A Multicenter, Randomized, Double-blind, Dose-conversion Study to Evaluate the Safety and Efficacy of Hormone Replacement Therapy With Armour® Thyroid Compared to Synthetic T4 (Levothyroxine) in Previously Hypothyroid Participants Who Are Euthyroid on T4 Replacement Therapy
Phase: PHASE2
Conditions: Hypothyroidism, Thyroid Disease, Euthyroid, Thyroid Gland, Thyroid Hormones
Sponsor: Allergan



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Protocol No. 3014-201-002
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Table of Contents
Title Page ....................................................................................................1
Protocol Amendment Summary of Changes Table .....................................2
Table of Contents.......................................................................................4
List of Tables ...............................................................................................7
1.
Protocol Summary ......................................................................8
1.1.
Synopsis........................................................................................8
1.2.
Schema........................................................................................11
1.3.
Schedule of Activities.................................................................13
2.
Introduction...............................................................................15
2.1.
Study Rationale...........................................................................17
2.2.
Background.................................................................................17
2.3.
Benefit/Risk Assessment ............................................................18
3.
Objectives and Endpoints ........................................................19
4.
Study Design..............................................................................20
4.1.
Overall Design ............................................................................20
4.1.1.
Clinical Hypotheses ....................................................................23
4.2.
Scientific Rationale for Study Design ........................................23
4.3.
Justification for Dose and/or Study Intervention 
Administration ............................................................................23
4.4.
End of Study Definition..............................................................24
5.
Study Population.......................................................................25
5.1.
Inclusion Criteria ........................................................................25
5.2.
Exclusion Criteria .......................................................................27
5.3.
Lifestyle Considerations .............................................................28
5.3.1.
Meals and Dietary Restrictions...................................................28
5.4.
Screen Failures............................................................................28
6.
Study Intervention....................................................................29
6.1.
Study Interventions Administered ..............................................29
6.2.
Preparation/Handling/Storage/Accountability............................30
6.3.
Measures to Minimize Bias: Randomization and Blinding........30
6.4.
Study Intervention Compliance ..................................................31
6.5.
Concomitant Therapy .................................................................31
6.5.1.
Prohibited Interventions Before the Study..................................32
6.5.2.
Permitted Interventions...............................................................32
6.5.3.
Rescue Medicine.........................................................................32
6.5.4.
Prohibited Medications/Supplements During the Study.............33
6.6.
Dose Modification ......................................................................33
6.7.
Intervention after the End of the Study.......................................34
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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal....................................................35
7.1.
Discontinuation of Study Intervention........................................35
7.2.
Participant Discontinuation/Withdrawal from the Study............35
7.3.
Lost to Follow-Up.......................................................................36
8.
Study Assessments and Procedures.........................................37
8.1.
Efficacy Assessments .................................................................37
8.1.1.
Study Intervention Administration Assessments........................37
8.1.2.
Sustained TSH Responders at Both the End of the Titration 
Period and the End of the Stabilization Period – Primary Efficacy
Endpoint......................................................................................37
8.1.3.
Secondary Endpoint....................................................................37
8.1.4.
Additional Efficacy Endpoints....................................................38
8.1.5.
Exploratory Endpoints ................................................................39
8.2.
Safety Assessments.....................................................................39
8.2.1.
Physical Examinations................................................................39
8.2.2.
Vital Signs...................................................................................40
8.2.3.
Electrocardiograms .....................................................................40
8.2.4.
Clinical Safety Laboratory Assessments ....................................40
8.2.5.
Safety Data Monitoring...............................................................41
8.3.
Adverse Events and Serious Adverse Events .............................41
8.3.1.
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information............................................42
8.3.2.
Method of Detecting Adverse Events and Serious Adverse 
Events..........................................................................................42
8.3.3.
Follow-up of Adverse Events and Serious Adverse Events .......42
8.3.4.
Regulatory Reporting Requirements for Serious Adverse 
Events..........................................................................................42
8.3.5.
Pregnancy....................................................................................43
8.3.6.
Adverse Events of Special Interest .............................................43
8.3.7.
Medication Errors .......................................................................43
8.4.
Treatment of Overdose ...............................................................44
8.5.
Pharmacokinetics........................................................................44
8.5.1.
Blood Pharmacokinetic Sampling Procedure .............................44
8.5.2.
Pharmacokinetic Sample Bioanalysis.........................................45
8.6.
Pharmacodynamics .....................................................................45
8.7.
Genetics ......................................................................................45
8.8.
Biomarkers and Other Assessments ...........................................45
8.9.
Health Economics and Outcomes...............................................45
9.
Statistical Considerations.........................................................46
9.1.
Statistical Hypotheses.................................................................46
9.2.
Sample Size Determination ........................................................46
9.3.
Populations for Analyses ............................................................46
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9.4.
Statistical Analyses.....................................................................47
9.4.1.
Efficacy Analyses .......................................................................47
9.4.2.
Safety Analyses...........................................................................49
9.4.3.
Pharmacokinetic Analyses..........................................................51
9.4.4.
Other Analyses............................................................................51
9.5.
Interim Analyses.........................................................................51
10.
Supporting Documentation and Operational 
Considerations...........................................................................52
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ............................................................................52
10.1.1.
Regulatory and Ethical Considerations.......................................52
10.1.2.
Financial Disclosure....................................................................52
10.1.3.
Informed Consent Process ..........................................................53
10.1.4.
Data Protection............................................................................53
10.1.5.
Data Quality Assurance ..............................................................53
10.1.6.
Source Documents ......................................................................54
10.1.7.
Study and Site Closure................................................................54
10.1.8.
Publication Policy.......................................................................54
10.1.9.
Compliance with Protocol...........................................................55
10.2.
Appendix 2: Clinical Laboratory Tests.......................................56
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.....................57
Definition of AE ........................................................................................57
Definition of SAE ......................................................................................59
Recording and Follow-Up of AEs and/or SAEs........................................61
Reporting of SAEs .....................................................................................63
10.4.
Appendix 4: Abbreviations.........................................................64
10.5.
Appendix 5: Standard Discontinuation Criteria..........................66
10.6.
Appendix 6: Study Tabular Summary ........................................67
10.7.
Appendix 7: Contraceptive Guidance and Collection of 
Pregnancy Information ...............................................................69
Contraception Guidance: ...........................................................................69
Pregnancy Testing:.....................................................................................70
Collection of Pregnancy Information: .......................................................71
10.8.
Appendix 8: Study Schedule Supplement ..................................72
10.8.1.
Screening (Visit 1)......................................................................72
10.8.2.
Double-blinded Treatment..........................................................72
10.8.3.
Early Termination .......................................................................75
10.9.
Appendix 9: Patient-Reported Outcomes Questionnaires, 
Descriptions, and Instructions – ThyPRO Questionnaire...........76
10.10.
Appendix 10: Levothyroxine and Armour Thyroid Doses.........87
11.
References..................................................................................88
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List of Tables
Table 4–1
Study Design ..................................................................................................... 21
Table 6–1
Capsule Composition of Doses ......................................................................... 29
Table 6-2
Study Interventions ........................................................................................... 30
Table 10-1
Protocol-required Safety Laboratory Assessments ........................................... 56
Table 10-2
Highly Effective and Acceptable Contraceptive Methods................................ 70
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1.
Protocol Summary
1.1.
Synopsis
Protocol Title: A multicenter, randomized, double-blind, dose-conversion study to evaluate the 
safety and efficacy of hormone replacement therapy with Armour® Thyroid compared to 
synthetic T4 (levothyroxine) in previously hypothyroid participants, who are euthyroid on T4 
replacement therapy
Protocol Number: 3014-201-002
Brief Protocol Title: A Phase 2, dose-conversion study of Armour® Thyroid compared to 
synthetic T4 (levothyroxine) in previously hypothyroid participants
Study Phase: 2
Study Rationale:
This study will evaluate the safe and effective dose conversion from synthetic T4 therapy to 
Armour Thyroid therapy in previously hypothyroid participants who are euthyroid on a stable 
dose of synthetic T4. This study is designed to demonstrate that treatment with matching doses 
of Armour Thyroid is noninferior to treatment with synthetic T4, specifically in reference to 
euthyroid status as determined by TSH measurements. In addition, this study will demonstrate 
the safe and tolerable use of Armour Thyroid in hypothyroid participants. Finally, symptoms of 
hypothyroidism will be monitored as exploratory endpoints to evaluate potential differences 
between Armour Thyroid and synthetic T4.
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1.2.
Schema
*
If a participant undergoes up to the maximum of 3 additional dose titrations starting at Week 18, the Titration 
Period may extend up to Week 36; therefore, the Stabilization Period may extend from Week 36 to Week 48
(remaining 12 weeks in duration). The Primary Endpoint will be measured at the end of the Titration Period 
and the end of the Stabilization Period.
During the Titration Period, study visits are split into parts “a” and “b” (ie, Visit 3a, Visit 3b, 
Visit 4a, Visit 4b) to allow for any dose titrations: 

Visits 3a and 4a are mandatory for all participants. Study assessments, including bloodwork 
for TSH, and study intervention dispensing will be performed.

Visits 3b and 4b are only required for participants needing a dose titration based on the data 
obtained from Visits 3a and 4a, respectively. A limited number of assessments and study
intervention dispensing will be performed at Visits 3b and 4b.
Visit 5 is designed as a transition visit between the Titration and Stabilization Periods and may
consist of a subset of visits (starting with Visit 5a [Week 18] and extending to Visit 5g
[Week 36], as needed). The last visit within Visit 5 serves as both the end of the Titration Period 
and the beginning of the Stabilization Period.

Participants with TSH levels within normal reference range at Visit 5a may enter the 
Stabilization Period (ie, their next visit will be Visit 6).

If participants’ TSH levels are out of normal reference range at Visit 5a, participants’ doses 
can be up- or down-titrated per the Investigators’ interpretation until their TSH levels are 
within the normal reference range by continuing the Titration Period beyond Week 18. If the 
Titration Period is continued, the participants’ doses can be up- or down-titrated 
approximately every 6 weeks until their TSH levels have normalized for up to a maximum of 
3 additional titrations (including the titration at Visit 5b). Once their TSH levels are within 
the normal reference range, participants may enter the Stabilization Period. Participants 
whose TSH levels have not normalized after the maximum of 3 additional titrations will not 
enter the Stabilization Period.
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1.3.
Schedule of Activities
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2.
Introduction
Hypothyroidism is a disease that affects an estimated 3.7% of the US population, translating to 
over 8 million patients based on the results of the National Health and Nutrition Examination 
Survey (NHANES 1999-2002; Aoki 2007). In hypothyroidism, the thyroid gland is underactive 
and is unable to produce a sufficient amount of thyroid hormone. The principal thyroid hormones 
are T3 (liothyronine, triiodothyronine [3, 5, 3′- triiodothyronine]) and T4 (levothyroxine, 
l-thyroxine, thyroxine). Thyroid hormones are required for normal growth, development, and the 
maintenance of metabolic homeostasis. These hormones enhance oxygen consumption by most 
tissues of the body and increase the basal metabolic rate and the metabolism of carbohydrates, 
lipids, and proteins (Armour Thyroid 2018). As such, these hormones exert profound effects on 
almost every organ in the body and are of particular importance in regard to cardiovascular 
function, bone metabolism, reproductive function, cognitive function, and in the maturation of 
the central nervous system (Armour Thyroid 2018, Synthroid 2018). 
Hypothyroid patients most commonly present with signs and symptoms of dry skin, fatigue, cold
sensitivity, weight gain, constipation, voice changes, and muscle cramps. Patients may also 
experience neurological disorders such as impaired memory, alterations in mood 
(eg, depression), and sleep apnea. Because of the deleterious consequences of hypothyroidism 
during the neonatal period and infancy, including mental retardation or cretinism and impaired 
growth and development in general, pregnant women and newborns are screened for thyroid 
hormone deficiency.
Hypothyroidism is typically characterized by high levels of TSH and low levels of T4. T4 is the 
main hormone produced by the thyroid gland whereas T3 is only secreted by the gland in small 
amounts. T3 is the metabolically active thyroid hormone and is predominantly produced by the 
peripheral monodeiodination of T4. The main treatment for hypothyroidism is thyroid hormone 
replacement therapy. The clinical practice guidelines for treating hypothyroidism, developed by 
the AACE and ATA, recommend treating hypothyroid patients with synthetic T4 (Garber 2012).
Treatment for hypothyroidism needs to be individualized, as dosing needs are dependent on 
several factors including a patient’s age, sex, body weight, absorption rate, and concomitant 
medical conditions (Garber 2012, Jonklaas 2014). Therefore, patients with identical baseline 
TSH values may have varying responses to the same dose of thyroid hormone replacement 
therapy. An approximate starting dose of synthetic T4 can be estimated using 1.6 µg/kg based on 
body mass but should be adjusted based on the factors noted above (Synthroid 2018). Approved 
doses of synthetic T4 range from 25 µg to 300 µg (Synthroid 2018) with multiple incremental 
doses; however, dosing greater than 200 µg daily could indicate issues with noncompliance or 
drug absorption (Garber 2012).
The clinical practice guidelines for treating hypothyroidism deem TSH to be the most reliable 
marker of adequacy of thyroid hormone replacement therapy and recommend incremental dose 
titrations guided by serum TSH levels (Garber 2012, Jonklaas 2014).  Clinical symptoms of 
hypothyroidism should be followed, but are not recommended for judging adequacy of treatment 
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as they lack sensitivity and specificity (Jonklaas 2014).  Instead, symptoms should be considered 
in the context of serum TSH values and other potential causes (Jonklaas 2014).
A subgroup of synthetic T4-treated patients continues to have persistent symptoms consistent 
with hypothyroidism that result in impaired well-being and quality of life despite having TSH 
levels within normal reference range (Cooper 2003, Kaplan 2003, Saravanan 2002, Walsh 2002, 
Walsh 2006). One of the reasons why these symptoms persist in patients on T4 therapy may be 
due to the relative tissue differences in T3 and T4 levels following hormone replacement therapy
(Escobar-Morreale 1995, Cooper 2003).
Despite the similar chemical structures of T3 and T4, T3 is the metabolically active hormone and 
therefore more potent than T4 (McDermott 2012). Intracellular deiodination is an important 
factor in generating intracellular T3. For instance, animal studies have shown that up to 80% of 
intracellular T3 in the brain is derived from monodeiodination of circulating T4 and only 20% is 
derived from T3 secreted by the thyroid gland (Fish 1987). One explanation for the apparent 
failure of T4 replacement therapy alone to satisfactorily control symptoms of hypothyroidism in 
some patients may be that T3 levels are not adequately restored in all tissues as was 
demonstrated in previous studies in thyroidectomized rats (Escobar-Morreale 1995, 
Escobar-Morreale 1996). Therefore, combined hormone replacement with T3 and T4 may more 
closely mimic production by the intact thyroid gland compared to T4 monotherapy.
For hypothyroidism patients who have persistent symptoms, signs, or inadequate efficacy despite 
synthetic T4 treatment, there are few options currently available. Synthetic T3 (brand name, 
Cytomel) is currently approved for use in the United States as a thyroid replacement hormone 
and could be used in addition to T4. Desiccated thyroid (porcine-derived) gland is also an option 
for thyroid hormone replacement that has been widely used for many years and was the 
predominant treatment choice for hypothyroid patients prior to the development of synthetic T4.
The active ingredient in Armour Thyroid is desiccated, powdered porcine thyroid gland (Thyroid 
Powder), which contains the protein thyroglobulin. Thyroglobulin is hydrolyzed in vivo to yield 
the thyroid hormones T3 and T4. Powdered porcine thyroid gland has been available since the 
early 1900s and is generally recognized as a replacement or supplemental therapy in certain 
patients with hypothyroidism. Armour Thyroid is currently indicated as treatment in primary 
(thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired 
hypothyroidism in adults (Armour Thyroid 2018). Similar to synthetic T4, dosing for Armour 
Thyroid needs to be individualized based on clinical response and laboratory parameters. As 
such, there are incremental doses of Armour Thyroid.
There is a strong demand from physicians as well as patients and advocacy groups for naturally
derived T3/T4 products, including Armour Thyroid. A recent hypothyroidism treatment survey
completed by 12,146 individuals found a higher median treatment satisfaction with desiccated 
thyroid compared to other treatments (synthetic T4 or synthetic T3 in addition to synthetic T4) 
(Peterson 2018). Patients on desiccated thyroid were also less likely to report issues with weight 
management, fatigue/energy, mood, and memory compared to those taking synthetic T4 alone or 
in combination with synthetic T3 (Peterson 2018). Despite the availability of synthetic T3 and 
T4 drug products for the treatment of hypothyroidism, Armour Thyroid was prescribed by over 
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109,000 physicians (> 4.7 million prescriptions) in the United States for the treatment of 
hypothyroidism in a 1-year period (August 2017 to July 2018).
2.1.
Study Rationale
This study will evaluate the safe and effective dose conversion from synthetic T4 therapy to 
Armour Thyroid therapy in participants who are euthyroid on a stable dose of synthetic T4. This 
study is designed to demonstrate that treatment with matching doses of Armour Thyroid is 
noninferior to treatment with synthetic T4, specifically in reference to euthyroid status as 
determined by TSH measurements. In addition, this study will demonstrate the safe and tolerable 
use of matching doses of Armour Thyroid to synthetic T4 in hypothyroid participants. Symptoms 
of hypothyroidism will be monitored as exploratory endpoints to evaluate potential differences 
between Armour Thyroid and synthetic T4.
2.2.
Background
The number of FDA-approved and commercially available options for the treatment of 
hypothyroidism are limited. Currently, synthetic T4 is the mainstay of thyroid replacement 
therapy and is the first-line, guideline-recommended treatment option for hypothyroid patients. If 
the results of T4 replacement are not satisfactory, then it can be supplemented or replaced with 
synthetic T3 (which is also FDA approved and commercially available) or desiccated thyroid.
Prior to the advent of synthetic T4 and synthetic T3, patients with hypothyroid disease were 
treated with desiccated thyroid. Desiccated thyroid is known to contain both thyroid hormones, 
T3 and T4, and successfully normalize TSH in hypothyroid patients. Although desiccated and 
purified thyroid has had a long history of therapeutic use, there are a limited number of clinical 
trials which demonstrate its effectiveness in comparison to the standard of care, synthetic T4.
To date, there has been 1 double-blinded, randomized study which compared desiccated thyroid 
(Armour Thyroid) to synthetic T4 (Hoang 2013); this single-center study was run by Walter 
Reed National Military Medical Center and was not sponsored by Allergan. A total of 
70 previously hypothyroid patients, then euthyroid on replacement therapy, were enrolled in this 
cross-over study and were randomized to either synthetic T4 or Armour Thyroid. The primary
endpoint of this study showed no difference between synthetic T4 and Armour Thyroid for 
symptom scores, health questionnaires, or neuropsychological tests. All patients remained within 
acceptable TSH range at the end of each study period, demonstrating that hypothyroid patients 
can be safely and effectively switched between synthetic T4 and Armour Thyroid.
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2.3.
Benefit/Risk Assessment
Participants with hypothyroidism may experience negative symptoms such as fatigue, weight 
gain, cold sensitivity, dry skin and hair loss as well as neurological symptoms such as impaired 
memory and mood alterations. Severe and uncontrolled hypothyroidism can lead to serious 
ailments, such as myxedema coma or crisis. Thus, it is important that all hypothyroid participants 
receive thyroid replacement therapy to ensure that TSH levels are normalized to a euthyroid 
status. Due to the risks of uncontrolled hypothyroid disease, this study will be actively controlled 
to ensure that all participants are receiving thyroid replacement therapy throughout the entirety
of the study.
Participants in this study may benefit from the close monitoring of their TSH values, leading to 
appropriate dose adjustments of either Armour Thyroid or synthetic T4.
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of Armour Thyroid may be found in the Investigator’s Brochure and the Package 
Insert (Armour Thyroid 2018).
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Table 4–1 Study Design
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5.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1.
Age
1.01
Participant must be 18 to 75 years of age, inclusive, at the time of signing the 
informed consent.
2.
Type of Participant and Disease Characteristics
2.01
Participants who have a diagnosis of primary hypothyroidism made ≥12 months 
before study entry (Visit 1). 
Note: Participants who have undergone total thyroidectomy for treatment of thyroid 
cancer may be eligible for enrollment if they:
a.
are > 5 years from the date of total thyroidectomy (or last thyroid surgery), 
b. have had no clinical evidence of recurrence, and
c.
have had serial measurements of thyroglobulin and anti-thyroglobulin since 
the time of surgery or treatment with radioactive iodine. All thyroglobulin 
values should have been undetectable and anti-thyroglobulin values within 
the normal reference range after surgery or starting 6 months after treatment 
with radioactive iodine (including values obtained at the Screening Visit 
[Visit 1])
2.02
Be on continuous thyroid replacement therapy with synthetic T4 for primary
hypothyroidism for at least 12 months immediately prior to the Screening Visit 
(Visit 1).
2.03
Be on a stable FDA-approved daily dose of synthetic T4 for a minimum of 3 months
prior to the Screening Visit (Visit 1).  Must enter the study on the same stable dose.
2.04
Have euthyroid status indicated by at least 1 documented TSH value within normal 
reference range (0.45-4.12 mIU/L, inclusive) at a minimum of 6 weeks and 
maximum of 12 months prior to the Screening Visit (Visit 1).  Also have a confirmed 
TSH value within the normal reference range drawn at the Screening Visit (Visit 1)
2.05
Have vision and hearing (hearing aid permissible) sufficient for compliance with 
testing procedures.
3.
Weight and Body Mass Index
3.01
Participants must have a BMI between 18 and 40 (inclusive) at Screening Visit 
(Visit 1).
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4.
Sex
4.01
Male or female
5.
Contraceptives
5.01
Male participants willing to minimize the risk of inducing pregnancy for the duration 
of the clinical study and follow-up period (35 days after last dose of study
intervention).
A male participant must agree to use contraception as detailed in Appendix 7 of this 
protocol starting at the Screening Visit (Visit 1), during the study intervention period 
and for at least 35 days after the last dose of study intervention and refrain from 
donating sperm during this period.
5.02
Female participants willing to minimize the risk of inducing pregnancy for the 
duration of the clinical study and follow-up period (35 days after last dose of study
intervention).
A female participant is eligible to participate if she is not pregnant (has a negative 
serum pregnancy result at the Screening Visit (Visit 1) and a negative urine 
pregnancy result at Baseline (Visit 2) prior to randomization; see Appendix 7), not 
breastfeeding, and at least 1 of the following conditions applies:
a. Not a female of CBP as defined in Appendix 7
OR
b. A female of CBP who agrees to follow the contraceptive guidance in Appendix 7
of this protocol starting at the Screening Visit (Visit 1) and for at least 35 days 
after the last dose of study intervention.
6.
Informed Consent
6.01
Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the ICF and in 
this protocol.
6.02
Written informed consent from the participant has been obtained prior to any
study-related procedures.
6.03
Written documentation has been obtained in accordance with the relevant country
and local privacy requirements, where applicable.
7.
Other
7.01
Able, as assessed by the Investigator, and willing to follow study instructions and 
likely to complete all required study visits.
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5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
1.
Medical Conditions
1.01
Any clinical condition or previous surgery that might affect the absorption, distribution, 
biotransformation, or excretion of Armour Thyroid or synthetic T4.
1.02
History of alcohol or other substance abuse within the previous 5 years.
1.03
Known or suspected allergy or intolerance to any ingredients of Armour Thyroid, 
including its excipients, levothyroxine (T4), other thyroid replacement medications, or 
pork products. 
2.
Prior/Concomitant Therapy
2.01
Have taken any prohibited concomitant medication that cannot meet the requirements 
prior to Baseline (Visit 2) as outlined in Section 6.5.1.
2.02
Have received active treatment with an investigational drug within 30 days or 
5 half-lives, whichever is longer, of Screening Visit (Visit 1).
2.03
Participant cannot be taking a daily dose of synthetic T4 that exceeds 200 µg at 
Screening Visit (Visit 1).
3.
Prior/Concurrent Clinical Study Experience
3.01
Current enrollment in an investigational drug or device study or participation in such a 
study within 60 days of entry into this study.
4.
Diagnostic Assessments
4.01
Clinically significant results according to the Investigator or designee, on physical 
examination, medical history, ECG, hematology, clinical chemistry, or urinalysis that 
may put the participant at significant risk, may confound the study results, or may
interfere significantly with the participant’s participation in the study.
4.02
Sitting systolic BP [≥ 140 mm Hg or ≤90 mm Hg] or sitting diastolic BP [≥90 mm Hg 
or ≤50 mm Hg] at the Screening Visit.
Note:  A total of 3 readings of BP and pulse will be taken.  The first reading should be 
rejected.  If either the second or third reading meets exclusion criteria, the participant 
should be excluded.
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4.03
Abnormal ECG results thought to be potentially clinically significant according to the 
Investigator or designee, or QT prolongation (QTcF ≥450 msec for male participants or 
≥470 msec for female participants) at the Screening Visit (Visit 1).
5.
Other
5.01
The participant has a concurrent disease, condition, or is in a situation which, in the 
Investigator’s opinion, may put the participant at significant risk, may confound the study
results, or may interfere significantly with the participant’s participation in the study.
5.02
Directly or indirectly involved in the conduct and administration of this study as an 
Investigator, sub-investigator, study coordinator, or other study staff member; or 
employee of the Sponsor or a first-degree family member, significant other, or relative 
residing with 1 of the above persons involved directly or indirectly in the study; or 
enrolled in the study at another clinical site.
5.3.
Lifestyle Considerations
5.3.1.
Meals and Dietary Restrictions
Participants will be required to undergo an overnight (minimum 5 hours) fast for all visits where 
laboratory assessments will be performed and will need to maintain a fasted condition for an 
additional 30 to 60 minutes after administration of study intervention for these visits.
1. Study intervention will be taken at least 30 to 60 minutes prior to the first meal with 
approximately 1 glass of water; water will be provided for participants at other times as 
desired.
2. Blood samples (with the exception of post-dose PK sampling) and thyroid-related 
assessments (specifically TSH, T3, T4, FT3, FT4) will be measured prior to study 
intervention administration.
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
CONSORT (Consolidated Standards of Reporting Trials) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failures) may be 
rescreened once after Sponsor approval.
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6.2.
Preparation/Handling/Storage/Accountability
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study intervention must be stored 
in a secure, environmentally controlled, and monitored area in accordance with the labeled 
storage conditions with access limited to the Investigator and authorized site staff.
3. The Investigator or study center is responsible for study intervention accountability, 
reconciliation, and record maintenance (ie, receipt, reconciliation, and final disposition 
records).
All unused study intervention and used kits must be returned to the Sponsor/designee or 
destroyed on site per site policy by the termination of the study. Final accountability will be 
performed when the study intervention is returned or prior to destruction.
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6.5.1.
Prohibited Interventions Before the Study
Participants must discontinue any of the medications listed in the table below for the specified 
period prior to Baseline (Visit 2). These medications are prohibited for the duration of the study.
Thyroid Replacement Therapy
Minimum Duration that Participants must 
be off Treatment Prior to Baseline
Synthetic T4
Thyroid supplements
Synthetic T3
Desiccated thyroid
0 days
12 months
12 months
12 months
The Investigator or Sponsor reserves the right to exclude a participant from participation in the 
study if a medication taken 14 or more days before the study start may interfere with the study
outcome (eg, a drug with prolonged half-life).
All medication taken since informed consent will be recorded in the eCRF.
The decision to administer a prohibited medication/intervention during the study period is done 
with the safety of the study participant as the primary consideration. When possible, the Sponsor
is to be notified before the prohibited medication/intervention is administered.
6.5.2.
Permitted Interventions
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with:

Indication

Dates of administration including start and end dates

Dosage information including dose and frequency
Therapy considered necessary for the participant’s welfare may be given at the discretion of the 
Investigator. If the permissibility of a specific medication/intervention is in question, please 
contact the Sponsor.
The Sponsor or designee should be contacted if there are any questions regarding concomitant or 
prior therapy.
Any medication taken during the study between the date of the first dose of study intervention
and the date of the EOS visit will be recorded in the eCRF as a concomitant medication; any
medication started after the EOS visit will not be considered a concomitant medication and 
should not be captured in the eCRF.
6.5.3.
Rescue Medicine
Rescue medicine is not applicable.
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Dose modification will be prohibited during the Stabilization Period of the study.
6.7.
Intervention after the End of the Study
Intervention after the EOS is not applicable.
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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
A premature discontinuation will occur if a participant who signs the ICF and receives 
intervention ceases participation in the study, regardless of circumstances, before the completion 
of the protocol-defined study procedures.
Reasons for discontinuation from the study intervention and/or the study may include the 
following commonly used or other acceptable terms (definitions are provided in Appendix 5):

Adverse event

Death

Lost to follow-up

Non-compliance with study drug

Other

Physician decision

Pregnancy

Site terminated by Sponsor

Study terminated by Sponsor

Withdrawal by participant 
7.1.
Discontinuation of Study Intervention
If a clinically significant finding is identified after enrollment, the Investigator or qualified 
designee will determine if the participant can continue treatment with the study intervention and
if any change in the participant’s management is needed. Any new clinically relevant finding 
should be reported as an AE. All efforts should be made to follow the participant until the EOS
to minimize the occurrence of missing data.
If a pregnancy is reported, see Appendix 7 and Section 8.3.5 (Pregnancy) for procedures.
See the Schedule of Activities for data to be collected at the time of study intervention 
discontinuation and follow-up and for any further evaluations that need to be completed.
7.2.
Participant Discontinuation/Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, 
or administrative reasons.

If the participant withdraws consent for disclosure of future information, the Sponsor may
retain and continue to use any data collected before such a withdrawal of consent.
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
If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records.  The 
Investigator should also notify the Sponsor so that any untested samples can be destroyed.

See the Schedule of Activities for data to be collected at the time of study discontinuation 
and follow-up and for any further evaluations that need to be completed.
7.3.
Lost to Follow-Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in the 
study.

Before a participant is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local equivalent 
methods). These contact attempts will be documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.
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Titration Period among the randomized participants who received at least 1 dose of study
intervention (Section 9.3).
Assessment
Timing
Measurement
Titration TSH 
Responder
End of Titration Period
TSH values measured at the end of the Titration Period 
to determine if the values are within the normal 
reference range.
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8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the Schedule of Activities.
8.2.1.
Physical Examinations

A complete physical examination will be performed and will include assessment of the 
following: general appearance, skin, head and neck (including ears, eyes, nose, and throat), 
lymph nodes, thyroid, respiratory, cardiovascular, abdomen, musculoskeletal (including 
spine and extremities), and neurological systems. Height will be measured at screening; 
weight will be measured at screening and end of study. BMI (kg/m2) will be calculated as the 
ratio of weight in kg/(height in cm/100)2. BMI will be calculated at screening and end of 
study.
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
Physical examinations will be completed by a trained physician or health professional 
licensed to perform physical examinations.
8.2.2.
Vital Signs
Vital signs will be assessed as follows:

BP, pulse rate, respiratory rate, and oral temperature will be assessed.

BP will be assessed using a sphygmomanometer.

BP and pulse measurements should be preceded by at least 5 minutes of rest for the 
participant in a quiet setting without distractions (eg, television, cell phones).

Vital signs will be taken before blood collection for laboratory tests. A total of 3 readings of 
BP and pulse will be taken consecutively, at least 1 to 3 minutes apart. The first reading 
should be rejected. The second and third readings will be used to make any study-related 
decisions. All three readings will be recorded. During the screening visit, if either the second 
or third reading meets exclusion criteria, the participant should be excluded.

Pre-dose vital signs must be assessed within a window of 0 to 120 minutes prior to study
intervention dosing.
8.2.3.
Electrocardiograms

The Sponsor will receive ECG data, including cardiologist assessments, in the data transfer.

Single 12-lead ECG will be performed and obtained as outlined in the Schedule of Activities
(Section 1.3) using an ECG machine that automatically calculates the heart rate and measures 
PR, QRS, QT, and QTcF intervals.

Pre-dose ECGs must be performed within a window of 0 to 120 minutes prior to study
intervention dosing.

The ECG tracing will be kept at the study center. Measurements will be recorded for the 
following parameters: heart rate, PR interval, QRS duration, QT interval, and QTc. All ECGs 
will be clinically interpreted by the Investigator or sub-investigator.

At screening, participants who have an abnormal QTcF according to the ranges specified in 
Section 5.2 will be excluded from the study.
8.2.4.
Clinical Safety Laboratory Assessments

See Appendix 2 for the list of clinical laboratory tests to be performed and the Schedule of 
Activities for the timing and frequency.

At screening, the Investigator or sub-investigator will assess the clinical significance of any 
values outside the reference ranges provided by the laboratory, and participants with 
abnormalities judged to be clinically significant will be excluded from the study.
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
The Investigator must review the laboratory report, document this review, and record any
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the Investigator to be more severe than expected for the participant’s condition.

All laboratory tests with values considered clinically significant during participation in the 
study or at the EOS should be repeated until the values return to normal or baseline or are no 
longer considered clinically significant by the Investigator.
o
If such values do not return to normal/baseline within a period of time judged reasonable 
by the Investigator, the etiology should be identified, and the Sponsor notified.
o
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the Schedule of Activities.
o
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the eCRF.
o
Serum pregnancy tests and urine dipsticks are to be used to conduct pregnancy tests by
the study personnel or designee at timepoints specified in the Schedule of Activities.
Urine dipstick results will be read locally. 
8.2.5.
Safety Data Monitoring
Safety data will be monitored during the study. If an unblinded safety review is needed, a data 
review committee (DRC) will be created in advance to review unblinded safety data. The 
purpose and procedure for this safety data review will be detailed in a DRC Charter and a 
companion analysis plan prior to the unblinded safety data review, should this review be 
performed. The methods to maintain study integrity, including restrictions of access to unblinded 
safety results before study completion will also be described in the DRC Charter.
8.3.
Adverse Events and Serious Adverse Events
The definitions of an AE and SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative).
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention or the study (see Section 7).
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8.3.1.
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information
All AEs and SAEs from the signing of the ICF until 35 days after the last dose of study
intervention will be collected at the time points specified in the Schedule of Activities
(Section 1.3), and as observed or reported spontaneously by study participants.
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Appendix 3. The Investigator will submit any updated SAE data to the Sponsor within 
24 hours of it being available.
Investigators are not obligated to actively seek AE or SAE information after conclusion of the 
study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the Investigator must promptly
notify the Sponsor.
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
8.3.2.
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3.
Follow-up of Adverse Events and Serious Adverse Events
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs/SAEs will be followed until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up (as defined 
in Section 7.3).
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation with 
other health care professionals.
New or updated information will be recorded in the originally completed eCRF.
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of receipt of 
the information.
8.3.4.
Regulatory Reporting Requirements for Serious Adverse Events

Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.
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
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/IECs, and Investigators.

An Investigator who receives an investigator safety report describing an SAE from the 
Sponsor will review and then file it and will notify the IRB/IEC, if appropriate according to 
local requirements.
8.3.5.
Pregnancy

Details of all pregnancies in female participants and female partners of male participants will 
be collected after the start of study intervention and until 35 days after the last dose of study
intervention.

If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 7.

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.3.6.
Adverse Events of Special Interest
Hypersensitivity has been identified as an AESI.  Hypersensitivity reactions to inactive 
ingredients have occurred in patients treated with thyroid hormone products. Hypersensitivity
reactions to active constituents may also occur.
Reports of this AESI warrant ongoing monitoring and prompt communication by the Investigator 
to the Sponsor as outlined in Appendix 3.
8.3.7.
Medication Errors
Medication error refers to any unintended error in the dosing and/or administration of the study
intervention as per instructions in the protocol. Medication errors generally fall into 4 categories 
as follows:

Wrong study intervention

Wrong dose/kit (including dosing regimen, strength, form, concentration, amount)

Wrong route of administration

Wrong participant (ie, not administered to the intended participant)
Medication errors include occurrences of overdose and underdose of the study intervention.
Overdose: Unintentional administration of a quantity of the study intervention given that is 
above the maximum recommended dose according to the protocol for the study intervention.
Underdose: Unintentional administration of a quantity of the study intervention given that is 
under the minimum recommended dose according to the protocol.
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
The Safety population includes all participants who take ≥ 1 dose of study intervention.

The PK population includes all participants who have at least 1 evaluable PK sample.
9.4.
Statistical Analyses
The SAP will be developed and finalized before database lock and unblinding, and will describe 
the participant populations to be included in the analyses, the detailed analyses of all analysis 
parameters for the study report, and procedures for accounting for missing, unused, and spurious 
data. This section is a summary of the planned statistical analyses of the primary, additional, and 
exploratory endpoints.
9.4.1.
Efficacy Analyses
The primary and secondary efficacy analysis will be performed on the ITT Population. 
Additional efficacy parameters on the ITT Population will be summarized descriptively by 
treatment group or by treatment dose level at each visit.
9.4.1.1.
Analysis Endpoints
The primary, secondary, additional, and exploratory efficacy endpoints are listed below.
Analyses will be defined in the following sections.
Primary efficacy endpoint:
The primary efficacy endpoint is the percent of participants who are Sustained TSH Responders, 
defined as participants whose TSH values are within the normal reference range of 0.45 to 
4.12 mIU/L, inclusive at both the end of the Titration Period and the end of the Stabilization 
Period among those participants in the ITT Population. If a participant is missing the TSH value 
at either the end of the Titration Period or at the end of the Stabilization Period, then this 
participant will be considered a sustained TSH non-responder.
Secondary efficacy endpoint (see Section 8.1.3):
The secondary efficacy endpoint is the percent of participants who are Titration TSH Responders
defined as participants whose TSH values are within the normal reference range at the end of the 
Titration Period among those participants in the ITT Population. If a participant is missing the 
TSH value at the end of the Titration Period, then this participant will be considered a titration 
non-responder.
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T3 and T4 taken prior to study intervention dose that day), vital sign values, ECG parameters, 
and physical examination findings. For each safety parameter of the clinical laboratory, vital 
sign, and ECG parameters, the last non-missing safety assessment before the first dose of study
intervention will be used as the baseline for all analyses of that safety parameter.
9.4.2.1.
Adverse Events
An AE will be considered a TEAE if:

The AE began on or after the date of the first dose of study intervention; or

The AE was present before the date of the first dose of study intervention, but increased in 
severity or became serious on or after the date of the first dose of study intervention
An AE that occurs more than 35 days after the last dose of study intervention will not be counted 
as a TEAE.
An AE will be considered a TESAE if it is a TEAE that additionally meets any SAE criteria.
The number and percentage of participants reporting TEAEs in each study intervention group
will be tabulated by system organ class and preferred term and by system organ class, preferred 
term, and severity.
The number and percentage of participants reporting treatment related TEAEs in each study 
intervention group will be tabulated by system organ class and preferred term.
If more than 1 AE is coded to the same preferred term for the same participant, the participant 
will be counted only once for that preferred term using the most severe and most related 
occurrence for the summarizations by severity and by relationship to study intervention.
Summary tables will be provided for participants with SAEs and participants with AEs leading to 
discontinuation if 5 or more participants reported such events. Listings of all AEs, SAEs, and 
AEs leading to discontinuation by participant will be presented.
The definitions of an AE and SAE can be found in Appendix 3.
9.4.2.2.
Clinical Laboratory Assessments
Descriptive statistics for clinical laboratory values (in SI units) at baseline (screening) and 
changes from baseline at each assessment will be presented by study intervention for each 
clinical laboratory assessment.
The criteria for PCS laboratory values will be detailed in the SAP. The number and percentage of 
participants who have PCS postbaseline clinical laboratory values will be tabulated by study
intervention at each assessment. The percentages will be calculated relative to the number of 
participants who have available non-PCS baseline values and at least 1 postbaseline assessment. 
The numerator will be the total number of participants with at least 1 PCS postbaseline value. A 
supportive listing of participants with PCS postbaseline values will be provided for the safety 
population. 
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10.
Supporting Documentation and Operational Considerations
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:
o
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines
o
Applicable ICH/ISO GCP guidelines
o
Applicable laws and regulations

The protocol, protocol amendments, ICF, investigator’s brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.

Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 

The Investigator will be responsible for the following:
o
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC
o
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
o
Providing oversight of the overall conduct of the study at the site and adherence to 
requirements of applicable local regulations, for example 21 CFR, ICH guidelines, the 
IRB/IEC, and European regulation 536/2014 for clinical studies (if applicable)
10.1.2.
Financial Disclosure
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study.
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10.1.3.
Informed Consent Process

The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding the 
study.

Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, HIPAA requirements, where applicable, and the IRB/IEC 
or study center.

The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.

A copy of the ICF(s) must be provided to the participant.
Participants who are rescreened are required to sign a new ICF.
10.1.4.
Data Protection

Participants will be assigned a unique identifier. Any participant records or datasets that are 
transferred to the Sponsor will contain the identifier only; participant names or any
information which would make the participant identifiable will not be transferred.

The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.

The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.5.
Data Quality Assurance

All participant data relating to the study will be recorded in eCRFs unless transmitted to the 
Sponsor or designee electronically (eg, laboratory data). The Investigator is responsible for 
verifying that data entries are accurate and correct by electronically signing the eCRF.

The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.

The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
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
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study
agreements, ICH GCP, and all applicable regulatory requirements.

Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.
10.1.6.
Source Documents

Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.

Data entered in the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. 
10.1.7.
Study and Site Closure
The Sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to:

Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor’s procedures, or GCP guidelines

Inadequate recruitment of participants by the Investigator

Discontinuation of further study intervention development
10.1.8.
Publication Policy

Allergan as the Sponsor has proprietary interest in this study. Authorship and manuscript 
composition will reflect cooperation between multiple Investigators and sites and Allergan 
personnel. Authorship will be established prior to the writing of the manuscript. As this study
involves multiple centers, no individual publications will be allowed prior to completion of 
the final report of the multicenter study except as agreed with Allergan.
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
The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data.

Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.9.
Compliance with Protocol
The Investigator is responsible for compliance with the protocol at the investigational site. A 
representative of the Sponsor will make frequent contact with the Investigator and his/her 
research staff and will conduct monitoring visits to review participant and study intervention 
accountability records for compliance with the protocol. Protocol deviations will be discussed 
with the Investigator upon identification. The use of the data collected for the participant will be 
discussed to determine if the data are to be included in the analysis. The Investigator will enter 
data that may be excluded from analysis as defined by the protocol deviation specifications. 
Significant protocol deviations will be reported to the IRB/IEC according to the IRB/IEC’s 
reporting requirements.
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c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or intervention that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether hospitalization occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective intervention of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life threatening or result in death or hospitalization but may
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually
be considered serious.
Examples of such events include invasive or malignant cancers, intensive 
intervention in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.
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10.4.
Appendix 4: Abbreviations
Abbreviation/Term
Definition
AACE
American Association of Clinical Endocrinologists
AE
adverse event
AESI
adverse event of special interest
ATA
American Thyroid Association
BMI
body mass index
BP
blood pressure
CBP
childbearing potential
CFR
Code of Federal Regulations
ECG
electrocardiogram, electrocardiographic
eCRF
electronic case report form
EOS
end of study
FDA
US Food and Drug Administration
FSH
follicle-stimulating hormone
FT3
free T3
FT4
free T4
GCP
Good Clinical Practice
HbA1c
ICF
hemoglobin A1c
informed consent form
IEC
independent ethics committee
IRB
institutional review board
ITT
intent-to-treat
IWRS
interactive web response system
MH
Mantel-Haenszel
PCS
potentially clinically significant
PK
pharmacokinetic
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate using the Fridericia formula 
(QTcF = QT/[RR]⅓)
SAE
serious adverse event
SAP
statistical analysis plan
T3
liothyronine, triiodothyronine (3, 5, 3′-triiodothyronine)
T4
levothyroxine, l-thyroxine, thyroxine
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Abbreviation/Term
Definition
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
TSH
thyroid-stimulating hormone
USP
United States Pharmacopeia
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10.5.
Appendix 5: Standard Discontinuation Criteria
CDISC Submission Value
CDISC Definition
Adverse event
Any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product 
and which does not necessarily have a causal relationship 
with this treatment. An adverse event (AE) can therefore be 
any unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with 
the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. For 
further information, see the ICH Guideline for Clinical 
Safety Data Management: Definitions and Standards for 
Expedited Reporting (modified from ICH E2A) Synonyms: 
side effect, adverse experience. See also serious adverse 
event, serious adverse experience. (CDISC glossary)
Completed
To possess every necessary or normal part or component or 
step; having come or been brought to a conclusion (NCI)
Death
The absence of life or state of being dead (NCI)
Lack of efficacy
The lack of expected or desired effect related to a therapy 
(NCI)
Lost to follow-up
The loss or lack of continuation of a subject to follow-up
Non-compliance with study drug
An indication that a subject has not agreed with or followed 
the instructions related to the study medication (NCI)
Other
Different than the one(s) previously specified or mentioned 
(NCI)
Physician decision
A position, opinion or judgment reached after consideration 
by a physician with reference to subject (NCI)
Pregnancy
Pregnancy is the state or condition of having a developing 
embryo or fetus in the body (uterus), after union of an 
ovum and spermatozoon, during the period from conception 
to birth. (NCI)
Protocol deviation
An event or decision that stands in contrast to the 
guidelines set out by the protocol (NCI)
Screen failure
The potential subject who does not meet one or more 
criteria required for participation in a trial
Site terminated by Sponsor
An indication that a clinical study was stopped at a 
particular site by its Sponsor (NCI)
Study terminated by Sponsor
An indication that a clinical study was stopped by its 
Sponsor (NCI)
Technical problems
A problem with some technical aspect of a clinical study, 
usually related to an instrument (NCI)
Withdrawal by subject
An indication that a study participant has removed itself 
from the study (NCI)
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10.7.
Appendix 7: Contraceptive Guidance and Collection of Pregnancy 
Information
Definitions:
Female of Childbearing Potential (CBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
Females in the following categories are not considered of CBP:
1. Premenarchal
2. Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormone replacement 
therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient.
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
Contraception Guidance:
Male Participants
Nonvasectomized male participants with female partners of CBP are eligible to participate if 
they agree to the following during the protocol-defined timeframe in Section 5.1:

Agree to use a male condom with spermicide plus partner use of a highly effective or 
acceptable method of contraception as described in Table 10-2, when having penile-vaginal 
intercourse with a woman of CBP who is not currently pregnant.
In addition, nonvasectomized male participants must refrain from donating sperm for the 
duration of the study and through 35 days after the last dose of study intervention.
Nonvasectomized male participants with a pregnant or breastfeeding partner must agree 
to use a male condom during each episode of penile penetration during the protocol-
defined timeframe.
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Female Participants
Female participants of CBP are eligible to participate if they agree to use a highly effective or 
acceptable method of contraception consistently and correctly as described in Table 10-2.
Table 10-2
Highly Effective and Acceptable Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependenta
Failure rate of < 1% per year when used consistently and correctly
Combined (estrogenb- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulation 

Oral 

Intravaginal 

Transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation

Oral 

Injectable 
Highly Effective Methods That Are User Independenta

Implantable progestogen-only hormonal contraception associated with inhibition of ovulation

IUD

IUS

Etonogestrel implant (ie, Nexplanon®)

Bilateral tubal occlusion (eg, Essure®, bilateral tubal ligation)

Intrauterine copper contraceptive (ie, ParaGard®)
Acceptable Methods
Acceptable birth control methods that result in a failure of more than 1% per year include:

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of 
action

Male or female condom with spermicide

Cap, diaphragm, or sponge with spermicide

Nonhormonal intrauterine device
A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-barrier methods) 
are also considered acceptable, but not highly effective, birth control methods.
a Typical use failure rates may differ from those experienced when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Estrogen-containing oral contraceptives may increase serum thyroxine-binding globulin (TBG) concentration.
Pregnancy Testing:

Female participants should be enrolled only after a negative serum pregnancy test at 
screening and a negative urine test (or serum test, if required by local regulation or IRB/IEC) 
at Visit 2.

Additional pregnancy testing should be performed at each study visit as defined in the 
Schedule of Activities in Section 1.3.

Serum pregnancy testing will be performed whenever pregnancy is suspected.
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Collection of Pregnancy Information:
Male Participants with Partners Who Become Pregnant

The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This applies 
only to male participants who receive study intervention.

The Investigator should inform the Sponsor within 24 hours of learning of the pregnancy.  
After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor. The female partner will also be followed to determine the outcome 
of the pregnancy. Information on the status of the mother and child will be forwarded to the 
Sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for the procedure.
Female Participants Who Become Pregnant 

The Investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate 
form and submitted to the Sponsor within 24 hours of learning of a participant’s pregnancy. 
The participant will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow-up information on the participant and the neonate, and the information 
will be forwarded to the Sponsor. Generally, follow-up will not be required for longer than 6 
to 8 weeks beyond the estimated delivery date. Any termination of pregnancy will be 
reported, regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
will be reported as an AE or SAE. Abnormal pregnancy outcomes (eg, spontaneous abortion, 
fetal death, stillbirth, congenital anomalies, ectopic pregnancy) or genetic abnormalities 
(whether leading to an elective abortion or not) are always considered to be an SAE and will 
be reported as such. Any poststudy pregnancy-related SAE considered reasonably related to 
the study intervention by the Investigator will be reported to the Sponsor as described in 
Section 8.3.4. While the Investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting.

Any female participant who becomes pregnant while participating in the study will be 
withdrawn from the study.
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