Multicenter, Prospective, Randomized Trial of Bronchoscopy With Ultrathin Bronchoscope and Radial Endobronchial Ultrasound (R-EBUS) With Fluoroscopy Versus Standard Fiberoptic Bronchoscopy (FB) With Fluoroscopy for Biopsy of Pulmonary Lesions
Phase: NA
Conditions: Pulmonary Lesions, Pulmonary Nodules, Pulmonary Mass
Sponsor: Medical University of South Carolina

Medical University of South Carolina 
PI:  Nichole T. Tanner, MD, MSCR 
Title: Multicenter, prospective, randomized trial of bronchoscopy with ultrathin bronchoscope and radial endobronchial 
ultrasound (R-EBUS) with fluoroscopy versus standard fiberoptic bronchoscopy (FB) with fluoroscopy for biopsy of 
pulmonary lesions  
9 November 2016 
 
 
1
  
  
Multicenter, prospective, randomized trial of bronchoscopy with ultrathin bronchoscope 
and radial endobronchial ultrasound (R-EBUS) with fluoroscopy versus standard 
fiberoptic bronchoscopy (FB) with fluoroscopy for biopsy of pulmonary lesions  
  
Principal Investigator: Nichole T. Tanner, MD, MSCR 
Co-Investigator: Gerard A. Silvestri, MD, MS 
  
Contact information: 
Gerard A. Silvestri, MD, MS 
Professor of Medicine 
Medical University of South Carolina 
Phone: 843-792-3167 
Fax: 843-792-0732 
Email: silvestri@musc.edu 
  
 
 

Medical University of South Carolina 
PI:  Nichole T. Tanner, MD, MSCR 
Title: Multicenter, prospective, randomized trial of bronchoscopy with ultrathin bronchoscope and radial endobronchial 
ultrasound (R-EBUS) with fluoroscopy versus standard fiberoptic bronchoscopy (FB) with fluoroscopy for biopsy of 
pulmonary lesions  
9 November 2016 
 
 
2
 
OBJECTIVES 
The goal of this study is to evaluate radial endobronchial ultrasound (R-EBUS) for the 
diagnosis of pulmonary lesions (≥1.5cm). Accessing pulmonary lesions is problematic 
because they are often not visible endobronchially, may not be large enough to be 
easily visualized by fluoroscopy for transbronchial biopsy (TBBx), and/or are surrounded 
by damaged lung making the transthoracic approach difficult. In this study, we hope to 
evaluate new technologies to aid in transbronchial biopsy using R-EBUS to facilitate 
location and sampling of tissue. 
 
SPECIFIC AIMS: 
1. To compare the diagnostic yield of R-EBUS with the BFP190 ultrathin bronchoscope 
and fluoroscopy versus standard fiberoptic bronchoscopy (FB) with fluoroscopy in the 
evaluation of lung lesions 1.5-5cm. 
2. To assess factors that may influence yield: 
        a. radiographic characteristics – size, location, distance from visible bronchus, 
            PET characteristics 
        b. procedural characteristics – number of passes, type of specimen obtained  
 [brush, forceps biopsy, site of biopsy (within vs. adjacent to lesion), rapid on-site 
 evaluation (ROSE) diagnosis 
  
I. BACKGROUND 
Pulmonary lesions are a common but difficult issue for primary care and specialty 
physicians and are often found incidentally on Chest X-Ray (CXR) or Computed 
Tomography (CT) scan.1 With the results of the National Lung Cancer Screening Trial 
demonstrating a reduction in lung cancer mortality with screening of high risk patients 
with low dose CT scan, the number of nodules detected requiring follow up is likely to 
increase exponentially as 25% of those screened had a detected lung abnormality. 2 In 
studies of incidentally detected nodules, the prevalence of malignancy ranges from 2-
82% 3, the problem for clinicians is deciding on the management and further diagnostic 
modalities to pursue.  
  
Current recommendations from the American College of Chest Physicians (ACCP) 
evidence-based guidelines for the management of pulmonary lesions begin with the 
determination of whether the lesion is stable or has benign calcification. 1,4 If the lesion 
is stable or benign, no further evaluation is warranted; otherwise, management 
decisions are based on surgical risk and on the clinical probability that the lesion is 
malignant.  For patients with <5% probability, repeat imaging is recommended at 
variable time intervals up to 2 years, and for patients with high probability of cancer 
(>65%), tissue diagnosis with VATS followed by resection is recommended. Those 
patients with lesions of intermediate probability for malignancy require more 
complicated evaluation. 
  

Medical University of South Carolina 
PI:  Nichole T. Tanner, MD, MSCR 
Title: Multicenter, prospective, randomized trial of bronchoscopy with ultrathin bronchoscope and radial endobronchial 
ultrasound (R-EBUS) with fluoroscopy versus standard fiberoptic bronchoscopy (FB) with fluoroscopy for biopsy of 
pulmonary lesions  
9 November 2016 
 
 
3
The various recommended procedures for obtaining tissue diagnosis in these 
intermediate cases include transthoracic needle aspiration (TTNA), surgery, and flexible 
bronchoscopy (FB). The diagnostic yield with FB varies with lesion size and location. 
Based on review of 10 studies using FB for diagnosing peripheral pulmonary nodules 
(PPN), the sensitivity is only 34% for lesions <2cm and has been found to be as low as 
14%. 5,6 The sensitivity increases to 63% when lesions are >2cm in size, but decreases 
as the distance from the hilum increases. A lesion having a bronchus sign (the finding of 
a CT-visible bronchus leading to the lesion) increases the success of transbronchial 
biopsy and brushing. 7 The ACCP recommends that nodules without a CT-bronchus 
sign should be pursued with TTNA unless radial endobronchial ultrasound (R-EBUS) is 
available.6 Bronchoscopy is commonly used for pulmonary masses, but the yield, while 
high, does not approach 100%. 
  
Several new technologies have evolved which allow clinicians to reach pulmonary 
lesions with bronchoscopy: electromagnetic navigation (ENB), ultrathin bronchoscope, 
R-EBUS, virtual bronchoscopy (VB), endobronchial ultrasound (EBUS), and guide 
sheath. 
  
ENB was designed to guide the bronchoscope and the physician to peripheral lesions, 
and has been likened to a global positioning system (GPS) for bronchoscopy. The four 
components necessary for ENB are an electromagnetic location board, a locatable 
sensor probe with steering that allows navigation through the bronchi, an extended 
working channel, and computer software that creates the VB images.8 This is a real-
time navigation system which has been found to have a diagnostic yield of 69-74% for 
PPN of any size and a pneumothorax rate of 0-7.5%. 8-12 Drawbacks of ENB include the 
high cost to purchase all the components, the need for extensive training and the 
complexity of the system for the general pulmonologist. 
  
EBUS has been evaluated for diagnosing and staging lesions, as a tool to assess both 
central and peripheral lesions, and to evaluate various layers of bronchi. 13-15 Linear 
EBUS has been shown to be effective for biopsy of mediastinal and hilar adenopathy for 
diagnosis and staging of potentially metastatic lung cancer, 16 but radial EBUS can be 
used to locate more peripheral pulmonary lesions for transbronchial biopsy. 17-22 With 
the addition of a guide sheath (Olympus Inc.) to maintain the position of the 
bronchoscope within/near the target lesion, the diagnostic yields range from 58% to as 
high as 86%, which is comparable to CT-guided TTNA. 17-19,22,23 The use of ultrasound 
allows real-time visualization outside the tracheobronchial tree and eliminates the risk of 
radiation exposure. 
  
A recent meta-analysis that included 39 studies of guided-bronchoscopy technologies 
for the diagnosis of pulmonary nodules demonstrated a pooled diagnostic yield of 70%, 
which is higher than the yield for traditional transbronchial biopsy. 24 The yield increased 
as the lesion size increased. The pneumothorax rate was 1.5%, which is significantly 
smaller than that reported for TTNA. This study demonstrated that the diagnostic yield 

Medical University of South Carolina 
PI:  Nichole T. Tanner, MD, MSCR 
Title: Multicenter, prospective, randomized trial of bronchoscopy with ultrathin bronchoscope and radial endobronchial 
ultrasound (R-EBUS) with fluoroscopy versus standard fiberoptic bronchoscopy (FB) with fluoroscopy for biopsy of 
pulmonary lesions  
9 November 2016 
 
 
4
of guided bronchoscopic techniques is better than that of traditional transbronchial 
biopsy for tissue sampling of pulmonary nodules; however, it concluded that further 
study is needed to determine its role in the evaluation of peripheral pulmonary lesions. 
The yield for bronchoscopy using R-EBUS with or without guide sheath is 73.4% and 
71.6%, respectively. 
  
RATIONALE 
Despite new technologies that have arisen in the last decade for bronchoscopic biopsy 
of peripheral pulmonary lesions, the sensitivity for FOB remains as low as 34% for 
lesions < 2cm and increases to around 63% for lesions >2cm in size, but decreases 
again as the distance from the hilum increases.  The use of R-EBUS as an adjunct is 
recommended as it increases diagnostic yield. A biopsy approach using R-EBUS 
through an ultrathin scope, guide sheath and fluoroscopy may increase the diagnostic 
yield of pulmonary lesions even further when compared to standard FB with 
fluoroscopy; it may also improve the utility of bronchoscopy for the diagnosis of 
peripheral pulmonary lesions thereby decreasing the need and risk associated with 
TTNA. This study will also evaluate the radiographic and procedural factors that have 
been described to influence that diagnostic yield.  
 
II. RESEARCH DESIGN AND METHODS 
This is a multi-center, prospective, randomized controlled trial to evaluate the diagnostic 
yield of two standard of care bronchoscopy procedures used to biopsy peripheral 
pulmonary lesions identified on chest CT: (1) standard FB using an adult standard 
bronchoscope (Olympus BF-180) with fluoroscopy, and (2) bronchoscopy using the 
BFP-190 ultrathin bronchoscope in combination with R-EBUS and guide sheath. 
 
Primary outcomes: Diagnostic yield of standard FB with fluoroscopy using standard 
adult bronchoscope versus bronchoscopy using ultrathin bronchoscope in combination 
with R-EBUS with or without guide sheath for lung lesions 1.5-5 cm. 
 
Secondary Outcomes: 
1) The radiographic and procedural factors that influence the diagnostic yield 
including the size and location of the lesion, the distance from the main carina, 
the number and type of specimens obtained, and the location of sampling within 
the lesion. 
2) Adverse event rates of hemoptysis and pneumothorax. 
 
DEFINITIONS: 
Lung lesions: solid nodules or masses 1.5-5 cm in diameter 
  
SUBJECT ENROLLMENT (See Figure 1): 
Subjects presenting to their standard of care pulmonologist in need of a bronchoscopic 
biopsy of their peripheral pulmonary lesion as part of their standard medical care, and 
who meet study inclusion/exclusion criteria, will be invited to participate. A total of 214 

Medical University of South Carolina 
PI:  Nichole T. Tanner, MD, MSCR 
Title: Multicenter, prospective, randomized trial of bronchoscopy with ultrathin bronchoscope and radial endobronchial 
ultrasound (R-EBUS) with fluoroscopy versus standard fiberoptic bronchoscopy (FB) with fluoroscopy for biopsy of 
pulmonary lesions  
9 November 2016 
 
 
5
patients will be enrolled. As this is a competitive enrollment study, MUSC will enroll up 
to 75 volunteers. Eligibility will be determined by each site PI. The PI or Co-I will explain 
the study to qualified subjects prior to obtaining consent. The subject will also be given 
an opportunity to review and sign documentation of HIPAA compliance and 
authorization.  
 
Inclusion criteria: 
Patients to be included for participation in this study are: 
1) Patients with a solid lung lesion 1.5-5cm identified on chest CT (obtained within 
previous 3 months) with the intention to undergo bronchoscopic evaluation. If the 
lesion is partially solid (i.e. there is a ground glass component) then the solid 
portion must make up >75% of the lesion and measure at 1.5-5cm.The decision 
to pursue biopsy will be made by the treating physician and agreed upon by the 
patient. This will include patients determined to have an intermediate risk of 
malignancy (5-65%) and those non-surgical candidate with higher risk lesions in 
need of diagnosis for alternative treatment. OR 
2) Patients with a solid lung lesion 1.5-5cm identified on chest CT (obtained within 
previous 3 months) that are surgical candidates with a high probability of cancer 
(>65%) will be referred for surgical evaluation. If the lesion is partially solid (i.e. 
there is a ground glass component) then the solid portion must make up >75% of 
the lesion and measure at 1.5-5cm. If the patient refuses surgery or if the 
surgeon requests a definitive diagnosis prior to surgery the patient will have the 
option to be included in this study.  All sites will use the same online calculator to 
document probability of malignancy.  
3) Patients whose targeted lung lesion is visualized with fluoroscopy 
4) Are at least 22 years old, 
5) Lack Bleeding disorders, and  
6) Are able to provide informed consent. 
 
Race and gender inclusion will reflect the population characteristics found in the 
respective regions. 
 
Exclusion criteria:  
Patients to be excluded from participation in this study are: 
1) Patients with a pure ground-glass opacity identified on chest CT 
2) Patients with endobronchial involvement seen on chest CT. 
3) Patients who refuse to participate,  
4) Are less than 22 years of age,  
5) Lack fitness to undergo flexible bronchoscopy as determined by the 
bronchoscopist prior to procedure, and  
6) Are unable to provide informed consent 
7) Pregnant 
 
 

Medical University of South Carolina 
PI:  Nichole T. Tanner, MD, MSCR 
Title: Multicenter, prospective, randomized trial of bronchoscopy with ultrathin bronchoscope and radial endobronchial 
ultrasound (R-EBUS) with fluoroscopy versus standard fiberoptic bronchoscopy (FB) with fluoroscopy for biopsy of 
pulmonary lesions  
9 November 2016 
 
 
6
 
INFORMED CONSENT: 
Informed consent will take place in a private environment (e.g. patient exam room), free 
from distractions. The PI or sub-PI will approach the subject at their standard of care 
clinic appointment or prior to their scheduled bronchoscopy and will explain the study to 
qualified subjects prior to obtaining consent. All individuals who obtain consent (PI, Co-I, 
and study coordinators) have completion certificates for the CITI Human Subjects 
Research Education Course. Interviews to obtain consent will not follow any stressful 
situation (e.g. patient being informed he/she may have cancer) and will not be 
conducted if patient has received any mind-altering medications or anesthesia. Patients 
will be assessed for their capacity to consent by the ability to show comprehension of 
the procedure, ask appropriate questions, and appear properly oriented. A signed copy 
of all consents and the HIPAA authorization document will also be given to consenting 
subjects. 
 
SUBJECT RANDOMIZATION 
Once informed consent is obtained, the site PI will open the next randomization 
envelope to reveal the assigned procedure. Randomization envelopes are provided by 
MUSC and are to be opened in order, as indicated by the numbering on the exterior of 
the envelope. Inside each envelope is the randomization assignment for that subject. 
The randomization schedule is determined in advance by a computer with the plan for 
1:1 randomization overall. 
 
BRONCHOSCOPY PROCEDURES: 
Patients will be randomized in a 1:1 fashion (107 in each arm) to undergo (1) standard 
FOB with fluoroscopy, or (2) R-EBUS with ultrathin bronchoscope (4.2 mm outer 
diameter with a 2 mm working channel) and guide sheath. This sample size will provide  
85% power to detect a 20% improvement in yield using R-EBUS with fluoroscopy. This 
assumes a diagnostic yield for standard FB with fluoroscopy of 50% and R-EBUS with 
fluoroscopy is 70%. This also assumes 2-sided hypothesis testing and an alpha level  
(i.e. significance level) of 0.05.If subjects have multiple pulmonary lesions, it will be 
predetermined which lesion will be targeted. After informed consent and randomization 
have been performed, the following will occur: 
 
(1) Prior to bronchoscopy: CT images will be obtained within 3 months of bronchoscopy 
and readily available for viewing during the bronchoscopic procedure. A de-identified 
copy of the CT and/or PET/CT report will be sent to the coordinating site (MUSC). 
 
 (2) At bronchoscopy: Moderate or deep sedation will be administered as deemed 
clinically appropriate by the procedure team. The time the bronchoscope is 
inserted and removed will be recorded. When sufficient sedation has been given, 
the bronchoscope (standard adult FB (Olympus BF-180 or 190) or ultrathin 
depending on randomization) will be introduced into the airway. Topical 
anesthesia with 1%- 2% lidocaine will be administered to the vocal cords, 

Medical University of South Carolina 
PI:  Nichole T. Tanner, MD, MSCR 
Title: Multicenter, prospective, randomized trial of bronchoscopy with ultrathin bronchoscope and radial endobronchial 
ultrasound (R-EBUS) with fluoroscopy versus standard fiberoptic bronchoscopy (FB) with fluoroscopy for biopsy of 
pulmonary lesions  
9 November 2016 
 
 
7
trachea, and right and left mainstem bronchi through the bronchoscope. The 
bronchoscope will be advanced as distally as possible under direct visualization. 
In cases in which the lesion cannot be located, the clinical judgment of the site PI 
will direct one or more of the following choices:  
 abort the procedure 
 crossover to standard bronchoscopy and brushing  
 BAL under fluoroscopy (even when lesion is not visualized under ultrasound) 
 another standard of care procedure 
 
(3) For Bronchoscopy plus R-EBUS: 
Once the ultrathin bronchoscope has been passed as distally as possible, the R-EBUS 
will be utilized. Depending on the number of generations of bronchi that are passed, a 
guide sheath (Olympus; external diameter 2mm [K201]) may be inserted into the 
ultrathin scope. The 20MHz mechanical R-EBUS probe (Olympus, UM-S20-17S) +/- the 
guide sheath covering will be introduced into the working channel of the bronchoscope 
and advanced to the lesion. An attempt to definitively locate the lesion with R-EBUS will 
be made. Fluoroscopy will be used to aide in locating the lesion, which will then be 
verified by R-EBUS. A de-identified jpeg image of the ultrasound image will be recorded 
and subsequently uploaded to the REDCap study data collection instrument. Once the 
lesion is located, the R-EBUS probe will be removed. The guide sheath will remain in 
place. Bronchial brush (Olympus BC-204D-2010 followed by a smooth transbronchial 
biopsy forceps (Olympus FB-233D)  will be introduced through the working channel with 
guide sheath to obtain pathologic and cytologic specimens. 1 brushing (standardized to 
10 strokes per brushing)will be performed followed by 5 transbronchial forceps biopsies. 
(Brush preparation: smear brushing sample, then cut brush and drop into cytolyte; fix 
slide with alcohol.) The R-EBUS probe will be reinserted after obtaining specimens to 
again verify the location of the lesion. 
If the ultrasound image seen following R-EBUS probe insertion is eccentric, a 
double hinged curette will be inserted into the working channel in an attempt to 
manipulate the position such that the ultrasound image of the lesion becomes 
concentric. 
If the bronchus identified on imaging cannot be reached by bronchoscopy, a 
double-hinged curette will be inserted into the working channel with the guide sheath, 
manipulated and directed to the bronchus and advanced with fluoroscopic guidance. 
The curette will be removed and the R-EBUS probe will be reinserted through the 
working channel with the guide sheath to confirm the location within the lesion. Once 
the targeted airway/lesion has been reached, biopsy specimens will be obtained with 
fluoroscopic imaging to verify positioning at the lesion. TBBx and brushing will be 
performed.  
 
(4) For Standard Bronchoscopy with Fluoroscopy: 
Once the standard FB (Olympus BF-180 or 190) is extended out into the airway as 
distally as possible, fluoroscopy will be used to aide in locating the lesion. Standard 
bronchial brush and standard smooth transbronchial biopsy forceps will be introduced to 

Medical University of South Carolina 
PI:  Nichole T. Tanner, MD, MSCR 
Title: Multicenter, prospective, randomized trial of bronchoscopy with ultrathin bronchoscope and radial endobronchial 
ultrasound (R-EBUS) with fluoroscopy versus standard fiberoptic bronchoscopy (FB) with fluoroscopy for biopsy of 
pulmonary lesions  
9 November 2016 
 
 
8
obtain pathologic and cytologic specimens. One brushing (standardized to 10 strokes 
per brushing) will be performed and placed on a slide for Rapid On-site evaluation by 
pathology. Five transbronchial biopsies will then be performed under fluoroscopy. Rapid 
On-Site Evaluation (ROSE) is performed for all subjects randomized to standard 
bronchoscopy. 
 
(5) Following both bronchoscopy procedures: 
A portable chest X-ray will be performed to look for pneumothorax. 
 
(6) For Non-diagnostic (including chronic inflammation) Procedures (either arm): 
If a diagnosis is not obtained after the procedure, further recommendations regarding 
treatment will be made by the treating physician. (i.e. follow-up CT chest, CT guided 
transthoracic needle aspiration, or surgery). In the standard FB arm, the bronchoscopist 
will have the option of using peripheral ultrasound with or without the ultrathin scope to 
attempt to identify the lesion. Specimens obtained must be kept separate and identified 
as having performed using R-EBUS (e.g. labelled “radial brush”, “radial biopsy”) and 
reflected in the case report form. If ROSE is non-diagnostic and/or indicates chronic 
inflammation, crossover to the Ultrathin bronchoscope with R-EBUS will take place. In 
those patients that cross over to the Ultrathin bronchoscope with R-EBUS the same 
protocol for those randomized to the ultrathin/R-EBUS arm will be followed (see #3). 
  
RISKS OF PROCEDURES: 
The greatest risks from bronchoscopy are related to moderate or deep sedation and the 
very act of passing a bronchoscope into the airway.  To mitigate risks of bronchoscopy 
all patients will be monitored by a nurse and a respiratory therapist during the 
procedure. In addition, oxygen saturation (using pulse oximetry) respiratory rate, blood 
pressure, ECG, and heart rate will be continuously monitored.  Patients will not be 
released until they are fully awake and medically stable. 
  
The risks associated with bronchoscopy are collapsed lung, breathing difficulty, vocal 
cord spasm, vomiting, dizziness, bronchial spasm, infection, low blood oxygen, heart 
attack and bleeding from biopsied site. The occurrence of these risks is extremely low.  
The measures to mitigate the risks are the same as for all bronchoscopy. To minimize 
the chance of bleeding, all patients will be questioned about tendency to bleed prior to 
bronchoscopy as per standard care. Anticoagulation with antiplatelet agents will be held 
according to guideline recommendations for that drug. 25If bleeding occurs, patients will 
be treated with direct pressure, local instillation of epinephrine or electrocautery. Vocal 
cord spasm will be prevented through the use of lidocaine on the vocal cords. Patients 
with lung disease may receive bronchodilators prior to bronchoscopy at the discretion of 
the performing bronchoscopist. There is no way to reduce the minimal risk of infection 
due to bronchoscopy since the scope must go through the naso or oropharynx. Patients 
are given supplemental oxygen and their oxygen level is continuously monitored using 
pulse oximetry. Patients ECG, heart rate, blood pressure, and blood oxygen are 
continuously monitored by a nurse, respiratory therapist and physician during the 

Medical University of South Carolina 
PI:  Nichole T. Tanner, MD, MSCR 
Title: Multicenter, prospective, randomized trial of bronchoscopy with ultrathin bronchoscope and radial endobronchial 
ultrasound (R-EBUS) with fluoroscopy versus standard fiberoptic bronchoscopy (FB) with fluoroscopy for biopsy of 
pulmonary lesions  
9 November 2016 
 
 
9
procedure. If there is any sign of a worsening in status, such as elevated heart rate, low 
oxygen, or ECG changes, the procedure will be aborted. 
 
RESEARCH ONLY RISKS 
Risk of breach in confidentiality 
Every effort will be made to protect the privacy of the research subjects.  All information 
and data related to this study will be maintained in secured, protected space, and 
access will be restricted to study personnel only. 
  
DATA COLLECTION: 
Prior to each site initiation, the site PI and staff will participate in an educational 
teleconference with the Coordinating Site PI to ensure that all personnel fully 
understand the protocol, data collection instrument, and any other study related issues 
or documents. Contact information, including the phone and pager numbers for the 
principal investigators and study staff will be provided to all sites 
Data on the following will be collected at all sites: radiographic characteristics, 
procedural characteristics, diagnostic yield, crossover to other procedures, confirmation 
of diagnosis, and complications: 
 
(1) Radiographic Information: 
The radiographic information collected will include location of the lesion, size of the 
lesion, distance from a visible bronchus, and PET characteristics. For R-EBUS 
procedures, a jpeg ultrasound image of the lesion will be recorded, anonymized, and 
uploaded to the REDCap study data collection instrument. The location of the lesion 
(side, lobe and segment, i.e. right upper lobe anterior segment, etc.) will be determined 
and recorded. The size of the lesion in longest axis diameter will be measured and 
recorded. The distance from the trachea as calculated as the number of generations 
from the main carina (first generation) to the lesion will be recorded.  All central and 
peripheral lesions considered intermediate risk will be included. If the patient has 
undergone a PET, the metabolic activity (measured SUV) will be recorded. 
 
(2) Procedural Characteristics: 
The procedural information will include the number of biopsy passes, types of biopsy 
performed (TBBx, , brush, BAL), and R-EBUS description of site of biopsy of the lesion 
(within vs. adjacent to) will be recorded. The time length of procedure, type and amount 
of sedation administered will also be recorded. 
 
(3) Diagnostic Yield and Crossover Procedures: 
Primary outcome of diagnostic yield will be determined from the results of the 
bronchoscopy. A biopsy that results in a specific diagnosis, either malignant or benign, 
will be assumed to be a true positive. Plan for further diagnostic management for 
patients who have a non-diagnostic biopsy (and/or biopsy indicating chronic 
inflammation) will be determined by the attending physician. Those patients will be 
followed for up to one year until a definitive diagnosis has been made (such as from 

Medical University of South Carolina 
PI:  Nichole T. Tanner, MD, MSCR 
Title: Multicenter, prospective, randomized trial of bronchoscopy with ultrathin bronchoscope and radial endobronchial 
ultrasound (R-EBUS) with fluoroscopy versus standard fiberoptic bronchoscopy (FB) with fluoroscopy for biopsy of 
pulmonary lesions  
9 November 2016 
 
 
10
surgical pathology), or the lesion has decreased on repeat CT imaging. Under standard 
procedure randomization, if ROSE indicates chronic inflammation, crossover to R-EBUS 
will take place. 
 
(4) Confirmation of Diagnosis: 
Confirmation of the diagnosis by surgery or repeat imaging will be recorded for those 
patients who have non-diagnostic results (including chronic inflammation) from the 
study procedures. If the patient is referred for surgery, the surgical pathology will be 
considered the final diagnosis. If the patient has follow-up imaging that shows resolution 
of the lesion, the lesion will be determined to be of benign etiology. To verify final 
diagnosis, a copy of the final pathology report from bronchoscopy and any pathology 
reports from subsequent surgical resection, will be de-identified and provided by the site 
to the coordinating center. 
 
(5) Complications: 
Adverse event rates will be documented. Pneumothorax will be documented by post-
biopsy CXR or chest ultrasonography, and the number requiring intervention, such as 
chest tube placement, will be recorded. Significant hemoptysis will be defined as 
bleeding noted at the time of procedure that requires a change in the level of care (e.g. 
outpatient to inpatient or inpatient to ICU) or a blood transfusion.  Other adverse events 
that are common to bronchoscopy described above in “Risks” section will be monitored 
and reported by the patient or nursing staff. 
 
DATA SAFETY MONITORING PLAN 
All subjects enrolled in the trial will undergo routine standard of care bronchoscopy that 
is indicated a medically necessary by their physicians. Prior to the bronchoscopic 
procedure, PIs will explain the risks associated with bronchoscopy, and verify that the 
research only risks have been explained, and that the subject has signed an informed 
consent form. There are no anticipated risks, outside of the risk for the standard of care 
procedures for this clinical trial. All subjects are required to read, understand, and sign 
the informed consent form associated with the research study. Each subject will be 
informed of post procedure symptoms of which to be aware that may represent adverse 
reactions to the bronchoscopy.  Symptoms that the patient will be informed to look out 
for include: 
 Pain or difficulty with swallowing 
 Difficulty breathing 
 Vomiting 
 Dizziness 
 Abdominal or chest pain 
 Continuous bright red blood in your sputum 
 Fever above 100.0 degrees Fahrenheit 
If the subject notes any of these symptoms, he/she is instructed to contact his/her 
physician, who will determine the course of action. All events are to be reported within 
48 hours of occurrence to the coordinating site (MUSC).  All adverse events (AEs) will 

Medical University of South Carolina 
PI:  Nichole T. Tanner, MD, MSCR 
Title: Multicenter, prospective, randomized trial of bronchoscopy with ultrathin bronchoscope and radial endobronchial 
ultrasound (R-EBUS) with fluoroscopy versus standard fiberoptic bronchoscopy (FB) with fluoroscopy for biopsy of 
pulmonary lesions  
9 November 2016 
 
 
11
be reviewed by the medical monitor within one month of their occurrence and 
summarized for review.  The PI at each site will be responsible for submitting this report 
to the IRB at his/her institution as required. AEs and other reportable events are defined 
below. 
 
Reportable Events 
(1) AEs 
AEs will be defined as  any untoward or unfavorable medical occurrence in a human 
subject, including any abnormal sign, symptom, or disease, temporally associated with 
the subject's participation in the research, whether or not considered related to the 
subject's participation in the research. Serious Adverse Events (SAEs) will be defined 
as any adverse event temporally associated with the subject's participation in research 
that meets any of the following criteria: 
* results in death; 
* is life-threatening; 
* requires inpatient hospitalization or prolongation of existing hospitalization; 
* results in a persistent or significant disability/incapacity; 
* results in a congenital anomaly/birth defect; or 
* any other adverse event that, based upon appropriate medical judgment,    
  may jeopardize the subject's health and may require medical or surgical  
  intervention to prevent one of the other outcomes listed in this definition. 
Site PIs will be responsible for identifying adverse events during the procedure and 
during the standard of care follow-up period. Site PIs will review adverse events 
experienced by subjects treated at their site during the procedure standard of care 
follow-up period and will record them in the medical record. Site PIs will review all 
adverse events, expected or unexpected, per standard medical care.  
Site PIs will classify AEs as expected or unexpected, and report AEs directly to the IRB 
per local IRB reporting policy. The lead investigator will capture all AEs occurring at all 
sites, including unanticipated AEs, in the REDCap data collection instrument. 
 
(2) Protocol Deviations 
Site PIs will be responsible for identifying and reporting all protocol deviations to the 
local IRB per local IRB reporting policy.  The lead investigator will capture protocol 
deviations occurring at all sites in the REDCap data collection instrument. 
 
(3) Protocol Amendments or Revisions 
Amendments or revisions to the protocol proposed at all sites will first be approved by 
the lead investigator. 
 
DATA STORAGE AND MAINTENANCE: 
Each site investigator will review the results, and the results will become part of the 
subject’s medical record and research record. Any clinical follow-up or repeat 
procedures will be dictated by the patient’s physician based on clinically relevant data 
and will not be influenced by enrollment into this study. To protect subject 

Medical University of South Carolina 
PI:  Nichole T. Tanner, MD, MSCR 
Title: Multicenter, prospective, randomized trial of bronchoscopy with ultrathin bronchoscope and radial endobronchial 
ultrasound (R-EBUS) with fluoroscopy versus standard fiberoptic bronchoscopy (FB) with fluoroscopy for biopsy of 
pulmonary lesions  
9 November 2016 
 
 
12
confidentiality, MUSC will receive all sites’ data as de-identified through use of the 6 
digit patient codes. All information and data related to this study will be stored in a 
secured, locked cabinet in MUSC Clinical Sciences Building Room 809. The privacy of 
subjects will be protected using a 6 digit computer generated random code. The key to 
the code will be kept in a password protected folder on the MUSC DB2 (\\DA) server; 
access to this folder is restricted to study personnel alone. 
 
Electronic Data will be entered and stored in the secure REDCap database created for 
this study. REDCap is a web-based application designed exclusively to support data 
capture for research studies.  It provides an intuitive interface for data entry, audit trails 
for tracking data manipulation and export procedures, procedures for importing data 
from external sources, advanced features such as branching logic and calculated fields, 
and automated export procedures for seamless data downloads to common statistical 
packages such as SPSS, SAS, Stata, and R. It was developed at Vanderbilt University 
(see http://redcap.vanderbilt.edu/consortium/index.php) and is ideal for remote data 
entry, as will be the case for this multi-center trial. 
 
III. STATISTICAL ANALYSIS: 
Statistical comparisons will be made using chi-square analysis where applicable.  
Sensitivity, specificity, positive and negative predictive value and accuracy of all 
procedures will be calculated.  A logistic regression analysis of factors influencing tissue 
quantity will be undertaken. 
 
Coordinating Center:  MUSC will be the designated coordinating center for this trial.  
MUSC will be responsible for development of the database, housing the data, working 
with the sites on IRB issues, patient enrollment, completion of on-line data collection 
instrument and validation of the data.  MUSC will also be responsible for payment to the 
sites when a patient’s case report form is complete and query-free.  Statistical support 
and interim analysis will be performed at MUSC by an in house statistician (Paul Nietert, 
PhD).  Interim results will be shared with all participating sites during teleconference 
meetings. 
  
Note:  The Medical University of South Carolina is the coordinating center for the 
study and there will be up to 8 collaborating centers participating in the study. 
This study will be completed using a competitive enrollment strategy.  That is sites will 
be paid on a per patient enrollment basis after completion of the procedure and case 
report form. The coordinating center has budgeted the time and resources necessary to 
manage this number of sites.  Further, author placement on manuscripts (after first and 
senior authorship) will be dependent on enrollment such that the more patients a site 
enrolls, the earlier their PI’s name will appear on the author list. 
 
 
REFERENCES: 

Medical University of South Carolina 
PI:  Nichole T. Tanner, MD, MSCR 
Title: Multicenter, prospective, randomized trial of bronchoscopy with ultrathin bronchoscope and radial endobronchial 
ultrasound (R-EBUS) with fluoroscopy versus standard fiberoptic bronchoscopy (FB) with fluoroscopy for biopsy of 
pulmonary lesions  
9 November 2016 
 
 
13
 1 Gould MK, Donington J, Lynch WR, et al. Evaluation of individuals with pulmonary 
nodules: when is it lung cancer? Diagnosis and management of lung cancer, 3rd 
ed: American College of Chest Physicians evidence-based clinical practice 
guidelines. Chest 2013; 143:e93S-120S 
2 Aberle DR, Adams AM, Berg CD, et al. Reduced lung-cancer mortality with low-dose 
computed tomographic screening. The New England journal of medicine 2011; 
365:395-409 
3 Wahidi MM, Govert JA, Goudar RK, et al. Evidence for the treatment of patients with 
pulmonary nodules: when is it lung cancer?: ACCP evidence-based clinical 
practice guidelines (2nd edition). Chest 2007; 132:94S-107S 
4 Ost D, Fein AM, Feinsilver SH. Clinical practice. The solitary pulmonary nodule. N 
Engl J Med 2003; 348:2535-2542 
5 Baaklini WA, Reinoso MA, Gorin AB, et al. Diagnostic yield of fiberoptic bronchoscopy 
in evaluating solitary pulmonary nodules. Chest 2000; 117:1049-1054 
6 Rivera MP, Mehta AC, Wahidi MM. Establishing the diagnosis of lung cancer: 
Diagnosis and management of lung cancer, 3rd ed: American College of Chest 
Physicians evidence-based clinical practice guidelines. Chest 2013; 143:e142S-
165S 
7 Gaeta M, Pandolfo I, Volta S, et al. Bronchus sign on CT in peripheral carcinoma of 
the lung: value in predicting results of transbronchial biopsy. AJR Am J 
Roentgenol 1991; 157:1181-1185 
8 Eberhardt R, Anantham D, Herth F, et al. Electromagnetic navigation diagnostic 
bronchoscopy in peripheral lung lesions. Chest 2007; 131:1800-1805 
9 Becker HC, Herth, F., Ernst A. Bronchoscopic biopsy of peripheral lung lesions under 
electromagnetic guidance: a pilot study. Journal of Bronchology 2005; 12:9-13 
10 Gildea TR, Mazzone PJ, Karnak D, et al. Electromagnetic navigation diagnostic 
bronchoscopy: a prospective study. Am J Respir Crit Care Med 2006; 174:982-
989 
11 Makris D, Scherpereel A, Leroy S, et al. Electromagnetic navigation diagnostic 
bronchoscopy for small peripheral lung lesions. Eur Respir J 2007; 29:1187-1192 
12 Schwarz Y, Greif J, Becker HD, et al. Real-time electromagnetic navigation 
bronchoscopy to peripheral lung lesions using overlaid CT images: the first 
human study. Chest 2006; 129:988-994 
13 Goldberg BB, Steiner RM, Liu JB, et al. US-assisted bronchoscopy with use of 
miniature transducer-containing catheters. Radiology 1994; 190:233-237 
14 Irani S, Hess T, Hofer M, et al. Endobronchial ultrasonography for the quantitative 
assessment of bronchial mural structures in lung transplant recipients. Chest 
2006; 129:349-355 
15 Kuo CH, Lin SM, Chen HC, et al. Diagnosis of peripheral lung cancer with three 
echoic features via endobronchial ultrasound. Chest 2007; 132:922-929 
16 Nakajima T, Yasufuku K, Iyoda A, et al. The evaluation of lymph node metastasis by 
endobronchial ultrasound-guided transbronchial needle aspiration: crucial for 
selection of surgical candidates with metastatic lung tumors. J Thorac 
Cardiovasc Surg 2007; 134:1485-1490 

Medical University of South Carolina 
PI:  Nichole T. Tanner, MD, MSCR 
Title: Multicenter, prospective, randomized trial of bronchoscopy with ultrathin bronchoscope and radial endobronchial 
ultrasound (R-EBUS) with fluoroscopy versus standard fiberoptic bronchoscopy (FB) with fluoroscopy for biopsy of 
pulmonary lesions  
9 November 2016 
 
 
14
17 Herth FJ, Ernst A, Eberhardt R, et al. Endobronchial ultrasound-guided 
transbronchial needle aspiration of lymph nodes in the radiologically normal 
mediastinum. Eur Respir J 2006; 28:910-914 
18 Kikuchi E, Yamazaki K, Sukoh N, et al. Endobronchial ultrasonography with guide-
sheath for peripheral pulmonary lesions. Eur Respir J 2004; 24:533-537 
19 Kurimoto N, Miyazawa T, Okimasa S, et al. Endobronchial ultrasonography using a 
guide sheath increases the ability to diagnose peripheral pulmonary lesions 
endoscopically. Chest 2004; 126:959-965 
20 Paone G, Nicastri E, Lucantoni G, et al. Endobronchial ultrasound-driven biopsy in 
the diagnosis of peripheral lung lesions. Chest 2005; 128:3551-3557 
21 Shirakawa T, Imamura F, Hamamoto J, et al. Usefulness of endobronchial 
ultrasonography for transbronchial lung biopsies of peripheral lung lesions. 
Respiration 2004; 71:260-268 
22 Yoshikawa M, Sukoh N, Yamazaki K, et al. Diagnostic value of endobronchial 
ultrasonography with a guide sheath for peripheral pulmonary lesions without X-
ray fluoroscopy. Chest 2007; 131:1788-1793 
23 Yamada N, Yamazaki K, Kurimoto N, et al. Factors related to diagnostic yield of 
transbronchial biopsy using endobronchial ultrasonography with a guide sheath 
in small peripheral pulmonary lesions. Chest 2007; 132:603-608 
24 Wang Memoli JS, Nietert PJ, Silvestri GA. Meta-analysis of guided bronchoscopy for 
the evaluation of the pulmonary nodule. Chest 2012; 142:385-393 
25 Baron TH, Kamath PS, McBane RD. Management of antithrombotic therapy in 
patients undergoing invasive procedures. The New England journal of medicine 
2013; 368:2113-2124 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Medical University of South Carolina 
PI:  Nichole T. Tanner, MD, MSCR 
Title: Multicenter, prospective, randomized trial of bronchoscopy with ultrathin bronchoscope and radial endobronchial 
ultrasound (R-EBUS) with fluoroscopy versus standard fiberoptic bronchoscopy (FB) with fluoroscopy for biopsy of 
pulmonary lesions  
9 November 2016 
 
 
15
 
 
 
Figure 1: Study Design 
 
 
 
Patient with Pulmonary 
Lesion 
(≥ 2cm)
Standard FOB with Fluro
- Brushing, Needle bx, 
Forceps bx, BAL
Non-diagnostic 
(includes inflammation)
R-EBUS with Ultrathin and 
Guide sheath
-Brushing, Needle bx, Forceps 
bx, BAL
Exclusion:
- < 22 years old
- Unable to consent
- Unfit for bronchoscopy
- Lesion high risk for malignancy 
(>60%)
Inclusion:
- ≥ 22 years old
- Fit for bronchoscopy
- Lesion intermediate risk for   
malignacy
- High risk lesion in non-surgical candidate or 
request for diagnosis prior to surgery
Cross-over