Conditions: Hypothyroidism Thyroid Disease Euthyroid Thyroid Gland Thyroid Hormones
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 284
Healthy volunteers: no

Brief summary:
This study will evaluate the safe and effective dose conversion from levothyroxine (synthetic T4) therapy to Armour Thyroid therapy in participants who are on a stable dose of levothyroxine and have thyroid stimulating hormone (TSH) levels within the normal reference range.

Detailed description:
This study will include will include a Screening Period, double-blinded Titration Period (at least 18 weeks, up to 36 weeks), and a double-blinded Stabilization Period (12 weeks).

Participants will be randomized to receive either their same dose of levothyroxine or an approximately, matching dose of Armour Thyroid, using a dose-conversion chart based on the United States Pharmacopeia (USP) Drug Information 2000, which states that 1 grain of Armour Thyroid is equivalent to 100 mcg of levothyroxine.

During the Titration Period, Investigators will have the option to up-or down-titrate a participant's dose as needed based on the participant's TSH level (normal reference range 0.45 - 4.12 mIU/L, inclusive). At Week 18, if a participant's TSH levels are not within the normal reference range, the Investigator may up-or down-titrate the dose by continuing the Titration Period beyond Week 18 for up to a maximum of 3 additional titrations at 6-week intervals. Participants whose TSH levels have not normalized after the maximum 3 additional titrations will not enter the Stabilization Period.

At the end of the Titration Period, participants with TSH levels within normal reference range may enter the Stabilization Period. Depending on whether a participant requires additional dose titration after the Week 18 visit, the Stabilization Period may end at Week 30, 36, 42, or 48.

Arms:
arm 1: Participants were randomized to receive Armour Thyroid at a dose corresponding to their pre-randomized dose of synthetic T4. During the first 18 to 36 weeks (titration period) the dose of Armour Thyroid could be titrated based on levels of thyroid stimulating hormone (TSH), in order to achieve TSH levels within the normal reference range (0.45 - 4.12 mIU/L, inclusive). Once TSH levels were within the normal reference range, participants continued to receive a stable dose of Armour Thyroid for an additional 12 weeks (stabilization period). arm 2: Participants were randomized to receive levothyroxine at their pre-randomized dose. During the first 18 to 36 weeks (titration period) the dose of levothyroxine could be titrated based on levels of TSH in order to achieve TSH levels within the normal reference range (0.45-4.12 mIU/L, inclusive). Once TSH levels were within the normal reference range, participants continued to receive a stable dose of levothyroxine for an additional 12 weeks (stabilization period).

Interventions: intervention 1: Armour® Thyroid intervention 2: Levothyroxine
Intervention descriptions: intervention 1: Administered orally once a day. the daily dose could range from 1/4 - 2 grains. intervention 2: Administered orally once a day; the daily dose could range from 25- 200 µg.

Protocol document:
Prot_000.pdf: 






CONFIDENTIAL
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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11.
References
Agresti A.  Categorical Data Analysis.  3rd ed.  Hoboken, NJ: John Wiley & Sons; 2013.
Aoki Y, Belin RM, Clickner R, Jeffries R, Phillips L, Mahaffey KR. Serum TSH and total T4 in 
the United States population and their association with participant characteristics: National 
Health and Nutrition Examination Survey (NHANES 1999-2002). Thyroid. 2007;17:1211-1223.
Armour Thyroid [package insert]. Madison, New Jersey: Allergan, Inc; 2018.
Cooper DS. Combined T4 and T3 therapy—back to the drawing board. JAMA. 
2003;290:3002-3004.
Escobar-Morreale HF, Obregón, MJ, Escobar del Rey F, Morreale de Escobar G. Replacement 
therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as 
studied in thyroidectomized rats. J Clin Invest. 1995;96:2828-2838.
Escobar-Morreale HF, Escobar del Rey F, Obregón, MJ, Morreale de Escobar G. Only the 
combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of 
the thyroidectomized rat. Endocrinology. 1996;137:2490-2502.
Fish LH, Schwartz HL, Cavanaugh J, Steffes MW, Bantle JP, Oppenheimer JH. Replacement 
dose, metabolism, and bioavailability of levothyroxine in the treatment of hypothyroidism. New
Engl J Med. 1987;316:764-770.
Garber JR, Cobin RH, Gharib H, Hennessey JV, Klein I, Mechanick JI, et al. Clinical practice 
guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical 
Endocrinologists and the American Thyroid Association. Thyroid. 2012;22:1200-1235.
Hoang TD, Olsen CH, Mai VQ, Clyde PW, Shakir MK. Desiccated thyroid extract compared 
with levothyroxine in the treatment of hypothyroidism: a randomized, double-blind, crossover 
study. J Clin Endocrinol Metab. 2013;98:1982-1990.
Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, et al.  Guidelines for the 
treatment of hypothyroidism. Thyroid.  2014;24:1670-1751.
Kaplan MM, Sarne DH, Schneider AB. Editorial: in search of the impossible dream? Thyroid 
hormone replacement therapy that treats all symptoms in all hypothyroid patients. J Clin 
Endocrinol Metab. 2003;88:4540-4542.
McDermott MT. Does combination T4 and T3 therapy make sense? Endocr Pract. 
2012;18:750-757.
Peterson SJ, Cappola AR, Castro MR, Dayan CM, Farwell AP, Hennessey JV, et al.  An online 
survey of Hypothyroid patients demonstrates prominent dissatisfaction.  Thyroid.  2018;1-16.
Saravanan P, Chau WF, Roberts N, Vedhara K, Greenwood R, Dayan CM. Psychological well-
being in patients on ‘adequate’ doses of L-thyroxine: results of a large, controlled community-
based questionnaire study. Clin Endocrinol. 2002;57:577-585.
Synthroid [package insert]. North Chicago, IL: AbbVie Inc; 2018.
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United States Pharmacopeia Drug Information: Drug Information for the Health Care 
Professional. Vol 1. 20th ed. Greenwood Village, CO: Thomson; 2000.
Walsh JP. Dissatisfaction with thyroxine therapy – could the patients be right? Curr Opin 
Pharmacol. 2002;2:717-722.
Walsh JP, Ward LC, Burke V, Bhagat CI, Shiels L, Henley D, et al. Small changes in thyroxine 
dosage do not produce measurable changes in hypothyroid symptoms, well-being, or quality of 
life: results of a double-blind, randomized clinical trial. J Clin Endocrinol Metab. 
2006;91:2624-2630.
Yan X, Su XG.  Stratified Wilson and Newcombe confidence intervals for multiple binomial 
proportions.  Stat Biopharm Res. 2010;2(3):329-335.
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SAP_001.pdf: 
Allergan 
3014-201-002 Statistical Analysis Plan
Armour Thyroid
1
1.0
TITLE PAGE
3014-201-002
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
STATISTICAL ANALYSIS PLAN
Version 2: 25 October 2021
Confidentiality Statement
This document is the property of Allergan Sales, LLC and may notin full or partbe 
passed on, reproduced, published, distributed to any person, or submitted to any regulatory 
authority without the express written permission of Allergan Sales, LLC.
NCT04124705


Allergan 
3014-201-002 Statistical Analysis Plan
Armour Thyroid
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2.0
TABLE OF CONTENTS
1.0
Title Page..........................................................................................................................................1
2.0
Table of Contents..............................................................................................................................2
3.0
List of Abbreviations ........................................................................................................................4
4.0
Introduction ......................................................................................................................................5
4.1
Study Design: .....................................................................................................................5
5.0
Objectives ....................................................................................................................................... 10
6.0
Populations For Analyses ............................................................................................................... 11
6.1
Intent-To-Treat Population............................................................................................... 11
6.2
Low baseline total T3 symptomatic Subset of ITT Population (ITT-T3)......................... 11
6.3
Safety Population ............................................................................................................. 11
6.4
Safety-T3 Population........................................................................................................ 11
7.0
Participant Disposition.................................................................................................................... 12
8.0
Demographics And Other Baseline Characteristics........................................................................ 13
9.0
Extent Of Exposure And Treatment Compliance ........................................................................... 14
9.1
Extent Of Exposure .......................................................................................................... 14
9.2
Measurement Of Treatment Compliance.......................................................................... 14
10.0
Efficacy Analyses ........................................................................................................................... 16
10.1
Primary Efficacy Endpoint and Analyses......................................................................... 16
10.2
Secondary Efficacy Endpoints.......................................................................................... 20
10.3
Multiple Comparisons Procedure ..................................................................................... 21
10.4
Additional and Exploratory Efficacy Endpoints............................................................... 21
11.0
Safety Analyses .............................................................................................................................. 23
11.1
Adverse Events................................................................................................................. 23
11.2
Clinical Laboratory Parameters........................................................................................ 24
11.3
Vital Signs........................................................................................................................ 27
11.4
Electrocardiogram ............................................................................................................ 27
11.5
Other Safety Parameters................................................................................................... 28
11.5.1
Physical Examination......................................................................................... 28
11.5.2
Potential Hy’s Law............................................................................................. 28
12.0
Health Outcomes Analyses............................................................................................................. 29
13.0
Interim Analysis.............................................................................................................................. 30
14.0
Determination of Sample Size ........................................................................................................ 31
15.0
Statistical Software ......................................................................................................................... 32
16.0
Data Handling Conventions............................................................................................................ 33
16.1
Baseline definition............................................................................................................ 33
16.2
Visit Time Windows......................................................................................................... 33
16.3
Repeated Or Unscheduled Assessments Of Safety Parameters........................................ 35
16.4
Missing Date Of The Last Dose Of Study Treatment ...................................................... 35


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16.5
Missing Severity Assessment For Adverse Events........................................................... 35
16.6
Missing Causal Relationship To Study Treatment For Adverse Events........................... 35
16.7
Missing Date Information For Adverse Events ................................................................ 35
16.8
Missing Date Information For Prior Or Concomitant Medications.................................. 37
16.8.1
Incomplete Start Date......................................................................................... 37
16.8.2
Incomplete Stop Date......................................................................................... 37
16.9
Character Values Of Clinical Laboratory Parameters ...................................................... 38
17.0
Changes To Analyses Specified In Protocol................................................................................... 40
18.0
Summary of Changes from the Original SAP................................................................................. 41
19.0
Appendix A: Justification for Non-inferiority Margin.................................................................... 42
20.0
Appendix B: Attributes of the estimand for primary and secondary endpoints.............................. 45
21.0
Appendix C: Thypro Questionnaire................................................................................................ 46
21.1
Scoring of the ThyPRO questionnaire.............................................................................. 46
21.2
Scoring of the ThyPRO-39 questionnaire......................................................................... 48
21.3
Patient-Reported Outcomes Questionnaires, Descriptions, and Instructions – ThyPRO 
Questionnaire.................................................................................................................... 51
22.0
References ...................................................................................................................................... 61
LIST OF TABLES
Table 4-1
Schedule Activities ............................................................................................8
Table 9-1
Capsule Composition of Doses........................................................................15
Table 11-1
Criteria for Potentially Clinically Significant Laboratory Tests......................26
Table 11-2
Criteria for Potentially Clinically Significant Vital Signs...............................27
Table 11-3
Criteria for Potentially Clinically Significant Electrocardiographic Values ...28
Table 16-1
Examples for Coding of Special Character Values for Clinical Laboratory 
Parameters
..............................................................................................................................
Table 19-1
The evaluation of study similarity between Study 3014-201-002 and KPCO 
study.
..........................................................................................................................43
Table 21-1
To the left is the raw score. The corresponding 0-100 score is tabulated for 
each scale separately. For example, a patient with a raw score on the Goiter Symptoms scale 
of 6 (e.g. because she answered “Some” to all three Goiter items), will have a 0-100 Goiter 
Symptoms score of 37. A raw score of 6 on the Tiredness scale, would yield a 0-100 score of 
50.
..........................................................................................................................50
LIST OF FIGURES
Figure 4-1
3014-201-002 Study Schematic.........................................................................6


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3.0
LIST OF ABBREVIATIONS
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
ALP
alkaline phosphatase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
ATH
Armour Thyroid
CFB
change from baseline
CDF
cumulative distribution function
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
eCRF
electronic case report form
ECG
electrocardiogram, electrocardiographic
EOT
end of trial
ITT
intent to treat
MAR
missing at random
MI
multiple imputation
OC
observed cases
PCS
potentially clinically significant
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate using the Bazett formula (QTcB = QT/(RR)½)
QTcF
QT interval corrected for heart rate using the Fridericia formula (QTcF = QT/(RR)⅓)
RM
rescue medication
SAE
serious adverse event
SAP
statistical analysis plan
SE
standard error
SI
Le Système International d’Unités (International System of Units)
SOC
system organ class
TBL
total bilirubin
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event


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3014-201-002 Statistical Analysis Plan
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4.0
INTRODUCTION
This statistical analysis plan (SAP) provides technical and detailed elaboration of the 
statistical analyses of the efficacy and safety data that will be performed for Study 3014-201-
002 as outlined and/or specified in a final protocol dated 28 May 2019 and the most recent 
amendment dated 16 Jan 2020. Specifications of tables, listings and figures are provided in a 
separate document.
4.1
STUDY DESIGN: 
Study 3014-201-002 is a randomized, double-blinded, parallel-group, active-controlled, 
multicenter, dose-conversion study in previously hypothyroid participants, who are euthyroid 
on a stable dose of T4 replacement therapy, to evaluate the efficacy and safety of replacement 
therapy with matching doses of Armour Thyroid in comparison to synthetic T4.
During the coronavirus disease 2019 (COVID-19) pandemic, the mitigation strategy of 
increasing enrollment has been implemented to overcome the loss of information from the 
impact of COVID-19. Approximately 284 total participants (an increased enrollment from 
the original planned sample size of 220 participants specified in the protocol) who meet 
eligibility criteria will be randomly assigned to study intervention in a 1:1 ratio 
(approximately 142 participants per arm), stratified by age (< 65 years, ≥ 65 years).
The study will last approximately 33 to 51 weeks (with a planned minimum of 7 visits and a 
maximum of 15 possible visits if participants require additional dose titration) and will 
include a Screening Period (up to 3 weeks), double-blinded Titration Period (at least 
18 weeks), and a double-blinded Stabilization Period (12 weeks). 
All participants entering the study will be controlled on a stable, FDA-approved, daily dose 
of synthetic T4 (i.e., euthyroid) for at least 3 months and will be randomized to either the 
same dose of synthetic T4 or a matching dose of Armour Thyroid during the first visit of the 
Titration Period (Visit 2). For each available dose of synthetic T4, up to 200 µg, a matching 
dose of Armour Thyroid will be employed according to a dose-conversion table based on the 
USP Drug Information 2000. Armour Thyroid and synthetic T4 will be administered as a 
single oral dose of 2 capsules (one of these capsules may be placebo), once-daily, on an 
empty stomach at least 30 to 60 minutes before the first meal. Serum TSH levels will be 
measured prior to study intervention administration during study visits.
During the Titration Period, participants will continue the same dose taken during the last 
visit or have their dose up- or down-titrated as needed per the Investigators’ interpretation of 
their TSH levels (normal reference range 0.45-4.12 mIU/L, inclusive). For example, 
Investigators should up-titrate the dose if the TSH value is above 4.12 mIU/L and down-
titrate the dose if the TSH value is below 0.45 mIU/L during the Titration Period. Other 
thyroid-related assessments and evaluation of thyroid clinical status will also be completed.
Investigators may only titrate participants’ doses, as needed, until the start of the Stabilization 
Period. Participants will remain on a stable dose during the Stabilization Period until the end 
of the study.


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Study schematic and schedule of evaluation are presented in Figure 4-1 and Table 4-1
respectively
Figure 4-1
3014-201-002 Study Schematic
-
*
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 (i.e., 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 total T3, 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.
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 (i.e., 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 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


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3014-201-002 Statistical Analysis Plan
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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 
can enter the Stabilization Period. Participants whose TSH levels have not normalized 
after the maximum of 3 additional titrations will not enter the Stabilization Period.

Participants who need dose titration beyond Week 18 will complete a study visit 
approximately every 6 weeks to determine if their TSH levels are within the normal 
reference range. At these visits, they will have the same assessments performed as 
those performed at Visit 5a including study intervention dispensing. These assessment 
visits will be labeled sequentially 5c (Week 24), 5e (Week 30), and 5g (Week 36), as 
needed.

Participants who need dose titration beyond Week 18 will also complete a study visit 
for additional study intervention dispensing. These study intervention visits will be 
labeled sequentially as 5b (Week 19), 5d (Week 25), and 5f (Week 31), as needed. 
Visit 5d and 5f will have all the same assessments and activities performed as Visit 
5b.
The Titration Period is at least 18 weeks in duration. Depending on whether a participant
requires additional dose titration after Visit 5a, the Titration Period may end at Week 18, 24, 
30, or 36 (up to a maximum of 3 additional titrations are allowed starting at Visit 5b).
The Stabilization Period is 12 weeks in duration. Depending on whether a participant requires 
additional dose titration after Visit 5a, the Stabilization Period may end at Week 30, 36, 42, 
or 48. If a participant undergoes the maximum of 3 additional dose titrations starting at Week 
5b, the Stabilization Period would be from Week 36 to Week 48.
Visit 6 may be at Week 24, 30, 36, or 42 depending on the number of additional titrations 
needed after Visit 5a. Visit 7 may be at Week 30, 36, 42, or 48 depending on the number of 
additional titrations needed after Visit 5a.


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Table 4-1
Schedule Activities
3014-201-002 Schedule of Activities
Screening
Titration Period
(Week 0 to Week 18a)
Stabilization Period
(Week 18a to Week 30c)
Early 
Termination
Visit Number
Visit 1
Visit 2
Visit 3a
Visit 3bd
Visit 4a
Visit 4bd
Visit 5ae
Visit 5bd,e
Visit 6f
Visit 7g
ET
Study Week
-3 to 0
0
6
7
12
13
18d
19
24
30
Visit Window
---
±3 days
±3 days
±3 days
±3 days
±3 days
±3 days
±3 days
±3 days
±3 days
Informed consent
X
Randomization
X
Inclusion/exclusion
X
X
Demographic data
X
Medical history
X
AEs
X
X
X
X
X
X
X
X
X
X
X
Clinical laboratoryb,h,n
X
X
X
X
X
X
X
X
Vital signsb,i
X
X
X
X
X
X
X
X
X
X
X
ECGb
X
X
X
X
X
X
X
X
Physical examinationj
X
X
X
BMI
X
X
X
Urine pregnancy testb
(females of CBP)
X
X
X
X
X
X
X
Serum pregnancy test 
(females of CBP)b,n
X
X
X
X
X
X
X
X
Serum TSH, T4, T3, FT3, 
FT4 (Thyroid-related 
assessments)b,n
X
X
X
X
X
X
X
X
Thyroglobulin and 
anti-thyroglobulinn,o
X
PK blood samplesk, n
X
X
Thyroid symptom 
questionnaire (ThyPRO 
Questionnaire)
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X


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Screening
Titration Period
(Week 0 to Week 18a)
Stabilization Period
(Week 18a to Week 30c)
Early 
Termination
Visit Number
Visit 1
Visit 2
Visit 3a
Visit 3bd
Visit 4a
Visit 4bd
Visit 5ae
Visit 5bd,e
Visit 6f
Visit 7g
ET
Study Week
-3 to 0
0
6
7
12
13
18d
19
24
30
Visit Window
---
±3 days
±3 days
±3 days
±3 days
±3 days
±3 days
±3 days
±3 days
±3 days
Evaluation of thyroid 
clinical statusl
X
X
X
X
X
X
X
X
Study intervention 
dispensing
X
X
X
X
X
X
X
X
Study intervention 
compliance
Xm
X
X
X
X
X
X
X
X
X
Study intervention 
collection
X
X
X
X
X
X
X
X
X
Potential for dose 
adjustment
X
X
X
AE = adverse event; BMI = body mass index; BP = blood pressure; CBP = childbearing potential; ECG = electrocardiogram; ET = early termination; FT3 = free T3; FT4 = free T4; 
IRB/IEC = institutional review board/independent ethics committee; PK = pharmacokinetic; T3 = liothyronine; T4 = levothyroxine; TSH = thyroid-stimulating hormone
a The Titration Period is at least 18 weeks in duration. Depending on whether a participant requires additional dose titration after Visit 5a, the Titration Period may end at Week 18, 
24, 30, or 36 (up to a maximum of 3 additional titrations are allowed starting at Visit 5b).
b These assessments will be pre-dose.
c The Stabilization Period is 12 weeks in duration. Depending on whether a participant requires additional dose titration after Visit 5a, the Stabilization Period may end at Week 30, 
36, 42, or 48. If a participant undergoes the maximum of 3 additional dose titrations starting at Week 5b, the Stabilization Period would be from Week 36 to Week 48.
d This study intervention dispensing visit is only applicable to participants needing a dose titration.
e Visit 5 is designed as a transition visit, which serves as both the end of the Titration Period and the beginning of the Stabilization Period. At Visit 5a (Week 18), if a participant’s 
TSH level is not within normal reference range, the participant may have his/her dose up- or down-titrated per the Investigator’s interpretation of his/her TSH level by continuing 
the Titration Period beyond Week 18 for additional visits, as needed. The additional study intervention dispensing visits will be labeled sequentially (Visit 5b, 5d, and 5f, as
needed). Visit 5d and 5f will have all the same assessments and activities performed as Visit 5b.  Additional assessment visits will be labeled sequentially (Visit 5c, 5e, 5g, as 
needed), and will have all the same assessments and activities performed as Visit 5a.
f Visit 6 may be at Week 24, 30, 36, or 42 depending on the number of additional titrations needed after Visit 5a.
g Visit 7 may be at Week 30, 36, 42, or 48 depending on the number of additional titrations needed after Visit 5a.
h Hematology, chemistry, urinalysis.
i BP, pulse rate; respiratory rate, and oral temperature
j Includes height and weight measurements (height at Screening Visit only)
k PK samples will be collected pre-dose and 2 hour (± 30 minutes) post-dose at Visits 2 and 7.  Additionally, the date and time of dose on the day of PK sampling will be recorded.
l This includes evaluation of hypothyroid symptoms, which will be documented in the eCRF.
m Compliance assessment at Visit 2 relates to the participant having taken his/her own synthetic T4 between Visit 1 and Visit 2.
n Participants will be required to undergo an overnight (minimum 5 hours) fast for all visits where laboratory assessments will be performed. Participants should also abstain from 
taking biotin 72 hours prior to clinical laboratory testing.
o Thyroglobulin and anti-thyroglobulin testing only applicable for participants who have undergone total thyroidectomy for treatment of thyroid cancer.


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5.0
OBJECTIVES
The study objective is to evaluate the efficacy and safety of hormone replacement therapy with 
matching doses of Armour Thyroid (ATH) in comparison to synthetic T4 in previously
hypothyroid participants who are euthyroid on synthetic T4 replacement therapy (25-200 μg T4 
daily). 
In addition, this study will validate the dose-conversion table by evaluating a safe and effective 
dose conversion from synthetic T4 to Armour Thyroid in participants who are euthyroid on a 
stable dose of synthetic T4.


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6.0
POPULATIONS FOR ANALYSES
6.1
INTENT-TO-TREAT POPULATION
The Intent-to-Treat (ITT) Population will consist of all randomized participants who took at least 
1 dose of study intervention.
6.2
LOW BASELINE TOTAL T3 SYMPTOMATIC SUBSET OF ITT
POPULATION (ITT-T3)
The low baseline total T3 symptomatic Population (abbreviated as ITT-T3 Population) will 
consist of all participants in the ITT Population who had a baseline total T3 < 87 ng/dL and a 
ThyPRO hypothyroidism symptom scale > 0.
6.3
SAFETY POPULATION
The Safety Population will consist of all participants who took at least 1 dose of study 
intervention.
6.4
SAFETY-T3 POPULATION
The Safety-T3 Population will consist of all participants who took at least 1 dose of study 
intervention and who had a baseline total T3 < 87 ng/dL and a ThyPRO hypothyroidism 
symptom scale > 0.


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7.0
PARTICIPANT DISPOSITION
The number and percentage of participants in the four analysis populations (ITT and ITT-T3
Populations, Safety and Safety-T3 Populations) will be summarized by treatment group and 
study center; the number of participants screened will be summarized overall only by study 
center.
Screen-failure participants (i.e., participants who consented to participate in the clinical study but 
were not randomized) and the associated reasons for failure to randomize will be tabulated for all 
screened participants. 
The number and percentage of participants who complete the double blind treatment period and 
of participants who prematurely discontinue during the same period will be presented for each 
treatment group and pooled across treatment groups for the ITT and ITT-T3 Populations. The 
reasons for premature discontinuation from the double blind treatment period as recorded on the 
termination pages of the electronic case report forms will be summarized (number and 
percentage) by treatment group for the ITT and ITT-T3 Populations. All participants who 
prematurely discontinue during the double-blind period will be listed by discontinuation reason 
for the ITT and ITT-T3 Populations.


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8.0
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS
Demographic parameters (e.g., age, race, ethnicity, sex) and other baseline characteristics 
(weight, BMI) will be summarized in total and by treatment group for the four analysis
populations (ITT and ITT-T3 Populations, Safety and Safety-T3 Populations).
Abnormalities in participants’ medical and surgical histories will be coded using the Medical 
Dictionary for Regulatory Activities, version 21.1 or newer. The number and percentage of 
participants with abnormalities in medical and surgical histories in each system organ class and 
preferred term will be summarized by treatment group for the ITT and ITT-T3 Populations.
Prior medication is defined as any medication started before the date of the first dose of double-
blind study treatment. Concomitant medication is defined as any medication taken on or after the 
date of the first dose of double-blind study treatment. Any prior medications started more than 30 
days before the date of the first dose of double-blind study treatment and any concomitant 
medications started after the date of the last dose of double-blind study treatment will not be 
presented in the summary tables, but will be included in the participant data listings.
Both prior and concomitant medication use will be summarized by the number and proportion of 
participants in each treatment group for the ITT and ITT-T3 Populations. The WHO Drug 
Dictionary, Version B2 March 2017 or newer, will be used to classify prior and concomitant 
medications by WHO Drug Anatomical/Therapeutic/Chemical category and drug preferred
name. Multiple medications used by a participant will only be counted once for the coded drug 
preferred name or therapeutic class.


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9.0
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE
9.1
EXTENT OF EXPOSURE
Exposure to the study treatment for the Safety and Safety-T3 Populations during the double-
blind treatment period will be summarized for treatment duration, calculated as the number of 
days from the date of the first dose of double-blind investigational product taken to the date of 
the last dose taken, inclusive. Descriptive statistics (number of participants, mean, SD, minimum, 
median, Q1, Q3 and maximum) will be presented by treatment group.
Mean daily dose (by period and overall mean) for the study treatment will be summarized using 
descriptive statistics (number of patients, mean, SD, median, minimum, Q1, Q3 and maximum). 
Overall modal daily dose and final daily dose will be summarized by the number and percentage 
of patients with a pre-specified dose.
Patient-years, defined as exposure to the study treatment in years, will be summarized by 
treatment for the Safety and Safety-T3 Populations.
9.2
MEASUREMENT OF TREATMENT COMPLIANCE
Dosing compliance for a specified period is defined as the total number of dose-numbers (daily 
single intervention based on dose level with two capsules, see Table 9-1) actually taken by a 
patient during that period divided by the number of dose-numbers that were expected to be taken 
during the same period multiplied by 100 by treatment group. The total number of dose-numbers 
actually taken during a specific period is calculated as the number of days in that period 
multiplied by the number of dose-numbers taken each day during that period. The number of 
dose-numbers expected to be taken for a specific treatment period will be calculated by 
multiplying the number of days in that period by the number of dose-numbers to be taken per 
day.
Descriptive statistics for study drug compliance will be presented by treatment group by period 
and for the whole double-blind treatment period, for the Safety and Safety-T3 Populations.


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10.0
EFFICACY ANALYSES
The efficacy analyses will be performed on the ITT Population or ITT-T3 Population, depending 
on the endpoints.
10.1
PRIMARY EFFICACY ENDPOINT AND ANALYSES
The primary efficacy endpoint is the achievement of TSH values 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 (sustained TSH responder). The primary estimand is the difference in the 
percentage of sustained TSH responders between the Armour Thyroid and synthetic T4 study 
intervention groups in the ITT Population. The number and percentage of sustained TSH 
responders will be summarized by treatment group in the ITT Population. Participants with a
missing TSH value at either the end of the Titration Period or at the end of the Stabilization 
Period will be handled based on Non-Responder Imputation incorporating multiple imputation to 
handle missing data due to Covid-19 (NRI-C), as outlined later in this section.
The non-inferiority (NI) hypothesis test for the primary efficacy endpoint, based on the ITT 
Population, will be performed at a 1-sided 2.5% level of significance (equivalent to a two-sided 
5% level of significance). The null hypothesis is that Armour Thyroid is inferior to synthetic T4, 
which will be tested against the alternative hypothesis that Armour Thyroid is non-inferior to 
synthetic T4, as follows:
:  −
  ≤−∆    :  −
  > −∆   
Where:  and 
 are the proportions of TSH responders in the Armour Thyroid and synthetic 
T4 study intervention groups, respectively;
 
The analysis of the primary efficacy endpoint will be performed on the ITT Population using 
stratum-adjusted Mantel-Haenszel by age group (age < 65 years or ≥ 65 years) as described in 
(Agresti 2013, p. 231). 
The stratified proportion difference is 
 
 
 p
p
 
ference in stratum h and 
.
The proportion difference in stratum h is computed as 
where 
is the proportion of TSH responder for ATH and 
is the proportion of TSH 
responder for synthetic T4 at stratum h. 
The variance of 
as 
where 
 
 
      
 
 
 
 
 
 
    
  
 
 
 
  
 
  




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Period and the end of Stabilization Period according to the normal reference range
(0.45-4.12 mIU/L, inclusive) based on the imputed values with the following exception:
The participants who have missing TSH values either at the end of the Titration Period or 
at the end of the Stabilization Period for reasons other than solely due to COVID-19 
infection or logistical restrictions related to the COVID-19 pandemic, the non-responder 
status will be assigned to these participants in the imputed datasets regardless of the 
imputed values.
Step 2. Analysis: Each of the 100 imputed datasets from Step 1.2 will be analyzed 
separately using the above mentioned stratified Mantel-Haenszel test.
Step 3. Pooling: The point estimate and 95% confidence interval of the stratified 
proportion difference from the 100 imputed datasets are combined into one overall result 
using PROC MIANALYZE. 
Sensitivity Analyses for the Primary Efficacy Endpoint
Participants who are missing TSH values either at the end of the Titration Period or at the end of 
the Stabilization Period will be assessed by the following sensitivity analyses. Additional 
sensitivity analyses will be performed if useful and appropriate.
Non-Responder Imputation
The non-responder imputation sensitivity analysis will be performed to investigate the impact of 
missing TSH values. If a participant has missing TSH values at either the end of the Titration 
Period or the end of the Stabilization Period, then this participant will be imputed as a TSH non-
responder.
Responder Imputation
The responder imputation sensitivity analysis will be performed to investigate the impact of 
missing TSH values. If a participant has missing TSH values at either the end of the Titration 
Period or the end of the Stabilization Period, then this participant will be imputed as a Sustained 
TSH responder. If a participant has the TSH value out of the normal reference range at the end of 
titration or stabilization, the participant will be considered as non-responder by the definition of 
sustained TSH response regardless of missing data.
Complete Case
Participants who have not completed the study or who are missing TSH values at either the end 
of the Titration Period or the end of the Stabilization Period will be excluded from the analysis. 
That is, the non-inferiority between Armour Thyroid and synthetic T4 will be established in the 
complete-case.


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NRI incorporating Multiple Imputation (NRI-MI)
The Non-Responder Imputation incorporating Multiple Imputation (NRI-MI) will be carried out 
for all the missing TSH values in the steps similar to the ones described above for NRI-C, with 
the exception of Step 1.2.
Step 1.2. Imputing Responder Status: In the imputed datasets from Step 1.1, the 
responder status (yes/no) will be derived from the TSH values at the end of Titration 
Period and the end of Stabilization Period according to the normal reference range (0.45-
4.12 mIU/L, inclusive) based on the imputed values with the following exception: For 
participants who prematurely discontinue from the study due to lack of efficacy, adverse 
events related to study drug, or death, the non-responder status will be assigned to these 
participants in the imputed datasets regardless of the imputed values.
Multiple Imputation
The Multiple Imputation (MI) analysis will be carried out for all the missing TSH values 
regardless of reasons for missingness in the steps similar to the ones described above for NRI-C, 
with the exception of Step 1.2.
Step 1.2. Imputing Responder Status: In the imputed datasets from Step 1.1, the 
responder status (yes/no) will be derived from the TSH values at the end of Titration 
Period and the end of Stabilization Period according to the normal reference range based 
on the imputed values. 
Tipping Point 
Tipping-point analysis will be performed to investigate the impact of missing TSH values on the 
study results, that is to identify difference of minimum numbers of Sustained TSH responders 
between treatment groups in the missing cohort which results in conclusion change (Yan, Lee 
and Li, 2007).
Stratified Newcombe Confidence Interval
For the sensitivity analyses of Non-Responder Imputation, Responder Imputation, and Complete 
Case, the 2-sided 95% confidence interval for stratified proportion difference will also be 
performed in the ITT Population using stratified Newcombe confidence interval, which is based 
on a stratified method with Cochran-Mantel-Haenszel weights (Yan and Su 2012).


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10.2
SECONDARY EFFICACY ENDPOINTS
The Achievement of Titration TSH Response 
The achievement of titration TSH Response is defined as TSH values that are within the normal 
reference range of 0.45 to 4.12 mIU/L, inclusive, at the end of the Titration Period (Titration 
TSH Responder). The secondary estimand is the difference in the percentage of Titration TSH 
Responders between the Armour Thyroid and synthetic T4 study intervention groups in the ITT
population. The number and percentage of titration TSH responders will be summarized by 
treatment group in the ITT Population along with the 2-sided 95% CI for the stratified proportion 
difference. The non-inferiority (NI) hypothesis test for the secondary efficacy endpoint, based on 
the ITT Population, will be performed at a 1-sided 2.5% level of significance (equivalent to a 
two-sided 5% level of significance). The analysis of the secondary efficacy endpoint will be 
performed on the ITT Population using stratum-adjusted Mantel-Haenszel by age group
(age < 65 years or ≥ 65 years) as described in the Section 10.1 (Agresti 2013, p. 231).
The Non-Responder Imputation incorporating multiple imputation to handle missing data due to 
Covid-19 (NRI-C) will be performed for participants who have missing TSH values at the end of 
the Titration Period similar to the primary efficacy analysis outlined in Section 10.1.
Sensitivity Analyses for the Secondary Efficacy Endpoint
Participants who are missing TSH values at the end of the Titration Period will be assessed by 
the following sensitivity analyses. Additional sensitivity analyses will be performed if useful and 
appropriate.
Non-Responder Imputation
The non-responder imputation sensitivity analysis will be performed to investigate the impact of 
missing TSH values. If a participant has missing TSH value at the end of the Titration Period, 
then this participant will be imputed as a titration TSH non-responder.
Responder Imputation
The responder imputation sensitivity analysis will be performed to investigate the impact of 
missing TSH values. If a participant has missing TSH value at the end of the Titration Period, 
then this participant will be imputed as a titration TSH responder.
Complete Case
Participants who have not completed the Titration Period or who have missing TSH values at the 
end of the Titration Period will be excluded from the analysis. 
NRI incorporating Multiple Imputation (NRI-MI)
The Non-Responder Imputation incorporating Multiple Imputation (NRI-MI) will be carried out 
for all the missing TSH values in the steps similar to the ones described above for NRI-C, with 
the exception of Step 1.2.






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11.0
SAFETY ANALYSES
The safety analysis will be performed on the Safety and Safety-T3 Populations. The safety 
parameters will include AEs, clinical laboratory measurements including fasting T3 and T4 (total 
T3, total T4, free T3 and free T4), 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 prior to or on the first dose of study intervention will be used 
as the baseline for all analyses of that safety parameter. Continuous variables will be summarized 
by number of patients and mean, SD, median, minimum, and maximum values. Categorical 
variables will be summarized by number and percentage of patients.
11.1
ADVERSE EVENTS
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA),
Version 19.0 or newer.
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.


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11.2
CLINICAL LABORATORY PARAMETERS
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.

Laboratory 
Assessments

Parameters
Thyroid-related

Serum TSH, T4, T3, FT4, and FT3
Thyroglobulin and 
anti-thyroglobulin

Thyroglobulin and anti-thyroglobulin testing only applicable for participants who 
have undergone total thyroidectomy for treatment of thyroid cancer
Hematology
Platelet count
RBC indices:
MCV
MCH
MCHC
%Reticulocytes
WBC count with 
differential (absolute):
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC count
Hemoglobin
Hematocrit
Clinical Chemistry
BUN
Potassium
AST
Total, direct and 
indirect bilirubin
Creatinine
Sodium
ALT
Total protein
Glucose 
Calcium
Alkaline 
phosphatase
Cholesterol, 
chloride, albumin
HbA1c
Routine Urinalysisa

Specific gravity

pH, glucose, protein, blood, ketones

Microscopic examination (if blood or protein is abnormal)
Pregnancy Testa

Urine and serum test (females of CBP)
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CBP = childbearing 
potential; FT3 = free T3; FT4 = free T4; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular 
hemoglobin concentration; MCV = mean corpuscular volume; RBC = red blood cell; T3 = liothyronine; T4 = 
levothyroxine; TSH = thyroid-stimulating hormone; WBC = white blood cell
a
Serum pregnancy tests will be standard at the Screening Visit (Visit 1) and Visit 7; local urine testing will be 
standard for all other visits, as specified in the schedule of activities, unless serum testing is required by local 
regulation or IRB/IEC.


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Clinical laboratory test values will be considered potentially clinically significant (PCS) if they 
meet either the lower-limit or higher-limit PCS criteria listed in Table 11-1. The number and 
percentage of participants who have PCS post-baseline 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 post-
baseline assessment. The numerator will be the total number of participants with at least 1 PCS 
post-baseline value. A supportive listing of participants with PCS post-baseline values will be 
provided for the Safety and Safety-T3 Populations.


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Table 11-1
Criteria for Potentially Clinically Significant Laboratory Tests
Parameter
SI Unit
Lower Limit
Higher Limit
CHEMISTRY
Albumin
g/L
< 0.9 * LLN
> 1.1 * ULN
Alanine Aminotransferase (ALT)
U/L
—
≥ 3 * ULN
Alkaline Phosphatase
U/L
—
≥ 3 * ULN
Aspartate Aminotransferase (AST)
U/L
—
≥ 3 * ULN
Calcium
mmol/L
< 0.9 * LLN
> 1.1 * ULN
Chloride
mmol/L
< 0.9 * LLN
> 1.1 * ULN
Cholesterol
mmol/L
—
> 1.6 * ULN
Creatinine
μmol/L
—
> 1.3 * ULN
Potassium
mmol/L
< 0.9 * LLN
> 2.0 * ULN
Glucose, Fasting
mmol/L
< 0.9 * LLN
> 1.4 * ULN
Sodium
mmol/L
< 0.9 * LLN
> 1.1 * ULN
Total Bilirubin
μmol/L
—
> 1.5 * ULN
Total Protein
g/L
< 0.9 * LLN
> 1.1 * ULN
Triglycerides, Fasting
mmol/L
—
≥ 3 * ULN
Urea (BUN)
mmol/L
—
> 1.2 * ULN
Magnesium
mmol/L
< 0.9 * LLN
> 1.1 * ULN
Bicarbonate
mmol/L
< 0.9 * LLN
> 1.1 * ULN
Phosphate
mmol/L
< 0.9 * LLN
> 1.1 * ULN
Uric Acid
μmol/L
< 0.9 * LLN
> 1.1 * ULN
HEMATOLOGY
Basophils Absolute Cell Count
109/L
—
> 3 * ULN
Eosinophils Absolute Cell Count
109/L
—
> 3 * ULN
Hematocrit
Ratio
< 0.9 * LLN
> 1.1 * ULN
Hemoglobin
g/L
< 0.9 * LLN
> 1.1 * ULN
Lymphocytes Absolute Cell Count 
109/L
< 0.8 * LLN
> 1.5 * ULN
MCH
PG
—
> 3 * ULN
MCHC
G/L
—
> 3 * ULN
MCV
fL
< 0.9 * LLN
> 1.1 * ULN
Monocytes Absolute Cell Count
109/L
—
> 3 * ULN
Neutrophils Absolute Cell Count
109/L
< 0.8 * LLN
> 1.5 * ULN
Platelet Count
109/L
< 0.5 * LLN
> 1.5 * ULN
Red Blood Cell Count (Erythrocyte Count)
1012/L
< 0.9 * LLN
> 1.1 * ULN
White Blood Cell Count
109/L
< 0.7 * LLN
> 1.5 * ULN
URINALYSIS
pH
< 0.9 * LLN
> 1.1 * ULN
Specific Gravity
—
> 1.1 * ULN
LLN: Lower limit of normal value provided by the laboratory.
ULN: Upper limit of normal value provided by the laboratory.


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11.3
VITAL SIGNS
Descriptive statistics for vital signs (systolic and diastolic BP, pulse rate, weight, respiration rate, 
and temperature) at baseline (screening) and changes from baseline at each assessment will be 
presented by study intervention.
Vital sign values will be considered PCS if they meet both the observed-value criteria and the 
change from baseline criteria listed in Table 11-2. The number and percentage of participants 
who have PCS post-baseline 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 post-baseline assessment. The numerator 
will be the total number of participants with at least 1 PCS post-baseline value. A supportive 
listing of participants with PCS post-baseline values will be provided for the Safety and Safety-
T3 Populations.
Table 11-2
Criteria for Potentially Clinically Significant Vital Signs
Parameter
Flag
Criteriaa
Observed Value
Change From Baseline
Sitting systolic 
blood pressure, 
mm Hg
High
≥ 140
Increase of ≥ 20
Low
≤ 90
Decrease of ≥ 20
Sitting diastolic 
blood pressure, 
mm Hg
High
≥ 90
Increase of ≥ 15
Low
≤ 50
Decrease of ≥ 15
Sitting pulse rate, 
bpm
High
≥ 100
Increase of ≥ 15
Low
≤ 50
Decrease of ≥ 15
Weight, kg
High
—
Increase of ≥ 7%
Low
—
Decrease of ≥7%
a
A post-baseline value is considered potentially clinically significant if it meets both the observed-value and the change 
from baseline criteria.
bpm = beats per minute.
11.4
ELECTROCARDIOGRAM
Descriptive statistics for ECG parameters (heart rate, PR interval, QRS duration, QT interval, 
and QTc) at baseline, EOS, changes from baseline at EOS, interim ECG parameters at baseline 
(pre-dose at each period), and changes from baseline at post-dose will be presented by study 
intervention.


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Electrocardiographic parameter values are considered PCS if they meet or exceed the 
higher-limit PCS criteria listed in Table 11-3. The number and percentage of participants who 
have PCS post-baseline ECG values will be tabulated by study intervention for EOS assessments 
and interim assessments. The percentages will be calculated relative to the number of 
participants who have available non-PCS baseline values and at least 1 post-baseline assessment. 
The numerator will be the total number of participants with at least 1 PCS post-baseline value. A 
supportive listing of participants with PCS post-baseline values will be provided, including the 
participant number and baseline and post-baseline values, for the Safety and Safety-T3 
Populations.
Table 11-3
Criteria for Potentially Clinically Significant Electrocardiographic Values
Parameter
Unit
Criterion Value a
Change from Baseline a
QRS duration
msec
≥ 150
—
PR interval
msec
≥ 250
—
QTcF interval for male
msec
> 450
Increase of > 60
QTcF interval for female
msec
> 470
Increase of > 60
a
post-baseline (end-of-study or post-dose) value will be considered potentially clinically significant if it meets the 
criterion value or the change from baseline or pre-dose value.
PCS = potentially clinically significant;
QTcF = QT interval/(60/RR)1/3.
11.5
OTHER SAFETY PARAMETERS
11.5.1
Physical Examination 
Any new physical examination abnormality identified on the post-baseline physical examination 
or any physical examination abnormality noted as worsened from Screening (Visit 1) to the post-
baseline physical examination will be reported as an AE if considered by the investigator to be 
clinically significant. No separate data analysis for physical exams is planned.
11.5.2
Potential Hy’s Law
Potential Hy’s Law criteria within a 24-hour window is defined by a post baseline elevation of 
alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3x ULN, along with total 
bilirubin (TBL) ≥ 2x ULN and a non-elevated alkaline phosphatase (ALP) < 2x ULN, all based 
on blood draws collected within a 24-hour period. 
Potential Hy’s Law criteria without time window (e-DISH) is defined by maximum of post 
baseline elevation of ALT or AST ≥ 3x ULN, along with maximum of post baseline elevation of 
TBL ≥ 2x ULN and a non-elevated alkaline phosphatase (ALP) < 2x ULN. 
Participants who meet the potential Hy’s Law criteria from the first dose of study drug to within 
35 days after the last dose of study treatment will be summarized. Supportive tabular displays 
will also be provided.


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12.0
HEALTH OUTCOMES ANALYSES
Analyses for health economics and outcomes parameters will be described in a separate 
document.


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13.0
INTERIM ANALYSIS
No interim analysis is planned for this study.




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15.0
STATISTICAL SOFTWARE
Statistical analyses will be performed using version 9.4 (or newer) of SAS on a Linux operating 
system.


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16.0
DATA HANDLING CONVENTIONS
16.1
BASELINE DEFINITION
Unless otherwise specified, the baseline value will be the last non-missing value obtained prior 
to or on the first treatment dose.
16.2
VISIT TIME WINDOWS
The following tables present the visits assigned for analyses and the corresponding range of 
treatment days (window) during which an actual visit may occur.
1) Participants for 18-week Titration Period Visit Time Windows for Analysis
Derived Visit
Window
Visit 2 Baseline
Day 1
Days ≤ 1
Visit 3a Week 6
Day 42
Days [2, 63]
Visit 4a Week 12
Day 84
Days [64, 105]
Visit 5a Week 18
Day 126
Days [106, last day of TP]
Visit 6 Week 24
Day 168
Days [first day of SP, 189]
Visit 7 Week 30
Day 210
Days > 189
2) Participants for 24-week Titration Period Visit Time Windows for Analysis
Derived Visit
Window
Visit 2 Baseline
Day 1
Days ≤ 1
Visit 3a Week 6
Day 42
Days [2, 63]
Visit 4a Week 12
Day 84
Days [64, 105]
Visit 5a Week 18
Day 126
Days [106, 147]
Visit 5c Week 24
Day 168
Days [148, last day of TP]
Visit 6 Week 30
Day 210
Days [first day of SP, 231]
Visit 7 Week 36
Day 252
Days > 231


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3) Participants for 30-week Titration Period Visit Time Windows for Analysis
Derived Visit
Window
Visit 2 Baseline
Day 1
Days ≤ 1
Visit 3a Week 6
Day 42
Days [2, 63]
Visit 4a Week 12
Day 84
Days [64, 105]
Visit 5a Week 18
Day 126
Days [106, 147]
Visit 5c Week 24
Day 168
Days [148, 189]
Visit 5e Week 30
Day 210
Days [190, last day of TP]
Visit 6 Week 36
Day 252
Days [first day of SP, 273]
Visit 7 Week 42
Day 294
Days > 273
4) Participants for 36-week Titration Period Visit Time Windows for Analysis
Derived Visit
Window
Visit 2 Baseline
Day 1
Days ≤ 1
Visit 3a Week 6
Day 42
Days [2, 63]
Visit 4a Week 12
Day 84
Days [64, 105]
Visit 5a Week 18
Day 126
Days [106, 147]
Visit 5c Week 24
Day 168
Days [148, 189]
Visit 5e Week 30
Day 210
Days [190, 231]
Visit 5g Week 36
Day 252
Days [232, last day of TP]
Visit 6 Week 42
Day 294
Days [first day of SP, 315]
Visit 7 Week 48
Day 336
Days > 315
TP = Titration Period; SP = Stabilization Period.
Last day of TP is the day of last TSH visit prior to visit 6.
First day of SP is defined as the last day of TP + 1.


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If the visit date is on or after the date of the first dose of double-blind study treatment, the study 
day is calculated by visit date – date of the first dose of double-blind investigational product + 1. 
If the visit date is before the date of the first dose of double-blind investigational product, the 
study day is calculated by visit date – date of the first dose of double-blind investigational 
product. Therefore, a negative day indicates a day before the start of the double blind
investigational product.
If a participant has 2 or more visits within the same window, the last visit with a non-missing 
value will be used for analysis.
The titration visits 5b, 5d, and 5f will be included in the analysis visits 5a, 5c, 5e, or 5g based on 
the definition of analysis visit window.
16.3
REPEATED OR UNSCHEDULED ASSESSMENTS OF SAFETY 
PARAMETERS
If a participant has repeated assessments before the start of double-blind treatment with 
investigational product, the results from the final assessment made before the date of the first 
dose will be used as baseline. If EOT assessments are repeated or unscheduled, the last post-
baseline assessment will be used as the EOT assessment for generating summary statistics. 
However, all post-baseline assessments will be used for PCS value determination, and all 
assessments will be presented in the data listings.
16.4
MISSING DATE OF THE LAST DOSE OF STUDY TREATMENT
When the date of the last dose of the double-blind investigational product is missing, all efforts 
should be made to obtain the date from the Investigator. If it is still missing after all efforts have 
been made, the last diary date will be used as the last dose date.
16.5
MISSING SEVERITY ASSESSMENT FOR ADVERSE EVENTS
If severity is missing for an AE that started before the date of the first dose of double-blind 
investigational product, an intensity of mild will be assigned. If severity is missing for an AE that 
started on or after the date of the first dose of double-blind investigational product, an intensity 
of severe will be assigned. The imputed values for severity assessment will be used for the 
incidence summary; the values will be shown as missing in the data listings.
16.6
MISSING CAUSAL RELATIONSHIP TO STUDY TREATMENT FOR 
ADVERSE EVENTS
If the causal relationship to the investigational product is missing for an AE that started on or 
after the date of the first dose of double-blind investigational product, a causality of yes will be 
assigned. The imputed values for causal relationship to double-blind treatment will be used for 
the incidence summary; the values will be shown as missing in the data listings.
16.7
MISSING DATE INFORMATION FOR ADVERSE EVENTS
The following imputation rules apply to cases in which the start date is incomplete (i.e., partial 
missing) for AEs.


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Missing day and month

If the year is the same as the year of the date of the first dose of double-blind 
investigational product, then the day and month of the date of the first dose of 
double-blind investigational product will be assigned to the missing fields.

If the year is prior to the year of the date of the first dose of double-blind investigational 
product, then December 31 will be assigned to the missing fields.

If the year is after the year of the date of the first dose of double-blind investigational 
product, then January 1 will be assigned to the missing fields.
Missing month only

The day will be treated as missing and both month and day will be replaced according to 
the above procedure.
Missing day only

If the month and year are the same as the month and year of the date of the first dose of 
double-blind investigational product, then the date of the first dose of double-blind 
investigational product will be assigned to the missing day.

If either the year is before the year of the date of the first dose of double-blind 
investigational product or if both years are the same but the month is before the month of 
the date of the first dose of double-blind investigational product, then the last day of the 
month will be assigned to the missing day.

If either the year is after the year of the date of the first dose of double-blind 
investigational product or if both years are the same but the month is after the month of 
the date of the first dose of double-blind investigational product, then the first day of the 
month will be assigned to the missing day.
If the stop date is complete and the imputed start date as above is after the stop date, the start 
date will be imputed by the stop date.
If the start date is completely missing and the stop date is complete, then the following algorithm 
is used to impute the start date:

If the stop date is on or after the date of the first dose of double-blind investigational 
product, the date of the first dose of double-blind investigational product will be assigned 
to the missing start date.

If the stop date is before the date of the first dose of double-blind investigational product, 
the stop date will be assigned to the missing start date.


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16.8
MISSING DATE INFORMATION FOR PRIOR OR CONCOMITANT 
MEDICATIONS
For prior or concomitant medications, excluding rescue medications, incomplete (i.e., partly 
missing) start dates and/or stop dates will be imputed. When the start date and the stop date are 
both incomplete for a participant, the start date will be imputed first.
16.8.1
Incomplete Start Date
The following rules will be applied to impute the missing numeric fields for an incomplete prior 
or concomitant medication start date. If the stop date is complete (or imputed) and the imputed 
start date is after the stop date, the start date will be imputed using the stop date.
Missing month and day

If the year of the incomplete start date is the same as the year of the first dose of study 
treatment, the month and day of the first dose of study treatment will be assigned to the 
missing fields

If the year of the incomplete start date is before the year of the first dose of study treatment, 
December 31 will be assigned to the missing fields

If the year of the incomplete start date is after the year of the first dose of study treatment, 
January 1 will be assigned to the missing fields
Missing month only

If only the month is missing, the day will be treated as missing and both the month and the 
day will be replaced according to the above procedure
Missing day only

If the month and year of the incomplete start date are the same as the month and year of the 
first dose of study treatment, the day of the first dose of study treatment will be assigned to 
the missing day

If either the year of the incomplete start date is before the year of the date of the first dose of 
study treatment or if both years are the same but the month of the incomplete start date is 
before the month of the date of the first dose of study treatment, the last day of the month 
will be assigned to the missing day.

If either the year of the incomplete start date is after the year of the date of the first dose of 
study treatment or if both years are the same but the month of the incomplete start date is 
after the month of the date of the first dose of study treatment, the first day of the month will 
be assigned to the missing day
16.8.2
Incomplete Stop Date
The following rules will be applied to impute the missing numeric fields for an incomplete prior 
or concomitant medication stop date. If the date of the last dose of study treatment is missing, 
impute it as descripted in Section 16.4. If the imputed stop date is before the start date (imputed 
or non-imputed start date), the imputed stop date will be equal to the start date.


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Missing month and day

If the year of the incomplete stop date is the same as the year of the last dose of study 
treatment, the month and day of the last dose of study treatment will be assigned to the 
missing fields

If the year of the incomplete stop date is before the year of the last dose of study treatment, 
December 31 will be assigned to the missing fields

If the year of the incomplete stop date is after the year of the last dose of study treatment, 
January 1 will be assigned to the missing fields
Missing month only

If only the month is missing, the day will be treated as missing and both the month and the 
day will be replaced according to the above procedure
Missing day only

If the month and year of the incomplete stop date are the same as the month and year of the 
last dose of study treatment, the day of the last dose of study treatment will be assigned to the 
missing day

If either the year of the incomplete stop date is before the year of the date of the last dose of 
study treatment or if both years are the same but the month of the incomplete stop date is 
before the month of the date of the last dose of study treatment, the last day of the month will 
be assigned to the missing day

If either the year of the incomplete stop date is after the year of the date of the last dose of 
study treatment or if both years are the same but the month of the incomplete stop date is 
after the month of the date of the last dose of study treatment, the first day of the month will 
be assigned to the missing day.
16.9
CHARACTER VALUES OF CLINICAL LABORATORY 
PARAMETERS
If the reported value of a clinical laboratory parameter cannot be used in a statistical summary 
table because, for example, the value is a character string rather than a numerical type, a coded 
value needs to be appropriately determined and used in the statistical analyses. However, the 
actual values as reported in the database will be presented in data listings.


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Table 16-1
Examples for Coding of Special Character Values for Clinical Laboratory Parameters
Laboratory Test (Unit)
Possible Lab Results
(in SI units)
Coded Value for Analysis
Chemistry: ALT
< 5
0
Chemistry: AST
< 5
0
Chemistry: Bilirubin, Total
< 2
0
Urinalysis: Glucose
= OR > 55, >= 55, > 0
Positive
<= 0, Negative
Negative
Urinalysis: Ketones
= OR > 8.0, >=8.0, > 0
Positive
<= 0, Negative
Negative
Urinalysis: pH
> 8.0, >= 8.0
8.0
>= 8.5,
8.5
Urinalysis: Protein
= OR > 3.0, >=3.0, > 0
Positive
<= 0
Negative








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21.0
APPENDIX C: THYPRO QUESTIONNAIRE 
21.1
SCORING OF THE THYPRO QUESTIONNAIRE
Each of the 13 ThyPRO scales is scored as a summary score and linearly transformed to 
range 0-100. This scoring procedure is described step by step below. 
Naming of items 
Each item is named TQ{relevant item number}. Item number is indicated left of each item in 
the questionnaire. Thus, the first item, 'sensation of fullness in the neck' is named TQ1A in 
the database. 
Scoring of responses 
Item responses are scored 
0 for 'Not at all' 
1 for 'A little' 
2 for 'Some' 
3 for 'Quite a bit' 
4 for 'Very much' 
Scale content 
Each scale consists of the following items: 
Goitre symptoms scale: TQ1A TQ1B TQ1C TQ1D TQ1E TQ1F TQ1G TQ1H TQ1I TQ1J 
TQ1K; 
Hyperthyroid symptoms scale: TQ1L TQ1M TQ1N TQ1O TQ1P TQ1R TQ1S TQ1T; 
Hypothyroid symptoms scale: TQ1Q TQ1CC TQ1DD TQ1EE; 
Eye symptoms scale: TQ1U TQ1V TQ1W TQ1X TQ1Y TQ1Z TQ1AA TQ1BB; 
Tiredness scale: TQ2A TQ2B TQ2C TQ2D TQ3A TQ3B TQ3C; 
Cognitive problems scale: TQ4A TQ4B TQ4C TQ4D TQ4E TQ4F; 
Anxiety scale: TQ5A TQ5B TQ5C TQ5D TQ5E TQ5F;


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Depressivity scale: TQ6A TQ6B TQ6C TQ6D TQ6E TQ6F TQ6G; 
Emotional Susceptibility scale: TQ7A TQ7B TQ7C TQ7D TQ7E TQ7F TQ7G TQ7H TQ7I; 
Impaired Social life scale: TQ8A TQ8B TQ8C TQ8D; 
Impaired Daily life scale: TQ9A TQ9B TQ9C TQ9D TQ9E TQ9F; 
Impaired Sexlife scale: TQ10A TQ10B; 
Cosmetic Complaints scale: TQ11A TQ11B TQ11C TQ11D TQ11E TQ11F; 
Scale scoring 
In principle, scales are scored by simply adding the response values (0-4) for all the items in 
a scale. Thus, if a patient answered 'Not at all' to all items in the Social impairment scale, the 
score would be 0; whereas if she answered 'Not at all' to two items, 'A little' to one item and 
'Some' to the last item, the score would be 3 (and max score would be 16). However, three 
additional features expand this procedure: reversal of positively worded items, imputation for 
individual missing item responses and linear transformation. 
Reversal of positively worded items 
As part of the scoring procedure, items 3A, 3B, 3C, 6F, 6G, 7H and 7I have to be reversed, 
i.e. 'Not at all' scored as 4, 'A little' as 3, 'Some' as 2, 'Quite a bit' as 1 and 'Very much' scored 
as 0.
Scales are transformed linearly to range 0-100 according to the formula 
Transformed score=(raw sum score/highest possible raw sum score)*100. 
Individual missing items will be imputed as follows. If half or more of the items in a scale is 
completed, missing items are substituted by the mean of the completed items. Otherwise, 
total score (or scale) will be set to missing.
For example, the abovementioned patient answering 'Not at all' to two items, 'A little' to one 
item and 'Some' to the last item, would have a raw score of 3 (0+0+1+2). Highest possible 
raw score would be 16 (4+4+4+4). The transformed 0-100 score would then be 3/16*100=19.


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21.2
SCORING OF THE THYPRO-39 QUESTIONNAIRE 
Each of the 13 ThyPRO-39 scales is scored as a summary score and transformed to range 0-
100. This scoring procedure is described step by step below. 
Naming of items 
Each item is named TQ{relevant item number}. Item number is indicated left of each item in 
the questionnaire. Thus, the first item, 'sensation of fullness in the neck' is named TQ1A in 
the database. 
Scoring of responses 
Item responses are scored 
0 for 'Not at all' 
1 for 'A little' 
2 for 'Some' 
3 for 'Quite a bit' 
4 for 'Very much'/'Completely' 
Scale content 
Each scale consists of the following items: 
Goitre symptoms scale: TQ1A TQ1C TQ1H 
Hyperthyroid symptoms scale: TQ1l TQ1M TQ1N TQ1T 
Hypothyroid symptoms scale: TQ1Q TQ1CC TQ1DD TQ1EE 
Eye symptoms scale: TQ1W TQ1X TQ1BB 
Tiredness scale: TQ2A TQ2C TQ3B 
Cognitive problems scale: TQ4A TQ4B TQ4F; 
Anxiety scale: TQ5B TQ5C TQ5E 
Depressivity scale: TQ6A TQ6E TQ6G 
Emotional Susceptibility scale: TQ7C TQ7D TQ7H 
Impaired Social life scale: TQ8A TQ8B TQ8C 
Impaired Daily life scale: TQ9A TQ9C TQ9E 
Cosmetic Complaints scale: TQ11A TQ11D TQ11E 


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Overall QoL: TQ12 
Composite scale: TQ2A TQ2C TQ3B TQ4A TQ4B TQ4F TQ5B TQ5C TQ5E TQ6A TQ6E 
TQ6G TQ7C TQ7D TQ7H TQ8A TQ8B TQ8C TQ9A TQ9C TQ9E TQ12 
Scoring the individual scales 
The raw scale scores are derived by simply adding the response values (0-4) for all the items in a 
scale. However, three additional features expand this procedure: 
1. reversal of positively worded items, 
2. imputation for individual missing item responses and 
3. 0-100 transformation. 
Reversal of positively worded items 
As part of the scoring procedure, items 3B, 6G and 7H have to be reversed, i.e. 'Not at all' 
scored as 4, 'A little' as 3, 'Some' as 2, 'Quite a bit' as 1 and 'Very much'/'Completely scored 
as 0. 
Imputation for individual missing items 
If half or more of the items in a scale is completed, missing items are substituted by the mean 
of the completed items. 
Linear transformation 
All scales (except for the Hypothyroid Symptoms, the Overall QoL scale and the Composite 
scale, see below) are transformed to range 0-100 according to Table 21-1 below: 


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Table 21-1
To the left is the raw score. The corresponding 0-100 score is tabulated for each 
scale separately. For example, a patient with a raw score on the Goiter Symptoms 
scale of 6 (e.g. because she answered “Some” to all three Goiter items), will have a 0-
100 Goiter Symptoms score of 37. A raw score of 6 on the Tiredness scale, would 
yield a 0-100 score of 50.
Transformation of the Hypothyroid Symptoms scale: 
The ThyPRO-39 Hypothyroid Symptoms is identical to the original ThyPRO Hypothyroid 
Symptoms scale and is thus transformed to 0-100 according to the formula 
Transformed score=(raw sum score/16)*100 
For example, if a patient answered 'Not at all' to two items, 'A little' to one item and 'Some' to 
the last item, she would have a raw score of 3 (0+0+1+2). The transformed 0-100 score 
would then be 3/16*100=19. 
Transformation of the Overall QoL-impact scale/item: 
The Overall QoL item (TQ12) is rescaled to 0-100 simply by taking the mean raw score and 
multiply by 25.
Scoring the Composite scale 
The Composite scale is based on the 22 items from the Tiredness, Cognition, Anxiety, 
Depressivity, Emotional Susceptibility, Impaired Social life Impaired Daily Life and Overall 
QoL scales: 
TQ2A TQ2C TQ3B TQ4A TQ4B TQ4F TQ5B TQ5C TQ5E TQ6A TQ6E TQ6G TQ7C 
TQ7D TQ7H TQ8A TQ8B TQ8C TQ9A TQ9C TQ9E TQ12 
The raw score is derived as described above, by summation (with imputation for missing), to 
range 0-88. The raw score is transformed to 0-100 according to the formula 
Transformed score=(raw sum score/88)*100
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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21.3
PATIENT-REPORTED OUTCOMES QUESTIONNAIRES, 
DESCRIPTIONS, AND INSTRUCTIONS – THYPRO 
QUESTIONNAIRE
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 


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22.0
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