Assessment of Safety of Air Travel in Patients With Birt-Hogg-Dube Syndrome
Conditions: Birt-Hogg-Dube Syndrome
Sponsor: University of Cincinnati

Assessment of Safety of Air Travel in Patients with Birt-Hogg-Dube Syndrome
NCT03040115
Study protocol
Document date: February 23, 2017

 
 
 
 
 
 
 
 
 
“Assessment of Safety of Air Travel in Patients with Diffuse 
Cystic Lung Disease” 
 
 
 
Rare Diseases Clinical Research Network 
Rare Lung Diseases Consortium 
NG Pilot Project 
Protocol Number: 5714 
Protocol Version: Amendment 1 
Date: February 23, 2017 
 
 
 
 
Study Chair:  Nishant Gupta, MD 
Assistant Professor 
Division of Pulmonary, 
Critical Care & Sleep Medicine 
The University of Cincinnati, MSB 6053 
231 Albert Sabin Way 
Cincinnati, OH 45267-0564 
 
Phone: (513) 558-4831 
FAX: (513) 558-4858 
Email: guptans@ucmail.uc.edu 
 
 
 
 
 
 
 
Statement of Use: This protocol is for research purposes only, and should not be copied, 
redistributed or used for any other purpose.  The procedures in this protocol are intended 
only for use by Consortium investigators in carefully controlled settings.  The Chair of this 
study should be consulted before using or attempting any procedure in this protocol.   
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Table of Contents 
1.0 
Overview ........................................................................................................................... 3 
 
Protocol Synopsis ........................................................................................................... 3 
 
Lay Summary ................................................................................................................. 5 
 
Detailed Description ....................................................................................................... 5 
 
Participating Investigators and Institutions (Contact Information) .................................. 6 
2.0 
Specific Aims (Hypothesis and Objectives) .................................................................. 7 
 
Hypothesis ...................................................................................................................... 7 
 
Objectives ....................................................................................................................... 7 
3.0 
Background ...................................................................................................................... 8 
4.0 
Study Design and Methods ............................................................................................. 9 
 
Overview ......................................................................................................................... 9 
 
Inclusion Criteria ............................................................................................................. 9 
 
Exclusion Criteria ............................................................................................................ 9 
 
Recruitment of participants ............................................................................................. 9 
 
Participant Retention ...................................................................................................... 9 
 
Data Elements ................................................................................................................ 9 
 
Schedule of Events ....................................................................................................... 10 
5.0 
Data and Safety Monitoring Plan .................................................................................. 11 
 
Study Oversight ............................................................................................................ 11 
 
Known Risks/Discomforts Associated with Study and Procedures .............................. 12 
 
Study Discontinuation (Observational) ......................................................................... 12 
 
Subject Discontinuation ................................................................................................ 12 
 
Data Quality and Monitoring Measures ........................................................................ 12 
6.0 
Statistical Considerations ............................................................................................. 13 
7.0 
Data Management .......................................................................................................... 14 
 
Data Management Responsibilities .............................................................................. 14 
 
Data Entry ..................................................................................................................... 14 
8.0 
Human Subjects ............................................................................................................. 15 
 
GCP Statement ............................................................................................................ 15 
 
Risks ............................................................................................................................. 15 
 
Benefits ......................................................................................................................... 15 
 
Recruitment .................................................................................................................. 15 
 
Written Informed Consent ............................................................................................. 15 
 
Process of Consent ...................................................................................................... 15 
9.0 
References ...................................................................................................................... 16 
10.0 Appendices ..................................................................................................................... 17 
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1.0 Overview 
 
 Protocol Synopsis 
Protocol Number: 
5714 
Protocol Title: 
Assessment of Safety of Air Travel in Patients with Diffuse Cystic 
Lung Disease 
Study Chair: 
Nishant Gupta, MD 
Statistician: 
Laura E James 
Consortium: 
Rare Lung Diseases 
Participating Sites: 
University of Cincinnati  
Activation Date: 
December 4, 2015 
Sample Size: 
300 subjects - 100 with Birt-Hogg-Dubé Syndrome (BHD), 200 
with Pulmonary Langerhans Cell Histiocytosis (PLCH) 
Target Enrollment Period: 
September 2015 – September 2016 
Study Design: 
This is a questionnaire-based study of patients with diffuse cystic 
lung diseases (DCLDs) to gather information relevant to safety of 
air travel, especially pertaining to the risk of pneumothorax 
associated with air travel. In addition, this study will be used to 
further characterize clinical aspects of disease and establish a 
contact registry for patients.  
Primary Study Objective(s): 
 
To define the risk of pneumothorax associated with air travel in 
patients with DCLD. 
Secondary Study 
Objective(s): 
 
To establish a contact registry for patients with BHD and 
PLCH 
 
To define the clinical phenotype of each DCLD in their 
respective cohort of patients 
 
To define current screening practices for surveillance of 
disease-specific anomalies (i.e. renal tumors in BHD) 
 
The study will enroll participants through the clinic network at the 
Rare Lung Disease Consortium (RLDC) and through the BHD 
and PLCH foundation websites. Participants will have access to 
the questionnaire via REDCap (an online data management 
system) and each participant will be provided a link to complete 
the survey. In case of lack of internet access or inability to 
complete the online questionnaire, a paper survey will be mailed 
out with a pre-paid envelope to return the survey.  
 
Inclusion Criteria: 
 
Adult, age 18 or older 
 
English literate 
 
Signed, dated informed consent; either given 
electronically or via paper form 
 
Diagnosis of BHD, or PLCH as defined by accepted 
clinical, histopathological and/or genetic criteria.  
 For BHD, diagnosis would include the presence of 
fibrofolliculomas/trichodiscomas on skin biopsy, or the 
presence of pathogenic FLCN mutations.  
 For PLCH, it would include characteristic radiographic 
findings and tissue biopsy consistent with PLCH 
(presence of CD1a positive Langerhans cells or 
stellate fibrosis in late stages). 
 
Exclusion Criteria: 
 
Inability to give informed consent 
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Outcome Measures: 
Number of pneumothoraces associated with air travel, estimated 
as a percentage of the number of flights taken. 
Statistical Considerations 
(sample size and analysis 
plan): 
Data from all surveys will be pooled together. The rate of 
pneumothorax will be estimated as a percentage of the number of 
flights taken. We will compare other disease and patient 
characteristics to try to determine factors associated with an 
increased risk of in-flight pneumothorax. 
Variables collected 
 
Contact information 
 
Demographics 
 
Age, gender, ethnicity 
 
Medical history 
 
Diagnosis 
 
Surveillance information for associated clinical 
anomalies, such as renal tumors in BHD 
 
Evaluation of dyspnea, other pulmonary problems and 
need for supplemental oxygen 
 
Family history 
 
Smoking history 
 
Pneumothorax information (diagnosis, management, 
measures to prevent prevention such as pleurodesis, 
relationship with flights) 
 
Flight history 
 
Effect of pneumothoraces on attitudes towards 
undertaking air travel 
 
Ethical and Scientific Review 
Procedures 
Institutional Review Board approval will be obtained. Informed 
consent will be obtained from participants. Every effort will be 
made to protect participant confidentiality according to privacy 
laws and medical record confidentiality regulations.  
Data Ownership 
Nishant Gupta, M.D. 
Sponsors (federal, state, 
foundation and industry 
support): 
National Institutes of Health (NIH) U54 
 
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 Lay Summary 
Birt-Hogg-Dubé syndrome (BHD) is an uncommon genetic disease characterized by tumors in 
the hair follicles and kidneys, as well as lung cyst formation. These lung cysts can rupture thus 
placing patients with BHD at a higher risk for development of pneumothoraces, or collapsed 
lungs.  
Pulmonary Langerhans cell histiocytosis (PLCH) is an uncommon disease characterized by the 
formation of cysts in the lungs, and is strongly associated with smoking cigarettes. Similar to 
BHD, patients with PLCH have an increased risk of development of pneumothoraces. 
 
The safety of air travel in patients with BHD and PLCH is not established. The concern with air 
travel in these diseases is related to the risk of cyst expansion with decreasing atmospheric 
pressure, which could lead to cyst rupture causing a pneumothorax. Safety of air travel has 
been studied for patients with lymphangioleiomyomatosis (LAM), another rare cystic lung 
disease. Based on the results from studies done in patients with LAM, recommendations 
regarding air travel are provided to patients with BHD and PLCH. The aim of this study is to 
conduct a survey-based assessment of patients with BHD and PLCH and establish the risk of 
pneumothorax associated with air travel in these diseases.  
 
As a follow up to the original protocol, we plan to re-contact all patients who gave us permission 
in the survey to contact them again. We will obtain results of their lung function tests and 
images of CT chest to correlate PFT data and cyst preponderance (size, number, volume etc.) 
with the risk for spontaneous pneumothorax.  
 
 Detailed Description 
The aim of this study is to conduct survey-based assessments for the safety of air travel in 
patients with BHD and PLCH. The study will enroll patients through the clinic network at Rare 
Lung Disease Consortium (RLDC) and through the BHD and PLCH foundation websites. 
Patients will have access to the questionnaire via REDCap (an online data management 
system) and each patient will be provided with a link to complete the survey. In case of lack of 
Internet access or inability to complete the online questionnaire, a paper survey will be mailed 
out with a pre-paid and addressed envelope to return the survey. Paper surveys returned to 
Nishant Gupta, MD 231 Albert Sabin Way, ML 0564, Cincinnati, OH 45267-0564 will be entered 
into REDCap by the clinical research coordinator. We plan on enrolling approximately 100 
patients with BHD and 200 patients with PLCH for the purpose of this study. Secondary aims of 
this study include further characterization of the clinical aspects of disease and to establish a 
contact registry for these patients, in order to facilitate future studies. 
 
This research will be accomplished as part of the Rare Lung Disease Clinical Network 
Consortium, with data stored and analyzed by the Data Management and Coordinating Center 
(DMCC) at the University of South Florida as part of the NIH-supported Rare Disease 
Consortium.   
 
 
 
 
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 Participating Investigators and Institutions (Contact Information) 
 
Principal Investigator:  
Nishant Gupta, M.D. 
University of Cincinnati Medical Center Director 
Division of Pulmonary and Critical Care Medicine 
MSB 6053 
231 Albert Sabin Way 
Cincinnati, OH 45267-0564  
Phone: (513) 558-4831 
Fax: (513) 558-4858 
Email: guptans@ucmail.uc.edu 
 
Sub Investigator: 
Scott Merriman 
University of Cincinnati Medical Center Director 
Department of Internal Medicine 
231 Albert Sabin Way 
Cincinnati, OH 45267-0564  
Phone: (513) 558-4831 
Fax: (513) 558-4858 
Email: merrimsr@ucmail.uc.edu 
 
Project Manager: 
Tammy Roads, CCRC 
University of Cincinnati 
Department of Internal Medicine 
Pulmonary, Critical Care & Sleep Medicine 
231 Albert Sabin Way, Room 6053-A 
Cincinnati, OH 45267-0564 
Phone: (513) 558-2148 
Fax: (513) 558-5848 
Email: roadst@ucmail.uc.edu 
 
Data Management and Coordinating Center (DMCC) PI: 
Jeffrey Krischer, Ph.D. 
University of South Florida  
3650 Spectrum Boulevard, Suite 100  
Tampa, Florida 33612 
Email: jpkrischer@epi.usf.edu 
Phone: (813) 396-9512 
 
DMCC Project Manager: 
Rosalie Holland 
University of South Florida 
3650 Spectrum Blvd, Suite 100 
Tampa, Florida 33612 
Phone: (813) 396-9296  
Email: Rosalie.Holland@epi.usf.edu
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2.0 Specific Aims (Hypothesis and Objectives) 
 
 Hypothesis 
The hypothesis to be tested is that air travel is safe in patients with diffuse cystic lung diseases, 
and there is no increased risk of pneumothorax in this disease population related to air travel.  
 
 Objectives 
1. To define the risk of pneumothorax related to air travel in patients with BHD and PLCH. 
 
2. To establish a contact registry for patients with BHD and PLCH, in order to facilitate 
participation in future trials. 
 
3. To describe the demographic and clinical characteristics of patients with BHD and PLCH, as 
well as ascertain clinical practices related to management and surveillance of related medical 
conditions, such as surveillance of renal tumors in patients with BHD.  
 
4. To determine the relationship between lung function, and radiographic cyst characteristics 
and the risk of spontaneous pneumothorax in patients with BHD and PLCH.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3.0 Background 
BHD is a rare, autosomal dominantly inherited genodermatosis characterized by the formation 
of hair follicle tumors, kidney tumors, and pulmonary cysts 1. Pulmonary cysts are seen in 80-
100% of patients with BHD 2,3, and lead to an increased risk of development of pneumothorax in 
these patients 2. Zbar et al., have reported that the risk of development of pneumothorax is 32-
fold higher in patients with BHD as compared to the general population 4.  
Atmospheric pressure changes have the potential to cause cyst expansion leading to an 
increased chance of cyst rupture causing a pneumothorax. Based on this risk, patients with 
BHD are advised to not undertake scuba diving 5, although no disease specific data exists for 
this recommendation. In general, air travel is considered to be safe in patients with diffuse cystic 
lung diseases 6, although disease specific data for safety of air travel in BHD are lacking.  
PLCH is a rare diffuse cystic lung disease seen most commonly in young-middle aged adults, 
and is associated with exposure to cigarette smoke in greater than 90% of patients 7. 
Approximately 15% of patients with PLCH develop a pneumothorax over their lifetime, with a 
recurrence rate of approximately 60% after a sentinel event 8. Similar to BHD, recommendations 
regarding air travel are given to patients with PLCH on the basis of extrapolation from other 
diseases.  
 
Having specific information about safety of air travel in BHD and PLCH will help these patients 
make informed decisions about air travel. We aim to conduct a questionnaire-based 
assessment of patients with BHD and PLCH to ascertain the risk of pneumothorax related to air 
travel. In the first part of this study we will distribute the questionnaires for BHD, followed later 
by the PLCH survey. In addition, we aim to establish a contact registry for these patients in 
order to answer future clinical questions.  
 
With the current amendment, we will re-contact patients with BHD and PLCH, who gave us the 
permission to contact them in future for other projects. We will ask permission to obtain their 
medical records, specifically their pulmonary function tests (PFTs), and CT scan(s) of the chest. 
We will correlate the PFT data and cyst features such as cyst number, size, and volume with the 
risk of spontaneous pneumothorax. These results will provide us the ability to do individual, 
patient-specific risk stratification for spontaneous pneumothorax in patients with BHD and 
PLCH. 
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4.0 Study Design and Methods 
 Overview 
Online surveys will be created in REDCap, a password protected data management software, 
and the links distributed to all patients via email. In case of lack of Internet access or personal 
preference, paper copies of the surveys will be mailed out to the patients along with a prepaid, 
addressed return envelope.  
 
 Inclusion Criteria 
 
Adult, age 18 or older 
 
English literate 
 
Signed, dated informed consent; either given electronically or via paper form; 
 
Diagnosis of BHD, or PLCH as defined by accepted clinical, histopathological and/or 
genetic criteria  
 For BHD, diagnosis would include the presence of 
fibrofolliculomas/trichodiscomas on skin biopsy, or the presence of pathogenic 
FLCN mutations.  
 For PLCH, diagnosis would include characteristic radiographic findings and 
tissue biopsy consistent with PLCH (presence of CD1a positive Langerhans cells 
or stellate fibrosis in late stages). 
 
 Exclusion Criteria 
 
Inability to give informed consent 
 
 Recruitment of participants 
Participants will be recruited from the network of clinics at the Rare Lung Disease-Clinic 
Network (RLD-CN). The RLDC is a collection of 30 LAM foundation clinics in US and 19 
worldwide. These clinics are a hub of many of the rare lung disease we wish to study. A survey 
of the clinic directors at the RLD-CN suggests that there are over 300 patients with BHD and 
greater than 700 patients with PLCH being followed currently in this network. In addition, we will 
seek assistance from the patient advocacy partners such as the BHD Foundation and the 
Histiocytosis Association to help with recruitment. We will also present our study to patients at 
national and regional meetings to encourage recruitment. For example, we will take our 
questionnaires to the International BHD symposium in September 2015 at Syracuse, NY to 
enable participants to enroll in the study and complete questionnaires at the conference.  
 
 Participant Retention 
This study does not require follow-up after completion of the survey, however participants may 
be contacted in the future to verify and update the contact information they provided for the 
registry. 
 
 Data Elements 
Data elements for this study include the following information about study participants: 
 
Contact information 
 
Demographics 
 
Age, gender, ethnicity 
 
Medical history 
 
Patient reported elements of diagnostic criteria and other clinical manifestations 
 
Surveillance information for associated clinical anomalies, such as renal tumors in BHD 
 
Evaluation of dyspnea, other pulmonary problems and need for supplemental oxygen 
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 
Family history 
 
Smoking history 
 
Pneumothorax information (diagnosis, management, measures to prevent prevention 
such as pleurodesis, relationship with flights) 
 
Flight history 
 
Effect of pneumothoraces on attitudes towards undertaking air travel 
 
Pulmonary function tests  
 
CT scans  
 
 Schedule of Events 
September 2015: Distribute links and paper copies of the questionnaires 
November 2015: Resend links and surveys to increase recruitment 
January 2016: Data Analysis 
April 2016: Manuscript submission 
April 2017: Contact patients and start obtaining medical records 
November 2017: Data Analysis 
April 2018: Manuscript submission
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5.0 Data and Safety Monitoring Plan 
The study protocol will be reviewed and approved by the National Institutes of Health (NIH) 
before submission to the University of Cincinnati’s IRB and the University of South Florida 
(USF) for approval. Participant enrollment may only begin with IRB approved consent forms. 
This is an observational study that meets the federal definition of minimal risk. 
 
Since this is a survey based registry study, traditional study monitoring will not occur. We do not 
expect any adverse events (AEs) nor will we solicit them. If participants contact USF to report 
an adverse reaction to participation on this registry, USF will report the adverse event to the 
USF IRB and the Consortium.  Otherwise patients will not be solicited for adverse events. 
The questionnaire data will be stored in a password protected electronic format in REDCap. 
Only the investigators will have access to the data files. Paper files will be kept in a locked 
cabinet in a locked office.  
 
The medical records will only be obtained after getting the required permissions from the 
patients. Since no intervention is being planned for the participants, there will be minimal risk, 
and we do not expect any adverse effects. The patient records will be kept in a locked cabinet at 
all times, and access restricted only to the study personnel.  
 
 
 Study Oversight 
The Study Chair has primary oversight responsibility of this study.  
 
 Definitions and Standards 
The Rare Diseases Clinical Research Network defines an adverse event as:  “…an unfavorable 
and unintended sign, symptom or disease associated with a participant’s participation in a Rare 
Diseases Clinical Research Network study.” 
 
Serious adverse events include those events that:  “result in death; are life-threatening; require 
inpatient hospitalization or prolongation of existing hospitalization; create persistent or 
significant disability/incapacity, or a congenital anomaly/birth defects.”  
 
An unexpected adverse event is defined as any adverse experience…the specificity or severity 
of which is not consistent with the risks of information described in the protocol.  
 
Expected adverse events are those that are identified in the research protocol as having been 
previously associated with or having the potential to arise as a consequence of participation in 
the study 
 
All reported adverse events will be classified using the Common Terminology Criteria for 
Adverse Events (CTCAE) developed and maintained by CTEP at National Cancer Institute.Only 
those events associated with the conduct of the study and as defined above are reportable.  
 
 Reporting Timeline 
 
Within 24 hours (of learning of the event), investigators must report any reportable Serious 
Adverse Event (SAE) that: 
Is considered life-threatening/disabling or results in death of subject 
-OR- 
Is Unexpected/Unanticipated  
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Investigators must report all other reportable SAEs within 5 working days (of learning of the 
event). 
All other (suspected) reportable AEs must be reported to the RDCRN within 20 working days 
of the notification of the event or of the site becoming aware of the event. 
 
Local institutional reporting requirements to IRBs, any CRU oversight committee and the FDA, if 
appropriate, remain the responsibility of the treating physician and the Study Chair. 
 
 RDCRN Adverse Event Data Management System (AEDAMS) 
Upon entry of a serious adverse event, the DMCC created Adverse Event Data Management 
System (AEDAMS) will immediately notify the Study Chair, site PIs, the Medical Review Officer, 
and any additional agencies of any reported adverse events via email.  
 
Serious adverse events: The committee appointed Medical Review Officer (MRO) determines 
causality (definitely not related, probably not related, possibly related, probably related, 
definitely related) of the adverse event. The MRO may request changes to the protocol or 
consent form as a consequence of the adverse event. A back-up notification system is in place 
so that any delays in review by the MRO beyond a specified period of time are forwarded to a 
secondary reviewer. The Adverse Event Data Management System (AEDAMS) maintains audit 
trails and stores data (and data updated) and communication related to any adverse event in 
the study. The DMCC will post aggregate reports of all adverse events (serious/not serious and 
expected, unexpected) for site investigators and IRBs. 
 
 Known Risks/Discomforts Associated with Study and Procedures 
There is a risk of breach of confidentiality. The risks of completing the questionnaires include 
fatigue, anxiety and the perception on the part of the patient that questions may be too personal. 
The patients will be informed in the consent that they can skip any questions they like, or opt out 
of the questionnaire portion of studies. 
 
 Study Discontinuation (Observational) 
This study will not have study discontinuation rules as it is a survey based registry study. The 
NIH and local IRBs (at their local site) have the authority to stop or suspend this trial at any time.  
 
 Subject Discontinuation 
All data acquired prior to termination for the reasons outlined below will be included in the 
primary analysis unless patient withdraws consent.  
 
Withdrawal of consent 
 
Withdrawal by the participant 
 
Withdrawal by the investigator 
 
 Data Quality and Monitoring Measures 
As much as possible data quality is assessed at the data entry point using intelligent on-line 
data entry via visual basic designed screen forms. Data element constraints, whether 
independent range and/or format limitations or ‘relative’ referential integrity limitations, can be 
enforced by all methods employed for data input. QA reports assess data quality post-data 
entry. As we note, data quality begins with the design of the data collection forms and 
procedures and incorporates reasonable checks to minimize transcription and omission errors.  
Of the more important quality assurance measures are the internal validity checks for 
reasonableness and consistency.  
 
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 
Data Monitoring: The RDCRN DMCC identifies missing or unclear data and generates a 
data query to the consortium administrator contact.  
 
Data Delinquency Tracking: The Data Management and Coordinating Center will monitor 
data delinquency on an ongoing basis.   
 
6.0 Statistical Considerations 
Data from all surveys will be pooled together. The rate of pneumothorax will be estimated as a 
percentage of the number of flights taken. We will compare other disease and patient 
characteristics to try to determine factors associated with an increased risk of in-flight 
pneumothorax. All analyses will be done by using SAS for Windows, version 9.4, Cary, NC.
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7.0 Data Management 
All study data will be collected via systems created in collaboration with the RDCRN Data 
Management and Coordinating Center and will comply with all applicable guidelines regarding 
patient confidentiality and data integrity. 
 
 Data Management Responsibilities 
Data to be obtained for each study participant in this study will be collected via REDCap. This 
data will subsequently be transmitted to the DMCC at the University of South Florida by distinct 
mechanisms using methods that are set forth by DMCC.  
 
Confidentiality:  Only investigators and other key personnel involved in the study will have 
access to individually identifiable private information about human subjects. 
 
 Data Entry 
Data collection for this study will be accomplished with online electronic case report 
forms.  Using encrypted communication links, on-line forms will be developed that contain the 
requisite data fields. 
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8.0 Human Subjects 
 
 GCP Statement 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki, and that are consistent with Good Clinical Practice and all applicable 
regulatory requirements. 
 
 Risks 
All efforts will be made to ensure that the data is secure and the privacy is maintained. There is 
a risk of breach of confidentiality. The risks of completing the questionnaires include fatigue, 
anxiety and the perception on the part of the patient that questions may be too personal. The 
patients will be informed in the consent that they can skip any questions they like, or opt out of 
the questionnaire portion of studies. 
 
 Benefits 
There are no direct benefits for participants from their involvement in this study.  The answers 
obtained from these studies could potentially help patients through informing clinical 
recommendations, for example, weighing the risk of travel given the risk of developing a 
pneumothorax associated with air travel. No compensation or incentives will be provided. 
 
 Recruitment 
Patients with BHD and PLCH will be recruited with the help of the RLD-CN and the respective 
patient advocacy groups, the BHD Foundation and the Histiocytosis Association. We expect to 
enroll over 100 patients with BHD and over 200 patients with PLCH in this study. Adult patients 
(18 years and older) will be eligible to participate in the study.  
 
 Written Informed Consent 
Written informed consent will be obtained from each participant before participation in the study. 
For the online survey, the informed consent portion will immediately precede the survey in 
REDCap.  Participants will be able to begin the survey only after certifying that they have read 
and understood the informed consent for the study.  
 
For those using paper forms, the participant’s willingness to participate in the study will be 
documented in writing in a consent form, which will be signed by the participant with the date of 
that signature indicated.  The investigator will keep the original signed consent forms and copies 
will be given to the participants.   
 
 Process of Consent 
Subjects are required to sign an informed consent prior to undertaking the survey in accordance 
with International Conference on Harmonization (ICH) E6; 4.8, “Informed Consent of Trial 
Subjects.”    
 
It will be clearly explained to the participants that they are free to refuse entry into the study and 
free to withdraw from the study at any time without prejudice to future treatment.  Written and/or 
oral information about the study in a language understandable by the participant will be given to 
all participants
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9.0 References 
 
1. 
Gupta N, Vassallo R, Wikenheiser-Brokamp KA, McCormack FX. Diffuse Cystic Lung 
Disease. Part II. American journal of respiratory and critical care medicine 2015;192:17-29. 
2. 
Toro JR, Pautler SE, Stewart L, et al. Lung cysts, spontaneous pneumothorax, and 
genetic associations in 89 families with Birt-Hogg-Dube syndrome. American journal of 
respiratory and critical care medicine 2007;175:1044-53. 
3. 
Furuya M, Tanaka R, Koga S, et al. Pulmonary cysts of Birt-Hogg-Dube syndrome: a 
clinicopathologic and immunohistochemical study of 9 families. The American journal of surgical 
pathology 2012;36:589-600. 
4. 
Zbar B, Alvord WG, Glenn G, et al. Risk of renal and colonic neoplasms and 
spontaneous pneumothorax in the Birt-Hogg-Dube syndrome. Cancer epidemiology, biomarkers 
& prevention : a publication of the American Association for Cancer Research, cosponsored by 
the American Society of Preventive Oncology 2002;11:393-400. 
5. 
Gupta N, Seyama K, McCormack FX. Pulmonary manifestations of Birt-Hogg-Dube 
syndrome. Familial cancer 2013;12:387-96. 
6. 
Hu X, Cowl CT, Baqir M, Ryu JH. Air travel and pneumothorax. Chest 2014;145:688-94. 
7. 
Gupta N, Vassallo R, Wikenheiser-Brokamp KA, McCormack FX. Diffuse Cystic Lung 
Disease. Part I. American journal of respiratory and critical care medicine 2015;191:1354-66. 
8. 
Mendez JL, Nadrous HF, Vassallo R, Decker PA, Ryu JH. Pneumothorax in pulmonary 
Langerhans cell histiocytosis. Chest 2004;125:1028-32. 
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10.0 
Appendices 
 
Appendix 1. Protocol Amendment History  
 
 
 
Date 
Protocol Version 
Summary of Changes 
02-23-17 
Amendment 1 
 
Re-contact patients with BHD and PLCH who gave 
us permission to contact them again for future 
studies 
 
 
 
Obtain permission to gather pulmonary function 
tests and CT chests 
 
 
 
Correlate PFT data and cyst features with the risk 
of spontaneous pneumothoraces 
 
 
 
Add Scott Merriman as a co-investigator to the 
protocol  
 
 
Updated statistician to Laura E James  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NIH Approved 02-28-17

CONFIDENTIAL 
                       Page 18 of 18 
23Feb2017 
 
 
 
Appendix 2.  Investigator Agreement and Signature Page 
 
Protocol Title:  Assessment of Safety of Air Travel in Patients with Diffuse Cystic Lung Disease 
 
RDCRN protocol number: 5714; UC IRB number:  
 
Amendment number:  
 
UC IRB Approval Date: _______________________________ 
 
The Institutional Review Board of the University of Cincinnati has approved this study and 
protocol. The signature of the Study Chair below documents this approval. 
 
 
_______________________________________________________      __________________ 
Study Chair (Printed)  
 
 
 
 
 
          Date 
 
_______________________________________________________ 
Study Chair (Signature) 
   
 
NIH Approved 02-28-17