Conditions: Thyroid Cancer Postsurgical Hypothyroidism
Keywords: levothyroxine
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 14
Healthy volunteers: no

Brief summary:
In some patients, levothyroxine liquid gel capsules may demonstrate superior absorption than the tablet option. Impaired absorption of thyroid hormone directly correlates to higher and more unpredictable TSH (thyroid stimulating hormone) levels.

The investigators therefore hypothesize that following thyroidectomy for Stage I/II differentiated thyroid cancer the gel capsule levothyroxine formulation will provide more predictable TSH results and in turn require fewer dose adjustments to achieve optimal hormone levels in the postoperative period.

The aim of this investigation is to compare the use of levothyroxine in liquid gel capsules to tablet form for TSH suppression following thyroidectomy for presumed stage I/II differentiated thyroid cancer.

Detailed description:
Ten patients will be randomized prior to surgery to receive levothyroxine in tablet form and ten patients will be randomized to receive in gel capsule form. Both forms will be encapsulated in order to allow double-blinding of the study.

The postoperative goal TSH will be between 0.1 and 0.5 mU/L (milli units per litre) in both arms.

Patients will be seen at weeks 6, 12 and 18 postoperatively and have TSH and Free T4 measured. The primary outcome is the number of patients at each visit that are at goal range TSH.

A secondary analysis will compare the dose changes required between the two groups in order to achieve goal TSH.

Another secondary analysis will investigate the patients' quality of life. Two different surveys (see secondary outcomes below) will be performed at both study entry and completion to compare the two groups.

Arms:
arm 1: Patients in this arm will receive levothyroxine tablets (encapsulated for blinding purposes) arm 2: Patients in this arm will receive levothyroxine gelcaps (encapsulated for blinding purposes)

Interventions: intervention 1: Levothyroxine
Intervention descriptions: intervention 1: Patients post-thyroidectomy will receive either levothyroxine in tablet form or in gelcaps. Initial dose 1.5-1.8 mcg per kg, orally and daily

Protocol document:
Prot_SAP_000.pdf: 
Official title: Levothyroxine replacement with liquid gel capsules or 
tablets in post-thyroidectomy low risk differentiated thyroid cancer 
patients. 
 
NCT number: NCT02946918 
Document date: 12/16/2018, Version 03 


 
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Summary of Proposed Protocol Amendments: 2/7/19 
 
• 
Cover page:  
o 
Removal of Lindsay Jacobs as sub-investigator (no longer employed at UT 
Southwestern) 
o 
Akrimax has sold Tirosint to IbSA Pharma 
• 
Given that levothyroxine (both in tablets and gelcaps are only available in specific 
dosages, the initial dose of medication is amended to allow a range (1.5-1.8 mcg/kg) rather 
than a specific weight based target of 1.7 mcg/kg 
• 
Study Objectives 2.1 
o 
“Descriptive statistics are of primary interest as this feasibility study is not powered to 
formally test a statistical hypothesis.” Added to primary objective to emphasize the 
feasibility/pilot nature of this trial. 
• 
Study Eligibility 3.0 
o 
Inclusion criteria: 
 
Preoperative cytology definition clarified to include suspicious as well as 
presumed differentiated thyroid cancer (surgical pathology is 
acknowledged as “gold standard” for diagnosis of malignancy) 
o 
Exclusion criteria: 
 
To provide clarification, concomitant medications that are not permissible 
for study participation due to effects on absorption or metabolism of 
thyroid hormone are listed specifically. 
 
Clarification of prior use of levothyroxine to state within one year of 
enrollment 
• 
Study Procedures: 5.1.6 
o 
Remove respirations from measured vital signs 
• 
Section 5.2 Time and Events Table 
o 
Screening procedures, enrollment and informed consent procedures allowed 
within 14 days 
o 
Visit 2, telephone contact can be made within 7 days of surgery 
o 
Thyroid treatment satisfaction questionnaire only at week 18 (not applicable prior 
to treatment) 
o 
Remove “dispensing study medication” at 18 week visit as a prescription is given 
instead 
o 
Postoperative visits will be given +/- 1 week to facilitate follow up visits 
• 
Address changes made to reflect relocation to West Campus Building 3 
 
 
 
 


 
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Levothyroxine replacement with liquid gel capsules or tablets in post-thyroidectomy low risk 
differentiated thyroid cancer patients. 
 
Pilot feasibility study, randomized, double blinded, stage 1 and 2  
 
Principal Investigator:  
Alexander Tessnow, MD 
 
 
 
 
UT Southwestern 
 
 
 
 
5323 Harry Hines Blvd, Dallas, Texas, 75390-882 
 
 
Phone  
214-645-2868  
 
 
Fax 
 
214-645-2828 
 
 
 
 
Alex.Tessnow@utsouthwestern.edu 
 
 
 
Biostatistician: 
 
Beverley Huet, MS, PSTAT 
 
 
 
 
UT Southwestern 
 
 
 
 
5323 Harry H Hines Blvd, Dallas, Texas, 75390-882 
 
Phone  
 
214-648-2788  
 
 
 
 
Beverley.Huet@utsouthwestern.edu 
 
 
Study Drug: 
 
 
Levothyroxine, Tirosint  
 
 
 
 
Levothyroxine, Synthroid 
 
 
Funding Source:  
IBSA Pharma, Inc 
 
 
Initial version: 
1.0, 04/03/2015 
 
Revised versions: 
2.0, 09/20/2018 
 
3.0, 12/16/2018 
 
 
 
UT Southwestern Medical Center (UTSW) 
West Campus Building 3, 8th Floor 
Attn: Division of Endocrinology 
2001 Inwood Rd 
Dallas, Texas 75390-8872 
 


 
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Signature Page 
 
Protocol  Version  3.0, 12/16/2018 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, including 
all statements regarding confidentiality, and according to local legal and regulatory requirements and 
applicable U.S. federal regulations and ICH guidelines. 
 
 
 
Principal Investigator (PI) Name:_____________________________ 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date:____________________ 
 


 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ...........................................................................................1 
STUDY SCHEMA .............................................................................................................1 
STUDY SUMMARY ..........................................................................................................3 
1.0 BACKGROUND AND RATIONALE ....................................................................3 
1.1 
Disease Background........................................................................................................ 3 
1.2 
Study Agent(s) Background and Associated Known Toxicities ....................................... 3 
1.3 
Other Agents .................................................................................................................... 3 
1.4 
Rationale .......................................................................................................................... 3 
1.5 
Correlative Studies .......................................................................................................... 3 
2.0 STUDY OBJECTIVES .............................................................................................3 
2.1 
Primary Objectives ........................................................................................................... 3 
2.2 
Secondary Objectives ...................................................................................................... 4 
2.3 
Exploratory Objectives ..................................................................................................... 4 
2.4 
Endpoints ......................................................................................................................... 4 
3.0 PATIENT ELIGIBILITY ........................................................................................4 
3.1 
Inclusion Criteria .............................................................................................................. 4 
3.2 
Exclusion Criteria ............................................................................................................. 4 
4.0 TREATMENT PLAN ...............................................................................................5 
4.1 
Treatment Dosage and Administration ............................................................................ 5 
4.2 
Dose Modifications .......................................................................................................... 5 
4.3 
Duration of Therapy ......................................................................................................... 6 
4.4 
Duration of Follow Up ...................................................................................................... 6 


 
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4.5 
Removal of Patients from Protocol Therapy .................................................................... 6 
5.0 STUDY PROCEDURES ..........................................................................................6 
5.1 
Screening/Baseline Procedures ...................................................................................... 6 
5.2 
Procedures During Treatment ......................................................................................... 7 
5.3 
Follow-up Procedures ...................................................................................................... 7 
5.4 
Time and Events Table .................................................................................................... 7 
5.5 
Removal of Subjects from Study ..................................................................................... 8 
6.0 ADVERSE EVENTS ................................................................................................8 
6.1 
Experimental Therapy...................................................................................................... 8 
6.2 
Adverse Event Monitoring ............................................................................................... 8 
6.3 
Steps to Determine If an Adverse Event Requires Expedited Reporting ...................... 10 
6.4 
Stopping Rules .............................................................................................................. 10 
7.0 DRUG INFORMATION ........................................................................................10 
7.1 
Levothyroxine ................................................................................................................ 11 
8.0 STATISTICAL CONSIDERATIONS ..................................................................13 
8.1 
Study Design/Study Endpoints ...................................................................................... 13 
8.2 
Sample Size and Accrual .............................................................................................. 13 
8.3 
Data Analyses Plans...................................................................................................... 13 
9.0 STUDY MANAGEMENT ......................................................................................13 
9.1 
Conflict of Interest .......................................................................................................... 15 
9.2 
Institutional Review Board (IRB) Approval and Consent ............................................... 14 
9.3 
Required Documentation ............................................................................................... 14 
9.4 
Registration Procedures .................................................................................................. 1 
9.5 
Data Management and Monitoring/Auditing .................................................................. 14 
9.6 
Adherence to the Protocol ............................................................................................. 16 


 
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9.7 
Amendments to the Protocol ......................................................................................... 17 
9.8 
Record Retention ........................................................................................................... 17 
9.9 
Obligations of Investigators ........................................................................................... 18 
10.0 REFERENCES ........................................................................................................19 
11.0 APPENDICES .........................................................................................................20 
11.0 
ThyTSQ  
 
11.2 
QoL-Thyroid 


 
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LIST OF ABBREVIATIONS  
FT4 
 
 
Free T4  
 
 
LT4 
 
 
Levothyroxine 
 
QoL-Thyroid   
Thyroid version Quality of Life Questionnaire  
 
TFT 
 
 
Thyroid Function Tests (TSH and FT4) 
 
TSH 
 
 
Thyroid Stimulating Hormone 
 
ThyTSQ 
 
Underactive Thyroid Treatment Satisfaction Questionnaire  
 
STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Levothyroxine tablet or gel formulation  
 
1.5-1.8 mcg per kg as initial post-surgical 
dose 
 
Continue daily therapy for 6 weeks x 3 cycles 
With dose assessment and titration based on target 
TSH values of 0.10 -0.50 
TSH at 
goal 
TSH not at 
goal 
 
Continue current daily dose of LT4 
 
LT4 dose adjustment 
Patient registration 
TSH Evaluation by blood test 


 
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STUDY SUMMARY 
Title 
Levothyroxine replacement with liquid gel capsules or tablets in post-
thyroidectomy low risk differentiated thyroid cancer patients. 
Short Title 
Post-surgical LT4 replacement gelcap vs tablet in patients with stage 1 
and 2 Differentiated Thyroid Cancer 
Protocol Number 
3.0 
Phase 
pilot, feasibility study  
Methodology 
 double blinded; randomized 
Study Duration 
4 years 
Study Center(s) 
Single-center  
Objectives 
The aim of this investigation is to compare the use of levothyroxine in 
liquid gel capsules to tablet form for TSH suppression following 
thyroidectomy for presumed stage I/II differentiated thyroid cancer.   
Number of Subjects 
20 
Diagnosis and Main 
Inclusion Criteria 
AJCC Stage I/II differentiated thyroid cancer,  post-thyroidectomy 
Study Product(s), Dose, 
Route, Regimen 
Synthroid and Tirosint levothyroxine formulations. Initial dose 1.5-1.8 
mcg per kg, orally and daily 
Duration of administration 
18 weeks 
Statistical Methodology 
Continuous variables will be summarized with mean and standard 
deviation; medians and ranges will be reported for skewed variables.  
We will construct 95% confidence intervals will be used to estimate 
liquid gel capsule treatment and tablet treatment responses at each 
study visit and to estimate differences between groups or visits within 
groups.   
 
 
 


 
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1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
 
Globally, the incidence of differentiated thyroid cancer has increased considerably over 
the past 25 years.  Numerous international studies have demonstrated this trend in Europe, 
Australia, South America and the Middle East.   Domestically the US has seen a steady annual 
increase in differentiated thyroid cancer from approximately 3.5 cases per 100,000 observed from 
1988-1998 to now approximately 8.7 cases per 100,000.  Not only are more patients being 
diagnosed with thyroid cancer but there is also a documented increase in the number of large 
tumors in these patients. Despite this increasing trend, the 10-year disease specific survival rate 
remains high at over 90%.  The overall positive prognosis of differentiated thyroid cancer can be 
attributed to the slow growing and rarely aggressive nature of this disease as well as the 
streamlined guidelines provided by the American Thyroid Association that are used in the 
treatment and management of these patients.  
 
Aside from radioactive iodine ablation, TSH suppression is one of the most basic yet effective 
postsurgical therapies used in the treatment of patients with thyroid cancer.  By maintaining 
higher than normal T4 levels with exogenous thyroid hormone replacement, the TSH is down 
regulated to lower than normal levels, which subsequently decreases remaining thyroidal cell 
activity and growth. As recommended by the American Thyroid Association’s most recent 
published guidelines, TSH suppression of 0.1 – 0.5 mU/L is recommended for all patients with 
low risk of reoccurrence. A large majority of stage I and II differentiated thyroid cancer patients fall 
into this low risk category.  Careful titration of levothyroxine is used to appropriately manage 
these patient’s TSH levels into this therapeutic window.   
 
There is limited data on the use of liquid gel capsules for the use of levothyroxine replacement 
and TSH suppression in post thyroidectomy patients with a history of thyroid cancer.  Studies 
have suggested that in some patients, levothyroxine liquid gel capsules demonstrate superior 
absorption than the tablet option. Impaired absorption of thyroid hormone directly correlates to 
higher and more unpredictable TSH levels. We therefore hypothesize that following 
thyroidectomy the gel capsule levothyroxine formulation will provide more predictable TSH results 
and in turn require fewer dose adjustments to achieve optimal hormone levels in the 
postoperative period.    
1.2 
Study Agent(s) Background and Associated Known Toxicities 
Both study agents are FDA approved formulations of levothyroxine. These therapies are 
considered safe and regularly used in the postsurgical management of hypothyroidism.  
1.3 
Rationale 
 Patients with AJCC Stage I/II differentiated thyroid cancer are recommended to have 
TSH suppression (goal 0.1-0.5 mU/L) during the immediate postoperative period to 
prevent recurrence.  As many of these patients do not have pre-existing thyroid synthetic 
dysfunction, they represent a treatment naïve population well suited to study initiation of 
levothyroxine therapy.   
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
2.1.1 
The aim of this investigation is to compare the use of levothyroxine in liquid gel 
capsules to tablet form for TSH suppression (target 0.1-0.5 MIU/L) following 
thyroidectomy for presumed stage I/II differentiated thyroid cancer. This will be 


 
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achieved by evaluating the number of patients in each group at the predefined 
target TSH range at each time interval (6, 12, and 18 weeks (+/- 1 week for each 
interval) postoperatively).  Descriptive statistics are of primary interest as this 
feasibility study is not powered to formally test a statistical hypothesis. 
2.2 
Secondary Objectives 
 
2.2.1 
To quantify the mean number of dose adjustments, and compare the two study 
agent group outcomes  
 
2.2.2 
To assess and compare quality of life differences between study groups using 
scores on QoL-Thyroid and ThyTSQ surveys  
2.3 
Endpoints 
The 18 week post-operative visit will serve as the endpoint of this study.  
3.0 
Subject ELIGIBILITY 
Eligibility waivers are not permitted. Subjects must meet all of the inclusion and exclusion criteria 
to be registered to the study. Study treatment may not begin until a subject is registered. 
3.1 
Inclusion Criteria 
3.1.1 
Preoperative cytology suspicious of or positive for differentiated thyroid cancer 
 
3.1.2 
Presumed AJCC tumor stage I or II 
 
3.1.3 
Planned total, near-total or completion thyroidectomy requiring lifelong thyroid 
hormone replacement.  
 
3.1.4 
Planned goal TSH suppression 0.1-0.5 mU/L for at least 18 weeks 
postoperatively 
 
3.1.5 
Normal serum TSH within 12 months preceding surgery 
 
3.1.6 
Age ≥ 18 years. 
 
3.1.7 
Ability to understand and the willingness to sign a written informed consent. 
3.2 
Exclusion Criteria 
 
3.2.1 
AJCC Stage III/IV differentiated thyroid cancer 
 
3.2.2 
Undifferentiated, Anaplastic or Medullary thyroid cancer 
 
3.2.3 
Planned postoperative TSH goal different than 0.1-0.5 mU/L 
 
3.2.4 
History of gastrointestinal mal-absorption or gastric bypass surgery 
 
3.2.5 
Pregnancy 
 
3.2.6 
Concurrent use of phenobarbital, carbamazepine, rifampin, amiodarone, or 
tyrosine kinase inhibitors 
 
3.2.7 
Use of levothyroxine within 12 months of enrollment 


 
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3.2.8 
Anticipated RAI treatment within 18 weeks of treatment 
 
4.0 
TREATMENT PLAN 
4.1 
Treatment Dosage and Administration 
 
4.1.2 
Initial dose of medication will be dispensed upon enrollment (Visit 1).  Refills will 
be dispensed at the Aston based research pharmacy at subsequent follow up 
visits.  
4.1.2 
The initial dose of both levothyroxine formulations will be based on the patient’s 
actual body weight: 1.5-1.8 mcg per kg. Medication dose will be adjusted at each 
follow up visit and titrated until goal TSH of 0.10 -0.50 is reached.   
 
4.1.2 
Treatment will be administered on an outpatient basis.  
 
 
 
 
REGIMEN DESCRIPTION 
 
Agent 
Premedications; 
Precautions 
 
Dose 
 
Route 
 
Schedule 
Trial Therapy 
Length  
Synthroid 
Take on an 
empty stomach 
first thing in the 
morning. Do not 
eat/drink or take 
other vitamins or 
medications 
within one hour 
of taking this 
medication.  
Initial dose: 
1.5-1.8 mcg per 
kg 
 
  
PO in the a.m. 
daily 
18 weeks  
 
Tirosint 
Take on an 
empty stomach 
first thing in the 
morning. Do not 
eat/drink or take 
other vitamins or 
medications 
within one hour 
of taking this 
medication. 
Initial dose: 
1.5-1.8 mcg per 
kg 
 
  
PO in the a.m. 
daily 
 
 
 
 
These medications will be self-administered. At every clinical follow up visit a pill count 
will be inventoried to confirm compliance.  
4.2 
Dose Modifications 
Levothyroxine doses will be titrated to achieve optimal suppression of TSH levels (0.10 – 
0.50).  Dose adjustments will be made at 6 and 12 week postoperative visits utilizing 
available levothyroxine doses or combinations thereof listed in section 7.1.  


 
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4.3 
Duration of Therapy 
• 
As thyroid hormone replacement is necessary for life following 
thyroidectomy, these patients will be treated with levothyroxine indefinitely.  
According to the American Thyroid Association guidelines, levothyroxine is 
the treatment of choice for thyroid hormone replacement. 
4.4 
Duration of Follow Up 
Subjects will not be followed after removal from treatment, as this therapy is standard of 
care and imposes no additional risk to the patients.  Subjects removed from treatment for 
unacceptable adverse events will be followed until resolution or stabilization of the 
adverse event.  
4.5 
Removal of Subjects from Protocol Therapy 
Subjects will be removed from therapy when any of the criteria listed in Section 5.5 apply. 
Notify the Principal Investigator, and document the reason for study removal and the date 
the subject was removed in the Case Report Form. The subject should be followed-up 
per protocol.  
5.0 
STUDY PROCEDURES 
5.1 Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only 
after obtaining informed consent. Assessments performed for clinical indications (not 
exclusively to determine study eligibility) may be used for baseline values even if the 
studies were done before informed consent was obtained. 
 
All screening procedures must be performed within 14 days prior to registration unless 
otherwise stated. The screening procedures include: 
5.1.1 Informed Consent 
5.1.2 Medical history 
Complete medical and surgical history, history of infections 
5.1.3 Demographics 
Age, gender, race, ethnicity 
5.1.4 Review subject eligibility criteria 
5.1.5 Review previous and concomitant medications 
5.1.6 Physical exam including vital signs, height (initial visit only) and weight 
Vital signs (temperature, pulse, blood pressure), weight 
5.1.7 
Serum chemistries – if not performed within the prior 12 months 
 
 
 
TSH 
 
 
 
FT4 
 
 
5.1.8 
Urine tests 
 
 
 
 
Pregnancy test (if female of child-bearing potential) 


 
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5.1.9 
Patient Quality of Life Questionnaires 
 
QoL-Thyroid 
5.2 
Time and Events Table [When appropriate, this may be referenced and included in 
the appendices rather than within the body of the protocol. Consider landscape 
format when necessary to include all of the appropriate procedures and tests] 
.  
 
 
 
 
Visit 
1 
2 
3 
4 
5 
Time 
Within 
14 days 
preop 
Postoperative 
Day #1-7 
     5-7 
weeks 
     11-
13     
weeks 
   17-19  
weeks 
Type 
Office 
Phone 
Office 
Office 
Office 
Consent 
x 
  
  
  
  
I&E criteria 
x 
  
  
  
  
Randomization 
x 
  
  
  
Physical exam 
x 
  
x  
x 
x 
Height 
x 
  
  
  
  
Vitals (weight, BP, pulse) 
x 
 x 
x 
x 
Labs (TSH, Free T4) 
X if not 
done 
within 
12 
months 
  
 x 
 x 
x 
Dispense trial drug 
 x 
 x 
x 
 
QoL questionnaires (QoL –Thyroid 
and   ThyTSQ) 
X (QOL 
ONLY)  
  
  
X 
AE and SAE assessment 
  
x 
x 
x 
Pregnancy test (if applicable) 
x 
 x 
x 
x 
Answer Study Related Questions 
x 
x 
x 
x 
x 


 
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5.3 Removal of Subject/Withdrawal from Study 
Subjects can be taken off the study treatment and/or study at any time at their own 
request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral or administrative reasons. The reason(s) for discontinuation will be 
documented and may include: 
5.3.1 
Subject voluntarily withdraws from treatment; 
5.3.2 
Subject withdraws consent (termination of treatment and follow-up); 
5.3.3 
Subject is unable to comply with protocol requirements; 
5.3.4 
Treating physician determines that the continuation on the study would not be in 
the subject’s best interest; 
5.3.5 
Lost to follow-up 
5.3.6 
Patient becomes pregnant during this study (this is a dose based study and 
pregnancy can affect hormone titration) 
 
6.0 
ADVERSE EVENTS 
6.1 
Experimental Therapy 
Synthroid and Tirosint are not experimental drugs. Levothyroxine therapy is standard of 
care.  
6.2 
Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those 
who will enroll in future studies using similar agents. Adverse events are reported in a 
routine manner at scheduled times during a trial. Additionally, certain adverse events 
must be reported in an expedited manner to allow for optimal monitoring of subject safety 
and care.  
 
All subjects experiencing an adverse event, regardless of its relationship to study drug, 
will be monitored until:  
 the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline;  
 any abnormal laboratory values have returned to baseline;  
 there is a satisfactory explanation other than the study drug for the changes 
observed; or 
 death. 
 
 
6.2.1 
Definition  
Adverse Events will be reported as indicated by the appropriate following table (see 
below).    
An adverse event is defined as any untoward or unfavorable medical occurrence in a 
human research study participant, including any abnormal sign (for example, abnormal 
physical exam or laboratory finding), symptom, clinical event, or disease, temporarily 


 
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associated with the subject’s participation in the research, whether or not it is considered 
related to the subject’s participation in the research. 
Adverse events encompass clinical, physical and psychological harms. Adverse events 
occur most commonly in the context of biomedical research, although on occasion, they 
can occur in the context of social and behavioral research. Adverse events may be 
expected or unexpected. 
Severity  
Adverse events will be graded by a numerical score according to the defined NCI 
Common Terminology Criteria for Adverse Events (NCI CTCAE) and version number 
specified in the protocol. Adverse events not specifically defined in the NCI CTCAE will 
be scored on the Adverse Event log according to the general guidelines provided by the 
NCI CTCAE and as outlined below.   
• 
Grade 1: Mild  
• 
Grade 2: Moderate 
• 
Grade 3: Severe or medically significant but not immediately life threatening 
• 
Grade 4: Life threatening consequences 
• 
Grade 5: Death related to the adverse event 
 
Serious Adverse Events  
ICH Guideline E2A and the UTSW IRB define serious adverse events as those events, 
occurring at any dose, which meets any of the following criteria:  
• 
Results in death   
• 
Immediately life-threatening  
• 
Results in inpatient hospitalization1,2 or prolongation of existing hospitalization  
• 
Results in persistent or significant disability/incapacity  
• 
Results in a congenital anomaly/birth defect  
• 
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. 
Note: A “Serious adverse event” is by definition an event that meets any of the above 
criteria. Serious adverse events may or may not be related to the research project. A 
serious adverse event determination does not require the event to be related to the 
research. That is, both events completely unrelated to the condition under study and 
events that are expected in the context of the condition under study may be serious 
adverse events, independent of relatedness to the study itself. As examples, a car 
accident requiring overnight hospitalization would be a serious adverse event for any 
research participant; likewise, in a study investigating end-stage cancer care, any 
hospitalization or death would be a serious adverse event, even if the event observed is a 
primary clinical endpoint of the study. Refer to the UTSW IRB website at 
http://www.utsouthwestern.net/intranet/research/research-administration/irb/study-
management/adverse-events.html to determine when a serious adverse event requires 
reporting to the IRB. 
1Pre-planned hospitalizations or elective surgeries are not considered SAEs. Note: If 
events occur during a pre-planned hospitalization or surgery, that prolong the existing 
hospitalization, those events should be evaluated and/or reported as SAEs.   


 
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2 NCI defines hospitalization for expedited AE reporting purposes as an inpatient hospital 
stay equal to or greater than 24 hours. Hospitalization is used as an indicator of the 
seriousness of the adverse event and should only be used for situations where the AE 
truly fits this definition and NOT for hospitalizations associated with less serious events. 
For example: a hospital visit where a patient is admitted for observation or minor 
treatment (e.g. hydration) and released in less than 24 hours. Furthermore, 
hospitalization for pharmacokinetic sampling is not an AE and therefore is not to be 
reported either as a routine AE or in an expedited report. 
6.2.2 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs): 
The phrase “unanticipated problems involving risks to subjects or others” is found, but not 
defined in the HHS regulations at 45 CFR 46, and the FDA regulations at 21 CFR 
56.108(b)(1) and 21 CFR 312.66. For device studies, part 812 uses the term 
unanticipated adverse device effect, which is defined in 21 CFR 812.3(s). Guidance from 
the regulatory agencies considers unanticipated problems to include any incident, 
experience, or outcome that meets ALL three (3) of the following criteria: 
• 
Unexpected in terms of nature, severity or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the subject 
population being studied;  
 
 
 
 
AND 
• 
Related or possibly related to participation in the research (possibly related means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); 
 
AND  
• 
Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. Note: According to OHRP, if the adverse event is serious, it would always 
suggest a greater risk of harm. 
 
Follow-up 
All adverse events will be assessed for 18 weeks and followed up according to good 
medical practices.  
  
6.3 
Steps to Determine If a Serious Adverse Event Requires Expedited Reporting to the 
SCCC DSMC and/or HRPP 
Step 1: Identify the type of adverse event using the NCI Common Terminology Criteria 
for Adverse Events (CTCAE v5).  
 
Step 2: Grade the adverse event using the NCI CTCAE v5. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy.  
Attribution categories are as follows: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE may NOT be related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 


 
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Note: This includes all events that occur within 30 days of the last dose of protocol 
treatment (alternatively, to the end of the acute adverse events reporting period as 
defined in section XX). Any event that occurs more than 30 days after the last dose of 
treatment (alternatively, during the late adverse event period as defined in section XX) 
and is attributed (possibly, probably, or definitely) to the agent(s) must also be reported 
as indicated in the sections below. 
 
Step 4: Determine the prior experience of the adverse event. Expected events are those 
that have been previously identified as resulting from administration of the treatment. An 
adverse event is considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in: 
• 
the current known adverse events listed in the Agent Information Section of this 
protocol (if applicable); 
• 
the drug package insert (if applicable); 
• 
the current Investigator’s Brochure (if applicable) 
• 
the Study Agent(s)/Therapy(ies) Background and Associated Known Toxicities 
section of this protocol 
 
6.3.1 
Reporting SAEs and UPIRSOs to the Simmons Comprehensive Cancer Center 
(SCCC) Data Safety Monitoring Committee (DSMC) 
 
All SAE/UPIRSOs at all sites, which occur in research subjects on protocols for which the 
SCCC is the DSMC of record require reporting to the DSMC regardless of whether IRB 
reporting is required. All SAEs/UPIRSOs occurring during the protocol-specified 
monitoring period should be submitted to the SCCC DSMC within 5 business days of the 
PI or delegated study team members awareness of the event(s). In addition, for 
participating centers other than UTSW, local IRB guidance should be followed for local 
reporting of serious adverse events. 
 
The UTSW study team is responsible for submitting SAEs/UPIRSOs to the SCCC DSMC 
Coordinator.  Hardcopies or electronic versions of the eIRB Reportable Event report; FDA 
Form #3500A forms, or other sponsor forms, if applicable; and/or any other supporting 
documentation available should be submitted to the DSMC Coordinator.  The DSMC 
Coordinator forwards the information onto the DSMC Chairman who determines if 
immediate action is required.  Follow-up eIRB reports, and all subsequent SAE/UPIRSO 
documentation that is available are also submitted to the DSMC Chair who determines if 
further action is required. (See Appendix III of the SCCC DSMC Plan for a template Serious 
Adverse Event Form which may be utilized when a sponsor form is unavailable and SAE 
submission to the eIRB is not required). 
  
 
If the event occurs on a multi-institutional clinical trial coordinated by the UTSW Simmons 
Comprehensive Cancer Center, the DOT Manager or lead coordinator ensures that all 
participating sites are notified of the event and resulting action, according to FDA 
guidance for expedited reporting. DSMC Chairperson reviews all SAEs/UPIRSOs upon 
receipt from the DSMC Coordinator.  The DSMC Chairperson determines whether action 
is required and either takes action immediately, convenes a special DSMC session 
(physical or electronic), or defers the action until a regularly scheduled DSMC meeting.  
 
 
  
Telephone reports to: 
 
 
 


 
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 Primary Investigator: Alexander Tessnow 
 (if fax report is not available) within 1 working day to 214-645-2868 
 
Written reports to: 
 
Primary Investigator: Alexander Tessnow 
Email: Alex.Tessnow@utsouthwestern.edu 
Fax: 214-645-2828 or deliver to West Campus Building 3, 8th floor Endocrine Office 
 
UTSW SCCC Data Safety Monitoring Committee Coordinator 
Email: SCCDSMC@utsouthwestern.edu 
Fax: 214-648-5949 or deliver to BLB.306 
 
UTSW Institutional Review Board (IRB) 
Submit a Reportable Event via eIRB with a copy of the final sponsor report as 
attached supporting documentation 
 
 
Reporting Unanticipated Problems Involving Risks to Subjects or Others 
(UPIRSOs) to the UTSW HRPP/IRB 
 
UTSW reportable event guidance applies to all research conducted by or on behalf of UT 
Southwestern, its affiliates, and investigators, sites, or institutions relying on the UT 
Southwestern IRB. Additional reporting requirements apply for research relying on a non-
UT Southwestern IRB. 
 
According to UTSW HRPP/IRB policy, UPIRSOs are incidents, experiences, outcomes, 
etc. that meet ALL three (3) of the following criteria: 
1. Unexpected in nature, frequency, or severity (i.e., generally not expected in a 
subject’s underlying condition or not expected as a risk of the study; therefore, not 
included in the investigator’s brochure, protocol, or informed consent document),AND 
2. Probably or definitely related to participation in the research, AND 
3. Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized.  Note: According to OHRP, if the adverse event is serious, it 
would always suggest a greater risk of harm. 
 
For purposes of this policy, UPIRSOs include unanticipated adverse device effects 
(UADEs) and death or serious injury related to a humanitarian use device (HUD).  
 
UPIRSOs must be promptly reported to the UTSW IRB within 5 working days of 
PI awareness. 
 
For research relying on a non-UT Southwestern IRB (external, central, or single IRB): 
 
Investigators relying on an external IRB who are conducting research on behalf of UT 
Southwestern or its affiliates are responsible for submitting LOCAL UPIRSOs to the UT 
Southwestern IRB within 5 working days of PI awareness. Investigators must report to 
their relying IRB according to the relying IRB’s policy. In addition, the external IRB’s 
responses or determinations on these local events must be submitted to the UT 
Southwestern IRB within 10 working days of receipt. 
 
Events NOT meeting UPIRSO criteria: 


 
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Events that do NOT meet UPIRSO criteria should be tracked, evaluated, summarized, 
and submitted to the UTSW HRPP/IRB at continuing review. 
 
For more information on UTSW HRPP/IRB reportable event policy, see 
https://www.utsouthwestern.edu/research/research-administration/irb/assets/policies-
combined.pdf. 
6.4 
Stopping Rules 
There are no stopping rules 
7.0 
DRUG INFORMATION 
7.1 
Levothyroxine 
 
• 
Other names for the drug(s): Tirosint, Synthroid 
 
• 
Classification - type of agent: Thyroid hormone 
 
• 
Mode of action: Synthetic levothyroxine is identical to that produced naturally in the 
human thyroid gland. 
 
• 
Storage and stability: room temperature 
 
• 
Protocol dose: Starting dose will be 1.5-1.8 mcg per kg, using the patient’s actual 
weight. Dose will be rounded to the nearest available incremental dose of the 
randomized formulation. Dose will be adjusted to next higher or next lower dose 
during follow up visits based on TSH values.  Doses can be initiated or adjusted by 
single or combination of preparations listed below.  Note: if dose requires use of 12.5 
mcg or 13 mcg, exact dose will be determined based on the brand to which the 
subject was randomized. This is due to gel capsules only available in 13 mcg while 
tablets can only be split to 12.5 mcg.   
 
• 
Route of administration for this study: oral 
 
• 
Incompatibilities: Must be taken on an empty stomach. Must wait at least 1 hour 
before taking food/water/other medications or vitamins 
 
• 
Availability: commercially available, both formulations will be encapsulated in a 
fashion to allow double blinding.  The available strengths above (including 12.5 mcg 
split from 25 mcg Synthroid) will be encapsulated by an outside compounding 
pharmacy.  The medication will be shipped directly to the Aston research pharmacy 
(8th floor) that will dispense all medication and will not be blinded.  The Aston 
pharmacy will be given the randomization code for the patient by the study 
statistician, Beverley Huet.  The pharmacy will dispense medication according to the 
randomization.   
 
• 
Side effects: Adverse Reactions associated with levothyroxine therapy are symptoms 
of hyperthyroidism due to therapeutic over-dosage.  
 
• 
Nursing implications: none 


 
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• 
Pharmacokinetics – from package inserts of Tirosint and Synthroid which is identical 
except for absorption. 
 
• 
Absorption: 
 
o 
Absorption of orally administered T4 from the gastrointestinal (GI) 
tract ranges from 40% to 80%. The majority of the levothyroxine 
dose is absorbed from the jejunum and upper ileum. The relative 
bioavailability of TIROSINT capsules compared to another marketed 
levothyroxine sodium tablet is approximately 103%. The relative 
bioavailability of SYNTHROID tablets, compared to an equal nominal 
dose of oral levothyroxine sodium solution, is approximately 93%.T4 
absorption is increased by fasting, and decreased in malabsorption 
syndromes and by certain foods such as soybeans. Dietary fiber 
decreases the bioavailability of T4. Absorption may also decrease 
with age. In addition, many drugs and foods affect T4 absorption. 
• 
Distribution 
o 
Circulating thyroid hormones are greater than 99% bound to plasma 
proteins, including thyroxine-binding globulin (TBG), thyroxine-
binding prealbumin (TBPA), and thyroxine-binding albumin (TBA), 
whose capacities and affinities vary for each hormone. The higher 
affinity of both TBG and TBPA for T4 partially explains the higher 
serum levels, slower metabolic clearance, and longer half-life of T4 
compared to T3. Protein-bound thyroid hormones exist in reverse 
equilibrium with small amounts of free hormone. Only unbound 
hormone is metabolically active. Many drugs and physiologic 
conditions affect the binding of thyroid hormones to serum proteins 
• 
Metabolism 
o 
T4 is slowly eliminated. The major pathway of thyroid hormone 
metabolism is through sequential deiodination. Approximately 80% of 
circulating T3 is derived from peripheral T4 by monodeiodination. The 
liver is the major site of degradation for both T4 and T3, with T4 
deiodination also occurring at a number of additional sites, including 
the kidney and other tissues. Approximately 80% of the daily dose of 
T4 is deiodinated to yield equal amounts of T3 and reverse T3 (r T3). 
T3 and r T3 are further deiodinated to diiodothyronine. Thyroid 
hormones are also metabolized via conjugation with glucuronides 
and sulfates and excreted directly into the bile and gut where they 
undergo enterohepatic recirculation. 
• 
Elimination 
o 
Thyroid hormones are primarily eliminated by the kidneys. A portion 
of the conjugated hormone reaches the colon unchanged and is 
eliminated in the feces. Approximately 20% of T4 is eliminated in the 
stool. Urinary excretion of T4 decreases with age. 
7.1.1 
Return and Retention of Study Drug 
The remaining drugs will be destroyed according to the UT Southwestern pharmacy 
policy.  
 
7.1.2 
Subject’s compliance with the study agents will be assessed at every clinical 
appointment. A pill count will be inventoried by the practitioner and recorded in the 
patient’s electronic medical record.  


 
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8.0 
STATISTICAL CONSIDERATIONS 
8.1 
Study Design/Study Endpoints 
 
This is a double blinded, randomized, single center study. The study will end at the 18 
week post-surgical follow up appointment.   
. 
8.2 
Sample Size and Accrual 
As this is a feasibility study it will only include 20 total, study-completed participants. Each 
arm of the study will include 10 patients. Descriptive statistics are of primary interest as 
this study is not powered to formally test a statistical hypothesis.  
8.3 
Data Analyses Plans 
Continuous variables will be summarized with mean and standard deviation; medians 
and ranges will be reported for skewed variables.  We will construct 95% confidence 
intervals will be used to estimate liquid gel capsule treatment and tablet treatment 
responses at each study visit and to estimate differences between groups or visits within 
groups.  This study has repeated measurements and these longitudinal data will be 
evaluated using a mixed linear model approach for repeated measures.   Due to the pilot 
nature of study any hypothesis testing will be interpreted cautiously.  The primary 
analysis data set will be the intention-to-treat analysis data set consisting of all 
randomized subjects who have at least one post-randomization study visit. All available 
data, including cases with missing data, will be included in the statistical analysis. 
Categorical variables, including any adverse events, will be summarized in detail with 
descriptive statistics.  P values of < 0.05 will be considered statistically significant. 
9.0 
STUDY MANAGEMENT 
9.1 
Conflict of Interest 
 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, 
or financial gain greater than the minimum allowable by their institution, etc.) must have 
the conflict reviewed by the UTSW COI Committee and IRB according to UTSW Policy 
on Conflicts of Interest.  All investigators will follow the University conflict of interest 
policy. 
 
9.2 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB must approve the consent form and 
protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the subject will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 


 
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provided to the subject and the investigator is assured that the subject understands the 
implications of participating in the study, the subject will be asked to give consent to 
participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the subject and by the person who conducted the 
informed consent discussion. 
9.3 Required Documentation (for multi-site studies) 
Not applicable 
9.4 Registration Procedures 
Not applicable 
9.5 Data Management and Monitoring/Auditing 
 
Trial monitoring will be conducted by no less than annually and refers to a regular interval 
review of trial related activity and documentation performed by the study team, which 
includes but is not limited to accuracy of case report forms, protocol compliance, timeless 
and accuracy of Velos entries and AE/SAE management and reporting. Documentation 
of trial monitoring will be maintained along with other protocol related documents and will 
be reviewed during internal audit.   
 
Toxicity and dose escalation reviews will be performed by the primary investigator, Dr. 
Tessnow at each follow up visit.  These reviews will be documented in the visit note and 
electronic medical record.  
 
9.6 Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study subject requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol.  
9.6.1 
Exceptions (also called single-subject exceptions or single-subject waivers): 
include any departure from IRB-approved research that is not due to an 
emergency and is: 
• intentional on part of the investigator; or 
• in the investigator’s control; or 
• not intended as a systemic change (e.g., single-subject exceptions to eligibility 
[inclusion/exclusion] criteria) 
 Reporting requirement: Exceptions are non-emergency deviations that require prospective 
IRB approval before being implemented. Call the IRB if your request is 
urgent. If IRB approval is not obtained beforehand, this constitutes a major 
deviation. 
9.6.2 
Emergency Deviations: include any departure from IRB-approved research that 
is necessary to:  
• avoid immediate apparent harm, or 
• protect the life or physical well-being of subjects or others 
 Reporting requirement: Emergency deviations must be promptly reported 


 
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to the IRB within 5 working days of occurrence. 
9.6.3 
Major Deviations (also called violations): include any departure from IRB-
approved research that: 
• 
Harmed or placed subject(s) or others at risk of harm (i.e., did or has the 
potential to negatively affect the safety, rights, or welfare of subjects or 
others), or 
• 
Affect data quality (e.g., the completeness, accuracy, reliability, or validity of 
the data) or the science of the research (e.g., the primary outcome/endpoint of 
the study) 
 Reporting requirement: Major deviations must be promptly reported to  
the IRB within 5 working days of PI awareness. 
 
9.6.4 
Minor Deviations: include any departure from IRB-approved research that: 
• 
Did not harm or place subject(s) or others at risk of harm (i.e., did not or did 
not have the potential to negatively affect the safety, rights, or welfare of 
subjects or others), or 
• 
Did not affect data quality (e.g., the completeness, accuracy, reliability, or 
validity of the data) or the science of the research (e.g., the primary 
outcome/endpoint of the study) 
 Reporting requirement: Minor deviations should be tracked and 
summarized in the progress report at the next IRB continuing review. 
9.7 Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator.  A summary of changes document outlining 
proposed changes as well as rationale for changes, when appropriate, is highly 
recommended.  When an amendment to the protocol substantially alters the study design 
or the potential risk to the patient, a revised consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the 
IRB for approval prior to implementation.  
9.8 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. 
 
Government agency regulations and directives require that the study investigator retain 
all study documentation pertaining to the conduct of a clinical trial. In the case of a study 
with a drug seeking regulatory approval and marketing, these documents shall be 
retained for at least two years after the last approval of marketing application in an 
International Conference on Harmonization (ICH) region. In all other cases, study 
documents should be kept on file until three years after the completion and final study 
report of this investigational study. 


 
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9.9 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The Principal Investigator is responsible for personally overseeing the treatment 
of all study patients. The Principal Investigator must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol 
and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and 
after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected and entered onto the Case Report Forms. Periodically, 
monitoring visits may be conducted and the Principal Investigator will provide access to 
his/her original records to permit verification of proper entry of data. At the completion of 
the study, all case report forms will be reviewed by the Principal Investigator and will 
require his/her final signature to verify the accuracy of the data. 
 


 
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10.0 
REFERENCES 
1. 
Rego-Iraeta A, Perez-Mendez LF, Mantinan B, Garcia-Mayor RV. Time trends for thyroid cancer 
in northwestern Spain: true rise in the incidence of micro and larger forms of papillary thyroid 
carcinoma. Thyroid. 2009;19(4):333-40. doi: 10.1089/thy.2008.0210. PubMed PMID: 19355823. 
2. 
Burgess JR. Temporal trends for thyroid carcinoma in Australia: an increasing incidence of 
papillary thyroid carcinoma (1982-1997). Thyroid. 2002;12(2):141-9. doi: 
10.1089/105072502753522374. PubMed PMID: 11916283. 
3. 
Cordioli MI, Canalli MH, Coral MH. Increase incidence of thyroid cancer in Florianopolis, Brazil: 
comparative study of diagnosed cases in 2000 and 2005. Arq Bras Endocrinol Metabol. 2009;53(4):453-
60. PubMed PMID: 19649384. 
4. 
Sisson JC. The increasing incidence of thyroid cancer in Saudi Arabia. Ann Saudi Med. 
1995;15(6):557-8. PubMed PMID: 17589008. 
5. 
Chen AY, Jemal A, Ward EM. Increasing incidence of differentiated thyroid cancer in the United 
States, 1988-2005. Cancer. 2009;115(16):3801-7. doi: 10.1002/cncr.24416. PubMed PMID: 19598221. 
6. 
Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, McIver B, Pacini 
F, Schlumberger M, Sherman SI, Steward DL, Tuttle RM. Revised American Thyroid Association 
management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 
2009;19(11):1167-214. Epub 2009/10/29. doi: 10.1089/thy.2009.0110. PubMed PMID: 19860577. 
7. 
Vita R, Fallahi P, Antonelli A, Benvenga S. The administration of L-thyroxine as soft gel capsule or 
liquid solution. Expert opinion on drug delivery. 2014;11(7):1103-11. doi: 
10.1517/17425247.2014.918101. PubMed PMID: 24896369. 
8. 
Wenzel KW, Kirschsieper HE. Aspects of the absorption of oral L-thyroxine in normal man. 
Metabolism: clinical and experimental. 1977;26(1):1-8. PubMed PMID: 834138. 
9. 
McMillan CV, Bradley C, Woodcock A, Razvi S, Weaver JU. Design of new questionnaires to 
measure quality of life and treatment satisfaction in hypothyroidism. Thyroid. 2004;14(11):916-25. doi: 
10.1089/thy.2004.14.916. PubMed PMID: 15671770. 
10.  
Ferrell BR, Hassey-Dow K, Grant M.  Measurement of the QOL in Cancer Survivors. Quality of Life 
Research. 1995; 4:523-531. 
 
 


 
Protocol SCCC-03315 
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STU022015-044, Tessnow, Form A, Mod_14, 07-29-19 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Cancer Center. Do not disclose or use except as authorized in writing by the 
study sponsor. 
  
                             Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016, 12/2018 
20 
 
11.0 
APPENDICES 
 
11.1  ThyTSQ 
 
Treatment Satisfaction Survey 
 
 
1. How satisfied are you with the current treatment for your underactive thyroid? 
Very 
Dissatisfied 
Dissatisfied 
 
Neutral 
 
Satisfied 
Very 
Satisfied 
0 
1 
2 
3 
4 
5 
6 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
 
2. How well do you feel the treatment is working? 
Very 
Dissatisfied 
Dissatisfied 
 
Neutral 
 
Satisfied 
Very 
Satisfied 
0 
1 
2 
3 
4 
5 
6 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
 
3. How convenient have you found your treatment to be recently (e.g. remembering to take the 
medication, getting prescriptions)? 
Very 
Dissatisfied 
Dissatisfied 
 
Neutral 
 
Satisfied 
Very 
Satisfied 
0 
1 
2 
3 
4 
5 
6 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
 
4. How satisfied are you with your understanding of your underactive thyroid? 
Very 
Dissatisfied 
Dissatisfied 
 
Neutral 
 
Satisfied 
Very 
Satisfied 
0 
1 
2 
3 
4 
5 
6 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
 
5. Would you encourage someone else with underactive thyroid to have your kind of treatment? 
Very 
Dissatisfied 
Dissatisfied 
 
Neutral 
 
Satisfied 
Very 
Satisfied 
0 
1 
2 
3 
4 
5 
6 


 
Protocol SCCC-03315 
________________________________________________________________________ 
STU022015-044, Tessnow, Form A, Mod_14, 07-29-19 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Cancer Center. Do not disclose or use except as authorized in writing by the 
study sponsor. 
  
                             Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016, 12/2018 
21 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
 
 
6. How well do you feel that the treatment is controlling symptoms of underactive thyroid? 
Very 
Dissatisfied 
Dissatisfied 
 
Neutral 
 
Satisfied 
Very 
Satisfied 
0 
1 
2 
3 
4 
5 
6 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
 
7. How satisfied would you be to continue with your present treatment and dose? 
Very 
Dissatisfied 
Dissatisfied 
 
Neutral 
 
Satisfied 
Very 
Satisfied 
0 
1 
2 
3 
4 
5 
6 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
 
8. Are there any other features of your recent treatment for underactive thyroid, causing either 
satisfaction or dissatisfaction, that have not been covered by the questionnaire? 
Yes 
No 
○ 
○ 
 
If yes, please describe: 
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________ 
 
 
 
 


 
Protocol SCCC-03315 
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CONFIDENTIAL 
This material is the property of the UTSW Simmons Cancer Center. Do not disclose or use except as authorized in writing by the 
study sponsor. 
  
                             Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016, 12/2018 
22 
 
 
 
11.2  
QoL-Thyroid 
 
 
Quality of Life Scale/THYROID 
Directions: We are interested in knowing how your experience of having thyroid cancer affects 
your quality of life.  Please answer all of the following questions based on how you have been 
feeling during the previous week. 
 
Physical Well Being 
1. To what extent have the following been a problem during your illness and treatment? 
a) Fatigue 
no problem     0    1    2    3    4    5    6    7    8    9    10   severe problem 
 
b) Appetite changes 
no problem     0    1    2    3    4    5    6    7    8    9    10   severe problem 
 
c) Aches or pain 
no problem     0    1    2    3    4    5    6    7    8    9    10   severe problem 
 
d) Sleep changes 
no problem     0    1    2    3    4    5    6    7    8    9    10   severe problem 
 
e) Constipation 
no problem     0    1    2    3    4    5    6    7    8    9    10   severe problem 
 
f) Menstrual changes or fertility 
no problem     0    1    2    3    4    5    6    7    8    9    10   severe problem 
 
g) Weight gain 
no problem     0    1    2    3    4    5    6    7    8    9    10   severe problem 
 
h) Tolerance to cold or heat 
no problem     0    1    2    3    4    5    6    7    8    9    10   severe problem 
 
i) Dry skin or hair changes 
no problem     0    1    2    3    4    5    6    7    8    9    10   severe problem 
 
j) Voice changes 
no problem     0    1    2    3    4    5    6    7    8    9    10   severe problem 
 
k) Motor skills/coordination 
no problem     0    1    2    3    4    5    6    7    8    9    10   severe problem 
 
l) Swelling/fluid retention 
no problem     0    1    2    3    4    5    6    7    8    9    10   severe problem 
 
 
2. Rate your overall physical health: 
extremely poor     0    1    2    3    4    5    6    7    8    9    10   excellent 
 
 


 
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study sponsor. 
  
                             Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016, 12/2018 
23 
Psychological Well Being Items 
3. How difficult is it for you to cope with your disease and treatment? 
not at all difficult   0    1    2    3    4    5    6    7    8    9    10   very difficult 
 
4. How good is your quality of life? 
Extremely poor    0    1    2    3    4    5    6    7    8    9    10   excellent 
 
5. How much happiness do you feel? 
none     0    1    2    3    4    5    6    7    8    9    10   a great deal 
 
6. Do you feel like you are in control of things in your life? 
None at all    0    1    2    3    4    5    6    7    8    9    10   completely 
 
7. How satisfying is your life? 
not at all    0    1    2    3    4    5    6    7    8    9    10   completely 
 
8. How is your present ability to concentrate or to remember things? 
extremely poor    0    1    2    3    4    5    6    7    8    9    10   excellent 
 
9. How useful do you feel? 
not at all    0    1    2    3    4    5    6    7    8    9    10   extremely 
 
10. Has your illness or treatment caused changes in your appearance? 
not at all    0    1    2    3    4    5    6    7    8    9   10  extremely 
 
11. Has your illness caused changes in your self-concept (the way you see yourself)? 
not at all    0    1    2    3    4    5    6    7    8    9   10   extremely 
 
12. How distressing were the following aspects of your illness and treatment: 
a) Initial diagnosis 
        not at all distressing    0    1    2    3    4    5    6    7    8    9   10  very distressing 
 
b) Surgeries 
        not at all distressing     0    1    2    3    4    5    6    7    8    9   10 very distressing 
 
c) Time since my treatment was completed 
 
         not at all distressing   0    1    2    3    4    5    6    7    8    9   10 very distressing 
 
13. How much anxiety do you have? 
none at all      0    1    2    3    4    5    6    7    8    9   10    a great deal 
 
14. How much depression do you have? 
none at all      0    1    2    3    4    5    6    7    8    9   10    a great deal 
 
15. To what extent are you fearful of: 
a) Future diagnostic tests 
no fear     0    1    2    3    4    5    6    7    8    9   10    extreme fear 
 
b) A second cancer 
no fear     0    1    2    3    4    5    6    7    8    9   10    extreme fear 
 
c) Recurrence of your cancer 
no fear     0    1    2    3    4    5    6    7    8    9   10    extreme fear 
 


 
Protocol SCCC-03315 
________________________________________________________________________ 
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CONFIDENTIAL 
This material is the property of the UTSW Simmons Cancer Center. Do not disclose or use except as authorized in writing by the 
study sponsor. 
  
                             Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016, 12/2018 
24 
d) Spreading (metastasis) of your cancer 
no fear     0    1    2    3    4    5    6    7    8    9   10  extreme fear 
 
 
Social Concerns 
16. How distressing has your illness been for your family? 
none at all      0    1    2    3    4    5    6    7    8    9   10  a great deal 
 
17. Is the amount of support you receive from others sufficient to meet your needs? 
none at all      0    1    2    3    4    5    6    7    8    9   10  a great deal 
 
18. Is your continuing health care interfering with your personal relationships? 
none at all      0    1    2    3    4    5    6    7    8    9   10  a great deal 
 
19. Is your sexuality impacted by your illness? 
none at all      0    1    2    3    4    5    6    7    8    9   10   a great deal 
 
20. To what degree has your illness and treatment interfered with your employment? 
a) Motivation to work 
no problem      0    1    2    3    4    5    6    7    8    9   10   severe problem 
b) Time away from work 
no problem      0    1    2    3    4    5    6    7    8    9   10   severe problem 
 
c) Productivity at work 
no problem      0    1    2    3    4    5    6    7    8    9   10   severe problem 
 
d) Quality of work 
no problem      0    1    2    3    4    5    6    7    8    9   10    severe problem 
 
 
21. To what degree has your illness and treatment interfered with your activities at home? 
a) Driving a car 
no problem      0    1    2    3    4    5    6    7    8    9   10    severe problem 
 
b) Household chores 
no problem      0    1    2    3    4    5    6    7    8    9   10    severe problem 
 
c) Preparing meals 
no problem      0    1    2    3    4    5    6    7    8    9   10    severe problem 
 
d) Leisure activities 
no problem      0    1    2    3    4    5    6    7    8    9   10    severe problem 
 
 
22. How much isolation do you feel is caused by your illness and treatment? 
none at all      0    1    2    3    4    5    6    7    8    9   10   a great deal 
 
 
23. How much financial burden have you incurred as a result of your illness and treatment? 
none at all      0    1    2    3    4    5    6    7    8    9   10   a great deal