughly 25-
100 items. There are no other direct benefits to the study patients, although some patients may gain 

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personal satisfaction through participation in research aimed at advancing knowledge of optimal 
treatment in a rare disease requiring repeated invasive operative interventions. 
 
 
10.0 
Reporting of Adverse Events Involving Risk to Participants or Others 
This is a non-intervention study and there is no DSMB. The Principal Investigator is responsible for 
monitoring protocol conduct and reporting any adverse events related to study procedures. Adverse 
Events (AE) reporting will include the reporting of any unanticipated AE if it is probably or 
definitely related to being in this study. Although AEs are not anticipated on this study, if they 
should occur, they will be reported to the participating sites IRB board as well as the Vanderbilt 
Institutional Review Board by the Principal Investigator as required. 
 
 
11.0 
Study Withdrawal/Discontinuation 
Study participants may withdraw from the study at any time by contacting the site specific PI, or the 
Coordinating Center PI Dr. Gelbard, or coordinating center research team staff. 
Subjects are free to withdraw from participation in the study at any time upon request.  
An investigator may terminate a study subject’s participation in the study if: 
 Any medical condition, event or situation occurs such that continued participation in the 
study would not be in the best interest of the subject. 
 The subject meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation.   
 
12.0 
Statistical Considerations 
Study Hypotheses 
1. There is variation in Time to Recurrence (TTR) between centers using similar surgical 
approaches for iSGS 
2. There is variation in TTR between centers using different surgical approaches for iSGS. 
3. The different surgical approaches are associated with unique tradeoffs in terms of voice, 
swallowing, breathing, and global quality of life.  
 
Sample Size Considerations 
The primary endpoint of this trial is time to recurrence. The sample size estimation is completed 
using the 95% confidence interval (CI) method.  With the proposed sample size of 1100 
(endoscopic therapy ≈ 800, open surgery ≈ 100 and endoscopic resection ≈ 100), the half-width of 

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the 95% confidence interval for the time to recurrence function will be less than .24 for endoscopic 
resection and open surgery groups, and will be less than .13 for the endoscopic dilation group.   
Final Analysis Plan 
The primary objective: The primary objective of this study is to evaluate the time to recurrence 
(TTR) among three possible treatment groups, i.e., open surgery, endoscopic dilation, and 
endoscopic resection.   
 
Data analysis plan for the primary endpoint: Demographic information will be tabulated.  
Descriptive statistics, including means, standard deviations, and ranges for continuous parameters, 
as well as percents and frequencies for categorical parameters, will be presented.  For the primary 
objective analysis, i.e., estimating the TTR with 95% confidence interval, the TTR time will be 
estimated using the Kaplan-Meier method with the 95% confidence interval (CI).  The Rothman 
CI, CI's based on Greenwoods variance, Thomas and Grunkemeier CI and the simultaneous 
confidence bands by Nair and Hall and Wellner will be reported. The logrank test will be used to 
compare the equality of survival curves.  The generalized Wilcoxon and log-likelihood tests will 
also be examined, as these tests weight the survival function differently from the logrank test, 
which gives more weight to later occurring events.  The Cox proportional hazards model will be 
applied to investigate potential prognostic factors, such as age on the TTR data.  The adjusted p-
values as well as the adjusted 95% confidence intervals from the Cox model will be reported. The 
adjusted hazard ratios and 95% CIs will be reported. 
 
The secondary objective: differential treatment quality of life trade-offs will be prospectively and 
systematically assessed using both validated “traditional” and “non-traditional” patient reported 
outcome measures (PRO). 4 “Traditional” PRO will measure disability related to voice (VHI-101), 
swallowing (EAT-102), breathing (COPD dyspnea3), and global quality of life (SF-124) (IR4). 4 
“Non-traditional” PROs focused on 1) social support5, participatory decision-making style6, 
disease anxiety and burden7 and fear of disease recurrence8 will also be administered at the initial 
visit. Responses to PROs tend to change in chronic disease states since severity of the measured 
concept is time-variable. This is particularly true for iSGS patients whose symptoms markedly 
improve after treatment and revert and worsen before subsequent treatments. To better understand 
the breadth of patient experience with this condition, PROs will employed at a priori determined 
intervals after diagnosis and treatment, (e.g. immediately pre-intervention, 3, 6, and 12, post-
intervention), to obtain a more accurate portrait of the survivorship experience related to the 
different therapeutic modalities.  
 
Data analysis plan for secondary endpoints: The secondary objective of this study is to evaluate 
the quality of life (QOL) scores, e.g., SF12, Dyspnea index, EAT-10, and VHI10, among three 
study groups. The 95% confidence interval (CI) method based on the Normal distribution will be 
applied to estimate the quality of life score among three study groups.  The mixed effect model 
will be applied to exam the correlation between the quality of life score and the study groups.  
 
The strategy to be used for developing the multivariable models for QOL involves the following 
steps: (1) Apply multiple imputation for missing covariate values to make good use of partial 
information. (2) Choose an appropriate statistical model based on the nature of the response variable. 

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(3) Decide on the allowable complexity of the model (i.e., the number of covariates) based on the 
effective sample size available. (4) Allow for nonlinear predictor effects using regression splines. (5) 
Incorporate pre-specified interactions. (6) Check distributional assumptions. (7) Adjust the variance-
covariance matrix for multiple imputation. (8) Quantify the clinical utility (discrimination ability) of 
the model. (9) Internally validate the calibration and discrimination of the model using the bootstrap 
approach, e.g., .632+ bootstrap, to estimate the model's likely performance on a new set of subjects. 
The statistical analyses will be completed by either R 3.1.1 or SAS 9.4 statistical program in this 
project 
 
Statistical strategy for addressing missing data: Given the enthusiasm of the iSGS population 
for this trial, we estimate a 90-95% response rate for the patient reported outcome measures in the 
cohort. Acknowledging this, it is possible that bias could be introduced due to missing data.  To 
account for this, we will use two approaches in cases where participants are alive but are missing 
PRO data: the multiple imputation model based on the Markov chain Monte Carlo method 
described above9 and a hierarchical hot-deck imputation approach10,11. We will perform sensitivity 
analyses compare the two methods to assess the validity of the two approaches. It is necessary to 
assume data are missing at random (MAR) to perform these types of pattern mixture imputation 
analyses11. In the hierarchical hot-deck imputation approach, participants with missing PRO data 
will be matched with at least 10 other participants with full data at the previous time point on the 
following variables: to voice (VHI-10), swallowing (EAT-10), breathing (COPD dyspnea), and 
general quality of life (SF-12), age, race, co-morbid disease, education and income. The order of 
matching will be determined by the dependent variable being examined. For the purposes of 
statistical testing, 10 complete data sets will be formed employing the hot-deck imputation 
approach11. Appropriate survey data analysis techniques will be performed using each data set, 
leading to 10 separate estimates of parameters and their covariances. We will use the 
mianalyze.relimp function in R to combine the parameter estimates and obtain covariance 
estimates which account for both within- and between-imputation sources of variation (MD-5). 
Inferences will be based on the combined parameter estimates and appropriate covariance 
structure. Our group has used this successfully in prior studies12,13.  
 
Strategy to address heterogeneity of treatment effect: Subgroup analysis is the most commonly 
used analytic approach for examining HTE14, and we will utilize an exploratory variant of this 
analysis in our approach. Definition of subgroups, endpoints, hypotheses, and modeling parameters 
will be derived in response to the data. An example of this would be the use of a backward model 
selection approach to identify treatment by covariate interactions. Some of the important types of 
subgroup variables will be: (1) demographic variables (e.g., age); (2) pathophysiologic variables 
(e.g., timing after recurrence, disease grade); (3) comorbidities (e.g., presence of diabetes); and (4) 
concomitant exposures (e.g., hormone replacement therapy, proton pump inhibitors). Additionally, 
“non-traditional” characteristics that affect patient decision-making (e.g. social support, patient 
decision-making style, disease related anxiety, baseline quality of life) will be collected to improve 
risk-adjustment and increase the individualization of the results. Although it is extremely difficult 
to obtain the sampling properties of subgroup effect estimators (e.g., standard errors), post hoc 
exploratory subgroup analyses may identify promising hypotheses that will be subject to more 
rigorous future examination. 

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Strategy to address confounding by selection bias:  Observational studies (like our proposed 
investigation) that lack randomization of subjects into treatment groups and must address selection 
bias to properly estimate the effect of treatment. We will apply a propensity scoring method (PSM) 
and instrumental variable (IV) method to adjust for observed and unobserved confounding, 
respectively. Propensity scoring will be used to mitigate the expected biases from observed 
confounding in the proposed observational study.  It is a balancing score that effectively makes the 
distribution of measured baseline covariates similar between treatment groups. This is important 
because the apparent difference in outcome between those treated with endoscopic dilation versus 
those treated with endoscopic resection or open anterior neck surgery may depend on 
characteristics that affected whether or not a patient received a given treatment instead of due to 
the actual effect of the treatment. This issue is relevant to our study Aims #2 and #3, but for 
illustrative purposes, the specific analytic approach will be described in the context of Aim #2. Its 
objective is to determine factors that affect time to stenosis recurrence in patients with idiopathic 
subglottic stenosis. In this analysis, the dependent variable is time to recurrence and the primary 
independent variable is treatment type: endoscopic dilation versus endoscopic excision or open 
anterior neck surgery of the affected portion of the trachea. 
There are three basic techniques for propensity score method: matching, stratification, and 
regression15. We plan to use two-step process of stratification and regression. Stratification 
consists of grouping subjects into strata determined by observed background characteristics; then 
comparing subjects between treatment groups directly. Propensity scoring on strata is particularly 
useful when there are large numbers of covariates, as is the case in this study. Conventionally, 
creation of five strata has been shown to remove 90% of bias due to the stratified variable16,17. The 
propensity score is then estimated using a logistic regression model, in which the treatment status 
is regressed on observed and stratified baseline characteristics. This allows for the formation of 
matched sets of patients who underwent endoscopic dilation, endoscopic resection or open anterior 
neck surgery for their iSGS based on similar propensity score values18. In essence, all collected 
and known confounding covariates will be collectively replaced by a single function of these 
covariates – the propensity score. Thus, the collection of known predictors is collapsed into a 
single predictor. Since time to recurrence is a continuous variable, the effect of treatment will be 
estimated as the difference between the mean time for patients in the endoscopic dilation versus 
endoscopic resection or open anterior neck surgery groups. Once treatment effect has been 
estimated using propensity scoring, variance of outcome effect and statistical significance can be 
estimated. Analysis of the propensity matched treatment groups can be accomplished by directly 
comparing outcomes between the three treatment groups. Multivariate regression will be 
performed to reduce bias due to residual differences in observed baseline covariates between 
groups.  
 
All known and measurable covariates and confounders will be collected and considered in the 
propensity score model. Incorporation to the multivariate model will be determined a priori based 
on their potential to confound or modify the association between treatment and time to recurrence, 
and include demographics (age, sex, race, socioeconomic status, geographic location, marital 
status), health (Charlson-Deyo score, body mass index), endocrinologic history (age of first 
menses, number of pregnancies, onset of menopause, use of hormone replacement therapy), 
Inflammatory biomarkers (high sensitivity CRP, Antinuclear Antibodies, Antineutrophil 

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Antibodies, Renal filtration rate), anatomic characteristics (airway scar length, degree of luminal 
obstruction, distance from the glottis), physiologic (gastroesophageal reflux disease testing, 
pulmonary function testing), social/behavioral [Social Support (FSSQ), Quality of life (SF12), 
Decision-making style (PDMstyle), Fear of Progression  (FoP-Q-SF)].  Provider-specific 
covariates will include the type of subspecialty training program, training location, procedural 
volume, and treatment criteria for open anterior neck surgery.  In addition, the model will include 
interaction terms for the associations of age with endocrinologic history, Charlson-Deyo score, and 
facility regions based on statistical evidence of effect modification and theoretical plausibility.  
 
Propensity scoring can only adjust for observed confounding variables such as those listed above 
not unobserved ones. Therefore, we will employ quantitative and limited variable (QLIM) to 
conduct instrumental variable analysis to adjust for unobserved confounding. The instrumental 
variable has to meet five specific assumptions: 1) potential outcomes for each patient are unrelated 
to treatment status of other patients, 2) instrument affects receipt of the treatment of interest, 3) this 
effect is always in the same direction, 4) instrument assigns treatment randomly, and 5) instrument 
has an effect on the outcome only through the treatment assignment19 . The instrument that we plan 
to use in this analysis is distance from the patient’s residence to the treating facility20,21.  The 
assumption is that the association between distance to the hospital and time to recurrence is due 
only to the effect of relative distance on treatment assignment after controlling for observed 
variables and not directly correlated with time to recurrence. This process will involve a two-stage 
process that first uses the instrument variable and other covariates to predict the treatment. A 
second stage estimates the outcome by the predicted treatment (from the first model) and other 
covariates22.  Using a two-stage approach has the advantage of incorporating the predicted 
treatment into the outcome model as it represents the portion of treatment selection related to 
distance from the treating facility. We will also adjust, when possible, for any instrument-outcome 
confounding, as confounding can still occur even with the instrumental variable procedure19. Other 
instruments will be considered if distance to treating facility is not found to meet the 
aforementioned assumptions or is found to significantly confound the outcome.   
 
 
13.0 
Ethics/Protection of Human Subjects:  
Ethical Standard.  The investigator will ensure that this study is conducted in full conformity with 
the principles set forth in The Belmont Report: Ethical Principles and Guidelines for the Protection 
of Human Subjects of Research, as drafted by the US National Commission for the Protection of 
Human Subjects of Biomedical and Behavioral Research (April 18, 1979) and codified in 45 CFR 
Part 46 and/or the ICH E6.  Additionally, internationally, the investigator will ensure that this study 
is conducted in full conformity with the Declaration of Helsinki, CIOMS, International Ethical 
Guidelines for Biomedical Research Involving Human Subjects (2002). 
 
In adherence to the National Institutes of Health (NIH) policy on education in the protection of 
human subject participants in the conduct of research (Available at 
grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html), all key personnel will have 
documentation attesting to their completion of institutional curricula in ethical research and the 
protection of human subject participants. 
 

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Institutional Review Board.  Each participating institutions must provide for the review and 
approval of this protocol and the associated informed consent documents and recruitment material 
by an appropriate IRB registered with the OHRP.  Any amendments to the protocol or consent 
materials must also be approved before they are placed into use. The protocol, informed consent 
form(s), recruitment materials and all participant materials will be submitted to the IRB for review 
and approval.  Approval of both the protocol and the consent form must be obtained before any 
participant is enrolled.  Any amendment to the protocol will require review and approval by the 
IRB before the changes are implemented in the study.   
 
13.1.a: Risks to the subjects 
Human Subjects Involvement and Characteristics: Participants are primarily women (with a rare 
male) newly diagnosed with idiopathic subglottic stenosis identified through clinician providers at 
one of 30 international sites. There are no racial/ethnic restrictions to enrollment. 
Sources of Materials: All eligible and willing patients will be asked to complete questionnaires 
(either written or by telephone, or email) at baseline, and at multiple time points after enrollment. 
Documented informed consent will be obtained from patients at the time of enrollment in the study, 
which will include permission to be contacted for future studies by KSP from participating centers.  
Potential Risks: Minimal risk is anticipated. There are no investigational treatments under study in 
this project. Study patients will be asked to answer questions on self-administered electronic, 
mailed, or telephone surveys, and self-reported health data (i.e. peak flow breathing measurements).  
Additionally, limited information from their routine medical care will be obtained. Patients will be 
informed that they can refuse to answer any of the questions. They will also be told that refusal to 
participate in the study will not in any way change or alter the care they will receive.  Patients will 
be told that survey data are to be obtained for research purposes only and that no individual results 
will be reported. The data will be kept strictly confidential. No data of any sort will be released to 
anyone outside the study for any reason. Individual patients are never identified in publications. 
13.1.b Adequacy of protection against risks 
Recruitment and Informed Consent: All of the study letters, forms, protocols and procedures used 
will be approved by the appropriate local IRBs. After identification by the site investigator, 
informed consent will be obtained; the patients will be sent a baseline survey. Those who do not 
respond will be contacted by telephone, verbal informed consent obtained, eligibility assessed and 
the baseline telephone (or email) interview performed.  At defined intervals post-enrolment, 
patients will be sent a follow-up electronic (or written) self-administered survey. Patients will be 
asked to complete these materials either digitally or in paper forms and return them in stamped, 
return addressed envelopes to the local study office..  
Protection against risk: Risks to the participants will be minimized by proper screening of potential 
candidates and strict adherence to confidentiality rules.  In addition, access to the Electronic Data 
Capture (EDC) system will be strictly restricted to authorized personnel. Data entry personnel and 
other users are provided secure access to the web-based application via standard Internet 
technologies (i.e., HTTPS), with tiered access permissions appropriate to their study role; such 

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access is granted only when the following criteria are met: 1) request for access is authorized by a 
study principal investigator or other designated key study personnel and is accompanied by a 
designation of the user’s role, to ensure appropriate level of access; and 2) the user completes 
training on system use, which may include a live training provided by our group and/or documented 
completion of a pre-recorded video training. 3) The user has appropriate training for protection of 
human subjects. 
All requests for user access, with documentation of fulfillment of the above criteria, are recorded in 
the permanent system documentation.   
 
13.1.c Potential benefits of the proposed research to subjects and others 
The risks for this study are minimal given the potential benefits to patients and society of any 
insights gained regarding the comparative effectiveness of idiopathic subglottic stenosis. There are 
no other direct benefits to the study patients, although some patients may gain personal satisfaction 
through participation in research aimed at advancing knowledge of a rare disease requiring repeated 
invasive operative interventions. 
13.1.d Importance of the knowledge to be gained 
Idiopathic subglottic stenosis (iSGS) is a rare disease manifesting in adults, characterized by severe 
airway obstruction.  Affecting the upper tracheal airway, the condition is life threatening, and when 
survived, life altering.  Both the disease and its therapies profoundly impact breathing2, 
communication3 and swallowing in affected patients.  Unfortunately, little is known about 
comparative effectiveness of the three most common therapies for iSGS; endoscopic dilation, 
endoscopic resection, and open anterior neck surgery. This research will generate new and 
important information that will help women with iSGS chose the optimal individualized therapy. 
Furthermore, it will provide a network and data infrastructure for future research into the etiology 
and optimal treatment strategy in iSGS. Given that minimal risk is involved in the study, the 
benefits greatly outweigh these risks. 
13.1.e Data and Safety Monitoring Plan: Not applicable. 
13.2 Inclusion of Women, Minorities and Children: 
13.2.a Inclusion of Women 
Women are included in this study, and in fact, comprise the majority of patients affected with 
idiopathic subglottic stenosis. 
13.2.b Inclusion of Minorities 
Preliminary results from our initial multicenter retrospective study (the NoAAC RP-01) suggest 
iSGS preferentially affects Caucasians.  However, all efforts will be made through this study to 
include affected patients of all racial/ethnic backgrounds. Given the number and geographic 
diversity of our study sites we believe we will generate a representative cohort of patients with 

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iSGS.  We have no reason a priori to believe that results from this study will not be applicable to all 
patients affected with iSGS. 
13.2.c Inclusion of Children:  No children are included in this study as iSGS a disease of adults.  
14.0 
Data Handling and Record Keeping.  The investigators are responsible for ensuring the accuracy, 
completeness, legibility, and timeliness of the data reported. The investigators will maintain 
adequate source documentation.   
Data Management Responsibilities.  Data collection and accurate documentation are the 
responsibility of the study staff under the supervision of the investigator.  All source documents and 
laboratory reports will be reviewed by the study team and data entry staff to ensure accuracy and 
completeness.  Unanticipated problems must be reviewed by the investigator or designee.   
Types of Data.  Multiple types of data will be collected.  Both clinical data (i.e. laboratory results, 
procedure notes etc.), as well as patient generated health data (i.e. surveys, patient reported health 
data, patient reported outcome measures), along with safety data (i.e. unanticipated problems) will 
be collected.  

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Schedule and Content of Report.  Biannual data reports will be generated as mandated by the 
Funding Agency PCORI.  These reports will include statistics on enrolment, endpoint analysis as 
specified in the statistical plan, and reports documenting data fidelity. 
Study Records Retention: Participants will be followed for about 60 months after date of consent 
and data will be recorded throughout that timeframe.  Most data will be taken from the patient case 
report form and the patient-completed surveys; however the electronic medical record or outside 
medical records may be reviewed to confirm self-reported information (i.e., any missing 
information).  Any printed documents will be kept in the PI or research team’s locked office. All 
data will be recorded in the electronic NoAACNet database which is a secure, password-protected 
database.  Research records will be retained for at least six years after completion of the research.  
 
 
15.0 
Participant Confidentiality 
Participant confidentiality is strictly held in trust by the investigators, study staff, and the sponsor(s) 
and their agents.  This confidentiality is extended to cover testing of biological samples and genetic 
tests in addition to any study information relating to participants. 
 
NoAAC PR-02 Study: Data Types Collected
Clinical'Data'
Pa+ent'Reported'
Outcomes'
Pa#ent'
Self8assessed'
Proxy'
Assessment'of'pa+ent'without'
interpreta+on'
Pa#ent'
Self8generated'or'otherwise'created'
Provided'from'clinical'report'(EMR)'
Proxy'
Sourced'from'pa+ent'
Directed'by'pa+ent'
Mechanical'Device'
Sourced'from'pa+ent'
Directed'by'pa+ent'
Clinician'
Clinician8assessment'of'pa+ent'
Laboratory'or'
Other'Clinical'
Facility'
Generated'in'the'context'of'clinical'
care'without'input'from'pa+ent'
Data$Source$
A" ributes*
Data$Type$
Pa+ent'Generated'Health'Data'
Mechanical'Device'
Sourced'from'pa+ent'
Directed'by'pa+ent'
Social'Network'
Sourced'from'pa+ent'
Directed'by'pa+ent'

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The study protocol, documentation, data, and all other information generated will be held in strict 
confidence.  No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor. 
 
Data collected from study participants will be maintained and stored in paper and electronic formats. 
Any paper study documents (such as signed consent forms, case report forms, or surveys and/or 
questionnaires) will be maintained in a secured location in the PI or Research Team’s locked office. 
 
The PI and his research team will conduct the study using Good Clinical Practice guidelines.  All 
will respect the confidentiality of the records being accessed and the data being input.  All 
authorized users will have individual usernames and passwords to access datasets.  The database has 
security measures in place to protect the data as delineated: access to the Electronic Data Capture 
(EDC) system will be strictly restricted to authorized personnel. Data entry personnel and other users 
are provided secure access to the web-based application via standard Internet technologies (i.e., 
HTTPS), with tiered access permissions appropriate to their study role; such access is granted only 
when the following criteria are met: 1) request for access is authorized by a study principal 
investigator or other designated key study personnel and is accompanied by a designation of the 
user’s role, to ensure appropriate level of access; and 2) the user completes training on system use, 
which may include a live training provided by our group and/or documented completion of a pre-
recorded video training. 3) The user has appropriate training for protection of human subjects. 
 
All requests for user access, with documentation of fulfillment of the above criteria, are recorded in 
the permanent system documentation.   
 
 
Participant’s personal information will remain confidential and will not be used if study information 
is published or presented at a scientific meeting.  
 
 
16.0    Publication/Data Sharing Policy.  
This study will comply with Public Access Policy from both PCORI and the NIH, which ensures 
that the public has access to the published results of NIH funded research. It requires scientists to 
submit final peer-reviewed journal manuscripts that arise from NIH funds to the digital archive 
PubMed Central upon acceptance for publication.   
Like PCORI, the NoAAC study team is committed to promoting the principles of transparency, 
replication and reproducibility in research. As soon as we received notification of funding, we would 
update the protocol for the three-year follow-up. We would not finalize it, however, until after the 
initial meetings of the full study team to ensure we captured patient partner opinions and generated a 
protocol that reflected what we truly intended to do. This would be submitted to PCORI and made 
available to other researchers, after approval from the PI (and the rest of the NoAAC Steering 
Committee study team). Additional study documentation (e.g., database design, programming code, 
and data definitions) would be shared with PCORI in the final year of the grant, as well as with 
requesting researchers, and any requesting peer-reviewed journals. 

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We will share all a complete, cleaned, de-identified copy of the final data set with PCORI in the 
third year of the grant.  Additionally, we will share all code books, meta-data related to the datasets 
and statistical programming code with PCORI in the third year of the grant and with any peer-
reviewed journals who requested this information in support of manuscripts that resulted from the 
project. We plan this approach with the upcoming submission of the NoAAC RP-01 results, are 
prepared to do this again in the future. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
17.0 
 References 
 
1. Maldonado F, Loiselle A, Depew ZS, et al. Idiopathic subglottic stenosis: An evolving therapeutic 
algorithm. The Laryngoscope 2014;124:498-503. 
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