Endoscopic Ultrasound With Fine Needle Biopsy Versus Fine Needle Aspiration With On-Site Cytopathology in the Evaluation of Solid Pancreatic Masses: Randomized Single Blinded Clinical Trial
Phase: NA
Conditions: Fine Needle Aspiration, Pancreatic Mass
Sponsor: Johns Hopkins University

NA_00093759 CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
ENDOSCOPIC ULTRASOUND WITH FINE NEEDLE BIOPSY VERSUS FINE NEEDLE 
ASPIRATION WITH ON-SITE CYTOPATHOLOGY IN THE EVALUATION OF SOLID 
PANCREATIC MASSES: RANDOMIZED SINGLE BLINDED CLINICAL TRIAL   
 
 
JHU Protocol #:  IRB00148609  
Study Phase: Phase 3 
Study Products: None 
Protocol Chair/Principle Investigator: Mouen Khashab MD 
Johns Hopkins Hospital 
Document Date: 8/18/2017 
NCT number: NCT03485924 
 
 
Coordinating Center  
Department of Medicine 
Division Gastroenterology and Hepatology  
1800 Orleans Street 
Baltimore, MD, 21287 
Mkhasha1@jhmi.edu 
 
IRB: Institutional Review Board 
Johns Hopkins School of Medicine 
1620 McElderry Street 
Reed Hall, Suite B-130 
Baltimore, MD 21205-1911 
 
Protocol Revision Record

NA_00093759 CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
1 
 
Table of Contents 
1. OBJECTIVES 
2 
1.1 STUDY DESIGN 
2 
1.2 PRIMARY OBJECTIVES 
2 
1.3 SECONDARY OBJECTIVES 
2 
2. BACKGROUND AND RATIONALE 
2  
2.1 BACKGROUND 
2 
2.2 RATIONALE 
3 
2.3 PARTICIPANT SELECTION 
3 
INCLUSION OF WOMEN, MINORITIES AND OTHER UNDERREPRESENTED POPULATIONS 
 
3. MULTICENTER GUIDELINES 
3 
4. QUALITY ASSURANCE 
4 
5. DATA SUBMISSION 
4 
6. ADVERSE EVENT REPORTING 
4 
7. PROCEDURE  PLAN 
5 
8. PATIENT FOLLOW-UP 
6 
8.1 ANTICIPATED RISKS 
7 
9. ADVERSE EVENT REPORTING REQUIREMENTS 
8 
9.1 DEFINITIONS 
8 
9.1.1 ADVERSE EVENT (AE) 
8 
9.1.2 SERIOUS ADVERSE EVENT (SAE) 
8 
9.2 PROCEDURES FOR AE AND SAE RECORDING AND REPORTING 
8 
9.3 REPORTING REQUIREMENTS 
9 
9.4 REPORTING TO THE STUDY TEAM 
9 
9.4.1 SERIOUS ADVERSE EVENT REPORTING 
9 
9.4.2 NON-SERIOUS ADVERSE EVENT REPORTING 
9 
9.5 REPORTING TO THE INSTITUTIONAL REVIEW BOARD (IRB) 
10 
9.6 REPORTING TO THE FOOD AND DRUG ADMINISTRATION (FDA) 
10 
9.7 REPORTING TO THE NIH OFFICE OF BIOTECHNOLOGY ACTIVITIES (OBA) 
10 
9.8 REPORTING TO THE INSTITUTIONAL BIOSAFETY COMMITTEE (IBC) 
10 
9.9 REPORTING TO HOSPITAL RISK MANAGEMENT 
10 
9.10 MONITORING OF ADVERSE EVENTS AND PERIOD OF OBSERVATION 
10 
10. DATA AND SAFETY MONITORING 
10 
10.1 DATA REPORTING 
10 
10.1.1 DATA SUBMISSION 
10 
10.2 AUDITING/MONITORING 
11 
11. REGULATORY CONSIDERATIONS 
11 
11.1 PROTOCOL REVIEW AND AMENDMENTS 
11 
11.2 INFORMED CONSENT 
11 
11.3 ETHICS AND GOOD CLINICAL PRACTICE (GCP) 
11 
11.4 STUDY DOCUMENTATION 
11 
11.5 RECORDS RETENTION 
12 
11.6 MULTI-CENTER GUIDELINES 
12 
12. STATISTICAL CONSIDERATIONS 
12 
13. SAFETY MONITORINGN AND STOPPING RULE 
13 
14. PUBLICATION PLAN 
13 
15. REFERENCES 
 
 
 
 
 

 
 
 
 
2 
 
1. 
OBJECTIVES 
The objective of this single center paired cohort study is to evaluate the diagnostic 
accuracy of EUS-FNA with ROSE compared to EUS-FNB without ROSE.  If EUS-FNB 
without ROSE is shown to be non-inferior to the current standard of care of EUS-FNA 
with ROSE in pancreatic lesions, this study has the potential to make EUS-guided tissue 
acquisition more economical (with elimination for the need for cytopathology staff onsite) 
as well as provide core histological specimen without sacrificing the overall diagnostic 
yield.    
 
1.1 
STUDY DESIGN 
Multicenter, Prospective, Single Blind, Randomized clinical trial. 
Patients will be randomly allocated (Using computerized software) with a 1:1 ratio either to 
the EUS-FNA with ROSE or FNB first group. 
 
1.2 
Primary Objectives 
To compare the diagnostic accuracy of fine-needle biopsy (FNB) sampling without rapid 
onsite evaluation (ROSE) with the fine needle aspiration (FNA) with ROSE in pancreatic 
mass lesions 
1.3 
Secondary Objectives 
To compare: 
Specimen adequacy 
Percentage of histology cores obtained 
Number of passes 
Rate of technical failures 
Adverse events 
 
 
2. 
BACKGROUND AND RATIONALE 
 
2.1 
Background 
Endoscopic ultrasound (EUS) guided fine needle aspiration (EUS-FNA) is the primary 
technique for tissue acquisition for pancreatic lesions.  Despite widespread adoption of 
the techniques, the diagnostic yield of EUS-FNA for pancreatic lesion is highly variable, 
with sensitivities ranging from 64-95%, specificities ranging from 75-100% and overall 
diagnostic accuracy ranging from 78-95%.   
 
Despite its mainstay as the primary technique for tissue acquisition, EUS-FNA has 
several limitations.  The standard EUS-FNA does not routinely provide core biopsy 
specimen with preserved tissue architecture, which is required for immunohistochemical 
staining and for definitive diagnosis of conditions, such as lymphoma, gastrointestinal 
stromal tumors, IgG-4-associated lymphoplasmacytic sclerosing pancreatitis.  
Furthermore, the diagnostic yield of EUS-FNA is highly dependent on the availability of 
bedside cytotechnologist or cytopathologist for rapid onsite evaluation (ROSE), which 
increases the overall cost required to perform EUS-FNA.   
 
Recently, multiple dedicated EUS fine needle biopsy (FNB) needles have been 
developed to obtain core specimens.  Early small studies have shown promising results 
with these EUS-FNB needles (1-6).   
 
The objective of this single center paired cohort study is to evaluate the diagnostic 
accuracy of EUS-FNA with ROSE compared to EUS-FNA with ROSE.  If EUS-FNB 

 
 
 
 
3 
 
without ROSE is shown to be non-inferior to the current standard of care of EUS-FNA 
with ROSE in pancreatic lesions, this study has the potential to make EUS-guided tissue 
acquisition more economical (with elimination for the need for cytopathology staff onsite) 
as well as provide core histological specimen without sacrificing the overall diagnostic 
yield.    
 
2.2 
RATIONALE 
 
 
   The rationale for this study is as follows: 
The objective of this single center paired cohort study is to evaluate the diagnostic 
accuracy of EUS-FNA with ROSE compared to EUS-FNA with ROSE.  If EUS-FNB 
without ROSE is shown to be non-inferior to the current standard of care of EUS-FNA 
with ROSE in pancreatic lesions, this study has the potential to make EUS-guided tissue 
acquisition more economical (with elimination for the need for cytopathology staff onsite) 
as well as provide core histological specimen without sacrificing the overall diagnostic 
yield.    
 
2.3 
PARTICIPANT SELECTION 
 
Eligibility Criteria 
Inclusion Criteria for Participants 
  Patient ≥ 18 years of age referred for EUS-guided biopsy for pancreatic mass lesions 
 
Exclusion Criteria 
 Refusal to consent form 
 Uncorrectable coagulopathy (INR > 1.5) 
 Uncorrectable thrombocytopenia (platelet < 50,000) 
 Uncooperative patients 
Pregnant women (women of childbearing age will undergo urine pregnancy testing, 
which is routine for all endoscopic procedures) 
 Medically unstable for sedation 
 Entirely cystic lesions 
 Lesions inaccessible to EUS 
 
Inclusion of Women, Minorities and Other Underrepresented Populations 
     This protocol is open to males and females of all races. 
 
3. 
MULTICENTER GUIDELINES 
 
Protocol Chair 
 
The Protocol Chair is responsible for performing the following tasks: 
• 
Coordinating, developing, submitting, and obtaining approval for the protocol as well 
as its subsequent amendments 
• 
Assuring that all participating institutions are using the correct version of the protocol. 
• 
Taking responsibility for the overall conduct of the study at all participating 
institutions and for monitoring the progress of the study. 
• 
Reviewing and ensuring reporting of Serious Adverse Events (SAE) 
• 
Reviewing data from all sites 
 
Coordinating Center 
 
The Coordinating Center is responsible for performing the following tasks: 

 
 
 
 
4 
 
• 
Ensuring that IRB approval has been obtained at each participating site prior to the 
first patient registration at that site, and maintaining copies of IRB approvals from 
each site. 
• 
Managing central patient registration. 
• 
Collecting and compiling data from each site. 
• 
Establishing procedures for documentation, reporting, and submitting of AE’s and 
SAE’s to the Protocol Chair, and all applicable parties. 
• 
Facilitating audits by securing selected source documents and research records from 
participating sites for audit, or by auditing at participating sites. 
 
Participating Sites 
 
Participating sites are responsible for performing the following tasks: 
• 
Following the protocol as written, and the guidelines of Good Clinical Practice (GCP). 
• 
Submitting data to the Coordinating Center. 
• 
Providing sufficient experienced clinical and administrative staff and adequate 
facilities and equipment to conduct a collaborative trial according to the protocol. 
• 
Maintaining regulatory binders on site and providing copies of all required documents 
to the Coordinating Center. 
• 
Collecting and submitting data according to the schedule specified by the protocol. 
 
4. 
QUALITY ASSURANCE 
Authorized representatives of the Coordinating Center may visit participating sites to perform 
audits or inspections, including source data verification.  The purpose of these audits or 
inspections is to systematically and independently examine all trial related activities and 
documents to determine whether these activities were conducted and data were recorded, 
analyzed, and accurately reported according to the protocol, Good Clinical Practice (GCP), and 
any applicable regulatory requirements. 
 
5. 
DATA SUBMISSION 
Data and/or completed case report forms must be transmitted by fax or e-mail to the 
Coordinating Center following the completion of each cycle as detailed in Section 16.1.1. Case 
report forms will be provided to participating sites by the Coordinating Center. 
 
6. 
ADVERSE EVENT REPORTING 
 
Definition of Adverse Event (AE) 
An adverse event is the development of an undesirable medical condition or the 
deterioration of a pre-existing medical condition following or during exposure to a 
procedure done, whether or not considered causally related to the procedure.  An 
undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., 
tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory 
findings, electrocardiogram).   
Definition of Serious Adverse Event (SAE) 
A serious adverse event is an AE occurring during the procedure or any time after the 
procedure, that fulfills one or more of the following criteria: 
• 
Results in death 
• 
Is immediately life-threatening 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital abnormality or birth defect 
• 
Is an important medical event that may jeopardize the patient or may require 
medical intervention to prevent one of the outcomes listed above 

 
 
 
 
5 
 
Protocol Chair 
The Protocol Chair is ultimately responsible for the required reporting of all adverse 
events. 
 
Coordinating Center 
The Coordinating Center is the central location for the collection and maintenance of 
documentation of adverse events and is responsible for submitting adverse event 
reports to the Protocol Chair promptly.  The Coordinating Center will maintain 
documentation of all adverse event reports for each participating site.  Adverse event 
reports submitted to the Coordinating Center must be signed and dated by the 
participating site’s Principal Investigator.  The Coordinating Center will provide 
appropriate forms to be used by all participating sites for reporting adverse events.  
Information to be provided must include: 
• 
Subject ID number, and initials 
• 
Date of the event 
• 
Description of the event 
• 
Description of site's response to the event 
• 
Assessment of the subject's condition 
• 
Subject's status on the study (on study, off study, etc.) 
• 
Attribution of event to study drug 
Participating Sites 
Participating sites are responsible for reporting adverse events to their IRB according to 
its specific requirements and to the Coordinating Center as follows: 
Fatal Events whether anticipated or unanticipated, and whether or not related to the 
study must be reported to the Coordinating Center within 24 hours of the 
participating site Principal Investigator's learning of the event. 
 
Serious and Unanticipated Adverse Events must be reported  
to the Coordinating Center within 24 hours of the participating site Principal 
Investigator's learning of the event.  
 
Other Serious Adverse Events which may result in a change to the protocol, 
informed consent, or risk to subjects as specified in the protocol must be reported 
within three (3) working days of the participating site Principal Investigator's learning 
of the event.  
 
Adverse Events which result in no change to protocol, informed consent, or risk to 
subjects must be reported to the Coordinating Center on a monthly basis.  
 
All SAEs must be collected whether or not they are considered causally related to the 
investigational procedure.  Investigators and other site personnel are responsible for 
reporting all casually related SAEs to their IRB and the Protocol Chair. 
 
 
7. 
PROCEDURE  PLAN  
 
All EUS/FNB and EUS/FNA will be performed using a linear array echoendoscope by 
one of seven experienced EUS physicians at JHH.  All patients will undergo both 
EUS/FNB and EUS/FNA.  Patients will be randomized to either FNB or FNA first by 

 
 
 
 
6 
 
means of computer-generated numbers. The endoscopist will not be blinded to the 
randomization; however, the study pathologist will be blinded to randomization. 
 
EUS/FNB will be performed using similar techniques for tissue acquisition as FNA 
using 22-g FNB needle (Medtronic SharkCore or Boston Scientific Acquire).  Lesions 
will be identified using EUS and punctured with the 22-g FNB needle (10-15 back 
and forth movements per needle pass, fanning as appropriate).  After the lesion is 
punctured, the stylet will be removed and 10cc suction will be applied.  FNB samples 
will be placed directly into formalin containers and sent to be processed by surgical 
pathology. 
 
EUS/FNA with ROSE will be performed using standard techniques via 22-g FNA 
needle (Cook Medical EchoTip Ultra or Boston Scientific Expect or Medtronic 
Beacon).  Lesions will be identified using EUS and punctured with the FNA needle 
(10-15 back and forth movements per needle pass, fanning as appropriate).  After 
the lesion is punctured, the stylet will be removed and 10cc suction will be applied.  
FNA specimens will be processed for ROSE using standard techniques with bedside 
smear slide evaluation and liquid-based cytology and cell-block preparation.   
 
The first randomization assigned EUS sampling technique will be used until 
adequate specimen is achieved (up to 3 passes total).  After 3 passes, the patient 
will undergo the other EUS sampling technique until adequate specimen is achieved 
(up to 3 passes total).  If inadequate biopsies are obtained after a total of 6 passes (3 
with initial tissue acquisition techniques, 3 with the other technique), the 
endosonographer will be permitted to utilize any EUS sampling technique preferred 
to obtain a diagnosis during the same procedure or at a later date.   
 
8. 
PATIENT FOLLOW-UP 
 
All patients will recover from their procedures according to standard practice. They 
will remain NPO the night after the procedure.  After finishing the procedure, all 
patients will be carefully monitored per standard protocol in the recovery room and 
be discharged when fully awake and pain-free. Patients will be contacted by 
telephone at 24-48 hours to ascertain and document any early adverse events that 
may have arisen.  Long-term clinical follow up will be based on clinical indications. 
 
To determine the safety of procedure, all pre, intra- and immediate post-procedure 
adverse events will be recorded and rated according to ASGE lexicon (7) for adverse 
events. Inpatients will be evaluated by study coordinator/PI on a daily basis during their 
hospitalization. Potential complications will be explained for patients at their discharge 
time and will be advised to refer whenever they have problems.  
 
a. Study duration and number of study visits required of research participants. 
Study duration: 2 years 
Number of subjects: 132 
Follow-up visits: 0 
 
b. Blinding, including justification for blinding or not blinding the trial, if applicable. 
Due to the nature of study, treatment team will be aware of patient’s group and it is 
not possible to make it double blinded. However, the study pathologist will be blinded 
to randomization. 

 
 
 
 
7 
 
 
c. Justification of why participants will not receive routine care or will have current 
therapy stopped. 
Routine care will be followed 
 
d. Justification for inclusion of a placebo or non-treatment group. 
N/A 
 
e. Definition of treatment failure or participant removal criteria. 
The first randomization assigned EUS sampling technique will be used until 
adequate specimen is achieved (up to 3 passes total).  After 3 passes, the patient 
will undergo the other EUS sampling technique until adequate specimen is achieved 
(up to 3 passes total).  If inadequate biopsies are obtained after a total of 6 passes (3 
with initial tissue acquisition techniques, 3 with the other technique), the 
endosongrapher will be permitted to utilize any EUS sampling technique preferred to 
obtain a diagnosis during the same procedure or at a later date.   
 
f. Description of what happens to participants receiving therapy when study ends or if a 
participant’s participation in the study ends prematurely. 
No change in medical care will be expected. 
 
8.1 
ANTICIPATED RISKS 
a. Medical risks, listing all procedures, their major and minor risks and expected 
frequency. 
We do not anticipate major risk or discomfort beyond that associated with the 
conventional procedure.  
1) Perforation: Only physicians specially trained in EUS will be performing these 
procedures. The exact risk is minimal (<1%). 
2) Infection: It is not standard practice to give antibiotics to all patients 
prophylactically for either percutaneous liver biopsy or EUS-FNA of non-cystic 
lesions. Therefore, no subjects will receive antibiotics prophylactically for EUS 
sampling except those patients at risk for infective endocarditis according to 
American Heart Association guidelines. 
3) Bleeding: The exact risk is minimal (1 in 5,000 chance). Doppler examination will 
be performed under EUS guidance prior to biopsy to ensure that the needle does not 
traverse a blood vessel. As a precautionary measure, furthermore, all patients will 
have PTT, PT/INR, hemoglobin, and platelet count checked prior to the procedure. 
Those below acceptable standards will not be offered inclusion into the study. 
Frequent vital signs will be measured and recorded. If vital signs are abnormal and 
prolonged, a repeat CBC and possibly CT scan will be performed after procedure to 
ensure the absence of internal or external hemorrhage. These measures should 
ensure any clinically significant hemorrhage is detected and treated in a timely 
manner.   
4) Pancreatitis: Will be detected by the presence of pain with or without nausea and 
vomiting after pancreatic biopsy. If present, the patient will be hospitalized, kept 
NPO, and receive IV hydration. 
 
b. Steps taken to minimize the risks. 
Adherence to the standard of practice of the Johns Hopkins Hospital Division of 
Gastroenterology will be kept (as described in part a).  
 

 
 
 
 
8 
 
c. Legal risks such as the risks that would be associated with breach of confidentiality. 
There are no legal risks associated with participation in this study.  All measures to 
protect confidentiality will be taken.    
 
d. Financial risks to the participants. 
None. 
 
 
9. 
ADVERSE EVENT REPORTING REQUIREMENTS 
9.1 
Definitions 
9.1.1 Adverse Event (AE) 
An adverse event (AE) is any undesirable sign, symptom or medical condition or 
experience that develops or worsens in severity after the procedure, even if the 
event is not considered to be related to the study.  
 
Abnormal laboratory values or diagnostic test results constitute adverse events 
only if they induce clinical signs or symptoms or require treatment or further 
diagnostic tests.  
9.1.2 Serious adverse event (SAE) 
A serious adverse event (SAE) is any adverse event  and regardless of causality 
that:  
• 
Results in death 
• 
Is life-threatening. Life-threatening means that the person was at 
immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction which hypothetically might have caused death had it 
occurred in a more severe form. 
• 
Prolongs inpatient hospitalization (prolonged a hospitalization beyond the 
expected length of stay). Hospitalization admissions and/or surgical 
operations scheduled to occur during the study period, but planned prior 
to study entry are not considered SAEs if the illness or disease existed 
before the person was enrolled in the trial, provided that it did not 
deteriorate in an unexpected manner during the trial (e.g., surgery 
performed earlier than planned 
• 
Results in persistent or significant disability/incapacity. Disability is 
defined as a substantial disruption of a person’s ability to conduct normal 
life functions. 
• 
Is a congenital anomaly or birth defect; or 
• 
Is an important medical event when, based upon appropriate medical 
judgment, it may jeopardize the participant and require medical or 
surgical intervention to prevent one of the outcomes listed above.  
 
Events not considered to be serious adverse events are hospitalizations for: 
• 
routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition, or for elective procedures 
• 
elective or pre-planned treatment for a pre-existing condition that did not 
worsen 
• 
emergency outpatient treatment for an event not fulfilling the serious 
criteria outlined above and not resulting in inpatient admission 
9.2 
Procedures for AE and SAE Recording and Reporting 
 

 
 
 
 
9 
 
Participating investigators will assess the occurrence of AEs and SAEs at all 
participant evaluation time points during the study.  
 
All AEs and SAEs whether reported by the participant, discovered during questioning, 
directly observed, or detected by physical examination, laboratory test or other means, 
will be recorded in the participant’s medical record and on the appropriate study-
specific case report forms.  
The description and the grading for the adverse events will be done according to 
ASGE severity scale. 
9.3 
Reporting Requirements 
Each investigative site will be responsible to report SAEs that occur at that institution 
to their respective IRB. It is the responsibility of each participating investigator to report 
serious adverse events to the study sponsor and/or others as described below.  
9.4 
Reporting to the Study Team 
9.4.1 Serious Adverse Event Reporting 
 
All serious adverse events that occur after the procedure, during the procedure, 
or within 30 days of the procedure must be reported to the Principle Investigator 
on the local institutional SAE form. This includes events meeting the criteria 
outlined in Section 11.1.2, as well as the following: 
 
• 
Grade 2 (moderate) and Grade 3 (severe) Events – Only events that are 
unexpected and possibly, probably or definitely related/associated with 
the intervention. 
• 
All Grade 4 (life-threatening or disabling) Events – Unless expected AND 
specifically listed in the protocol as not requiring reporting. 
• 
All Grade 5 (fatal) Events – When the participant is enrolled and actively 
participating in the trial OR when the event occurs within 30 days of the 
last study intervention.  
• 
Progressive disease will be reported within 7 days 
 
Note: If the participant is in long term follow up, report the death at the time of 
continuing review.  
 
Participating investigators must report each serious adverse event to the overall 
Principal Investigator within one business day of learning of the occurrence. In 
the event that the participating investigator does not become aware of the 
serious adverse event immediately (e.g., participant sought treatment 
elsewhere), the participating investigator is to report the event within one 
business day of learning of it and document the time of his or her first awareness 
of the adverse event.  
 
Report serious adverse events by telephone, email or facsimile to: 
 
 
 
Mouen Khashab, MD 
 
 
Telephone Number:  443-287-1960 
 
 
Email: mkhasha1@jhmi.edu  
 
 
Fax: 443-683-8335 
 
 
Emergency Contact #:  443-509-3388  (mobile)  
 

 
 
 
 
10 
 
Within the subsequent 1-2 business day from initial report, the participating 
investigator must provide follow-up information on the serious adverse event. 
Follow-up information should describe whether the event has resolved or 
continues, if and how the event was treated, and whether the participant will 
continue or discontinue study participation. 
9.4.2 Non-Serious Adverse Event Reporting  
 
Non-serious adverse events will be not be reported Reporting to the Institutional 
Review Board (IRB) 
Investigative sites should report serious adverse events to their respective IRB 
according to the local IRB’s policies and procedures in reporting adverse events. A 
copy of the submitted institutional SAE form should be forwarded to: 
 
 
 
 
 
Mouen Khashab, MD 
 
 
Telephone Number:  443-287-1960 
 
 
Email: mkhasha1@jhmi.edu  
 
 
Fax: 443-683-8335 
 
 
Emergency Contact #:  443-509-3388  (mobile)  
 
9.5 
Reporting to the Food and Drug Administration (FDA) 
N/A 
 
 
9.6 
Reporting to the NIH Office of Biotechnology Activities (OBA) 
N/A 
 
 
9.7 
Reporting to the Institutional Biosafety Committee (IBC) 
N/A 
 
9.8 
Reporting to Hospital Risk Management 
Participating investigators will report to their local Risk Management office any subject 
safety reports or sentinel events that require reporting according to institutional policy. 
9.9 
Monitoring of Adverse Events and Period of Observation 
All adverse events, both serious and non-serious, and deaths that are encountered 
from initiation of study intervention, throughout the study, and within 30 days of the last 
study intervention should be followed to their resolution, or until the participating 
investigator assesses them as stable, or the participating investigator determines the 
event to be irreversible, or the participant is lost to follow-up. The presence and 
resolution of AEs and SAEs (with dates) should be documented on the appropriate 
case report form and recorded in the participant’s medical record to facilitate source 
data verification.  
 
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, 
and/or monitoring visit to obtain additional case details deemed necessary to 
appropriately evaluate the SAE report (e.g., hospital discharge summary, consultant 
report, or autopsy report).  
 
Participants should be instructed to report any serious post-study event(s) that might 
reasonably be related to participation in this study. Participating investigators should 
notify the Overall  Investigator or respective IRB of any unanticipated death or adverse 
event occurring after a participant has discontinued or terminated study participation 
that may reasonably be related to the study.   

 
 
 
 
11 
 
 
10. DATA AND SAFETY MONITORING 
10.1 Data Reporting 
Case report forms will be provided for all study mandated data points and should 
be submitted based on the deadlines detailed in Section 10.1.2 
10.1.1 Data Submission  
Case report forms should be submitted to the JHBox account 
 
10.2 Auditing/Monitoring  
A data safety and monitoring board (DSMB) will be appointed (TBD). The DSMB will 
be responsible for reviewing all major complications (perforation, hospitalization for > 
48 hours, bleeding requiring transfusion, deaths etc). If any serious adverse event is 
noted during the study then the DSMB will be required to meet.  
 
11. REGULATORY CONSIDERATIONS 
11.1 Protocol Review and Amendments 
This protocol, the proposed informed consents, all forms of participant information 
related to the study and any other necessary documents must be submitted, reviewed 
and approved by a properly constituted IRB governing each study location. This will 
occur following approval by the Coordinating Center IRB. 
Any changes made to the protocol must be submitted as amendments and must be 
approved by the IRB prior to implementation. Any changes in study conduct must be 
reported to the IRB. The overall Principal Investigator will disseminate protocol 
amendment information to all participating investigators.  
All decisions of the IRB concerning the conduct of the study must be made in writing. 
11.2 Informed Consent 
All participants must be provided a consent form describing each portion of this study 
and providing sufficient information for participants to make an informed decision about 
their participation in this study. The formal consent of a participant, using the IRB 
approved consent form, must be obtained before the participant is involved in any 
study-related procedure. The consent form must be signed and dated by the 
participant or the participant’s legally authorized representative, and by the person 
obtaining the consent. The participant must be given a copy of the signed and dated 
consent document. The original signed copy of the consent document must be 
retained in the medical record or research file.  
11.3 Ethics and Good Clinical Practice (GCP) 
This study is to be conducted according to the following considerations, which 
represent good and sound research practice: 
• 
E6 Good Clinical Practice: Consolidated Guidance 
www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129515.pdf  
• 
US Code of Federal Regulations (CFR) governing clinical study conduct and 
ethical principles that have their origin in the Declaration of Helsinki 
o Title 21 Part 11 – Electronic Records; Electronic Signatures 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr11_02.html 
o Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html  
o Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html  
o Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html  

 
 
 
 
12 
 
o Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html  
• 
State laws  
It is understood that deviations from the protocol should be avoided, except when 
necessary to eliminate an immediate hazard to a research participant. In such case, 
the deviation must be reported to the IRB according to the local reporting policy.  
11.4 Study Documentation 
The investigator must prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each 
research participant. This information enables the study to be fully documented and 
the study data to be subsequently verified. 
 
Original source documents supporting entries in the case report forms include but are 
not limited to hospital records, clinical charts, laboratory and pharmacy records, 
recorded data from automated instruments, microfiches, photographic negatives, 
microfilm or magnetic media, and/or x-rays.  
11.5 Records Retention 
All study-related documents must be retained for the maximum period required by 
applicable federal regulations and guidelines or institutional policies.  
 
11.6 Multi-center Guidelines 
• 
Overall Principal Investigator/Coordinating Center is responsible for distributing 
all Safety Reports to all participating institutions for submission to their 
individual IRBs for action as required. 
• 
Mechanisms will be in place to ensure quality assurance, protocol compliance, 
and adverse event reporting at each site.  
 
12. STATISTICAL CONSIDERATIONS  
Overview: This study is designed as a non-inferiority trial.  
Considering a success rate of 85% in the FNA with ROSE group, based published 
studies, we selected a non-inferiority margin (∂) of 10%, in accordance with the 
USFDA recommendations (8). Based on the following formula (9):   
 
 
 
n = f(α, β) × [πs × (100 − πs) + πe × (100 − πe)] / (πs − πe − d)2  
 
where πs and πe are the true percent 'success' in the standard and experimental 
treatment group respectively, and 
f(α, β) = [Φ-1(α) + Φ-1(β)]2 
Φ-1 is the cumulative distribution function of a standardized normal deviate 
 
We calculated that our trial will require enrolling 120 patients for power of 80% and 
two sided α of 0.05. 
 
 Taking into consideration a 10% dropout rate, the total patients to be enrolled=132 
 
Baseline demographics, pre-, intra- and post-intervention data will be prospectively 
collected on data collection forms which will be maintained in an electronic database 
system.  Results will be reported as mean ± standard deviation (SD) for quantitative 
variables and percentages for categorical variables. The groups will be compared 
using the Student’s t- test or Wilcoxon rank sum test for continuous variables and the 
chi-square test (or Fisher’s exact test if required) for categorical variables. To compare 

 
 
 
 
13 
 
diagnostic accuracy between two EUS sampling techniques, we will use McNemar’s 
test. Statistical significance will be based on two-sided design-based tests evaluated 
at α = 0.05. All statistical analyses will be performed using STATA. 
 
a. Endpoints: 
 Primary:  
 
Diagnostic accuracy will be defined as (true positive + true negative)/all samples.   
The final diagnosis will be based on one of the following criteria: (i) surgical pathology 
specimen from patients who underwent surgical resection; (ii) cytological or 
histopathological diagnosis of malignancy in patients with unresectable disease with 
appropriate imaging and clinical course of disease; (iii) cytological and 
histopathological diagnosis of benign disease with an appropriate clinical course of 
disease for minimum of 6 months. 
 
Secondary:  
 
1. Specimen adequacy 
This will be defined as the proportion of samples in which a final histopathological 
diagnosis could be made.   
 
2. Percentage of histology cores obtained 
This will be defined as the proportion of samples in which a visible histology core 
biopsy was obtained 
 
3. Number of passes 
Number of passes required for diagnosis 
 
4. Rate of technical failures 
Technical failure was defined as the inability to perform the procedure, including 
the need to change the needle 
 
5. Adverse events 
All pre, intra- and immediate post-procedure adverse events will be recorded and 
rated according to ASGE lexicon for adverse events.  
 
 
13. SAFETY MONITORINGN AND STOPPING RULE 
The DSMB will perform a blinded analysis after enrolment and initial outpatient follow-
up of 50% of the study cohort. 
 
Interim analysis will be performed at 50% recruitment. If a > 20% difference in 
sensitivity is found between both methods then the study will be terminated early 
 
14. PUBLICATION PLAN 
 
The study team will aim to publish the study results within 24 months of the end of data 
collection in a peer reviewed journal. 
 
 

  
NA_00091840 (J1403) CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
14 
 
15. References 
 
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prospective comparison study. Endoscopy 2013;45: 792 – 798 
 
2.Vanbiervliet G, Napoleon B, Saint Paul MC et al. Core needle versus standard needle for 
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3.Strand DS, Jeffus SK, Sauer BG et al. EUS-guided 22-gauge fine-needle aspiration versus 
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