Clinical trial NCT01974284
Conditions: Papillary Thyroid Cancer
Sponsor: Yale University
Start date: 2014-03-01; Completion date: 2017-06-29
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
We assess the effectiveness of percutaneous ethanol ablation for the treatment of thyroid cancer.

Detailed description:
We hypothesize that percutaneous ethanol ablation (PEA) for primary papillary thyroid microcarcinoma (PTMC) has equivalent oncologic outcomes to current treatment options including observation, thyroid lobectomy and total thyroidectomy. In addition, we hypothesize that it will yield superior long-term quality of life, including measures of pain, voice, and cosmesis than standard surgical therapy (total thyroidectomy). If our hypotheses are correct, the findings of this study have the potential to fundamentally change clinical management of this group of patients.

This study was changed from its initial design: a 2 arm study comparing PEA to surgery (Amended April 30, 2015). The change in design was made based on several discussions within Yale Endocrine Surgery, with patients diagnosed with PTMC, and knowledge of other institutions performing PEA for PTMC as standard of care.

The study team had been contacted by numerous potential subjects interested in PEA who were unwilling to be randomized to surgery. Because patients interested in PEA appeared to be firmly against the idea of thyroidectomy, we believed that we would be unable to enroll sufficient patients to this study as the protocol originally stood.

Arms: arm 1: The experimental group of the study is comprised of patients that will undergo percutaneous ethanol ablation for the management of papillary thyroid microcarcinoma.
Interventions: intervention 1: percutaneous ethanol ablation
Intervention descriptions: intervention 1: The volume of 99% ethanol to be injected is calculated using a standardized formula. Ethanol is instilled with a needle under ultrasound guidance after administration of local anesthesia.

Protocol documents:
Prot_SAP_000.pdf: 
Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 1 of 47 
 
 
YALE UNIVERSITY 
 
                                  HUMAN INVESTIGATION COMMITTEE 
 
                                     Application to Involve Human Subjects in Biomedical Research 
100 FR1 (2013-1)  
 
 
 
 
SECTION I: ADMINISTRATIVE INFORMATION 
 
Title of Research Project: Percutaneous ethanol ablation for treatment of primary papillary thyroid 
microcarcinoma 
Principal Investigator: Glenda Callender, MD 
 
Yale Academic Appointment: Assistant Professor, 
Department of Surgery, Endocrine Surgery 
 
Department: Surgery, Section of Endocrine Surgery 
Campus Address:  
330 Cedar Street FMB 130C 
New Haven, CT, 06510 
Campus Phone:  
203-737-2036 
Fax:  
203-785-2498 
Pager:  
E-mail:  
glenda.callender@yale.edu 
Protocol Correspondent Name & Address (if different than PI): 
Glenda Callender, MD 
330 Cedar Street FMB 120  
New Haven, CT 06510 
 
Campus Phone:  
203-737-2170 
Fax:  
E-mail:  
glenda.callender@yale.edu 
Yale Cancer Center CTO Protocol Correspondent Name & Address (if applicable): 
n/a 
Campus Phone:  
Fax:  
E-mail:  
Business Manager: 
Campus Phone : 
Fax : 
E-mail 
DATE STAMPED-RECEIVED 
PROTOCOL NUMBER 
Please refer to the HIC website for application 
instructions and information required to complete 
this application.  The Instructions are available at 
http://www.yale.edu/hrpp/forms-
templates/biomedical.html  
Submit the original application and one (1) copy 
of all materials including relevant sections of the 
grant which funds this project (if applicable) to 
the HIC.   
HIC OFFICE USE ONLY 
APPROVED BY THE YALE UNIVERSITY HIC ON 13 APRIL 2016 VALID THROUGH 25 MARCH 2017


Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 2 of 47 
 
 
Investigator Interests: 
Does the principal investigator, or do any research personnel who are responsible for the design, 
conduct or reporting of this project or any of their family members (spouse or dependent child) 
have an incentive or interest, financial or otherwise, that may affect the protection of the human 
subjects involved in this project, the scientific objectivity of the research or its integrity? Note: 
The Principal Investigator (Project Director), upon consideration of the individual’s role and 
degree of independence in carrying out the work, will determine who is responsible for the 
design, conduct, or reporting of the research.  
See Disclosures and Management of Personal Interests in Human Research 
http://www.yale.edu/hrpp/policies/index.html#COI  
ο  Yes  
 No  
 
Do you or does anyone on the research team who is determined by you to be responsible for the 
design, conduct or reporting of this research have any patent (sole right to make, use or sell an 
invention) or copyright (exclusive rights to an original work) interests related to this research 
protocol? 
ο  Yes  
 No  
 
 
 
If yes to either question above, list names of the investigator or responsible person: 
 
 
 
The Yale University Principal Investigator, all Yale University co-investigators, and all Yale 
University individuals who are responsible for the design, conduct or reporting of research must 
have a current financial disclosure form on file with the University’s Conflict of Interest Office. 
Yale New Haven Hospital personnel who are listed as con-investigators on a protocol with a 
Yale University Principal Investigator must also have a current financial disclosure form on file 
with the University’s Conflict of Interest Office. If this has not been done, the individual(s) 
should follow this link to the COI Office Website to complete the 
form:  http://www.yale.edu/coi/   
 
NOTE: The requirement for maintaining a current disclosure form on file with the University’s 
Conflict of Interest Office extends primarily to Yale University and Yale-New Haven Hospital 
personnel.  Whether or not they are required to maintain a disclosure form with the 
University’s Conflict of Interest Office, all investigators and individuals deemed otherwise 
responsible by the PI who are listed on the protocol are required to disclose to the PI any 
interests that are specific to this protocol. 
 
 
 
 
 
 
Faculty Advisor:(required if PI is a student, 
resident, fellow or other trainee)         
  NA 
 
Yale Academic Appointment: 
 
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Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 3 of 47 
 
 
 
 
SECTION II: GENERAL INFORMATION 
 
1. Performing Organizations:  Identify the hospital, in-patient or outpatient facility, school or 
other agency that will serve as the location of the research.  Choose all that apply: 
  
a. Internal Location[s] of the Study: 
 Magnetic Resonance Research Center  
 
 Yale University PET Center 
     (MR-TAC)    
 
 
 
 
 YCCI/Church Street Research Unit (CSRU) 
 Yale Cancer Center/Clinical Trials Office (CTO)    
 YCCI/Hospital Research Unit (HRU) 
Yale Cancer Center/Smilow 
 
 
 YCCI/Keck Laboratories 
 Yale-New Haven Hospital  
 
 
 Yale-New Haven Hospital—Saint Raphael Campus 
 Cancer Data Repository/Tumor Registry 
 Specify Other Yale Location: 
Department of Radiology, Section of Interventional Radiology 
 
 
 
 
b. External Location[s]: 
 APT Foundation, Inc. 
 
 
 
 Haskins Laboratories 
 Connecticut Mental Health Center 
 
 John B. Pierce Laboratory, Inc. 
 Clinical Neuroscience Research Unit (CNRU) 
Veterans Affairs Hospital, West Haven 
 
 Other Locations, Specify:  
 
 
 International Research Site  
(Specify location(s)): 
 
 
c. Additional Required Documents (check all that apply): 
 N/A 
*YCCI-Scientific and Safety Committee (YCCI-SSC)  
Approval Date:  
*Pediatric Protocol Review Committee (PPRC) 
 
Approval Date:  
*YCC Protocol Review Committee (YRC-PRC) 
 
Approval Date: 
 
*Dept. of Veterans Affairs, West Haven VA HSS 
 
Approval Date:  
*Radioactive Drug Research Committee (RDRC) 
 
Approval Date:  
 YNHH-Radiation Safety Committee (YNHH-RSC) 
 
Approval Date:  
 Magnetic Resonance Research Center PRC (MRRC-PRC) 
Approval Date:  
 YSM/YNHH Cancer Data Repository (CaDR)  
 
Approval Date:  
 Dept. of Lab Medicine request for services or specimens form 
 Imaging on YNHH Diagnostic Radiology equipment request form (YDRCTO request) found 
at  http://radiology.yale.edu/research/ClinTrials.aspx) 
*Approval from these committees is required before final HIC approval is granted. See instructions 
for documents required for initial submission and approval of the protocol. Allow sufficient time for 
these requests. Check with the oversight body for their time requirements. 
 
2. Probable Duration of Project: State the expected duration of the project, including all 
follow-up and data analysis activities.  
 
We plan to recruit patients over 3 years and follow patients for 5 years after their procedures. 
After initial treatment, patients will be followed every 6 months for the first two years, and 
then annually for the next 3 years. Interim data analysis will be performed every 6 months. 
 
APPROVED BY THE YALE UNIVERSITY HIC ON 13 APRIL 2016 VALID THROUGH 25 MARCH 2017


Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 4 of 47 
 
 
 
 
3. Research Type/Phase: (Check all that apply) 
a. Study Type 
   
  Single Center Study 
   
 Multi-Center Study 
Does the Yale PI serve as the PI of the multi-site study? Yes 
 
No 
 
  
 Coordinating Center/Data Management 
  
 Other:  
 
 
b. Study Phase 
 N/A 
    
  Pilot 
 Phase I 
 Phase II 
 Phase III 
 Phase IV 
    
 Other (Specify)  
 
 
4. Area of Research: (Check all that apply) Note that these are overlapping definitions and 
more than one category may apply to your research protocol. Definitions for the following 
can be found in the instructions section 4c: 
  Clinical Research: Patient-Oriented 
   
 
  Clinical Research: Outcomes and  
 Clinical Research: Epidemiologic and Behavioral  
                 Health Services 
 Translational Research #1 (“Bench-to-Bedside”)      
  Interdisciplinary Research 
 Translational Research #2 (“Bedside-to-Community”)  
 Community-Based Research 
 
 
5.   Is this study a clinical trial? Yes 
 
No 
 
NOTE the current ICMJE (International Committee of Medical Journal Editors) definition of a 
clinical trial: “any research study that prospectively assigns human participants or groups of humans 
to one or more health-related interventions to evaluate the effects on health outcomes.” Health-related 
interventions include any intervention used to modify a biomedical or health-related outcome (for 
example, drugs, surgical procedures, devices, behavioral treatments, dietary interventions, and 
process-of-care changes). Health outcomes include any biomedical or health-related measures 
obtained in patients or participants, including pharmacokinetic measures and adverse events” 
  
If yes, where is it registered? 
  
 
Clinical Trials.gov registry 
 
  
 
Other (Specify)  
 
Registration of clinical trials at their initiation is required by the FDA, NIH and by the ICMJE. 
 
If this study is registered on clinicaltrials.gov, there is new language in the consent form and compound 
authorization that should be used. 
For more information on registering clinical trials, including whether your trial must be 
registered, see the YCCI webpage, http://ycci.yale.edu/researchers/ors/registerstudy.aspx or 
contact YCCI at 203.785.3482) 
6. Does the Clinical Trials Agreement (CTA) require compliance with ICH GCP (E6)?  
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Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 5 of 47 
 
Yes 
 No
 
 
 
 
7. Will this study have a billable service? A Billable Service is defined as a service or procedure 
that will be ordered, performed or result in charging in EPIC for individuals who are enrolled in 
a clinical research study, regardless if the charge is intended to be paid by the subject/their 
insurance or the research study. 
 
Yes 
  No
 
If you answered "yes", this study will need to be set up in OnCore Support 
http://medicine.yale.edu/ymg/systems/ppm/index.aspx  
 
8. Are there any procedures involved in this protocol that will be performed at YNHH or one of 
its affiliated entities?  Yes 
   No ___  If Yes, please answer questions a through c and note 
instructions below.  If No, proceed to Section III. 
 
a. Does your YNHH privilege delineation currently include the specific procedure that you 
will perform?  Yes.  Dr. Arici, from Interventional Radiology, will perform the interventional 
radiology procedures.  Percutaneous ethanol ablation of a variety of targets is within the 
scope of interventional radiology practice.  Drs. Udelsman, Carling, Callender and Quinn 
will perform the surgical procedures.  Total thyroidectomy with central neck dissection is a 
routine procedure in an endocrine surgery practice. 
 
b. Will you be using any new equipment or equipment that you have not used in the past for   
     this procedure?  No. 
  
c. Will a novel approach using existing equipment be applied? 
     No. Percutaneous ethanol ablation is a well-established method for management of recurrent  
      thyroid cancer nodal metastasis in patients that are not amenable to surgery.  It is also a   
      recognized treatment modality in patients with certain benign thyroid nodules.  
  
If you answered “no” to question 8a, or "yes" to question 8b or c, please contact the YNHH 
Department of Physician Services (688-2615) for prior approval before commencing with your 
research protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 6 of 47 
 
 
 
SECTION III: FUNDING, RESEARCH TEAM AND TRAINING 
 
1. Funding Source: Indicate all of the funding source(s) for this study. Check all boxes that apply. 
Provide information regarding the external funding source.  This information should include 
identification of the agency/sponsor, the funding mechanism (grant or contract), and whether 
the award is pending or has been awarded. Provide the M/C# and Agency name (if grant-
funded).  If the funding source associated with a protocol is “pending” at the time of the 
protocol submission to the HIC (as is the case for most NIH submissions), the PI should note 
“Pending” in the appropriate section of the protocol application, provide the M/C# and 
Agency name (if grant-funded) and further note that University (departmental) funds support 
the research (until such time that an award is made).   
 
PI  
Title of Grant 
Name of Funding Source  
Funding 
Funding Mechanism 
Glenda 
Callender, MD 
 
Investigator 
 
Department of Surgery 
  Federal 
  State 
  Non Profit 
  Industry 
  Other For 
Profit  
 Other 
 
Internal 
Department 
Funding 
 
 
Grant-M#            
Contract#  
Contract Pending 
  Investigator/Department 
Initiated 
  Sponsor Initiated 
  Other, Specify: 
 
Robert 
Udelsman, MD, 
MBA 
 
 
Investigator 
 
Department of Surgery 
Chair of Surgery 
  Federal 
  State 
  Non Profit 
  Industry 
  Other For 
Profit  
 Other 
 
Internal 
Department 
Funding 
 
 
Grant-M#            
Contract#  
Contract Pending 
  Investigator/Department 
Initiated 
  Sponsor Initiated 
  Other, Specify: 
 
APPROVED BY THE YALE UNIVERSITY HIC ON 13 APRIL 2016 VALID THROUGH 25 MARCH 2017


Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 7 of 47 
 
Tobias Carling, 
MD, PhD 
 
Investigator 
 
Department of Surgery 
 
  Federal 
  State 
  Non Profit 
  Industry 
  Other For 
Profit  
 Other 
 
Internal 
Department 
Funding 
 
 
Grant-M#            
Contract#  
Contract Pending 
  Investigator/Department 
Initiated 
  Sponsor Initiated 
  Other, Specify: 
 
Courtney 
Quinn, MD, MS 
 
 
Investigator 
 
Department of Surgery 
  Federal 
  State 
  Non 
Profit 
  Industry 
  Other 
For Profit  
 Other 
Internal 
Department 
Funding 
 
Grant-M#            
Contract#  
Contract Pending 
Investigator/Department 
Initiated 
  Sponsor Initiated 
  Other, Specify:  
 
Melih Arici, 
MD 
 
 
Investigator 
 
Department of Radiology 
  Federal 
  State 
  Non 
Profit 
  Industry 
  Other 
For Profit  
 Other 
Internal 
Department 
Funding 
 
Grant-M#            
Contract#  
Contract Pending 
Investigator/Department 
Initiated 
  Sponsor Initiated 
  Other, Specify:  
 
Jonathan 
Kirsch, MD 
 
 
Investigator 
 
 
Department of Radiology 
  Federal 
  State 
  Non 
Profit 
  Industry 
  Other 
For Profit  
 Other 
Internal 
Department 
Funding 
 
Grant-M#            
Contract#  
Contract Pending 
Investigator/Department 
Initiated 
  Sponsor Initiated 
  Other, Specify:  
 
APPROVED BY THE YALE UNIVERSITY HIC ON 13 APRIL 2016 VALID THROUGH 25 MARCH 2017


Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 8 of 47 
 
Elizabeth Holt, 
MD, PhD 
 
 
Investigator 
 
 
Department of Internal 
Medicine 
  Federal 
  State 
  Non 
Profit 
  Industry 
  Other 
For Profit  
 Other 
Internal 
Department 
Funding 
 
Grant-M#            
Contract#  
Contract Pending 
Investigator/Department 
Initiated 
  Sponsor Initiated 
  Other, Specify:  
 
Adebowale J. 
Adeniran, MD 
 
Investigator 
 
 
Department of Pathology 
  Federal 
  State 
  Non 
Profit 
  Industry 
  Other 
For Profit  
 Other 
Internal 
Department 
Funding 
 
Grant-M#            
Contract#  
Contract Pending 
Investigator/Department 
Initiated 
  Sponsor Initiated 
  Other, Specify:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRB Review fees are charged for projects funded by Industry or Other For-Profit Sponsors.  
Provide the Name and Address of the Sponsor Representative to whom the invoice should be 
sent.  Note: the PI’s home department will be billed if this information is not provided. 
Send IRB Review Fee Invoice To: 
 
 
Not applicable 
 
 
 
 
 
 
 
APPROVED BY THE YALE UNIVERSITY HIC ON 13 APRIL 2016 VALID THROUGH 25 MARCH 2017


Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 9 of 47 
 
2. Research Team:  List all members of the research team. Indicate under the affiliation column whether 
the investigators or study personnel are part of the Yale faculty or staff, or part of the faculty or staff 
from a collaborating institution, or are not formally affiliated with any institution. ALL members of 
the research team MUST complete Human Subject Protection Training (HSPT) and Health 
Insurance Portability and Accountability Act (HIPAA) Training before they may be listed on the 
protocol.  See NOTE below. 
 
NOTE: The HIC will remove from the protocol any personnel who have not completed required training.  
 
 
 
A personnel protocol amendment will need to be submitted when training is completed. 
 
 
 
 
APPROVED BY THE YALE UNIVERSITY HIC ON 13 APRIL 2016 VALID THROUGH 25 MARCH 2017


Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 10 of 
47 
 
SECTION IV: 
 PRINCIPAL INVESTIGATOR/FACULTY ADVISOR/ DEPARTMENT CHAIR 
AGREEMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
As the principal investigator of this research project, I certify that: 
 The information provided in this application is complete and accurate. 
 I assume full responsibility for the protection of human subjects and the proper conduct of the 
      research. 
 Subject safety will be of paramount concern, and every effort will be made to protect subjects’ 
      rights and welfare. 
 The research will be performed according to ethical principles and in compliance with all federal, 
      state and local laws, as well as institutional regulations and policies regarding the protection of   
      human subjects. 
 All members of the research team will be kept apprised of research goals. 
 I will obtain approval for this research study and any subsequent revisions prior to my initiating   the study or 
any change and I will obtain continuing approval of this study prior to the expiration date of any approval 
period. 
 I will report to the HIC any serious injuries and/or other unanticipated problems involving risk to 
      participants. 
 I am in compliance with the requirements set by the University and qualify to serve as the 
      principal investigator of this project or have acquired the appropriate approval from the  
      Dean’s Office or Office of the Provost, or the Human Subject Protection Administrator at 
      Yale-New Haven Hospital, or have a faculty advisor. 
 I will identify a qualified successor should I cease my role as principal investigator and facilitate a 
smooth transfer of investigator responsibilities. 
 
 
 
 
 
 
 
 
 
 
 
 
  
     Glenda Callender, MD 
        PI Name (PRINT) and Signature 
 
 
 
 
Date 
APPROVED BY THE YALE UNIVERSITY HIC ON 13 APRIL 2016 VALID THROUGH 25 MARCH 2017


Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 11 of 
47 
 
 
 
 
 
As the faculty advisor of this research project, I certify that: 
 The information provided in this application is complete and accurate. 
 This project has scientific value and merit and that the student or trainee investigator has the  
      necessary resources to complete the project and achieve the aims. 
 I will train the student investigator in matters of appropriate research compliance, protection of 
      human subjects and proper conduct of research. 
• The research will be performed according to ethical principles and in compliance with all federal, 
state and local laws, as well as institutional regulations and policies regarding the protection of  
human subjects. 
 The student investigator will obtain approval for this research study and any subsequent revisions 
      Prior to initiating the study or revision and will obtain continuing approval prior to the expiration 
      of any approval period. 
 The student investigator will report to the HIC any serious injuries and/or other unanticipated  
      problems involving risk to participants.  
 I am in compliance with the requirements set forth by the University and qualify to serve as 
      the faculty advisor of this project. 
 
 
 
 
___________  
______ 
 
 
 
_____ 
    Advisor Name (PRINT) and Signature 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
Signature of PI 
 
 
 
 
 
Date 
APPROVED BY THE YALE UNIVERSITY HIC ON 13 APRIL 2016 VALID THROUGH 25 MARCH 2017


Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 12 of 
47 
 
Department Chair’s Assurance Statement 
Do you know of any real or apparent institutional conflict of interest (e.g., Yale ownership of a 
sponsoring company, patents, licensure) associated with this research project? 
 Yes (provide a description of that interest in a separate letter addressed to the HIC.) 
  No 
 
As Chair, do you have any real or apparent protocol-specific conflict of interest between yourself and 
the sponsor of the research project, or its competitor or any interest in any intervention and/or method 
tested in the project that might compromise this research project? 
Yes (provide a description of that interest in a separate letter addressed to the HIC) 
 No 
 
I assure the HIC that the principal investigator and all members of the research team are qualified by 
education, training, licensure and/or experience to assume participation in the conduct of this research 
trial. I also assure that the principal investigator has departmental support and sufficient resources to 
conduct this trial appropriately. 
 
    
 
 
__________________________________         
 
 
 
 _________ 
 
 
Robert Udelsman, MD, MBA 
 
 
 
 
                                              
   
Chair Name (PRINT) and Signature   
     
  
 
 Date      
 
    
 
 
 
    
Department:  Department of Surgery 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPROVED BY THE YALE UNIVERSITY HIC ON 13 APRIL 2016 VALID THROUGH 25 MARCH 2017


Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 13 of 
47 
 
 
YNHH Human Subjects Protection Administrator Assurance Statement 
Required when the study is conducted solely at YNHH by YNHH health care providers. 
 
As Human Subject Protection Administrator (HSPA) for YNHH, I certify that: 
 I have read a copy of the protocol and approve it being conducted at YNHH. 
 I agree to notify the IRB if I am aware of any real or apparent institutional conflict of interest. 
 The principal investigator of this study is qualified to serve as P.I. and has the support of the hospital 
for this research project. 
 
  ______________________________________ 
 
 
 
 
 
 
 
 
    YNHH HSPA Name (PRINT) and Signature         
 
 
Date 
 
 
 
 
For HIC Use Only 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date Approved  
 
 
 
Human Investigation Committee Signature 
 
This protocol is valid through ______________________________________________ 
 
 
 
APPROVED BY THE YALE UNIVERSITY HIC ON 13 APRIL 2016 VALID THROUGH 25 MARCH 2017


Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 14 of 
47 
 
 
SECTION V: RESEARCH PLAN 
 
1. Statement of Purpose: State the scientific aim(s) of the study, or the hypotheses to be tested.  
 
 
Primary Objectives 
 
The primary objective of the study is to determine the effect of percutaneous ethanol ablation on: 
a) Quality of life, through the SF-36 form 
b) Thyroid-related symptoms, through the Thyroid Symptom Questionnaire (TSQ) 
c) Pain (BPI), voice (VHI) and cosmesis (POSAS) 
d) Reduction and/or elimination of size of primary thyroid microcarcinoma 
 
Secondary Objectives 
 
A secondary objective of the study is to confirm the safety, feasibility, and cost of treating 
primary papillary thyroid microcarcinoma with percutaneous ethanol ablation. 
 
Another secondary objective of the study is the assessment of oncologic outcomes, including 
disease-free survival and overall survival (exploratory endpoints). 
 
2. Background: Describe the background information that led to the plan for this project. 
Provide references to support the expectation of obtaining useful scientific data. 
 
Papillary thyroid cancer (PTC) is the most common endocrine malignancy.  It is 
estimated that approximately 60,220 people in the United States will be diagnosed with  
thyroid cancer in 2013 [1].  The incidence of PTC has risen more rapidly over the past  
decades than that of any other malignancy (annual incidence rate in 1990: 5.50 per 100,000; 
in 2010: 13.83 per 100,000) [2, 3]. One reason for the increasing incidence of PTC is the 
widespread availability and use of high-resolution neck ultrasonography; more PTCs are 
being diagnosed than previously because patients are undergoing diagnostic studies.   
However, an actual increase of incidence of PTC has also been documented [3]. The largest 
contributing factor to the rising incidence of PTC is the diagnosis of papillary thyroid 
microcarcinomas (PTMC) [4, 5]. The World Health Organization (WHO) defines PTMC as a 
papillary thyroid cancer measuring 10 mm or less in greatest dimension [6]. Because the 
prognosis of patients with PTC is generally very favorable, even when the tumor is diagnosed at 
a larger size, there is considerable debate regarding the optimal management of PTMCs that are 
often incidentally discovered. Clinicians must balance the overall very low morbidity of PTMCs 
with the potential morbidity of treatment. 
APPROVED BY THE YALE UNIVERSITY HIC ON 13 APRIL 2016 VALID THROUGH 25 MARCH 2017


Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 15 of 
47 
 
PTMCs are actually very common:  autopsy studies have demonstrated that up to 35.6% 
of people who have died from other causes are found to have occult thyroid cancer at  
autopsy [7-9].  The vast majority of these cancers remain silent throughout a patient’s  
lifetime. Since PTMCs are indolent tumors that may never progress to a clinically significant 
degree, clinicians have begun to question whether they can be treated with less than the  
currently accepted standard of care for localized PTC per American Thyroid Association 
guidelines:  total thyroidectomy (with or without central neck lymph node dissection) or  
thyroid lobectomy in select situations. 
The morbidity of thyroidectomy is largely related to the surgical procedure.  Total 
thyroidectomy is associated with a recurrent laryngeal nerve injury in 1.1-2.1% and  
permanent hypoparathyroidism with lifelong dependence on calcium in 1.5-2.9% of patients 
[10-13].  The cognitive and psychological consequences after thyroidectomy can also be a 
challenge in the post-operative period, despite adequate thyroid hormone replacement [14-19]. 
Although thyroid hormone replacement is effective in the majority of patients, a  
substantial proportion remain symptomatic and fail to regain a normal sense of well-being 
[17]. A case-control study in the United Kingdom showed that post-surgical patients on 
levothyroxine (T4) replacement displayed significant impairment in their psychological well-
being, even with a normal TSH [20]. Furthermore, 34.4% of the patients who underwent a  
total thyroidectomy and had a recent normal TSH stated that they were dissatisfied with their 
overall health status [20]. Additional studies have shown that combination replacement with 
levothyroxine (T4) and liothyronine (T3) therapy did not improve mood and cognitive 
performance compared to standard T4 monotherapy [21-23]. 
Some centers currently recommend thyroid lobectomy alone, instead of total 
thyroidectomy, for patients with small, well-differentiated PTCs.  In a retrospective analysis  
of 889 patients, Nixon and colleagues from Memorial Sloan-Kettering Cancer Center  
compared the outcomes of patients undergoing thyroid lobectomy versus total thyroidectomy  
for small, well-differentiated PTCs and found no significant differences between both  
groups.  The extent of surgery had no effect on overall survival or locoregional recurrence  
rates.  Notably, those patients who underwent thyroid lobectomy were not followed with serum 
thyroglobulin levels or annual ultrasonography, which is routinely done for patients who have 
undergone total thyroidectomy; therefore, it is possible that some locoregional recurrences were 
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Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 16 of 
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not detected in the thyroid lobectomy group.  The authors concluded that patients with small, 
well-differentiated PTCs could be safely managed with thyroid lobectomy alone [24]. 
A center in Japan has gone one step further by managing select patients with PTMC 
using observation alone. Ito and colleagues hypothesized that most PTMCs do not require 
immediate surgery, and therefore, they began an observational trial in 1993 [25].  Patients  
who were diagnosed with PTC measuring less than 1 cm were offered two options:   
observation without surgery or standard surgical treatment. The observation group was  
followed to determine whether the tumor size had changed or whether lymph node metastasis 
had developed.   Patients with progressive disease subsequently underwent standard surgical 
therapy. The authors compared the outcomes of 340 patients who underwent observation and 
1055 patients who underwent immediate surgery. In the observation group, 109 patients 
eventually underwent surgical treatment, but 231 patients (68%) continue to be observed  
after more than 20 years of follow-up. The authors concluded that observation is safe in  
select patients with PTMCs in the absence of unfavorable tumor features, and in the event of 
disease progression, patients can undergo surgery without a clinically significant difference  
in outcome.  
Although thyroid lobectomy and observation are less invasive than total  
thyroidectomy, thyroid lobectomy is still associated with risks, and many patients and  
healthcare providers are uncomfortable with simple observation when cancer is involved.  
Therefore, neither thyroid lobectomy nor observation seems to strike the ideal balance in the 
treatment of PTMC.  Percutaneous ablative therapy may accomplish this goal. 
Percutaneous ethanol ablation has not previously been used as a treatment for primary 
PTC, but has been shown to be an effective treatment for recurrent PTC in patients who are  
not candidates for surgery for various reasons (medical comorbidity, unacceptably high risk  
of complications due to extensive prior surgery or radiation) [26-29].  Percutaneous ethanol 
ablation has successfully treated known metastatic lymphadenopathy from PTC as measured  
by decreased tumor volume and blood flow to the nodal metastases [27]. 
Heilo and colleagues from the Mayo Clinic evaluated the efficacy of percutaneous 
ethanol ablation in the treatment of patients with PTC metastatic to a limited number of  
cervical lymph nodes.  Their retrospective review included 63 patients with PTC and 109 
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Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 17 of 
47 
 
 cervical lymph nodes with metastasis. Mean observation time was 38.4 months (range 3 to 72 
months). A total of 101 of the 109 (93%) metastatic lymph nodes responded to percutaneous 
ethanol ablation, 92 with a complete response and 9 with a partial response. Two lymph  
nodes did not respond, and four lymph nodes demonstrated progressive disease. Two lymph 
nodes previously considered successfully treated showed evidence of recurrent malignancy 
during follow-up [28].   
Percutaneous ethanol ablation has also been performed for benign thyroid disease,  
such as focal and diffuse autonomy of the thyroid, benign nodules, and cystic lesions.  This 
procedure has not gained widespread acceptance, although there is accumulating evidence of  
the efficacy and safety of this therapeutic tool. [30-32]. Livraghi and colleagues first  
proposed percutaneous ethanol ablation in 1990 as an alternative novel therapeutic tool for  
the treatment of autonomously functioning thyroid nodules (AFTN) [31]. Other centers 
subsequently published small series and case reports describing successful percutaneous  
ethanol ablation of amiodarone-induced thyrotoxicosis, AFTN in pregnancy, and large  
AFTNs (nodule volume > 40 mL) [33] [34] [35-37]. Importantly, when surgery is  
subsequently necessary in patients who have undergone percutaneous ethanol ablation of  
benign thyroid nodules, surgical resection remains feasible and does not appear to carry 
increased risk due to scarring [38].  
Percutaneous ethanol ablation of benign thyroid disease is generally well tolerated. A 
very common adverse effect is transient pain at the injection site. Additional transient  
adverse effects include dysphonia in 3.9%, worsening of thyrotoxicosis in 1.1%, self-limited 
fever in 5% and hematoma in 1.8% [37, 39]. There exists a single case report from Germany 
describing severe ethyl toxic necrosis of the larynx and overlying skin in a patient who 
previously underwent ethanol instillation as a treatment for an AFTN.  The patient almost 
immediately developed aphonia and severe odynophagia, and was admitted to the hospital  
for eleven days.  Topical ointment, intravenous and inhaled steroids, and intravenous  
antibiotics were administered.  The patient did not require invasive therapy in the acute  
setting, and the voice returned to near normal within 2 weeks.  Follow-up ultrasound several 
months after the procedure demonstrated that the target nodule was essentially unchanged, 
suggesting that the majority of the instilled ethanol was actually injected into the subcutaneous 
tissue and larynx instead of into the thyroid.  Six months after the initial procedure, follow-up 
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Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 18 of 
47 
 
laryngoscopy demonstrated that a right false vocal fold cyst had developed; this was successfully 
resected endoscopically ten months after the initial procedure [30]. 
In summary, the rising incidence of PTMC in asymptomatic patients is real, and there  
is no indication that this trend is beginning to plateau.  Standard surgical therapy, even if  
limited to thyroid lobectomy, may be considered over-treatment of patients with PTMCs.  
Although observation alone may be sufficient for some patients, it may be preferable to treat  
the cancer in lieu of observation.  A minimally-invasive technique such as percutaneous  
ethanol ablation may strike a balance between the low overall risk of PTMC and the minimal 
morbidity of this treatment.  Percutaneous ethanol ablation has not been reported to have  
been used for primary thyroid cancers, but has been used to successfully treat benign thyroid 
disease as well as PTC recurrences and metastatic lymph nodes.  Percutaneous ethanol  
ablation may prove to be a safe alternative to either surgical intervention or observation for 
patients with PTMC. 
 
References: 
 
1. 
Howlader, N.N., AM, SEER cancer Statistics Review. 2013. 
2. 
Pacini, F., Management of papillary thyroid microcarcinoma: primum non nocere! J Clin 
Endocrinol Metab, 2013. 98(4): p. 1391-3. 
3. 
Ito, Y. and A. Miyauchi, A therapeutic strategy for incidentally detected papillary 
microcarcinoma of the thyroid. Nat Clin Pract Endocrinol Metab, 2007. 3(3): p. 240-8. 
4. 
Enewold, L., et al., Rising thyroid cancer incidence in the United States by demographic 
and tumor characteristics, 1980-2005. Cancer Epidemiol Biomarkers Prev, 2009. 18(3): 
p. 784-91. 
5. 
Chen, A.Y., A. Jemal, and E.M. Ward, Increasing incidence of differentiated thyroid 
cancer in the United States, 1988-2005. Cancer, 2009. 115(16): p. 3801-7. 
6. 
Lloyd R, D.L.R., Heitz P et al World Health Organization Classification of Tumours: 
pathology and genetics of tumours of the endocrine organs. International Agency for 
Research on Cancer (IARC) Press, Lyon. 2004. 
7. 
Fukunaga, F.H. and R. Yatani, Geographic pathology of occult thyroid carcinomas. 
Cancer, 1975. 36(3): p. 1095-9. 
8. 
Harach, H.R., K.O. Franssila, and V.M. Wasenius, Occult papillary carcinoma of the 
thyroid. A "normal" finding in Finland. A systematic autopsy study. Cancer, 1985. 56(3): 
p. 531-8. 
9. 
Thorvaldsson, S.E., et al., Latent thyroid carcinoma in Iceland at autopsy. Pathol Res 
Pract, 1992. 188(6): p. 747-50. 
10. 
Christou, N. and M. Mathonnet, Complications after total thyroidectomy. J Visc Surg, 
2013. 
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Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 19 of 
47 
 
11. 
Thomusch, O., et al., Multivariate analysis of risk factors for postoperative complications 
in benign goiter surgery: prospective multicenter study in Germany. World J Surg, 2000. 
24(11): p. 1335-41. 
12. 
Duclos, A., et al., Influence of experience on performance of individual surgeons in 
thyroid surgery: prospective cross sectional multicentre study. BMJ, 2012. 344: p. d8041. 
13. 
Bellantone, R., et al., Total thyroidectomy for management of benign thyroid disease: 
review of 526 cases. World J Surg, 2002. 26(12): p. 1468-71. 
14. 
Regalbuto, C., et al., Effects of either LT4 monotherapy or LT4/LT3 combined therapy in 
patients totally thyroidectomized for thyroid cancer. Thyroid, 2007. 17(4): p. 323-31. 
15. 
Bunevicius, R., et al., Effects of thyroxine as compared with thyroxine plus 
triiodothyronine in patients with hypothyroidism. N Engl J Med, 1999. 340(6): p. 424-9. 
16. 
Bunevicius, R. and A.J. Prange, Mental improvement after replacement therapy with 
thyroxine plus triiodothyronine: relationship to cause of hypothyroidism. Int J 
Neuropsychopharmacol, 2000. 3(2): p. 167-174. 
17. 
Kaplan, M.M., D.H. Sarne, and A.B. Schneider, In search of the impossible dream? 
Thyroid hormone replacement therapy that treats all symptoms in all hypothyroid 
patients. J Clin Endocrinol Metab, 2003. 88(10): p. 4540-2. 
18. 
Toft, A.D., Thyroid hormone replacement--one hormone or two? N Engl J Med, 1999. 
340(6): p. 469-70. 
19. 
Siegmund, W., et al., Replacement therapy with levothyroxine plus triiodothyronine 
(bioavailable molar ratio 14 : 1) is not superior to thyroxine alone to improve well-being 
and cognitive performance in hypothyroidism. Clin Endocrinol (Oxf), 2004. 60(6): p. 
750-7. 
20. 
Saravanan, P., et al., Psychological well-being in patients on 'adequate' doses of l-
thyroxine: results of a large, controlled community-based questionnaire study. Clin 
Endocrinol (Oxf), 2002. 57(5): p. 577-85. 
21. 
Wekking, E.M., et al., Cognitive functioning and well-being in euthyroid patients on 
thyroxine replacement therapy for primary hypothyroidism. Eur J Endocrinol, 2005. 
153(6): p. 747-53. 
22. 
Walsh, J.P., et al., Combined thyroxine/liothyronine treatment does not improve well-
being, quality of life, or cognitive function compared to thyroxine alone: a randomized 
controlled trial in patients with primary hypothyroidism. J Clin Endocrinol Metab, 2003. 
88(10): p. 4543-50. 
23. 
Sawka, A.M., et al., Does a combination regimen of thyroxine (T4) and 3,5,3'-
triiodothyronine improve depressive symptoms better than T4 alone in patients with 
hypothyroidism? Results of a double-blind, randomized, controlled trial. J Clin 
Endocrinol Metab, 2003. 88(10): p. 4551-5. 
24. 
Nixon, I.J., et al., Thyroid lobectomy for treatment of well differentiated intrathyroid 
malignancy. Surgery, 2012. 151(4): p. 571-9. 
25. 
Ito, Y., et al., An observational trial for papillary thyroid microcarcinoma in Japanese 
patients. World J Surg, 2010. 34(1): p. 28-35. 
26. 
Shin, J.E., J.H. Baek, and J.H. Lee, Radiofrequency and ethanol ablation for the treatment 
of recurrent thyroid cancers: current status and challenges. Curr Opin Oncol, 2013. 25(1): 
p. 14-9. 
27. 
Hay, I.D. and J.W. Charboneau, The coming of age of ultrasound-guided percutaneous 
ethanol ablation of selected neck nodal metastases in well-differentiated thyroid 
carcinoma. J Clin Endocrinol Metab, 2011. 96(9): p. 2717-20. 
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Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 20 of 
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28. 
Heilo, A., et al., Efficacy of ultrasound-guided percutaneous ethanol injection treatment 
in patients with a limited number of metastatic cervical lymph nodes from papillary 
thyroid carcinoma. J Clin Endocrinol Metab, 2011. 96(9): p. 2750-5. 
29. 
Lewis, B.D., et al., Percutaneous ethanol injection for treatment of cervical lymph node 
metastases in patients with papillary thyroid carcinoma. AJR Am J Roentgenol, 2002. 
178(3): p. 699-704. 
30. 
Mauz, P.S., et al., Complications of ultrasound guided percutaneous ethanol injection 
therapy of the thyroid and parathyroid glands. Ultraschall Med, 2005. 26(2): p. 142-5. 
31. 
Livraghi, T., et al., Treatment of autonomous thyroid nodules with percutaneous ethanol 
injection: preliminary results. Work in progress. Radiology, 1990. 175(3): p. 827-9. 
32. 
Bennedbaek, F.N., S. Karstrup, and L. Hegedus, Percutaneous ethanol injection therapy 
in the treatment of thyroid and parathyroid diseases. Eur J Endocrinol, 1997. 136(3): p. 
240-50. 
33. 
Monzani, F., et al., Percutaneous ethanol injection therapy of autonomous nodule and 
amiodarone-induced thyrotoxicosis. Thyroidology, 1994. 6(3): p. 99-102. 
34. 
Cortelazzi, D., et al., Resolution of hyperthyroidism in a pregnant woman with toxic 
thyroid nodule by percutaneous ethanol injection. Thyroid, 1995. 5(6): p. 473-5. 
35. 
Mazzeo, S., et al., Percutaneous injection of ethanol to treat autonomous thyroid nodules. 
AJR Am J Roentgenol, 1993. 161(4): p. 871-6. 
36. 
Lippi, F., et al., Treatment of solitary autonomous thyroid nodules by percutaneous 
ethanol injection: results of an Italian multicenter study. The Multicenter Study Group. J 
Clin Endocrinol Metab, 1996. 81(9): p. 3261-4. 
37. 
Ferrari, C., E. Reschini, and A. Paracchi, Treatment of the autonomous thyroid nodule: a 
review. Eur J Endocrinol, 1996. 135(4): p. 383-90. 
38. 
Crescenzi, A., et al., Morphological changes in a hyperfunctioning thyroid adenoma after 
percutaneous ethanol injection: histological, enzymatic and sub-microscopical alterations. 
J Endocrinol Invest, 1996. 19(6): p. 371-6. 
39. 
Schumm-Draeger, P.M., Ultrasound-guided percutaneous ethanol injection in the 
treatment of autonomous thyroid nodules--a review. Exp Clin Endocrinol Diabetes, 1998. 
106 Suppl 4: p. S59-62. 
 
 
 
3. Research Plan: Summarize the study design and research procedures using non-technical 
language that can be readily understood by someone outside the discipline. Be sure to 
distinguish between standard of care vs. research procedures when applicable, and include 
any flowcharts of visits specifying their individual times and lengths. Describe the setting in 
which the research will take place. 
 
The purpose of this study is to evaluate a new treatment option for the management of primary 
papillary thyroid microcarcinoma (PTMC). Patients referred to Yale Endocrine Surgery for 
management of cytology-proven PTMC (PTC measuring 1 cm or less in diameter) will be 
offered inclusion into the study.  (See page 24 for specific exclusion criteria.)  After enrollment, 
patients will be assigned to percutaneous ethanol ablation (PEA) of the primary PTMC.  
Importantly, PEA will not be offered to patients outside of inclusion in the study. 
 
After informed consent is obtained, baseline evaluation includes the following tests: 
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Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 21 of 
47 
 
a) Baseline ultrasound assessment to confirm size and location of PTMC 
b) Baseline laryngoscopy before initiation of treatment 
c) Baseline quality of life assessment (“SF-36”; Appendix 1) 
d) Baseline pain assessment (“Brief Pain Inventory”, BPI; Appendix 2) 
e) Baseline voice assessment (“Voice Handicap Index”, VHI; Appendix 3) 
f) Baseline symptom assessment (“Thyroid Symptom Questionnaire”, TSQ; Appendix 4) 
 
The SF-36 is a set of easily-administered quality-of-life measures and is a validated tool to 
evaluate patient quality of life [40-42].  The VHI is an established tool used to assess voice after 
an intervention [43-45]. The BPI is a simple, well-accepted instrument for the objective 
assessment of pain [46-48]. The TSQ is a 12-item based questionnaire assessing specific thyroid 
related symptoms. 
 
Therapy 
a. Percutaneous ethanol ablation 
Patients in the PEA group will constitute the sole treatment group of the study.  These patients 
will be scheduled for an outpatient procedure with Dr. Melih Arici from Interventional 
Radiology.  The volume of 99% ethanol to be injected is calculated using a standardized formula 
(Ethanol Volume= length × width × height × π / 6) and instilled with a 3-4 cm long 22-25-gauge 
needle under ultrasound-guidance after administration of local anesthesia. If the patient cannot 
tolerate the procedure despite adequate local anesthesia, they will be offered conscious sedation. 
Conscious sedation is a combination of medicines to help you relax (a sedative) and to block 
pain (an anesthetic) during a medical. You will probably stay awake but may not be able to 
speak.  
 
It is usually safe, however, overmedication could result in respiratory depression. The patient 
will be monitored carefully during the entire procedure and the appropriate equipment will be 
employed if needed. 
 
The procedure itself usually takes only about 60-90 minutes and the patient will be observed for 
2-3 hours in the hospital before discharge home. 
 
All patients will receive a phone call to their home 48 hours after the PEA procedure and will be 
assessed for pain level and voice quality (BPI and VHI).  
 
Every patient will be scheduled for a post-procedure visit in the endocrine surgery clinic 
approximately 7 – 14 days after their procedure.  The post-procedure clinic visit will include the 
following assessments: 
a) Evaluation of the wound after the intervention 
b) Follow-up ultrasound assessment 
c) Follow-up laryngoscopy after treatment 
d) Follow-up quality of life assessment (SF-36) 
e) Follow-up pain assessment (BPI) 
f) Follow-up voice assessment (VHI) 
g) Follow-up symptom assessment (TSQ) 
h) Cosmesis assessment (“Patient and Observer Scar Assessment Scale”, POSAS; Appendix 
5) 
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Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 22 of 
47 
 
 
During this clinic visit, a thorough evaluation will be performed of the patient’s injection site. An 
endocrine surgeon will evaluate the injection site during this visit using POSAS, a validated tool 
for the evaluation of surgical scars [49-52]. 
 
Formal cancer restaging for patients will take place every 6 months for the first two years and 
then annually for the following 3 years.  These clinic visits will include a thorough clinical 
examination, surveillance ultrasonography of the neck (thyroid bed, central and bilateral lateral 
neck lymph nodes), laboratory tests (TSH, free T4, Tg, TgAb), quality of life assessment, pain 
assessment, voice assessment, symptom assessment, and cosmesis assessment. 
 
Disease progression based on radiographic images utilizing the RECIST (Response Evaluation 
Criteria in Solid Tumors) criteria will result in recommendation to patient for total 
thyroidectomy. Disease progression is defined by ≥ 20% increase of diameter of any residual 
visible tumor, a ≥ 5mm absolute increase in size of any residual visible tumor, appearance of 
new metastasis to central or lateral neck lymph nodes by ultrasound and FNA biopsy, or 
appearance of new distant metastases [53]. 
 
Duration of Project and Follow Up 
 
Patients will be recruited over 3 years and followed for 5 years after the procedure.  After initial 
treatment, patients will be followed every 6 months for the first two years, and then annually for 
the next 3 years. The data will be analyzed on an annual basis. 
 
 
 
 
References: 
 
1. 
Miccoli, P., et al., The impact of thyroidectomy on psychiatric symptoms and quality of 
life. J Endocrinol Invest, 2007. 30(10): p. 853-9. 
2. 
Adler, J.T., et al., Preserving function and quality of life after thyroid and parathyroid 
surgery. Lancet Oncol, 2008. 9(11): p. 1069-75. 
3. 
Weber, T., et al., Effect of parathyroidectomy on quality of life and neuropsychological 
symptoms in primary hyperparathyroidism. World J Surg, 2007. 31(6): p. 1202-9. 
4. 
Cohen, S.M., et al., Creation and validation of the Singing Voice Handicap Index. Ann 
Otol Rhinol Laryngol, 2007. 116(6): p. 402-6. 
5. 
Jacobson, B.H., The Voice Handicap Index (VHI): Development and Validation. 
American Journal of Speech-Language Pathology, 1997. 6: p. 66-70. 
6. 
Jung, S.P., et al., A New Subfascial Approach in Open Thyroidectomy: Efficacy for 
Postoperative Voice, Sensory, and Swallowing Symptoms. A Randomized Controlled 
Study. Ann Surg Oncol, 2013. 
7. 
Keller, S., et al., Validity of the brief pain inventory for use in documenting the outcomes 
of patients with noncancer pain. Clin J Pain, 2004. 20(5): p. 309-18. 
8. 
Cleeland, C.S. and K.M. Ryan, Pain assessment: global use of the Brief Pain Inventory. 
Ann Acad Med Singapore, 1994. 23(2): p. 129-38. 
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Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 23 of 
47 
 
9. 
Tan, G., et al., Validation of the Brief Pain Inventory for chronic nonmalignant pain. J 
Pain, 2004. 5(2): p. 133-7. 
10. 
Fearmonti, R., et al., A review of scar scales and scar measuring devices. Eplasty, 2010. 
10: p. e43. 
11. 
Draaijers, L.J., et al., The patient and observer scar assessment scale: a reliable and 
feasible tool for scar evaluation. Plast Reconstr Surg, 2004. 113(7): p. 1960-5; discussion 
1966-7. 
12. 
van de Kar, A.L., et al., Reliable and feasible evaluation of linear scars by the Patient and 
Observer Scar Assessment Scale. Plast Reconstr Surg, 2005. 116(2): p. 514-22. 
13. 
Casserly, P., R. Kirby, and C. Timon, Outcome measures and scar aesthetics in minimally 
invasive video-assisted parathyroidectomy. Arch Otolaryngol Head Neck Surg, 2010. 
136(3): p. 260-4. 
14. 
Carling T, Carty SE, Ciarleglio MM, et al.  American Thyroid Association design and feasibility 
of a prospective randomized controlled trial of prophylactic central lymph node dissection for 
papillary thyroid carcinoma. Thyroid 2012;22:237-44. 
 
 
 
4. Genetic Testing    N/A 
 
A. Describe 
i. the types of future research to be conducted using the materials, specifying if 
immortalization of cell lines, whole exome or genome sequencing, genome wide 
association studies, or animal studies are planned 
ii. the plan for the collection of material or the conditions under which material will 
be received 
iii. the types of information about the donor/individual contributors that will be 
entered into a database 
iv. the methods to uphold confidentiality 
 
B. What are the conditions or procedures for sharing of materials and/or distributing for 
future research projects? 
C. Is widespread sharing of materials planned? 
D. When and under what conditions will materials be stripped of all identifiers? 
E. Can donor-subjects withdraw their materials at any time, and/or withdraw the identifiers 
that connect them to their materials? 
i. How will requests to withdraw materials be handled (e.g., material no longer 
identified: that is, anonymized) or material destroyed)? 
 
F. Describe the provisions for protection of participant privacy 
G. Describe the methods for the security of storage and sharing of materials  
 
5. Subject Population: Provide a detailed description of the types of human subjects who will 
be recruited into this study. 
 
The Yale Endocrine Surgery program is the largest provider of surgical care for patients with 
endocrine disorders in the State of Connecticut. Yale Endocrine Surgery serves as both a 
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Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 24 of 
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primary treatment site and a tertiary referral center for patients from surrounding counties and 
neighboring states. Statistics describing the demographic distribution of the population seeking 
care by endocrine surgeons are incomplete at this time, but as we begin enrollment into our 
studies, we anticipate that will be able to compile and update descriptive statistics on the 
demographics of our population.  In this capacity, we will be able to compare the demographic 
distribution of patients enrolled to the county-level statistics. 
 
6. Subject classification: Check off all classifications of subjects that will be specifically 
recruited for enrollment in the research project. Will subjects who may require additional 
safeguards or other considerations be enrolled in the study? If so, identify the population of 
subjects requiring special safeguards and provide a justification for their involvement. 
 
None.  All patients referred to Yale Endocrine Surgery who meet inclusion criteria and do 
not meet exclusion criteria will be offered enrollment into the study.  It is possible that the 
study will eventually include patients who also incidentally belong to one of the following 
classifications, but no attempt will be made to specifically enroll patients from a particular 
vulnerable population. 
 
 Children 
 
 
 Healthy  
 
 Fetal material, placenta, or dead fetus 
 Non-English Speaking 
 Prisoners  
 Economically disadvantaged persons 
 Decisionally Impaired 
 Employees  
 Pregnant women and/or fetuses 
 Yale Students  
 
 Females of childbearing potential 
 
NOTE: Is this research proposal designed to enroll children who are wards of the state as 
potential subjects? 
 Yes  
  No (If yes, see Instructions section VII #4 for further 
requirements) 
 
 
7. Inclusion/Exclusion Criteria: What are the criteria used to determine subject inclusion or    
exclusion? 
Inclusion Criteria: 
1. Age 18 years and older 
2. Diagnosis:  single, cytology-proven papillary thyroid carcinoma measuring 1 cm 
or less in diameter (microcarcinoma, T1a), without visible extrathyroidal 
extension, and with negative central and lateral neck lymph nodes by ultrasound 
 
Exclusion criteria: 
1. Patient refusal to participate 
2. History of prior thyroid or parathyroid surgery 
3. History of prior recurrent laryngeal nerve injury 
4. Inability to make decisions or comply with follow up 
5. Co-existing indication for thyroidectomy 
6. Aggressive cytologic or molecular features 
7. Multifocal papillary thyroid carcinoma 
8. Pregnant or breast-feeding 
9. Anatomically unfavorable location of the tumor (proximity to recurrent laryngeal 
nerve or trachea)  
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Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 25 of 
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10. Documented or suspected distant metastasis 
11. History of prior radiation to neck or face 
12. Family history of  pathological thyroid cancer 
 
Points of Clarification 
1. Presence of BRAF V600E mutation is not automatic exclusion 
2. Co-existing benign thyroid condition is not automatic exclusion 
3.  Family history of incidentally identified, asymptomatic, papillary 
microcarcinoma is not automatic exclusion 
 
 
8. How will eligibility be determined, and by whom?  
 
All patients referred to Yale Endocrine Surgery who meet eligibility criteria and do not meet 
exclusion criteria will be offered enrollment in the study.  The attending endocrine surgeon 
(Drs. Udelsman, Carling, Callender or Quinn) will determine eligibility at the time of the 
initial clinic visit. 
 
 
9. Risks: Describe the reasonably foreseeable risks, including risks to subject privacy, 
discomforts, or inconveniences associated with subjects participating in the research.  
 
 
According to the literature, percutaneous ethanol ablation of a thyroid lesion is generally well 
tolerated.  A common adverse effect is transient pain at the injection site. Additional transient 
adverse effects include dysphonia in 3.9%, worsening of thyrotoxicosis in 1.1%, self-limited 
fever in 5% and hematoma in 1.8% [37, 39]. There exists a single case report from Germany 
describing severe ethyl toxic necrosis of the larynx and overlying skin in a patient who 
previously underwent ethanol instillation as a treatment for an autonomously functioning 
thyroid nodule (AFTN).  The patient almost immediately developed aphonia and severe 
odynophagia, and was admitted to the hospital for eleven days.  Topical ointment, 
intravenous and inhaled steroids, and intravenous antibiotics were administered.  The patient 
did not require invasive therapy in the acute setting, and the voice returned to near normal 
within 2 weeks.  Follow-up ultrasound several months after the procedure demonstrated that 
the target nodule was essentially unchanged, suggesting that the majority of the instilled 
ethanol was actually injected into the subcutaneous tissue and larynx instead of into the 
thyroid.  Six months after the initial procedure, follow-up laryngoscopy demonstrated that a 
right false vocal fold cyst had developed; this was successfully resected endoscopically ten 
months after the initial procedure [30].  Finally, there is a risk of 
recurrence or progression of the PTMC. If follow-up ultrasound examinations demonstrate 
recurrence or progression, patients will be offered thyroidectomy as standard-of-care 
treatment. 
 
There exist non-physical risks with this type of study.  One of these is the potential loss of 
privacy.  In order to ensure confidentiality within the study, patients are assigned unique 
identifiers.  All electronic data files for this study will either be stored as password-protected 
files on the secure Yale ITS server or in the Yale Clinical Trials Management System 
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Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 26 of 
47 
 
(OnCore). OnCore is accessed through Yale-networked computers and access is granted only 
to appropriate study personnel. Any files that contain protected health information will be 
maintained separately from the rest of other data files and only on the secure server or in 
OnCore. Ability to access the files is restricted to study investigators.  
 
References: 
 
1. Christou, N. and M. Mathonnet, Complications after total thyroidectomy. J Visc Surg, 
2013. 
2. Thomusch, O., et al., Multivariate analysis of risk factors for postoperative complications 
in benign goiter surgery: prospective multicenter study in Germany. World J Surg, 2000. 
24(11): p. 1335-41. 
3. Duclos, A., et al., Influence of experience on performance of individual surgeons in 
thyroid surgery: prospective cross sectional multicentre study. BMJ, 2012. 344: p. d8041. 
4. Bellantone, R., et al., Total thyroidectomy for management of benign thyroid disease: 
review of 526 cases. World J Surg, 2002. 26(12): p. 1468-71. 
5. Ferrari, C., E. Reschini, and A. Paracchi, Treatment of the autonomous thyroid nodule: a 
review. Eur J Endocrinol, 1996. 135(4): p. 383-90. 
6. Schumm-Draeger, P.M., Ultrasound-guided percutaneous ethanol injection in the 
treatment of autonomous thyroid nodules--a review. Exp Clin Endocrinol Diabetes, 1998. 
106 Suppl 4: p. S59-62. 
7. Mauz, P.S., et al., Complications of ultrasound guided percutaneous ethanol injection 
therapy of the thyroid and parathyroid glands. Ultraschall Med, 2005. 26(2): p. 142-5. 
 
10. 
Minimizing Risks: Describe the manner in which the above-mentioned risks will be 
minimized. 
 
 
 
In order to minimize risk in the treatment group, i.e. the percutaneous ethanol ablation group, 
all procedures will be performed by a single interventional radiologist, Dr. Melih Arici, who 
has prior experience with ethanol ablation and extensive experience with percutaneous 
procedures. 
 
In order to minimize risk of surgery in patients with disease progression after percutaneous 
ethanol ablation, a high-volume surgeon from Yale Endocrine Surgery will perform all 
surgical procedures. Thyroidectomy performed by a high-volume surgeon is associated with 
better outcomes. 
 
In order to maintain confidentiality, data will be coded and only authorized personnel will have 
access to this information. 
 
 
11. Data and Safety Monitoring Plan: Include an appropriate Data and Safety Monitoring Plan 
(DSMP) based on the investigator’s risk assessment stated below. (Note: the HIC will make 
the final determination of the risk to subjects.) For more information, see the Instructions, 
page 24. 
APPROVED BY THE YALE UNIVERSITY HIC ON 13 APRIL 2016 VALID THROUGH 25 MARCH 2017


Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 27 of 
47 
 
 
a. What is the investigator’s assessment of the overall risk level for subjects 
participating in this study?  
Greater than minimal risk 
 
b. If children are involved, what is the investigator’s assessment of the overall risk level 
for the children participating in this study?  
N/A.  No children will be participating in this study. 
 
The principal investigator or the Human Investigation Committee (HIC) have the 
authority to stop or suspend the study or require modifications. This protocol presents greater 
than minimal risks to the subjects.  The offered treatment modalities are considered routine in 
the course of standard clinical care.  Although highly unexpected, serious unanticipated and 
related adverse events or unanticipated problems involving risks to subjects or others will be 
reported in writing within 5 days to the HIC (using the appropriate forms on the website) and 
the Department of Surgery. The principal investigator will apprise fellow investigators and 
study personnel of all adverse events that occur during the conduct of the research project 
during regular study meetings and e-mails when urgent, as these events are reviewed by the 
principal investigator.  
 
The principal investigator will assess study data on a continuing basis.  All individuals will 
be recruited without bias for ethnicity, race, gender or age.  Any identifying information will 
remain confidential. All electronic data files for this study will either be stored as password-
protected files on an encrypted, password-protected computer, in the Yale Clinical Trials 
Management System (OnCore), or on the secure Yale ITS server. OnCore is accessed through 
Yale-networked computers and access is granted only to appropriate study personnel. Any files 
that contain protected health information will be maintained separately from the rest of other 
data files and only on the secure server or in OnCore. The research team will only give this 
coded information to others to carry out this research study. We do not anticipate any adverse 
events with regard to safety.  Should anything unexpected occur, we will comply with current 
HIC reporting requirements.  We will complete annual reports to the HIC about study progress.   
 
There is a theoretical risk that percutaneous ethanol ablation may not work and the 
microcarcinoma may progress. 
 
Since it is not possible to predict with certainty the absolute risk in any given individual or 
in advance of first-hand experience with the proposed study methods, we provide a plan for 
monitoring the data and safety of the proposed study as follows: 
 
The principal investigator will report the following types of events to the IRB: 
a) Adverse events that are serious or life-threatening 
a. Unanticipated (or anticipated but occurring with a greater frequency than 
expected) 
b. Possibly, probably, or definitely related to the drug/device/intervention; and 
 
b) Other unanticipated problems involving risks to subjects or others. 
 
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Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 28 of 
47 
 
Moderate Risk DSMP 
 
1.Personnel responsible for the safety review and its frequency: 
 
The principal investigator will be responsible for monitoring the data, assuring protocol compliance, and 
conducting the safety reviews at the specified frequency, which must be conducted at a minimum of every 
6 months (including when reapproval of the protocol is sought). During the review process, the principal 
investigator (monitor) will evaluate whether the study should continue unchanged, require 
modification/amendment, or close to enrollment. Either the principal investigator, the IRB or Yale Cancer 
Center Data and Safety Monitoring Committee (DSMC) have the authority to stop or suspend the study or 
require modifications. 
 
2.The risks associated with the current study are deemed moderate for the following reasons: 
(choose those that apply) 
 
1.We do not view the risks associated with the percutaneous ethanol injection for PTMC as minimal.  
2.Given the now established safety and validity of percutaneous ethanol ablation in the current literature 
for benign thyroid lesions, we do not view the proposed studies as high risk. 
 
Although we have assessed the proposed study as one of moderate risk, the potential exists for anticipated 
and/or unanticipated adverse events, serious or otherwise, to occur since it is not possible to predict with 
certainty the absolute risk in any given individual or in advance of first-hand experience with the 
proposed study methods. Therefore we provide a plan for monitoring the data and safety of the proposed 
study as follows: 
 
3.Attribution of Adverse Events: 
Adverse events will be monitored for each subject participating in the study and attributed to the study 
procedures / design by the principal investigator Dr. Glenda Callender according to the following 
categories: 
 
a.)Definite: Adverse event is clearly related to investigational procedure(s)/agent(s). 
b.)Probably: Adverse event is likely related to investigational procedure(s)/agent(s). 
c.)Possible: Adverse event may be related to investigational procedure(s)/agent(s). 
d.)Unlikely: Adverse event is likely not to be related to the investigational procedure(s)/agent(s). 
e.)Unrelated:Adverse event is clearly not related to investigational procedure(s)/agent(s). 
 
4.Plan for Grading Adverse Events: 
 
The following scale will be used in grading the severity of adverse events noted during the study: 
 
1.Mild adverse event 
2.Moderate adverse event 
3.Severe 
 
5.Plan for Determining Seriousness of Adverse Events: 
 
Serious Adverse Events: 
In addition to grading the adverse event, the PI will determine whether the adverse event meets the 
criteria for a Serious Adverse Event (SAE). An adverse event is considered serious if it: 
 
1. Is life-threatening OR 
2. results in in-patient hospitalization or prolongation of existing hospitalization OR 
APPROVED BY THE YALE UNIVERSITY HIC ON 13 APRIL 2016 VALID THROUGH 25 MARCH 2017


Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 29 of 
47 
 
3. Results in persistent or significant disability or incapacity OR 
4. results in a congenital anomaly or birth defect OR 
5. Results in death OR 
6. 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, OR 
7. Adversely affects the risk/benefit ratio of the study 
 
An adverse event may be graded as severe but still not meet the criteria for a Serious Adverse Event. 
Similarly, an adverse event may be graded as moderate but still meet the criteria for an SAE. It is 
important for the PI to consider the grade of the event as well as its “seriousness” when determining 
whether reporting to the IRB is necessary. 
 
6.Plan for reporting Reportable Adverse Events and other unanticipated problems involving risks 
to subjects or others to the IRB 
 
The principal investigator will report the following types of events to the IRB: a) adverse events that are 
serious or life-threatening AND unanticipated (or anticipated but occurring with a greater frequency than 
expected) AND possibly, probably or definitely related to the drug/device/intervention; and b) other 
unanticipated problems involving risks to subjects or others. 
 
These adverse events or unanticipated problems involving risks to subjects or others will be reported to 
the IRB in accordance with IRB Policy 710, using the appropriate forms found on the website. 
 
7.Plan for reporting adverse events to co-investigators on the study, as appropriate the protocol’s 
research monitor(s), e.g., industrial sponsor, Yale Cancer Center Data and Safety Monitoring 
Committee (DSMC), Protocol Review Committee (PRC), DSMBs, study sponsors, funding and 
regulatory agencies, and regulatory and decision-making bodies. 
 
For the current study, the following individuals, funding, and/or regulatory agencies will be notified 
(choose those that apply): 
 
 
All Co-Investigators listed on the protocol. 
 
Yale Cancer Center Data and Safety Monitoring Committee (DSMC) 
 
National Institutes of Health 
 
Food and Drug Administration (Physician-Sponsored IND #_______) 
 
Medical Research Foundation (Grant______) 
 
The principal investigator Dr. Glenda Callender will conduct a review of all adverse events upon 
completion of every study subject. The principal investigator will evaluate the frequency and 
severity of the adverse events and determine if modifications to the protocol or consent form are 
required. 
 
 
12. Statistical Considerations: Describe the statistical analyses that support the study design. 
 
The Yale Center for Analytical Science was consulted to assist with statistics and will contribute 
to this study (Fangyong Li, MPH). 
 
The primary aim of this study is to evaluate the effect of PEA on patient-related outcomes.  The 
primary endpoint will be symptom assessment using the Thyroid Symptom Questionnaire (TSQ) 
APPROVED BY THE YALE UNIVERSITY HIC ON 13 APRIL 2016 VALID THROUGH 25 MARCH 2017


Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 30 of 
47 
 
at the patient’s 12-month visit. In addition, quality of life assessment (QOL) using SF36, pain 
assessment using BPI and voice assessment using VHI will be performed.  
 
A secondary aim of this study is to evaluate the safety and feasibility of using PEA to treat 
primary PTMC. Consequently, we will monitor potential adverse events at the first clinic visit, 
including dysphonia, thyrotoxicosis, fever, hematoma, and skin necrosis. By analyzing these 
variables, the study team hopes to evaluate the safety and feasibility of this treatment modality. 
 
Given the excellent prognosis of patients with PTMC (100% 5-yr survival), we do not expect any 
death events, progression, and recurrence related to the procedure in a feasible follow-up period.  
Therefore, the oncologic outcomes, including disease-free interval and overall survival (up to 5-
yr follow-up), will be collected but will only serve as exploratory endpoints, evaluated at 5-year 
follow-up. 
 
Descriptive statistics, including mean and standard deviation for continuous variables and 
frequency and percentage for categorical variables, will be used to summarize patient 
characteristics. The adverse events will be investigated in order to assess the safety of the new 
procedure. The primary analysis will be comparing the pre-operative TSQ score to the post-
operative TSQ score. Using standard deviation of 6.38 as reported in the DEPTH (DEPression 
and THyroid) study [54], the sample size of 16 achieves 90% power to detect a difference of 
5.65 between pre- and post-PEA with a type I error of 0.05 using a paired t-test. This effect size 
is equivalent to one-level difference in responses for 6 items (such as from “Much worse” to 
“Little worse”), or three-level differences in responses for 2 items (such as from “Much worse” 
to “Much better”), etc. 
 
Similarly, a power analysis was performed for QOL. The Physical Component and Mental 
Component of SF-36 will be used. The standard deviations, 9.7 and 11.0 for patients with thyroid 
disease, respectively, were used to estimate statistical power. The sample size of 16 in each 
group achieves 90% power to detect a difference of 8.6 in SF-36 Physical Component summary 
score and 9.8 in Mental Component summary score between the PEA and thyroidectomy groups 
with a type I error of 0.05. 
 
Time and motion studies and a cost analysis will also be conducted. 
 
 
 
 
 
 
 
 
 
APPROVED BY THE YALE UNIVERSITY HIC ON 13 APRIL 2016 VALID THROUGH 25 MARCH 2017


Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 31 of 
47 
 
SECTION VI: RESEARCH INVOLVING DRUGS, BIOLOGICS, RADIOTRACERS, PLACEBOS AND 
DEVICES 
 
 
If this section (or one of its parts, A or B) is not applicable, state N/A and delete the rest of the 
section. 
 
A.  DRUGS, BIOLOGICS and RADIOTRACERS 
 
1. Identification of Drug, Biologic or Radiotracer: What is (are) the name(s) of the drug(s)  
biologic(s) or radiotracer(s) being used? Identify whether FDA approval has been granted and for what 
indication(s).  
Percutaneous ethanol injection is approved by the FDA and is a well-accepted treatment 
modality for the management of metastatic thyroid carcinoma to the neck, as well as benign 
thyroid cysts or autonomic nodules [27, 28, 30-32, 36, 55]. The injection of ethanol has been also 
used successfully in the cure of liver tumors [56-61].  
 
1. 
Hay, I.D. and J.W. Charboneau, The coming of age of ultrasound-guided percutaneous 
ethanol ablation of selected neck nodal metastases in well-differentiated thyroid 
carcinoma. J Clin Endocrinol Metab, 2011. 96(9): p. 2717-20. 
2. 
Heilo, A., et al., Efficacy of ultrasound-guided percutaneous ethanol injection treatment 
in patients with a limited number of metastatic cervical lymph nodes from papillary 
thyroid carcinoma. J Clin Endocrinol Metab, 2011. 96(9): p. 2750-5. 
3. 
Mauz, P.S., et al., Complications of ultrasound guided percutaneous ethanol injection 
therapy of the thyroid and parathyroid glands. Ultraschall Med, 2005. 26(2): p. 142-5. 
4. 
Livraghi, T., et al., Treatment of autonomous thyroid nodules with percutaneous ethanol 
injection: preliminary results. Work in progress. Radiology, 1990. 175(3): p. 827-9. 
5. 
Lippi, F., et al., Treatment of solitary autonomous thyroid nodules by percutaneous 
ethanol injection: results of an Italian multicenter study. The Multicenter Study Group. J 
Clin Endocrinol Metab, 1996. 81(9): p. 3261-4. 
6. 
Bennedbaek, F.N., S. Karstrup, and L. Hegedus, Percutaneous ethanol injection therapy 
in the treatment of thyroid and parathyroid diseases. Eur J Endocrinol, 1997. 136(3): p. 
240-50. 
7. 
Verde, G., et al., Ultrasound guided percutaneous ethanol injection in the treatment of 
cystic thyroid nodules. Clin Endocrinol (Oxf), 1994. 41(6): p. 719-24. 
8. 
Shiina, S., et al., Percutaneous ethanol injection in the treatment of liver neoplasms. AJR 
Am J Roentgenol, 1987. 149(5): p. 949-52. 
9. 
Ebara, M., et al., Percutaneous ethanol injection for the treatment of small hepatocellular 
carcinoma. Study of 95 patients. J Gastroenterol Hepatol, 1990. 5(6): p. 616-26. 
10. 
Shiina, S., et al., A randomized controlled trial of radiofrequency ablation with ethanol 
injection for small hepatocellular carcinoma. Gastroenterology, 2005. 129(1): p. 122-30. 
11. 
Livraghi, T., et al., Small hepatocellular carcinoma: treatment with radio-frequency 
ablation versus ethanol injection. Radiology, 1999. 210(3): p. 655-61. 
12. 
Castells, A., et al., Treatment of small hepatocellular carcinoma in cirrhotic patients: a 
cohort study comparing surgical resection and percutaneous ethanol injection. 
Hepatology, 1993. 18(5): p. 1121-6. 
 
APPROVED BY THE YALE UNIVERSITY HIC ON 13 APRIL 2016 VALID THROUGH 25 MARCH 2017


Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 32 of 
47 
 
13. 
Ohnishi, K., et al., Prospective randomized controlled trial comparing percutaneous 
acetic acid injection and percutaneous ethanol injection for small hepatocellular 
carcinoma. Hepatology, 1998. 27(1): p. 67-72. 
All protocols which utilize a drug, biologic or radiotracer not approved by, but regulated by, the FDA, 
or a radiotracer regulated by the RDRC, must provide the following information:  NOT APPLICABLE 
a. What is the Investigational New Drug (IND) number assigned by the FDA? 
b. Who holds the IND?  
c. All protocols which utilize a radiotracer not approved by, but regulated by the FDA must 
provide the IND number: _______________ 
Alternatively, use of the investigational radiotracer may be under RDRC/RSC oversight: (check 
if appropriate)_____________ 
 
For all investigational radiotracers, attach a copy of the RDRC/RSC application (for 
radioisotopes used in the PET Center, PET Center personnel may complete this step) 
Go to http://rsc.med.yale.edu/login.asp?url=myApps.asp.  When you have logged in, complete 
the application and attach a copy to this submission.     NOT APPLICABLE 
 
Alternatively, an exemption from IND filing requirements may be sought for a clinical 
 investigation of a drug product that is lawfully marketed in the United States. If there is no IND and 
 an exemption is being sought, review the following categories and complete the category that applies 
 (and delete the inapplicable categories): NOT APPLICABLE 
 
2.  Background Information: Provide a description of previous human use, known risks, and data 
addressing dosage(s), interval(s), route(s) of administration, and any other factors that might 
influence risks. If this is the first time this drug is being administered to humans, include relevant 
data on animal models.  
 
 
Percutaneous ethanol injection is approved by the FDA and is a well-accepted treatment 
modality for the management of metastatic thyroid cancer in the neck, as well as benign thyroid 
cysts or nodules.  Ethanol (99%) is injected through the skin into the thyroid tissue under 
ultrasound guidance and it has been reported in the literature that 0.1 to 1.0 cc ethanol is 
sufficient for the successful ablation of a PTMC [27, 28, 30-32, 36, 55]. The actual volume of 
ethanol to be instilled into a particular tumor will be calculated through a standard formula 
(Ethanol Volume= length × width × height × π / 6). Based on our experience and the existing 
literature, we believe that most PTMCs will be completely treated with a single procedure, given 
the small size of the tumors (≤1 cm).  However, if follow-up ultrasound demonstrates residual 
tumor after initial treatment, re-treatment will be permitted. 
 
1. 
Howlader, N.N., AM, SEER cancer Statistics Review. 2013. 
2. 
Pacini, F., Management of papillary thyroid microcarcinoma: primum non nocere! J Clin 
Endocrinol Metab, 2013. 98(4): p. 1391-3. 
3. 
Ito, Y. and A. Miyauchi, A therapeutic strategy for incidentally detected papillary 
microcarcinoma of the thyroid. Nat Clin Pract Endocrinol Metab, 2007. 3(3): p. 240-8. 
4. 
Enewold, L., et al., Rising thyroid cancer incidence in the United States by demographic 
and tumor characteristics, 1980-2005. Cancer Epidemiol Biomarkers Prev, 2009. 18(3): 
p. 784-91. 
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Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 33 of 
47 
 
5. 
Chen, A.Y., A. Jemal, and E.M. Ward, Increasing incidence of differentiated thyroid 
cancer in the United States, 1988-2005. Cancer, 2009. 115(16): p. 3801-7. 
6. 
Lloyd R, D.L.R., Heitz P et al World Health Organization Classification of Tumours: 
pathology and genetics of tumours of the endocrine organs. International Agency for 
Research on Cancer (IARC) Press, Lyon. 2004. 
7. 
Fukunaga, F.H. and R. Yatani, Geographic pathology of occult thyroid carcinomas. 
Cancer, 1975. 36(3): p. 1095-9. 
8. 
Harach, H.R., K.O. Franssila, and V.M. Wasenius, Occult papillary carcinoma of the 
thyroid. A "normal" finding in Finland. A systematic autopsy study. Cancer, 1985. 56(3): 
p. 531-8. 
9. 
Thorvaldsson, S.E., et al., Latent thyroid carcinoma in Iceland at autopsy. Pathol Res 
Pract, 1992. 188(6): p. 747-50. 
10. 
Christou, N. and M. Mathonnet, Complications after total thyroidectomy. J Visc Surg, 
2013. 
11. 
Thomusch, O., et al., Multivariate analysis of risk factors for postoperative complications 
in benign goiter surgery: prospective multicenter study in Germany. World J Surg, 2000. 
24(11): p. 1335-41. 
12. 
Duclos, A., et al., Influence of experience on performance of individual surgeons in 
thyroid surgery: prospective cross sectional multicentre study. BMJ, 2012. 344: p. d8041. 
13. 
Bellantone, R., et al., Total thyroidectomy for management of benign thyroid disease: 
review of 526 cases. World J Surg, 2002. 26(12): p. 1468-71. 
14. 
Regalbuto, C., et al., Effects of either LT4 monotherapy or LT4/LT3 combined therapy in 
patients totally thyroidectomized for thyroid cancer. Thyroid, 2007. 17(4): p. 323-31. 
15. 
Bunevicius, R., et al., Effects of thyroxine as compared with thyroxine plus 
triiodothyronine in patients with hypothyroidism. N Engl J Med, 1999. 340(6): p. 424-9. 
16. 
Bunevicius, R. and A.J. Prange, Mental improvement after replacement therapy with 
thyroxine plus triiodothyronine: relationship to cause of hypothyroidism. Int J 
Neuropsychopharmacol, 2000. 3(2): p. 167-174. 
17. 
Kaplan, M.M., D.H. Sarne, and A.B. Schneider, In search of the impossible dream? 
Thyroid hormone replacement therapy that treats all symptoms in all hypothyroid 
patients. J Clin Endocrinol Metab, 2003. 88(10): p. 4540-2. 
18. 
Toft, A.D., Thyroid hormone replacement--one hormone or two? N Engl J Med, 1999. 
340(6): p. 469-70. 
19. 
Siegmund, W., et al., Replacement therapy with levothyroxine plus triiodothyronine 
(bioavailable molar ratio 14 : 1) is not superior to thyroxine alone to improve well-being 
and cognitive performance in hypothyroidism. Clin Endocrinol (Oxf), 2004. 60(6): p. 
750-7. 
20. 
Saravanan, P., et al., Psychological well-being in patients on 'adequate' doses of l-
thyroxine: results of a large, controlled community-based questionnaire study. Clin 
Endocrinol (Oxf), 2002. 57(5): p. 577-85. 
21. 
Wekking, E.M., et al., Cognitive functioning and well-being in euthyroid patients on 
thyroxine replacement therapy for primary hypothyroidism. Eur J Endocrinol, 2005. 
153(6): p. 747-53. 
22. 
Walsh, J.P., et al., Combined thyroxine/liothyronine treatment does not improve well-
being, quality of life, or cognitive function compared to thyroxine alone: a randomized 
controlled trial in patients with primary hypothyroidism. J Clin Endocrinol Metab, 2003. 
88(10): p. 4543-50. 
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Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 34 of 
47 
 
23. 
Sawka, A.M., et al., Does a combination regimen of thyroxine (T4) and 3,5,3'-
triiodothyronine improve depressive symptoms better than T4 alone in patients with 
hypothyroidism? Results of a double-blind, randomized, controlled trial. J Clin 
Endocrinol Metab, 2003. 88(10): p. 4551-5. 
24. 
Nixon, I.J., et al., Thyroid lobectomy for treatment of well differentiated intrathyroid 
malignancy. Surgery, 2012. 151(4): p. 571-9. 
25. 
Ito, Y., et al., An observational trial for papillary thyroid microcarcinoma in Japanese 
patients. World J Surg, 2010. 34(1): p. 28-35. 
26. 
Shin, J.E., J.H. Baek, and J.H. Lee, Radiofrequency and ethanol ablation for the 
treatment of recurrent thyroid cancers: current status and challenges. Curr Opin Oncol, 
2013. 25(1): p. 14-9. 
27. 
Hay, I.D. and J.W. Charboneau, The coming of age of ultrasound-guided percutaneous 
ethanol ablation of selected neck nodal metastases in well-differentiated thyroid 
carcinoma. J Clin Endocrinol Metab, 2011. 96(9): p. 2717-20. 
28. 
Heilo, A., et al., Efficacy of ultrasound-guided percutaneous ethanol injection treatment 
in patients with a limited number of metastatic cervical lymph nodes from papillary 
thyroid carcinoma. J Clin Endocrinol Metab, 2011. 96(9): p. 2750-5. 
29. 
Lewis, B.D., et al., Percutaneous ethanol injection for treatment of cervical lymph node 
metastases in patients with papillary thyroid carcinoma. AJR Am J Roentgenol, 2002. 
178(3): p. 699-704. 
30. 
Mauz, P.S., et al., Complications of ultrasound guided percutaneous ethanol injection 
therapy of the thyroid and parathyroid glands. Ultraschall Med, 2005. 26(2): p. 142-5. 
31. 
Livraghi, T., et al., Treatment of autonomous thyroid nodules with percutaneous ethanol 
injection: preliminary results. Work in progress. Radiology, 1990. 175(3): p. 827-9. 
32. 
Bennedbaek, F.N., S. Karstrup, and L. Hegedus, Percutaneous ethanol injection therapy 
in the treatment of thyroid and parathyroid diseases. Eur J Endocrinol, 1997. 136(3): p. 
240-50. 
33. 
Monzani, F., et al., Percutaneous ethanol injection therapy of autonomous nodule and 
amiodarone-induced thyrotoxicosis. Thyroidology, 1994. 6(3): p. 99-102. 
34. 
Cortelazzi, D., et al., Resolution of hyperthyroidism in a pregnant woman with toxic 
thyroid nodule by percutaneous ethanol injection. Thyroid, 1995. 5(6): p. 473-5. 
35. 
Mazzeo, S., et al., Percutaneous injection of ethanol to treat autonomous thyroid nodules. 
AJR Am J Roentgenol, 1993. 161(4): p. 871-6. 
36. 
Lippi, F., et al., Treatment of solitary autonomous thyroid nodules by percutaneous 
ethanol injection: results of an Italian multicenter study. The Multicenter Study Group. J 
Clin Endocrinol Metab, 1996. 81(9): p. 3261-4. 
37. 
Ferrari, C., E. Reschini, and A. Paracchi, Treatment of the autonomous thyroid nodule: a 
review. Eur J Endocrinol, 1996. 135(4): p. 383-90. 
38. 
Crescenzi, A., et al., Morphological changes in a hyperfunctioning thyroid adenoma after 
percutaneous ethanol injection: histological, enzymatic and sub-microscopical 
alterations. J Endocrinol Invest, 1996. 19(6): p. 371-6. 
39. 
Schumm-Draeger, P.M., Ultrasound-guided percutaneous ethanol injection in the 
treatment of autonomous thyroid nodules--a review. Exp Clin Endocrinol Diabetes, 1998. 
106 Suppl 4: p. S59-62. 
40. 
Miccoli, P., et al., The impact of thyroidectomy on psychiatric symptoms and quality of 
life. J Endocrinol Invest, 2007. 30(10): p. 853-9. 
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Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 35 of 
47 
 
41. 
Adler, J.T., et al., Preserving function and quality of life after thyroid and parathyroid 
surgery. Lancet Oncol, 2008. 9(11): p. 1069-75. 
42. 
Weber, T., et al., Effect of parathyroidectomy on quality of life and neuropsychological 
symptoms in primary hyperparathyroidism. World J Surg, 2007. 31(6): p. 1202-9. 
43. 
Cohen, S.M., et al., Creation and validation of the Singing Voice Handicap Index. Ann 
Otol Rhinol Laryngol, 2007. 116(6): p. 402-6. 
44. 
Jacobson, B.H., The Voice Handicap Index (VHI): Development and Validation. 
American Journal of Speech-Language Pathology, 1997. 6: p. 66-70. 
45. 
Jung, S.P., et al., A New Subfascial Approach in Open Thyroidectomy: Efficacy for 
Postoperative Voice, Sensory, and Swallowing Symptoms. A Randomized Controlled 
Study. Ann Surg Oncol, 2013. 
46. 
Keller, S., et al., Validity of the brief pain inventory for use in documenting the outcomes 
of patients with noncancer pain. Clin J Pain, 2004. 20(5): p. 309-18. 
47. 
Cleeland, C.S. and K.M. Ryan, Pain assessment: global use of the Brief Pain Inventory. 
Ann Acad Med Singapore, 1994. 23(2): p. 129-38. 
48. 
Tan, G., et al., Validation of the Brief Pain Inventory for chronic nonmalignant pain. J 
Pain, 2004. 5(2): p. 133-7. 
49. 
Fearmonti, R., et al., A review of scar scales and scar measuring devices. Eplasty, 2010. 
10: p. e43. 
50. 
Draaijers, L.J., et al., The patient and observer scar assessment scale: a reliable and 
feasible tool for scar evaluation. Plast Reconstr Surg, 2004. 113(7): p. 1960-5; discussion 
1966-7. 
51. 
van de Kar, A.L., et al., Reliable and feasible evaluation of linear scars by the Patient 
and Observer Scar Assessment Scale. Plast Reconstr Surg, 2005. 116(2): p. 514-22. 
52. 
Casserly, P., R. Kirby, and C. Timon, Outcome measures and scar aesthetics in 
minimally invasive video-assisted parathyroidectomy. Arch Otolaryngol Head Neck Surg, 
2010. 136(3): p. 260-4. 
53. 
van Persijn van Meerten, E.L., H. Gelderblom, and J.L. Bloem, RECIST revised: 
implications for the radiologist. A review article on the modified RECIST guideline. Eur 
Radiol, 2010. 20(6): p. 1456-67. 
54. 
Bould, H., et al., Investigation of thyroid dysfunction is more likely in patients with high 
psychological morbidity. Fam Pract, 2012. 29(2): p. 163-7. 
55. 
Verde, G., et al., Ultrasound guided percutaneous ethanol injection in the treatment of 
cystic thyroid nodules. Clin Endocrinol (Oxf), 1994. 41(6): p. 719-24. 
56. 
Shiina, S., et al., Percutaneous ethanol injection in the treatment of liver neoplasms. AJR 
Am J Roentgenol, 1987. 149(5): p. 949-52. 
57. 
Ebara, M., et al., Percutaneous ethanol injection for the treatment of small hepatocellular 
carcinoma. Study of 95 patients. J Gastroenterol Hepatol, 1990. 5(6): p. 616-26. 
58. 
Shiina, S., et al., A randomized controlled trial of radiofrequency ablation with ethanol 
injection for small hepatocellular carcinoma. Gastroenterology, 2005. 129(1): p. 122-30. 
59. 
Livraghi, T., et al., Small hepatocellular carcinoma: treatment with radio-frequency 
ablation versus ethanol injection. Radiology, 1999. 210(3): p. 655-61. 
60. 
Castells, A., et al., Treatment of small hepatocellular carcinoma in cirrhotic patients: a 
cohort study comparing surgical resection and percutaneous ethanol injection. 
Hepatology, 1993. 18(5): p. 1121-6. 
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Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 36 of 
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61. 
Ohnishi, K., et al., Prospective randomized controlled trial comparing percutaneous 
acetic acid injection and percutaneous ethanol injection for small hepatocellular 
carcinoma. Hepatology, 1998. 27(1): p. 67-72. 
 
 
 
3.  Source:  a) Identify the source of the drug or biologic to be used.  
Percutaneous ethanol ablation is a standard procedure performed in the section of Interventional 
Radiology and the department has sufficient amounts of ethanol stocked in adequate storage. 
 
  
 
 
  
b) Is the drug provided free of charge to subjects? 
 Yes  
 No 
 
  
    If yes, by whom?  
 
4.  Storage, Preparation and Use: Describe the method of storage, preparation, stability information, 
and for parenteral products, method of sterilization and method of testing sterility and 
pyrogenicity.  
 
Check applicable Investigational Drug Service utilized: 
     
   YNHH IDS                                                                      
   Yale Cancer Center  
     
   CMHC Pharmacy                                                          
  West Haven VA 
     
   PET Center                                                          
    None       
     
    Other:  
Note: If the YNHH IDS (or comparable service at CMHC or WHVA) will not be utilized, explain in 
detail how the PI will oversee these aspects of drug accountability, storage, and preparation.   
   
 
5.  Use of Placebo: 
Not applicable to this research project 
 
If use of a placebo is planned, provide a justification which addresses the following: 
a.  
Describe the safety and efficacy of other available therapies. If there are no other 
available therapies, state this. 
 
b.   State the maximum total length of time a participant may receive placebo while on the study.  
 
c.   Address the greatest potential harm that may come to a participant as a result of  receiving     
       placebo.  
 
d.   Describe the procedures that are in place to safeguard participants receiving placebo.  
 
6. Use of Controlled Substances: 
 
Will this research project involve the use of controlled substances in human subjects? 
 
 Yes  
No  See HIC Application Instructions to view controlled substance listings.  
 
 
If yes, is the use of the controlled substance considered: 
 
 Therapeutic: The use of the controlled substance, within the context of the research, has the 
potential to benefit the research participant. 
 
 Non-Therapeutic: Note, the use of a controlled substance in a non-therapeutic research study 
involving human subjects may require that the investigator obtain a Laboratory Research License. 
Examples include controlled substances used for basic imaging, observation or biochemical 
studies or other non-therapeutic purposes. See Instructions for further information. 
 
7. Continuation of Drug Therapy After Study Closure   
 Not applicable to this project 
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Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 37 of 
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Are subjects provided the opportunity to continue to receive the study drug(s) after the study has 
ended? 
 
 Yes   If yes, describe the conditions under which continued access to study drug(s) may apply 
as well as conditions for termination of such access.  
 
 
 
 No    If no, explain why this is acceptable. 
 
 
 B.  DEVICES 
 
1. Are there any investigational devices used or investigational procedures performed at YNHH, e.g., 
YNHH Operating Room or YNHH Heart and Vascular Center?  Yes 
  No 
 
If Yes, please be aware of the following requirements: 
 
a. A YNHH New Product/Trial Request Form must be completed;   
 
b. Your request must be reviewed and approved by a Hospital Committee before 
patients may be scheduled; and   
 
c. The notice of approval from YNHH must be submitted to the HIC for the protocol 
file.  
 
Please contact Gina D’Agostino, gina.d’agostino@ynhh.org or 203-688-5052, to initiate the 
process.  
 
2. What is the name of the device to be studied in this protocol? 
 
Has this device been FDA approved? 
 Yes  
 No 
If yes, state for what indication. 
 
3. Background Information: Provide a description of previous human use, known risks, and any 
other factors that might influence risks. If this is the first time this device is being used in humans, 
include relevant data on animal models.  
 
4. Source:  
a) Identify the source of the device to be used.  
 
b) Is the device provided free of charge to subjects? 
 Yes  
 No 
 
5. What is the PI’s assessment of risk level (significant or non-significant) associated with the use of 
the device?  
 
 Significant Risk (SR) Device Study: A study of a device that presents a potential for serious 
risk to the health, safety, or welfare of a participant and 1) is intended as an implant; 2) is used in 
supporting or sustaining human life; or otherwise prevents impairment of human health; 3) is of 
substantial importance in diagnosing, curing, mitigating or treating disease, or otherwise prevents 
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Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 38 of 
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impairment of human health; or 4) otherwise presents a potential for serious risk to the health, 
safety, or welfare of a participant.    
 
Significant Risk Devices require an Investigational Device Exemption (IDE) issued by the FDA. 
 
What is the IDE number assigned by the FDA?  
 
Did the FDA approve this IDE as Category A (experimental/investigational) or as Category B 
(non-experimental/investigational)? 
 
Who holds the IDE? 
 
 Non-Significant Risk (NSR) Device Study: A study of a device that does not meet the   
definition for a significant risk device and does not present a potential for serious risk to the health, 
safety, or welfare of participants.  Note that if the HIC concurs with this determination, an IDE is 
not required. 
 
6.  Abbreviated IDE or Exempt IDE: There are abbreviated requirements for an IDE and there also 
are exemptions to the requirement for an IDE.  See the criteria in the HIC Application Instructions, 
Section VI.B.4 at 
http://www.yale.edu/hrpp/resources/docs/100FR1aHICProtocol_Application_Instructions5-25-
11.pdf to determine if these pertain to this study. 
 
  
 Abbreviated IDE or Exempt IDE – If criteria set forth in the HIC Application Instructions 
are met, copy and paste the completed relevant section from the Instructions into this application. 
 
7.   Investigational device accountability: 
State how the PI, or named designee, ensures that an investigational device is used only in 
accordance with the research protocol approved by the HIC, and maintains control of the 
investigational device as follows: 
Maintains appropriate records, including receipt of shipment, inventory at the site, dispensation or 
use by each participant, and final disposition and/or the return of the investigational device (or 
other disposal if applicable): 
Documents pertinent information assigned to the investigational device (e.g., date, quantity, batch 
or serial number, expiration date if applicable, and unique code number): 
Stores the investigational device according to the manufacturer's recommendations with respect to 
temperature, humidity, lighting, and other environmental considerations: 
Ensures that the device is stored in a secure area with limited access in accordance with applicable 
regulatory requirements: 
Distributes the investigational device to subjects enrolled in the IRB-approved protocol: 
 
 
 
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Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 39 of 
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SECTION VII: RECRUITMENT/CONSENT AND ASSENT PROCEDURES  
 
 
1. Targeted Enrollment: Give the number of subjects: 
a.   Targeted for enrollment at Yale for this protocol:  40 
b. If this is a multi-site study, give the total number of subjects targeted across all sites    
N/A 
 
2. Indicate recruitment methods below.  Attach copies of any recruitment materials that will be used. 
 
 Flyers 
 
 
 
 
 Internet/Web Postings 
 
 
 Radio 
 Posters  
 
 
 
 Mass E-mail Solicitation  
 
 Telephone 
 Letter 
 
 
 
  
 Departmental/Center Website 
 
 Television 
 Medical Record Review  
 
 Departmental/Center Research Boards 
 Newspaper 
 Departmental/Center Newsletters 
 Web-Based Clinical Trial Registries 
 
 YCCI Recruitment database 
 
 Clinicaltrials.gov Registry (do not send materials to HIC) 
 Other (describe):  Patients who meet eligibility criteria will be approached by an attending surgeon 
at Yale Endocrine Surgery and will be asked about their interest in enrollment into the study. 
 
3.  Recruitment Procedures:  
a. Describe how potential subjects will be identified. 
A letter will be sent to referring endocrinologists to raise awareness for this clinical 
trial. This letter will inform the endocrinologists about the general study purpose, study 
design, and potential inclusion and exclusion criteria. All potential patients will be 
referred to Yale Endocrine Surgery for final assessment of eligibility. We include a 
copy of this letter with the amendment form.  
 
All patients referred to Yale Endocrine Surgery who meet eligibility criteria and do not 
meet exclusion criteria will be offered enrollment in the study.  The attending endocrine 
surgeon (Drs. Udelsman, Carling, Callender or Quinn) will determine eligibility at the 
time of the initial clinic visit. 
 
b. Describe how potential subjects are contacted.  
Potential subjects will be approached during their regularly scheduled Yale Endocrine 
Surgery clinic appointment. 
  
c. Who is recruiting potential subjects?  
Attending endocrine surgeons at Yale Endocrine Surgery will approach patients to 
discuss their interest in enrollment.  Referring physicians who have heard about the 
study may also refer patients specifically for a discussion of enrollment into the study.  
Patients who have heard about the study may self-refer for a discussion of enrollment 
into the study. 
 
 
 
4. Screening Procedures 
a. Will email or telephone correspondence be used to screen potential subjects for 
eligibility prior to the potential subject coming to the research office? 
 Yes 
 No 
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Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 40 of 
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b.  If yes, identify below all health information to be collected as part of screening and 
check off any of the following HIPAA identifiers to be collected and retained by the 
research team during this screening process.  N/A 
 
 
 
 
5. Assessment of Current Health Provider Relationship for HIPAA Consideration: 
Does the Investigator or any member of the research team have a direct existing clinical 
relationship with any potential subject?  
 Yes, all subjects 
 Yes, some of the subjects 
No 
 
If yes, describe the nature of this relationship. 
All patients, who are enrolled in this study, will have clinical relationship with the principle 
investigator, as they will undergo surveillance for their procedure for 5 years. They will be 
scheduled for follow up clinic visits, initially by the surgical team (first clinic visit after 
procedure) and afterwards by Dr. Elizabeth Holt (also included in protocol; member of study 
team). For details of follow up clinic visits please see Appendix 6. 
 
 
 
6. Request for waiver of HIPAA authorization: (When requesting a waiver of HIPAA Authorization 
for either the entire study, or for recruitment purposes only.  Note: if you are collecting PHI as part of 
a phone or email screen, you must request a HIPAA waiver for recruitment purposes.) 
N/A 
Choose one: For entire study: ______ For recruitment purposes only: ______ 
i. Describe why it would be impracticable to obtain the subject’s authorization for 
use/disclosure of this data; 
ii. If requesting a waiver of signed authorization, describe why it would be 
impracticable to obtain the subject’s signed authorization for use/disclosure of this 
data; 
 
By signing this protocol application, the investigator assures that the protected 
health information for which a Waiver of Authorization has been requested will not 
be reused or disclosed to any person or entity other than those listed in this 
application, except as required by law, for authorized oversight of this research 
study, or as specifically approved for use in another study by an IRB. 
 
Researchers are reminded that unauthorized disclosures of PHI to individuals outside of the Yale 
HIPAA-Covered entity must be accounted for in the “accounting for disclosures log”, by subject 
name, purpose, date, recipients, and a description of information provided.  Logs are to be 
forwarded to the Deputy HIPAA Privacy Officer. 
 
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Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 41 of 
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7. Required HIPAA Authorization: If the research involves the creation, use or disclosure of 
protected health information (PHI), separate subject authorization is required under the 
HIPAA Privacy Rule. Indicate which of the following forms are being provided: 
 
  
 Compound Consent and Authorization form 
 
  
 HIPAA Research Authorization Form 
 
N/A 
 
 
8. Consent Personnel: List the names of all members of the research team who will be obtaining 
consent/assent.  
a.    Glenda Callender, MD 
b. Robert Udelsman, MD, MBA 
c.    Tobias Carling, MD, PhD 
d. Courtney Quinn, MD 
e.    Melih Arici, MD 
f.    Jonathan Kirsch, MD 
g. Jennifer Malinowski, PhD, MS 
h. Elizabeth Holt, MD, PhD 
i.    Patricia Donovan, RN, MBA 
 
9. Process of Consent/Assent: Describe the setting and conditions under which consent/assent will 
be obtained, including parental permission or surrogate permission and the steps taken to ensure 
subjects’ independent decision-making.  
 
Patients will be consented in the Yale Endocrine Surgery clinic during their evaluation.  This study 
does not involve children or patients without decision-making capacity.  
 
 
 
10. Evaluation of Subject(s) Capacity to Provide Informed Consent/Assent: Indicate how the 
personnel obtaining consent will assess the potential subject’s ability and capacity to consent to the 
research being proposed.  
 
The patient will be assessed by a physician before obtaining informed consent/ assent. It is the duty 
of the physician to use his/her clinical judgment to determine if the patient has the ability and 
capacity to make his or her decision regarding medical treatment. In some circumstances, the 
patient may lack the mental capability to consent for the planned procedure. Circumstances such as 
being under the influence of drugs or alcohol may constitute grounds that the patient is temporarily 
incompetent to consent and the patient will not be consented for the planned procedure. Patients 
suffering from dementia are also considered incompetent to consent and the study team will 
exclude the patients from the study.  
In the absence of any concerns about the patient’s ability to consent, the patient will be asked to 
sign the consent for the procedure. 
 
 
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Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 42 of 
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11. Documentation of Consent/Assent: Specify the documents that will be used during the 
consent/assent process. Copies of all documents should be appended to the protocol, in the same 
format that they will be given to subjects.  
 
We include our “Adult Informed Consent Form”. We do not plan to enroll patients into the study 
who are decisionally impaired or minors that would require assent forms or child assent forms, 
respectively. 
 
 
12. Non-English Speaking Subjects: Explain provisions in place to ensure comprehension for 
research involving non-English speaking subjects. Translated copies of all consent materials must 
be submitted for approval prior to use.  
 
We will not include non-English speaking subjects for this study. 
 
 
13. Consent Waiver: In certain circumstances, the HIC may grant a waiver of signed consent, or 
a full waiver of consent, depending on the study. If you will request either a waiver of consent, 
or a waiver of signed consent for this study, complete the appropriate section below.   
 
 Not requesting a consent waiver  
 
 Requesting a waiver of signed consent 
       
 Requesting a full waiver of consent 
    
 
A. Waiver of signed consent: (Verbal consent from subjects will be obtained. If PHI is 
collected, information in this section must match Section VII, Question 6) 
 Requesting a waiver of signed consent for Recruitment/Screening only  
If requesting a waiver of signed consent, please address the following: 
a. Would the signed consent form be the only record linking the subject and the research? 
 Yes  
 No 
b. Does a breach of confidentiality constitute the principal risk to subjects?  
 Yes  
 No 
 
 
 
 
 
OR 
 
c. Does the research activity pose greater than minimal risk?  
 Yes If you answered yes, stop. A waiver cannot be granted.  Please note: 
Recruitment/screening is generally a minimal risk research activity   
 No  
AND 
d. Does the research include any activities that would require signed consent in a non-
research context? 
 Yes  
 No 
 
 Requesting a waiver of signed consent for the Entire Study (Note that an information 
sheet may be required.) 
 
  
If requesting a waiver of signed consent, please address the following: 
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Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 43 of 
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a. Would the signed consent form be the only record linking the subject and the research? 
 Yes  
 No 
b. Does a breach of confidentiality constitute the principal risk to subjects?  
 Yes  
 No 
 
 
 
 
 
OR 
 
c. Does the research pose greater than minimal risk? 
 Yes If you answered yes, stop. A 
waiver cannot be granted.    
 No  
AND 
d. Does the research include any activities that would require signed consent in a non-
research context? 
 Yes  
 No 
 
  
 B. Full waiver of consent: (No consent from subjects will be obtained for the activity.)  
 Requesting a waiver of consent for Recruitment/Screening only  
a. Does the research activity pose greater than minimal risk to subjects?   
 Yes  If you answered yes, stop. A waiver cannot be granted. Please note: 
Recruitment/screening is generally a minimal risk research activity  
 No 
 
  
b. Will the waiver adversely affect subjects’ rights and welfare? 
 Yes  
 No 
 
  
c. Why would the research be impracticable to conduct without the waiver?  
 
d. Where appropriate, how will pertinent information be returned to, or shared with 
subjects at a later date?  
 
 
 Requesting a full waiver of consent for the Entire Study (Note: If PHI is 
collected, information here must match Section VII, question 6.) 
 
  
 
If requesting a full waiver of consent, please address the following: 
 
 
  
a. Does the research pose greater than minimal risk to subjects?   
 Yes  If you answered yes, stop. A waiver cannot be granted.   
 No 
 
  
b. Will the waiver adversely affect subjects’ rights and welfare? 
 Yes  
 No 
 
  
c. Why would the research be impracticable to conduct without the waiver?  
 
d. Where appropriate, how will pertinent information be returned to, or shared with 
subjects at a later date?  
 
 
SECTION VIII: PROTECTION OF RESEARCH SUBJECTS 
 
    Confidentiality & Security of Data: 
a. What protected health information (medical information along with the HIPAA identifiers) 
about subjects will be collected and used for the research?    
We will collect sufficient information about each enrollee such that should they move away 
from Yale-New Haven or they become otherwise “lost-to-follow-up”, we can continue to 
track them using state and nationally-available resources such as the National Death Index, 
APPROVED BY THE YALE UNIVERSITY HIC ON 13 APRIL 2016 VALID THROUGH 25 MARCH 2017


Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 44 of 
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Social Security Death Index and the Connecticut Tumor Registry.  To ensure this, we will be 
collecting the following PHI on each enrollee: 
 
1) Full given and surname 
2) Location (city and state) and date of birth 
3) Social Security Number 
4) Current residential address and best contact phone number 
5) Medical record number for Yale New Haven Hospital 
 
b. How will the research data be collected, recorded and stored?  
 
Data will be collected from both direct patient interview and extraction from the medical 
record. These data will be input into the OnCore clinical trials management system directly 
from the medical record.  Patient surveys, which are completed in paper format, will be stored 
in a single, locked file cabinet and kept separate from all the remaining study documents; these 
data will be input into the OnCore clinical trials management system.  An electronic database 
will be created from the data contained in OnCore. This database will serve as a standalone 
product to allow us to track participants and samples.  It will be stored on  the limited-access 
Yale secure server. The data in OnCore will be kept indefinitely; the research database will be 
de-identified one year after the end of the study and the data kept in this anonymous form 
indefinitely on the secure server. 
 
c.    How will the digital data be stored? 
 CD  
 DVD  
 Flash Drive  
 Portable Hard    
       Drive  
 Secured Server 
 Laptop Computer  
 Desktop Computer  
 Other 
 
d.    What methods and procedures will be used to safeguard the confidentiality and security of     
the identifiable study data and the storage media indicated above during and after the subject’s 
participation in the study? 
Do all portable devices contain encryption software? 
 Yes   
 No 
         If no, see http://hipaa.yale.edu/guidance/policy.html 
 
All electronic data files for this study will either be stored as password-protected files on an 
encrypted, password-protected computer, in the Yale Clinical Trials Management System 
(OnCore), or on the limited-access secure Yale ITS server. OnCore is accessed through Yale-
networked computers and access is granted only to appropriate study personnel. Any files 
that contain protected health information will be maintained separately from the rest of other 
data files and only on the secure server or in OnCore. 
 
The research database that contains the participant data will be maintained on the secure Yale 
server  and will be de-identified  at the end of the study   Access to this database will be 
restricted to the small subset of individuals responsible for study operations.  In this manner, 
we hope to minimize the risk of breach of confidentiality by limiting access to the PHI and 
its link to the anonymous unique identifiers. 
  
e.    What will be done with the data when the research is completed? Are there plans to   
       destroy identifiable data?  
 
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Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 45 of 
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At the end of the study, personally identifiable data in the research database will be de-
identified or deleted using specific software to “securely” delete a selective file. Information 
regarding this software will be obtained from ITS at the time that it is needed. Personally 
identifiable data that exists in OnCore cannot be de-identified or destroyed. Access to the 
OnCore data will remain restricted. 
 
f.   Who will have access to the protected health information (such as the research sponsor, the  
investigator, the research staff, all research monitors, FDA, Yale Cancer Center Data and 
Safety Monitoring Committee (DSMC), SSC, etc.)? (please distinguish between PHI and de-
identified data)  
  
 All of our paper survey forms will be stored in a single locked file cabinet located in the 
Department of Surgery.  Access to the file cabinets will be limited to Dr. Glenda Callender, 
PI of the study, and Dr. Jennifer Malinowski, Administrative Coordinator of the study. 
 
All electronic data will be kept either in the Yale OnCore clinical trials management system or 
on secure Yale servers with access limited to study personnel. PHI in OnCore cannot be 
destroyed or de-identified; access to the OnCore data is restricted. PHI in the research 
database will be de-identified after the study conclusion. This anonymized research data will 
be maintained on the secure Yale server.  
 
g.   If appropriate, has a Certificate of Confidentiality been obtained? 
       
We are not collecting data that would require a Certificate of Confidentiality. 
 
h.   Are any of the study procedures likely to yield information subject to mandatory reporting   
requirements? (e.g. HIV testing – reporting of communicable diseases; parent interview -
incidents of child abuse, elderly abuse, etc.). Please verify to whom such instances will need 
to be reported.  
   
 
No. 
 
SECTION IX: POTENTIAL BENEFITS 
 
 
Potential Benefits: Identify any benefits that may be reasonably expected to result from the 
research, either to the subject(s) or to society at large. (Payment of subjects is not considered a 
benefit in this context of the risk benefit assessment.)  
 
 
An ongoing debate exists as to the optimal management of patients with PTMC.  Options 
vary from total thyroidectomy to thyroid lobectomy to observation only.  Many patients 
undergo total thyroidectomy; it is considered the standard-of-care treatment in the United 
States.  However, morbidity is a concern in thyroid surgery.  Surgical complications, such as 
hoarseness or hypoparathyroidism, and postoperative metabolic/psychological disturbances 
(that can occur in spite of adequate hormone replacement) can profoundly impact patient 
quality of life.  It has been shown that the majority of patients with PTMC can be followed 
safely with observation close surveillance, without a significant difference in patient 
outcome.  The option of percutaneous ethanol ablation allows for actual treatment of the 
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Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 46 of 
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cancer, which is an advantage over observation, but it is considerably less invasive than total 
thyroidectomy. 
 
We are offering a new treatment option for patients with PTMC, which could fundamentally 
change patient management. Percutaneous ethanol ablation is an established tool for the 
management of metastatic thyroid cancer or patients with benign primary thyroid conditions 
who are not ideal surgical candidates.  By introducing this approach for patients with 
PTMC, we can potentially change current patient management and avoid the more invasive 
procedure in many patients (i.e. total thyroidectomy) by treatment of the cancer with a 
minimally invasive and low risk intervention. 
 
 
         SECTION X: RESEARCH ALTERNATIVES AND ECONOMIC CONSIDERATIONS 
 
1.     Alternatives: What other alternatives are available to the study subjects outside of the research? 
 
Total thyroidectomy, thyroid lobectomy, or observation (observation is currently only 
performed as part of a protocol). 
 
2. 
Payments for Participation (Economic Considerations): Describe any payments that will be 
made to subjects, the amount and schedule of payments, and the conditions for receiving this 
compensation.  
 
None 
 
3. 
Costs for Participation (Economic Considerations): Clearly describe the subject’s costs 
associated with participation in the research, and the interventions or procedures of the study that 
will be provided at no cost to subjects.  
 
 
 
The treatment in this study may be considered standard of care and it is anticipated that the 
patient’s health insurance will cover all expenditures for the procedure, i.e percutaneous 
ethanol ablation. The follow-up visits will be performed by an endocrine surgeon from our 
department and the follow-up tests and visits are routine tests that are standard of care for 
surveillance of PTC. 
 
4. 
In Case of Injury: This section is required for any research involving more than minimal risk. 
 
a.   Will medical treatment be available if research-related injury occurs?  
 
        Yes 
b.   Where and from whom may treatment be obtained?  
If a patient is injured as a direct result of this research, he/she will receive treatment. The 
study investigators will assist in the coordination of care with caregivers close to the 
subject’s residence. The patient or their health insurance will be expected to cover the cost 
of the treatment. No additional compensation for injury or lost wages is provided. 
c. Are there any limits to the treatment being provided?  
  There are no limitations. 
d. Who will pay for this treatment?  
The patient or their health insurance. 
APPROVED BY THE YALE UNIVERSITY HIC ON 13 APRIL 2016 VALID THROUGH 25 MARCH 2017


Principle Investigator: Glenda Callender                                                                           HIC# 1312013168 
4/13/2016                                                                                                                        Page 47 of 
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e. How will the medical treatment be accessed by subjects?  
  Patients are instructed to call our office (available 24/7) with any questions or concerns. 
APPROVED BY THE YALE UNIVERSITY HIC ON 13 APRIL 2016 VALID THROUGH 25 MARCH 2017