A Phase 2, Multicenter, Non-Randomized, Open-Label, Single Arm, Self-controlled Study of XP-8121 For the Treatment of Adult Subjects With Hypothyroidism
Phase: PHASE2
Conditions: Hypothyroidism
Sponsor: Xeris Pharmaceuticals

XP-8121-120 Protocol Cover Page 
 
Study Title:  
A Phase 2, Multicenter, Non-Randomized, Open-Label, Single 
Arm, Self-controlled Study of XP-8121 For the Treatment of Adult 
subjects with Hypothyroidism 
Most Recent Document 
Version Date: 
07 May 2023 
NCT No. 
NCT05823012 
 
 
 
 
IND No. 
153502 
 

 
 
 
 
1. 
TITLE PAGE 
 
 
 
A Phase 2, Multicenter, Non-Randomized, Open-Label, Single Arm, 
Self-controlled Study of XP-8121 For the Treatment of Adult 
Subjects with Hypothyroidism 
 
Study Number: 
XP-8121-120 
Phase: 
2 
IND Number: 
153502 
Study Drug: 
XP-8121 (Levothyroxine Sodium)  
Sponsor: 
Xeris Pharmaceuticals, Inc. 
Chicago, IL USA 60607 
Medical Monitor: 
Valentina Conoscenti, MD  
Date of Protocol: 
Version 1.0: 06 February 2023 
Amendment 1 (Version 2.0): 08 March2023 
Amendment 2 (Version 3.0): 07 May 2023 
 
GCP Statement: 
This study is to be performed in full compliance with International 
Council for Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use (ICH) and all applicable local 
Good Clinical Practice (GCP) and regulations. All required study 
documentation will be archived as required by regulatory authorities. 
Confidentiality Statement: 
This document is confidential. It contains proprietary information of 
Xeris (the Sponsor). Any viewing or disclosure of such information 
that is not authorized in writing by the Sponsor is strictly prohibited. 
Such information may be used solely for the purpose of reviewing or 
performing this study. 
 
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SUMMARY OF REVISIONS: PROTOCOL VERSION 2.0 TO VERSION 3.0 
This protocol was amended to clarify information in the protocol in response to an 
advice/information request by the Division of General Endocrinology at the Center for Drug 
Evaluation and Research at the United States Food and Drug Administration (US FDA) dated 
20 April 2023. Additional clarifications have been made to support consistent conduct of the 
study. 
Affected 
Sections/Tables 
Summary of Revisions Made 
Rationale 
General 
Minor formatting updates and 
clarifications. 
Updated wording to increase 
specificity of procedures and 
timing. 
Administrative update. 
Section 1 
Added new protocol version. 
Updated address ZIP code. 
Administrative update. 
Summary of Revisions 
Appendix F 
Replaced description of changes 
made to the protocol with the 
changes included for Protocol 
Version 2.0 to Version 3.0. 
Moved prior revisions for 
Protocol Version 1.0 to Version 
2.0 to Appendix F. 
Administrative update.  
Section 2 
Synopsis was updated to align 
with changes in main body of 
protocol. 
Administrative update. 
Table 2 
 
Added footnote ‘n’ to the 
procedure of “XP-8121 
administration” and removed 
from the individual assessments. 
Clarification of guidance on the timing 
of XP-8121 dose administration. 
Table 2, footnote ‘c’ 
Included a reference to the 
weekly visits to be conducted 
every 7 days.  
Clarified that assessments at the 
weekly visits includes the 
administration of XP-8121. 
Procedural clarification. 
Table 2, footnote ‘g’ 
Section 8.1, Inclusion 
Criterion (IC) #8 
Section 12.3 
Section 12.8.4 
Appendix B 
Specified that heart rate/pulse is 
measured in triplicate and that 
the average resting heart 
rate/pulse is to be used to assess 
eligibility. Clarified terminology 
to refer to heart rate/pulse. 
Clarified terminology in protocol for 
heart rate/pulse as the same measurement 
and that it should be performed in 
triplicate. 
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Affected 
Sections/Tables 
Summary of Revisions Made 
Rationale 
Table 2, footnote ‘i’ 
Table 2, footnote ‘o’ 
Section 7.1 
Section 7.4.2 
Section 8.1, IC#3 
Section 8.1, IC#4 
Section 11.1 
Section 11.3.1 
Included the study reference 
ranges for free T4 and TSH, as 
applicable. 
Recommended FDA update. 
Table 2, footnote ‘j’ 
Switched location of footnote to 
‘XP-8121 administration’ rather 
than ‘Free and total T4’. 
Administrative update. 
Table 2, footnote ‘k’ 
Section 8.2, Exclusion 
Criterion (EC) #23 
Section 12.8.8 
Aligned language with the 
update to the EC#23 exception 
for prescription benzodiazepines. 
Clarification of eligibility criteria, as 
prescription benzodiazepines are not a 
prohibited medication. 
Table 2, footnote ‘n’ 
Clarified information referencing 
the dose titration and adjustment 
criteria. 
Administrative update. 
Table 2, footnote ‘n’ 
Section 10.5 
Appendix A 
Updated with the timing of the 
administration of XP-8121. It is 
to occur every 7 days, within 
±2 hours of the time of 
administration of the XP-8121 
SC initiation dose. 
Clarification of guidance on the timing 
of XP-8121 dose administration. 
Section 5.5 
Section 7.1 
Section 7.4.1 
Section 7.4.2 
Section 7.4.3 
Section 11.2 
Section 13.5.1 
Section 13.5.1.1 
Appendix A 
Clarified description of dose 
conversion to specify that the 
dose conversion factor will be 
based on μg of the daily oral 
levothyroxine and weekly 
XP-8121 SC. 
Recommended FDA update. 
Section 6.1.3 
Clarified description of 
exploratory objectives to include 
both the Titration and 
Maintenance Periods 
Recommended FDA update. 
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Affected 
Sections/Tables 
Summary of Revisions Made 
Rationale 
Section 7.1 
Included a summary of the total 
duration of treatment at the 
stable dose of XP-8121 (eg, 
6 weeks). 
Clarification of study design to address 
FDA recommendation/comment. 
Section 8.2, EC#25 
Included additional guidance for 
exclusion of patients with a 
history of clinically significant 
or uncontrolled conditions that 
could jeopardize the safety of the 
subject or impact the validity of 
the study results. 
Recommended FDA update. 
Section 8.4 
Clarified the description of the 
subject withdrawal criteria. 
Clarified to improve clarity of the unique 
withdrawal criteria in this study related 
to achieving an adequate and tolerable 
replacement dosage. 
Section 11.1 
Included guidance for potential 
to re-screen subjects with 
Medical Monitor approval. 
Updated to include procedure for the 
management of re-screening potential 
subjects. 
Section 11.1 
Included guidance to align with 
the eligibility requirement for 
normalized TSH for at least 
3 months prior to Screening 
(documented by local 
laboratory). 
Procedural clarification. 
Section 11.1 
Section 12.8.7 
Included guidance for the 
potential to repeat Screening 
visit laboratory assessments for 
clinical safety with Medical 
Monitor approval. 
Updated to include procedure for 
management of potential subjects with 
abnormal Screening visit laboratory 
assessments for clinical safety. 
Section 12.8.4 
Clarified that each of the 
triplicate measurements for 
blood pressure and heart rate are 
to be entered in the eCRF. 
Procedural clarification. 
Section 13.4 
Clarified definition of Completer 
Population to include subjects 
who exhibit normalized TSH 
throughout the Maintenance 
Period. 
Recommended FDA update. 
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Affected 
Sections/Tables 
Summary of Revisions Made 
Rationale 
Section 13.5.1.1 
Updated to clarify population to 
be included in the analysis of the 
primary endpoints will be those 
in the Completer population with 
primary hypothyroidism only. 
And to reference that additional 
sensitivity analysis (if 
applicable) will be described in 
the statistical analysis plan. 
Clarification to align with FDA 
recommendation/comment. 
Section 13.5.2 
Updated endpoints to include a 
separate endpoint for the 
proportion of subjects enrolled 
with normalized TSH throughout 
the Maintenance Period. 
Endpoint clarified to indicate 
that the blood thyroid hormone 
concentrations would be 
assessed during the Titration and 
Maintenance Periods. 
Clarification to align with FDA 
recommendation/comment. 
Section 13.5.2.1 
Clarified that the secondary 
endpoints will be analyzed for 
the safety population for subjects 
with hypothyroidism only and 
for all subjects, as applicable.  
In addition, the analysis will be 
performed for subjects with 
normalized TSH throughout the 
Maintenance Period and at the 
End of Maintenance Period 
Clarification to align with FDA 
recommendation/comment. 
Section 13.5.3.1 
Clarified that the exploratory 
endpoints will be analyzed for 
the safety population for subjects 
with primary hypothyroidism 
only and for all subjects, as 
applicable. 
Clarification to align with FDA 
recommendation/comment. 
Section 13.7.1 
Removed reference to the 
collection of frequency 
information for a specific AE 
report. 
AE frequency is assessed at the overall 
level of occurrence during the study. The 
study does not include an investigator 
assessment of frequency of occurrence 
for each AE reported by a subject. 
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INVESTIGATOR’S AGREEMENT 
 
I have received and read the protocol for XP-8121-120 and associated documents and agree to 
conduct the study as outlined. I agree to maintain the confidentiality of all information received 
or developed in connection with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 
 
 
 
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PROCEDURES IN CASE OF EMERGENCY 
Table 1: 
Emergency Contact Information 
Role in Study 
Name & Title 
Email Address & Telephone 
Number 
Medical monitor &  
24-hr emergency contact 
Valentina Conoscenti, MD 
Medical Director 
Clinical Research 
Xeris Pharmaceuticals, Inc. 
 
  
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2. 
SYNOPSIS 
Name of 
Sponsor/ 
Company: 
Xeris Pharmaceuticals, Inc. 
Name of 
Investigational 
Product: 
XP-8121  
Name of Active 
Ingredient: 
Levothyroxine Sodium 
Title: 
A Phase 2, Multicenter, Non-Randomized, Open-Label, Single Arm, Self-controlled Study of 
XP-8121 For the Treatment of Adult Subjects with Hypothyroidism 
Study number 
XP-8121-120 
Sites 
Multicenter study conducted in the United States (US) 
Clinical phase  
2 
 
Study 
background & 
rationale 
 
Xeris Pharmaceuticals, Inc. (Xeris) is developing a novel formulation of levothyroxine, 
XP-8121, for subcutaneous (SC) injection. XP-8121 was developed to mitigate many of the 
challenges associated with oral formulations of levothyroxine. XP-8121 is expected to 
provide patients with a therapy that will require less frequent dosing, thereby potentially 
improving treatment adherence, and that will bypass the gastrointestinal (GI) tract, thereby 
mitigating limitations of oral therapy (eg, drug-food and drug-drug interactions, GI 
conditions affecting drug absorption, intact swallowing function).  
In the first Phase 1 study of XP-8121 in healthy subjects conducted by Xeris (XP-8121-101), 
the pharmacokinetic (PK) of XP-8121 as a single dose of 300 µg following SC administration 
was evaluated. XP-8121 PK was compared to that of intravenous (IV) administration of 300 
µg levothyroxine sodium and oral (PO) administration of 300 µg Eltroxin® (levothyroxine 
sodium) tablets (3 × 100 µg). Interpretation of the study results obtained from this study were 
limited as only estimations for maximum plasma concentration (Cmax), time to maximum 
concentration (Tmax), and area under the drug concentration-time curve (AUC) across the 
sample collection period (0-312 hours (hr)) could be considered interpretable. The 300-µg 
dose of levothyroxine administered to healthy subjects as XP-8121 (SC), or via IV and PO 
routes was not sufficient to allow estimation of the baseline-corrected elimination constant 
and half-life.  
Xeris shared the results from Study XP-8121-101 with the Food and Drug Administration 
(FDA), and based upon feedback received, Study XP-8121-108 was conducted to 
characterize additional doses, to allow more robust understanding of the XP-8121 absorption 
and elimination kinetics and to allow an evaluation of dose proportionality. Following FDA 
evaluation of the XP-8121-108 safety and PK data obtained following SC administration of 
600 µg and 1200 µg XP-8121, FDA permitted additional dose of XP-8121 1500 µg to be 
evaluated to characterize dose proportionality across the potential range of clinical doses. In 
Study XP-8121-108, no notable differences in the safety results between the 600 μg, 1200 μg, 
and 1500 μg doses of XP-8121 were observed, and no XP-8121 studied dose was different 
from Synthroid® 600 μg PO with respect to the safety results. Predicted geometric mean AUC 
at steady state for XP-8121 at 1200 µg was similar to the predicted geometric mean AUC at 
steady state for Synthroid at 300 µg. Based on PK modeling, an XP-8121 SC weekly dose of 
4 times the daily Synthroid PO dose is estimated to provide similar exposure (AUC). 
Therefore, this study will use a 4X conversion factor to calculate the target μg dose for 
weekly XP-8121 SC from the μg dose for daily levothyroxine PO. 
Based upon the known safety and toxicity profile of levothyroxine, published use of oral 
levothyroxine as a weekly dose regimen, and observed and expected PK profile of XP-8121, 
the doses proposed in this investigation are safe for use in the clinical trial setting and are 
appropriate to determine the dose range of XP-8121 to normalize Thyroid Stimulating 
Hormone (TSH). 
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Objectives: 
Primary Objective 
• 
To assess the safety and tolerability of XP-8121 after once-weekly SC injections in 
adult subjects with hypothyroidism  
• 
To determine a target dose conversion factor from stably dosed oral levothyroxine to 
XP-8121 in patients with hypothyroidism 
Secondary Objectives 
• 
To determine a dose range of XP-8121 capable of maintaining normalized TSH 
following a switch from stable replacement therapy with oral levothyroxine  
• 
To evaluate a safe initiation dose of XP-8121 based on the prior stable dose of oral 
levothyroxine  
• 
To evaluate a safe titration scheme for dosing XP-8121 to TSH target 
Exploratory Objectives 
• 
To characterize the dynamics of thyroid hormones and TSH in blood during and after 
titration (ie, Titration and Maintenance Periods) with XP-8121  
• 
To characterize the PK of plasma thyroid hormones following multiple once-weekly 
XP-8121 SC injections in adult subjects with hypothyroidism  
• 
To compare patient treatment satisfaction between daily oral levothyroxine and once-
weekly XP-8121 SC injections 
Endpoints: 
Primary endpoints: 
• 
Safety endpoints collectively include incidence, frequency, severity, and relationship to 
study drug of treatment-emergent adverse events (TEAEs), including clinically 
significant vital sign measurements, safety laboratory test results, electrocardiograms 
(ECGs), and physical examinations  
• 
Tolerability assessments include Modified Draize Scale and Injection Site Discomfort 
assessments 
• 
Geometric mean ratio of the weekly dose of XP-8121 SC (in μg) to the daily dose of 
oral levothyroxine (aka dose conversion factor), where the XP-8121 dose corresponds to 
the administration immediately preceding collection of blood TSH used to determine 
normalization at the end of Maintenance Period  
Secondary endpoints: 
• 
Proportion of subjects enrolled with normalized TSH throughout the Maintenance 
Period  
• 
Proportion of subjects enrolled with normalized TSH at the end of Maintenance Period  
• 
Blood thyroid hormone concentrations (total thyroxine, free thyroxine (fT4) and TSH) 
following the first dose of XP-8121 and after titration (ie, during the Titration and 
Maintenance Periods) 
Exploratory Endpoints:  
• 
Observed values and changes from baseline values in thyroid hormones (total and fT4) 
and TSH during the Titration and Maintenance Periods 
• 
Pharmacokinetic profile of plasma thyroid hormones (thyroxine [T4] and 
triiodothyronine [T3]) during the 168-hr PK period (PK substudy only):  
− 
Tmax 
− 
Cmax and Cmax normalized by dose (Cmax/Dose) 
− 
AUC from time 0 to 168 hr post-dose (AUC0-168hr) and AUC0-168hr normalized by 
dose (AUC0-168hr /Dose) 
− 
If supported by the data, the following additional parameters may be calculated: 
− Total apparent clearance (CL/F) 
• 
Comparison of the score of Convenience, Overall Satisfaction, and Effectiveness 
domain of the Treatment Satisfaction Questionnaire for Medication (TSQM-9) between 
oral levothyroxine and once-weekly XP-8121 SC treatments  
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• 
Summary of results from the Subject Preference Survey 
Number of 
subjects: 
A total of up to approximately 44 subjects who meet all the inclusion criteria and none of the 
exclusion criteria will be enrolled into the study. Approximately 12 subjects will be enrolled 
in the PK substudy. 
Duration of 
subject 
participation: 
Participation will last for up to approximately 16 weeks (~4 months). 
 
Study design: 
This is a non-randomized, open-label, single arm, self-controlled study of XP-8121 to 
determine a target dose conversion factor from stably dosed oral levothyroxine to XP-8121 in 
patients with hypothyroidism and to assess the safety and tolerability of XP-8121 after once-
weekly SC injections. This study includes the following periods: Screening, Titration Period, 
and Maintenance Period. The study will conclude with an End of Maintenance Visit or Early 
Termination (ET) Visit. 
Screening will be performed within 28 days of the planned start of the Titration Period. 
Subjects will be required to be on a stable dose of oral levothyroxine (Synthroid or an FDA-
approved generic equivalent), or in the PK substudy, Synthroid only, for at least 3 months 
prior to Screening. Subjects will also be required to have a normal TSH documented during 
Screening via the central laboratory (study reference range: 0.47 to 4.68 μIU/mL) and for at 
least 3 months prior to Screening according to local laboratory reference ranges. 
If a potential subject does not meet the eligibility requirements described in the protocol on 
initial Screening, they may be eligible to re-screen only if their medical condition has 
changed and increases the likelihood that they would meet the study eligibility criteria. Such 
re-screenings will be exceptional circumstances, and all re-screenings require prior 
permission of the study Medical Monitor before they begin. Repeating Screening visit 
laboratory assessments for clinical safety (with Medical Monitor approval) and repeating a 
Screening test (eg, fT4 and/or TSH) that has been found to be technically flawed will not be 
considered re-screening. 
The XP-8121 initiation dose will correspond to 50% of the target dose (in μg) of weekly 
XP-8121 SC, which is calculated as the current daily oral levothyroxine dose (in μg) 
multiplied by 4, rounded up to the nearest 50 μg.  
During the Titration Period, subjects will come into the clinic once a week for 2 through up to 
8 weeks, as applicable, for dosing administration. Based on free thyroxine (fT4) levels, 
XP-8121 will be titrated biweekly (every other week) by intervals of 25% of the target dose. 
TSH and T4 (free and total) will be checked weekly. A safety check will be completed 72 hr 
after the initial dose and each escalation during the Titration Period. If fT4 exceeds the upper 
limit of normal during titration, the XP-8121 dosage will be lowered and held at the 
previously tolerated dose. Otherwise, titration will continue as scheduled. Titration should not 
be stopped or interrupted prior to the target dosage unless the Investigator is concerned about 
the possibility of overdosage or a drug-related adverse event occurs. In such cases, the 
Investigator and Medical Monitor should confer prior to establishment of the Maintenance 
dose.  
Once subjects have completed the Titration Period, they will continue at the same dose of 
XP-8121 in the Maintenance Period for 4 weeks, returning to the Clinical Research Unit 
(CRU) on a weekly basis for dosing. An End of Maintenance Visit will be performed at Day 
29 (1 week after the last XP-8121 dose). Subjects not achieving an adequate fT4 at ≤125% of 
the target dose or the maximum weekly dose of 1500 μg may also continue into the 
Maintenance Period at the discretion of the Investigator and after conferring with the Medical 
Monitor.  
During Week 4 of the Maintenance Period, a subgroup of subjects (~12) who have been on a 
stable dose of Synthroid for at least 3 months prior to Screening and who have maintained 
adequate trough fT4 and total T4 levels will participate in a PK substudy. Subjects will be 
housed in the CRU for 9 days and 8 nights to undergo PK sample collections at specified 
timepoints. 
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After completing the Maintenance Period, subjects will complete the study with the End of 
Maintenance Visit and will subsequently restart their previous daily levothyroxine PO dose 
that they were taking before the study. Adverse events (AEs) that are ongoing at the End of 
Maintenance Visit will be recorded on the CRF and followed until resolution or maximally 
up to 14 days after the End of Maintenance Visit or Early Termination Visit. 
For subjects who dropped out or have been discontinued from the study, an ET Visit will 
occur 14 days (±2 days) after the last dose of XP-8121. 
Diagnosis and 
main entry 
criteria: 
Inclusion Criteria 
To be eligible, a subject must meet all the following inclusion criteria: 
1. Provide written informed consent.  
2. Male or female between the ages of 18 and 65 years (inclusive) at Screening, with 
chronic hypothyroidism and on a stable dose of oral levothyroxine (Synthroid or an 
FDA-approved generic equivalent to Synthroid) or, if in the PK substudy, Synthroid only 
for at least 3 months.  
3. TSH within the normal range at Screening (study reference range: 0.47 to 4.68 μIU/mL) 
and at least 3 months prior to Screening (documented by local laboratory). 
4. Free T4 within the normal range at Screening (study reference range: 0.78 to 1.42 ng/dL). 
5. Women of childbearing potential (WOCBP) must have a negative urine pregnancy test at 
Screening and agree to use medically accepted contraception (except for contraceptives 
containing estrogen for PK substudy subjects only), or abstinence throughout the study.  
6. Body mass index (BMI) 18 to 40 kg/m² at Screening.  
7. Average triplicate blood pressure (BP) reading for systolic BP >90 mmHg and <150 
mmHg and diastolic BP >40 mmHg and <100 mmHg at Screening.  
8. Average triplicate resting heart rate/pulse >40 bpm or <100 bpm at Screening.  
9. Agrees to return to the CRU for all study visits, and if a part of the substudy PK group, 
remain at the CRU to comply with all required study procedures. 
Exclusion Criteria 
To be eligible a subject must not meet any of the following exclusion criteria: 
1. History of hypersensitivity to levothyroxine (any formulation).  
2. Current dose of oral levothyroxine based on body weight >2 μg/kg/day. 
3. Current levothyroxine total daily dose either <50 μg or >375 μg.  
4. Current use of combined thyroid treatment (i.e., Synthroid plus liothyronine or Synthroid 
plus Armour Thyroid) and/or any other levothyroxine aside from those used in the study. 
5. Has renal insufficiency (serum creatinine > 3.0 mg/dL) or end-stage renal disease 
requiring renal replacement therapy. 
6. Has any diagnosed hepatic disease affecting liver functionality or serum ALT or AST 
>3 times the upper limit of normal (ULN) 
7. Has hepatic synthetic insufficiency (eg, serum albumin <3.0 g/dL). 
8. Has hematocrit of <33.5% for females and <38.7% for males. 
9. Has hemoglobin of <10.8 g/dL for females and <12.8 g/dL for males. 
10. Has clinically significant ECG abnormalities at Screening. 
11. Has congestive heart failure, New York Heart Association (NYHA) Class III or IV. 
12. Has history of myocardial infarction, unstable angina, or revascularization within 
6-months prior to Screening. 
13. Has history of a cerebrovascular accident within 6 months prior to Screening with major 
neurological deficits. 
14. Has active malignancy within 5 years prior to Screening (except: basal cell or squamous 
cell skin cancers). 
15. Has had major surgical operation within 60 days prior to Screening or planned surgical 
operation during the study. 
16. Has a current bleeding disorder or platelet count <50 ×109/L. 
17. Has donated blood or plasma within 7 days prior to Screening Visit or plans to donate 
within 7 days prior to Screening or during the study.  
18. Use of supplements containing biotin within 7 days prior to Screening and during the 
study.  
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19. Participated in a clinical study within 30 days or 5 half-lives of the study drug prior to 
Screening.  
20. Current use or history of using anticoagulants 14 days prior to Screening (Use of aspirin 
greater than 325 mg/day is excluded). 
21. Hemoglobin A1C (HbA1c) >8% at Screening.  
22. History of active substance or alcohol abuse within the 12 months prior to Screening. 
Abuse of alcohol defined as an average weekly intake of >21 units (1 unit is equivalent to 
a half pint of beer, 1 serving of hard liquor, or 1 glass of wine).  
23. Positive urine drug screen (except: if the results are positive for a benzodiazepine that is 
being taken as a prescribed concomitant medication, as defined and documented in 
accordance with the protocol). 
24. Positive blood screen for human immunodeficiency virus (HIV), hepatitis B surface 
antigen (HBsAg), or hepatitis C antibodies at Screening.  
25. Has a history of clinically significant or uncontrolled gastrointestinal, neurologic, 
hematologic, endocrine (with the exception of hypothyroidism), oncologic, pulmonary, 
immunologic, psychiatric, or cardiovascular disease, or any other condition which would 
jeopardize the safety of the subject or impact the validity of the study results,  
OR 
Any reason the Investigator or designee deems exclusionary.  
26. For PK substudy only: Use of any estrogen-containing compound within 14 days prior 
to Day 1 of the Titration Period and throughout the study.  
27. For PK substudy only: On medical examination (at Screening) by the Investigator or 
designee, has inadequate or difficult venous access that may jeopardize the quality or 
timing of the PK samples.  
Treatment(s): 
Subjects will receive single doses of XP-8121 on a weekly basis. The XP-8121 SC initiation 
dose (in μg) will correspond to 50% of the target weekly XP-8121 SC dose, which is 
calculated as the current daily oral levothyroxine dose (in μg) multiplied by 4, rounded up to 
the nearest 50 μg. XP-8121 will be titrated biweekly by intervals of 25% of the target dose, 
based on each subject's adequate trough fT4 level, up to a maximum of 125% of the target 
dose or 1500 µg (whichever is lower). 
Investigational 
product: 
 XP-8121 (levothyroxine sodium) 100 to 1500 µg SC injection 
Comparator/ 
Reference 
therapy: 
N/A 
PK parameters 
(if appropriate): 
PK parameters will be derived from the approximately 12 subjects who participate in the PK 
substudy from total T4 and total T3 plasma concentrations and will include Cmax, Tmax, 
AUC0-168hr, and other PK parameters, as appropriate. 
Statistical 
methods: 
Descriptive statistics will be calculated for continuous variables, including number of 
non-missing observations (N), arithmetic mean, standard deviation (SD), median, minimum, 
and maximum, and where applicable for PK parameters, the percent coefficient of variation 
(CV%), geometric mean, and geometric CV%. Descriptive statistics for categorical variables 
will consist of counts and percentages. The statistical models that will be used to analyze the 
primary endpoint of dose conversion factor and exploratory endpoint of TSQM-9 domain 
scores are described below; additional details of the testing procedures not included here, 
including handling of missing data, will be described in the Statistical Analysis Plan (SAP). 
Sample size 
determination 
Assuming a between-subject coefficient of variation of 0.5 and a within-subject, between 
measurements correlation of 0.5, a sample size of 38 subjects will have 80% power to reject 
the null hypothesis that the dose conversion factor is less than 3.2X or more than 5X, in favor 
of the alternative hypothesis that the dose conversion factor is between 3.2X and 5X (in 
another words, within 80% and 125% of the proposed 4X conversion factor derived from 
population pharmacokinetic (PPK) modeling). For the exploratory endpoint of TSQM-9, 
assuming a standard deviation of differences of 20, a sample size of 34 subjects will have 
80% power to detect a difference of 10 in means (domain scores range from 0 to 100) with a 
5% two-sided significance level (α=0.05). Taking into consideration study non-completers 
and non-normalizers of TSH at study end, a total of 44 subjects will be enrolled.  
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Analysis sets: 
Safety Population: All subjects who receive at least 1 dose of XP-8121. 
Completer Population: All subjects who complete the Maintenance Period and exhibited 
normalized TSH throughout the Maintenance Period while on a stable dose for approximately 
6 weeks. 
PK Population: All safety population subjects who participated in the PK substudy, who do 
not have any major protocol deviations affecting the PK endpoints and for whom a sufficient 
number of samples is available to determine at least one PK parameter. 
Endpoint 
analysis: 
The final dose conversion factor will be assessed by comparing the ln-transformed final 
XP-8121 dose (in μg) that maintains normalized TSH throughout the Maintenance Period to 
the ln-transformed daily oral levothyroxine dose (in μg) the subject was taking before the 
study, using a linear mixed effects model with treatment as fixed effects, and subject as 
random effect. Geometric least square means (LSMs), geometric mean ratios, and 90% 
confidence intervals (CIs) will be presented. This endpoint will be analyzed using the 
Completer population for subjects with primary hypothyroidism only. Additional sensitivity 
analyses that include subjects with secondary/tertiary hypothyroidism, subjects with dose 
adjustment, and/or subjects that maintain normal free T4 may be conducted. The details of 
the sensitivity analyses will be described in the SAP. 
Analysis of safety endpoints will be described in the section below. 
Secondary endpoints will be analyzed for the safety population, for subjects with primary 
hypothyroidism only and for all subjects, if applicable. Subjects with normalized TSH 
throughout the Maintenance Period and at the end of Maintenance Period will be presented 
by number and percentage of subjects referenced to the safety population and the number of 
subjects entering the Maintenance Period, along with corresponding 95% CIs. TSH, total and 
free T4 measures following the first dose of XP-8121 will be summarized using descriptive 
statistics. Number and percentage of subjects with results outside the normal ranges will be 
tabulated. 
All exploratory endpoints will be analyzed for the safety population, for subjects with 
primary hypothyroidism only and for all subjects, if applicable, except for PK endpoints 
which will be analyzed for the PK population only. TSH, total and free T4 measures and 
changes from baseline will be summarized by each protocol-specified timepoint using 
descriptive statistics. Total plasma concentrations and plasma PK parameters will be 
summarized for all subjects in the PK Population, using descriptive statistics (N, arithmetic 
mean, SD, CV%, median, minimum, maximum, geometric mean, and geometric CV%). 
The analysis of the exploratory endpoint of TSQM-9 domain scores will be gated on results 
from the primary endpoint analysis. The three domain scores will be hierarchically analyzed 
to ensure control of the family-wise type I error rate at the 0.05 level, with the Convenience 
score first, Overall Satisfaction score second, and Effectiveness third. Hypothesis tests for the 
three domain scores will be based on null hypotheses that assume no difference between oral 
levothyroxine and once-weekly XP-8121 SC treatments. Each domain score will be 
compared between the two treatments using a paired t-test. Subject counts and percentages 
for each answer to each question from the Subject Preference Survey will also be presented. 
Safety analyses: 
All safety and tolerability analyses will be performed on the Safety Population. Safety data 
will be collected and summarized by study period (Titration Period, Maintenance Period). No 
formal hypotheses will be tested on safety data. Adverse events will be summarized by the 
number and percentage of subjects who experienced at least one AE of the following 
categories in each study period: any AE, any TEAE, any drug-related TEAE, any severe 
TEAE, any serious TEAEs, any drug-related SAE, any SAE leading to death, any TEAE 
leading to premature discontinuation of study drug, and any SAE leading to premature study 
drug discontinuation. Laboratory evaluations, vital sign measurements, and ECG assessments 
will be summarized by study period and protocol-specified timepoint within each study 
period. Local tolerability (using Modified Draize Scale and Injection Site Discomfort 
questionnaires) will be summarized by protocol-specified timepoint following SC injections 
of XP-8121.  
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f: 
12-lead ECG to be assessed prior to vital signs and blood draws. ECGs will be taken after remaining in the supine position for at least 10 minutes. Note that at 
Screening only, the order of ECGs, vital signs, and blood draw procedures are allowed to vary. All potentially clinically significant automated ECG readings 
should be repeated within 5 minutes of the reading. If potentially clinically significant reading is confirmed, then the ECG will be sent to a local cardiologist 
for review (Section 12.8.5). See Section 11.5 for further details on procedure order. Table 3 outlines windows for assessment timepoints. 
g: 
Vital signs: triplicate measurements of systolic and diastolic BP and heart rate/pulse will be taken at intervals of 1 to 2 minutes after being in a supine position 
for at least 10 minutes. Respiratory rate and oral body temperature will also be measured. When the time of scheduled vital sign measurements coincide with a 
blood draw, vital sign measurements are to be performed before the blood draw where possible, ensuring the blood draw is within the window specified in the 
protocol. See Section 11.5 for further details on procedure order. Table 3 outlines windows for assessment timepoints. 
h: 
Clinical Safety Laboratory evaluation (hematology, chemistry, and urinalysis): Clinical safety laboratory testing will be performed at Screening, the 
beginning and the end of the Maintenance Period, and the ET Visit, if needed. Subjects are required to fast from all food and drink except water for ≥10 hr 
prior to collection when glucose values will be obtained. Fasting will not be required for the other safety laboratory testing, and when a safety recheck is 
deemed necessary and the glucose value is not included. See Section 11.5  for further details on procedure order. 
i: 
Each subject’s qualification fT4 level must be within the normal range (study reference range: 0.78 to 1.42 ng/dL) at Screening. During the Titration Period, 
subjects will come into the clinic once a week for 2 up to 8 weeks, as applicable, for dosing administration. Based on fT4 levels, XP-8121 will be titrated 
biweekly by intervals of 25% of the target dose. See Section 7.4.2 for further details on dose titration and adjustment criteria during the Titration Period. 
Table 3 outlines windows for assessment timepoints. 
j: 
Once subjects have completed the Titration Period, they will continue at the same dose of XP-8121 in the Maintenance Period for 4 weeks unless the 
conditions described in Section 7.4.3 are met.  
k: 
Urine drug screen: Repeat urine drug screens are permitted for suspected false positive results. If results of the drug screen are positive for a prescribed 
benzodiazepine, then the subject is eligible to participate in the study. See Section 12.8.8 for description of urine drug screen. 
l: 
A urine pregnancy test is required during the Screening Period to confirm eligibility for women of childbearing potential only. A urine pregnancy test also will 
be performed every 2 weeks (ie, Weeks 1, 3, 5 and 7) during the Titration Period, at Day 1 (Week 1) of the Maintenance Period, at the End of Maintenance 
Visit and, if applicable, at the ET Visit. If the urine pregnancy test results are positive, a serum pregnancy test will be performed for confirmation. 
m: 
Oral levothyroxine administration: Subjects must be receiving a stable dose of oral levothyroxine (Synthroid or an FDA-approved generic equivalent to 
Synthroid) or, if in the PK substudy, Synthroid for at least 3 months prior to Screening to be eligible for trial. During Screening subjects will continue their 
prescribed daily dose of oral levothyroxine. After all other procedures at the End of Maintenance Visit, subjects will restart their previously prescribed daily 
oral levothyroxine, at the dose they were taking before the study.  
n: 
XP-8121 administration: The XP-8121 SC initiation dose will correspond to 50% of the target XP-8121 dose, which is calculated as the current daily oral 
levothyroxine dose multiplied by 4, rounded up to the nearest 50 μg. Based on fT4 levels XP-8121 will be titrated biweekly by intervals of 25% of the target 
dose. See Section 7.4.2 and Section 7.4.3 for further details about dose titration and dose adjustment criteria during the Titration and Maintenance Periods, 
respectively. The time of weekly (every 7 days) XP-8121 SC dose administration will remain consistent throughout the study and will occur within ±2 hours of 
the time of the XP-8121 SC initiation dose (Section 10.5). 
o: 
A subgroup of subjects (~12), who have been on Synthroid for at least 3 months prior to Screening and who have maintained adequate trough T4 (free and 
total) levels in the Maintenance Period will participate in a PK substudy. The study reference ranges for T4 (free and total) and TSH are: 0.78 to 1.42 ng/dL 
(fT4), 5.53 to 10.96 μg/dL (total T4), and 0.47 to 4.68 μIU/mL (TSH). During Week 4 of the Maintenance Period, subjects will be housed in the CRU for 
9 days and 8 nights to undergo PK sample collections at specified timepoints as outlined in Table 5. Subjects will be admitted to the CRU on Maintenance Day 
21 (day prior to XP-8121 administration and initiation of PK sampling) and discharged from the CRU on Maintenance Day 29 (168 hr PK sample). 
p: 
Modified Draize Scale: Injection site erythema and edema will be assessed using Modified Draize Scales 30 (±5) minutes after injection of XP-8121. If the 
Draize score is >1 at 30 minutes, the subject will be discharged, and a follow up visit will be scheduled at 24 (±3) hr post-dose to allow the Investigator or 
designee to complete an assessment of the injection site using the Modified Draize Scale. 
q: 
Injection Site Discomfort evaluations: Injection site discomfort will be assessed at 10 (±2) minutes) after injection of XP-8121 using the Numeric Rating 
Scale for Injection Discomfort, and subjects will complete a Site Discomfort Description and Duration Questionnaire 10 (±2) minutes after injection.  
r: 
Subject Preference Survey: Survey will be completed during the End of Maintenance Visit or Early Termination Visit.  
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s: 
TSQM-9: During first visit of the Titration Period prior to dosing, subjects will be asked to complete the questionnaire regarding their oral levothyroxine use. 
Subjects will also complete on Maintenance Day 22 after the last administration of XP-8121. 
t: 
All AEs and non-study medications must be recorded on the subjects’ eCRF from the time of consent and followed until resolution or maximally up to 
14 days after the End of Maintenance. Medications used prior to the time of informed consent will be recorded as prior medications.  
 
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3. 
TABLE OF CONTENTS  
1. 
TITLE PAGE ................................................................................................................1 
SUMMARY OF REVISIONS: PROTOCOL VERSION 2.0 TO VERSION 3.0 ...........................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................6 
PROCEDURES IN CASE OF EMERGENCY ...............................................................................7 
2. 
SYNOPSIS ...................................................................................................................8 
3. 
TABLE OF CONTENTS ...........................................................................................18 
LIST OF TABLES .........................................................................................................................22 
LIST OF FIGURES .......................................................................................................................22 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................23 
5. 
INTRODUCTION ......................................................................................................25 
5.1. 
Hypothyroidism ..........................................................................................................25 
5.2. 
Existing Parenteral Replacement ................................................................................26 
5.3. 
Limitations with Levothyroxine Administered Orally ...............................................26 
5.4. 
XP-8121 for Subcutaneous Injection ..........................................................................27 
5.4.1. 
Clinical Experience .....................................................................................................27 
5.4.1.1. 
Study XP-8121-101 ....................................................................................................27 
5.4.1.2. 
Study XP-8121-108 ....................................................................................................28 
5.5. 
Current Study (XP-8121-120) Design and Dose Range Rationale ............................29 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................31 
6.1. 
Objectives ...................................................................................................................31 
6.1.1. 
Primary Objective .......................................................................................................31 
6.1.2. 
Secondary Objectives .................................................................................................31 
6.1.3. 
Exploratory Objectives ...............................................................................................31 
7. 
INVESTIGATIONAL PLAN .....................................................................................32 
7.1. 
Overall Study Design and Plan ...................................................................................32 
7.2. 
Number of Subjects ....................................................................................................33 
7.2.1. 
Subject Replacement ..................................................................................................33 
7.3. 
Treatment Assignment ................................................................................................33 
7.4. 
Dose Titration and Adjustment Criteria .....................................................................33 
7.4.1. 
Target XP-8121 Dose Definition and Calculation ......................................................33 
7.4.2. 
Titration Period ...........................................................................................................33 
7.4.3. 
Maintenance Period ....................................................................................................34 
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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................35 
8.1. 
Subject Inclusion Criteria ...........................................................................................35 
8.2. 
Subject Exclusion Criteria ..........................................................................................35 
8.3. 
Duration of Subject Participation ...............................................................................36 
8.4. 
Subject Withdrawal Criteria .......................................................................................36 
8.5. 
Study Termination ......................................................................................................37 
8.6. 
Lifestyle Considerations .............................................................................................37 
8.6.1. 
Contraception ..............................................................................................................37 
8.6.2. 
Other Restrictions .......................................................................................................37 
8.6.2.1. 
Alcohol Consumption .................................................................................................37 
8.6.2.2. 
Fasting.........................................................................................................................37 
9. 
TREATMENT OF SUBJECTS ..................................................................................38 
9.1. 
Description of Study Drug ..........................................................................................38 
9.1.1. 
XP-8121 ......................................................................................................................38 
9.2. 
Concomitant Medications ...........................................................................................38 
9.2.1. 
Prohibited Medications ...............................................................................................38 
9.3. 
Treatment Compliance ................................................................................................38 
9.4. 
Randomization and Blinding ......................................................................................38 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................39 
10.1. 
Study Drug ..................................................................................................................39 
10.2. 
Study Drug Packaging and Labeling ..........................................................................39 
10.3. 
Study Drug Storage .....................................................................................................39 
10.3.1. 
XP-8121 Storage .........................................................................................................39 
10.4. 
Study Drug Preparation ..............................................................................................39 
10.5. 
Administration and Dose ............................................................................................39 
10.6. 
Study Drug Accountability .........................................................................................40 
10.7. 
Study Drug Handling and Disposal ............................................................................40 
11. 
STUDY SCHEDULE .................................................................................................41 
11.1. 
Screening (Day -28 to Day -1) ....................................................................................41 
11.2. 
Titration Period ...........................................................................................................42 
11.3. 
Maintenance Period ....................................................................................................43 
11.3.1. 
XP-8121 Pharmacokinetic Substudy ..........................................................................43 
11.3.2. 
End of Maintenance Visit ...........................................................................................44 
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11.4. 
Early Termination Visit ..............................................................................................44 
11.5. 
Order of Procedures ....................................................................................................45 
12. 
ASSESSMENT OF SAFETY .....................................................................................46 
12.1. 
Adverse and Serious Adverse Events .........................................................................46 
12.1.1. 
Definition of Adverse Events .....................................................................................46 
12.1.1.1. 
Adverse Event .............................................................................................................46 
12.1.1.2. 
Serious Adverse Event ................................................................................................46 
12.1.1.3. 
Other Adverse Event (OAE) .......................................................................................46 
12.2. 
Relationship to Study Drug ........................................................................................46 
12.3. 
Recording Adverse Events .........................................................................................47 
12.4. 
Reporting Adverse Events ..........................................................................................47 
12.5. 
Adverse Event Reporting Requirements to Regulatory Authorities ...........................48 
12.6. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
Reported as Adverse Events and Serious Adverse Events .........................................48 
12.7. 
Subject Monitoring .....................................................................................................49 
12.8. 
Other Safety Parameters .............................................................................................49 
12.8.1. 
Subject Blood Volumes to be Drawn Over the Course of the Study ..........................49 
12.8.2. 
Physical Examination .................................................................................................50 
12.8.3. 
Weight, Height, BMI ..................................................................................................50 
12.8.4. 
Vital Sign Measurements ............................................................................................50 
12.8.5. 
Electrocardiogram .......................................................................................................50 
12.8.6. 
Local Tolerability .......................................................................................................50 
12.8.7. 
Clinical Safety Laboratory Assessments ....................................................................51 
12.8.8. 
Urine Drug Screen ......................................................................................................51 
12.8.9. 
Pregnancy Testing ......................................................................................................52 
13. 
STATISTICS ..............................................................................................................53 
13.1. 
Sample Size Determination ........................................................................................53 
13.2. 
Subject Disposition .....................................................................................................53 
13.3. 
Demographic and Baseline Characteristics ................................................................53 
13.4. 
Analysis Populations ..................................................................................................53 
13.5. 
Study Endpoints ..........................................................................................................54 
13.5.1. 
Primary Endpoints ......................................................................................................54 
13.5.1.1. 
Analysis of Primary Endpoint (Dose Conversion Factor) ..........................................54 
13.5.2. 
Secondary Endpoints ..................................................................................................54 
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13.5.2.1. 
Analysis of Secondary Endpoints ...............................................................................54 
13.5.3. 
Exploratory Endpoints ................................................................................................55 
13.5.3.1. 
Analysis of Exploratory Endpoints .............................................................................55 
13.6. 
Pharmacokinetics ........................................................................................................55 
13.7. 
Safety and Tolerability................................................................................................55 
13.7.1. 
Adverse Events ...........................................................................................................56 
13.7.2. 
Laboratory Evaluations, Vital Sign Measurements, and Electrocardiograms ............56 
13.7.3. 
Prior and Concomitant Medications ...........................................................................56 
13.7.4. 
Local Tolerability .......................................................................................................56 
13.7.5. 
Physical Examinations ................................................................................................57 
13.8. 
Other Assessments ......................................................................................................57 
13.9. 
Statistical Issues ..........................................................................................................57 
13.9.1. 
Missing or Imputed Data ............................................................................................57 
13.9.2. 
Interim Analysis ..........................................................................................................57 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................58 
14.1. 
Study Monitoring ........................................................................................................58 
14.2. 
Audits and Inspections ................................................................................................58 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................59 
16. 
ETHICS ......................................................................................................................60 
16.1. 
Ethics Review .............................................................................................................60 
16.2. 
Ethical Conduct of the Study ......................................................................................60 
16.3. 
Written Informed Consent ..........................................................................................60 
17. 
DATA MANAGEMENT ...........................................................................................61 
18. 
DATA HANDLING AND RECORDKEEPING .......................................................62 
18.1. 
Inspection of Records .................................................................................................62 
18.2. 
Retention of Records ..................................................................................................62 
19. 
PUBLICATION POLICY ..........................................................................................63 
20. 
LIST OF REFERENCES ............................................................................................64 
21. 
APPENDICES ............................................................................................................65 
APPENDIX A. TITRATION ALGORITHM .............................................................................66 
APPENDIX B. SIGNS AND SYMPTOMS OF HYPERTHYROIDISM ..................................67 
APPENDIX C. INJECTION SITE DISCOMFORT ASSESSMENT ........................................68 
APPENDIX D. SUBJECT PREFERENCE SURVEY ...............................................................70 
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APPENDIX E. MODIFIED DRAIZE SCALE ...........................................................................71 
APPENDIX F. SUMMARY OF PRIOR CHANGES TO PROTOCOL ....................................72 
Rationale and Summary of Changes from Protocol Version 1.0 to Version 2.0 ...........................72 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................7 
Table 2: 
Schedule of Assessments ............................................................................................14 
Table 3: 
Timing Window Allowances for T4 and TSH, Electrocardiogram, and Vital 
Sign Measurements .....................................................................................................17 
Table 4: 
Abbreviations and Specialist Terms ...........................................................................23 
Table 5: 
Pharmacokinetic Sample Timepoints .........................................................................44 
Table 6: 
Number and Volume of Blood Collections for Subjects Not Participating in 
Pharmacokinetic Substudy ..........................................................................................49 
Table 7: 
Number and Total Volume of Blood Collections for Subjects Participating in 
Pharmacokinetic Substudy ..........................................................................................49 
Table 8: 
Clinical Safety Laboratory Tests ................................................................................51 
Table 9: 
Signs/Symptoms of Indicative of Hyperthyroidism ...................................................67 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schema .................................................................................................33 
 
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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Table 4: 
Abbreviations and Specialist Terms 
Abbreviation 
Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical 
AUC 
Area under the drug concentration-time curve 
AUC0-last 
Area under the drug concentration-time curve from time 0 to time of the last 
measured concentration  
AUC0-12hr 
Area under the drug concentration-time curve from time 0 to 12 hr 
AUC0-24hr 
Area under the drug concentration-time curve from time 0 to 24 hr 
AUC0-48hr 
Area under the drug concentration-time curve from time 0 to 48 hr 
AUC0-72hr 
Area under the drug concentration-time curve from time 0 to 72 hr 
AUC0-132hr 
Area under the drug concentration-time curve from time 0 to 132 hr 
AUC0-144hr 
Area under the drug concentration-time curve from time 0 to 144 hr 
AUC0-168hr 
Area under the drug concentration-time curve from time 0 to 168 hr 
BMI 
Body mass index 
BP 
Blood pressure 
bpm 
Beats Per Minute 
cGMP 
Current Good Manufacturing Practices  
CI 
Confidence interval 
CL/F 
Total Apparent Clearance 
Cmax 
Maximum plasma concentration 
CRF 
Case report form 
CRU 
Clinical research unit 
CSR 
Clinical study report 
CV 
Coefficient of variation 
DMSO 
Dimethyl sulfoxide 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ET 
Early termination 
FDA 
Food Drug and Administration 
fT4 
Free (protein-unbound) thyroxine 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
HbA1C 
Hemoglobin A1C 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus  
HIV 
Human immunodeficiency virus 
hr 
Hour or Hours 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IM 
Intramuscular 
IRB 
Institutional Review Board 
IV 
Intravenous 
LSM 
Least square mean 
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Abbreviation 
Definition 
MDMA 
3,4-Methylenedioxymethamphetamine 
MedDRA 
Medical Dictionary for Regulatory Activities 
NRS 
Numeric Rating Scale 
NYHA 
New York Heart Association  
OAE 
Other Adverse Event 
OTC 
Over the counter 
PK 
Pharmacokinetic 
PO 
Oral administration  
PPK 
Population pharmacokinetic 
PT 
Preferred term 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SD 
Standard deviation 
SOC 
System organ classification 
T3 
Triiodothyronine 
T4 
Thyroxine  
TEAE 
Treatment-emergent adverse event 
Tmax 
Time to maximum concentration 
TMF 
Trial master file 
TSH 
Thyroid-stimulating hormone 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
WHO 
World Health Organization 
WHO-DD 
World Health Organization Drug Dictionary 
WOCBP 
Women of childbearing potential 
Xeris 
Xeris Pharmaceuticals 
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5. 
INTRODUCTION 
Xeris Pharmaceuticals, Inc. (Xeris) has developed a novel formulation of levothyroxine, 
XP-8121 (levothyroxine sodium for subcutaneous (SC) injection) to mitigate challenges 
associated with oral (PO) formulations of levothyroxine, which can include interference with 
absorption (e.g., simultaneous ingestion with calcium, iron, certain foods, other drugs, and 
conditions that impair gastric acidification or intestinal absorption, such as celiac disease). For 
this reason, patients are usually instructed to ingest oral levothyroxine on an empty stomach 30 
to 60 minutes before food intake. Further, a once weekly dosing schedule, as provided by 
XP-8121, could improve adherence that is adversely affected by unintentionally missed daily 
doses. Finally, SC administration of XP-8121 could alleviate burdens associated with 
swallowing difficulties or other barriers to taking daily medication.  
The first Phase 1 study of XP-8121 in healthy subjects conducted by Xeris (XP-8121-101) 
evaluated the safety and pharmacokinetics (PK) of XP-8121 300 μg following SC administration 
of a single dose as compared with identical doses of intravenous (IV) and oral levothyroxine 
sodium (Eltroxin, 3 x 100 μg). XP-8121 was well tolerated with treatment-emergent adverse 
events (TEAEs) similar in incidence and severity across treatment arms. Estimations of 
maximum plasma concentration (Cmax), time to maximum concentration (Tmax), and area under 
the drug concentration-time curve (AUC) across the sample collection period (0 to 312 hr) were 
considered interpretable. As expected, XP-8121, levothyroxine IV, and Eltroxin PO were not 
bioequivalent, i.e.., Cmax and AUC from time 0 to time of the last measured concentration 
(AUC0-last) geometric least-squares mean (LSM) ratios did not satisfy absolute or relative 
bioavailability criteria for bioequivalence. See Section 5.4.1.1 for additional details. 
In the second Phase 1 study (XP-8121-108), single SC doses of XP-8121 600 μg, 1200 μg, and 
1500 μg were compared with a single oral dose of Synthroid 600 μg. TEAEs in the XP-8121 
arms were typically mild and similar in frequency and severity across dose groups. Overall, there 
were no relevant safety finding differences between the three XP-8121 doses, nor between 
XP-8121 and Synthroid. Baseline-adjusted plasma levothyroxine levels analyzed by 
noncompartmental analysis showed that compared to oral Synthroid, XP-8121 was associated 
with slower absorption (ie, longer Tmax), lower Cmax, and greater overall exposure (AUC0-last) to 
thyroxine. Plasma thyroxine mean Cmax after oral Synthroid 600 μg was approximately 2.2-fold 
higher than following XP-8121 600 μg SC, while being roughly equivalent to the mean Cmax 
after XP-8121 1500 μg SC. See Section 5.4.1.2 for additional details. 
Population pharmacokinetics (PPK) modeling based on the above data suggested that at steady-
state, approximately equivalent mean plasma exposure to levothyroxine could be achieved in 
healthy volunteers by converting a daily oral dose to a once-weekly dose of XP-8121 as follows 
(daily levothyroxine PO dose x 4 = once weekly target dose XP-8121). Study XP-8121-120 will 
determine whether a target conversion factor when switching from daily oral levothyroxine 
replacement therapy with Synthroid or a generic equivalent to weekly XP-8121 is 
approximately 4. 
5.1. 
Hypothyroidism 
The thyroid gland is responsible for the synthesis, storage, and release of the thyroid hormones, 
thyroxine (T4) and triiodothyronine (T3) [Colucci et al, 2013]. These hormones are nuclear 
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receptor-activating and regulate critical metabolic processes that are vital for normal growth, 
development, and health throughout life.  
Deficiency of circulating T4 or T3 is known as hypothyroidism. Most commonly in developed 
countries, the primary cause of hypothyroidism is autoimmune destruction of the glands 
responsible for thyroid hormone synthesis, also known as Hashimoto’s disease or autoimmune 
thyroiditis. Other causes of primary hypothyroidism (thyroid hormone production/release 
deficits) include other forms of thyroid inflammation, iatrogenic causes (surgery and radiation 
sequelae and certain medications, iodine deficiency, et al). Uncommonly, thyroid synthesis is 
impaired at birth (congenital). Hypothyroidism can also result from problems with TSH 
production/secretion or action (secondary hypothyroidism, most commonly because of pituitary 
tumor or trauma) or from hypothalamic dysregulation of pituitary function (tertiary 
hypothyroidism). Rare syndromes of resistance to the actions of thyroid hormone can also 
resemble more typical hypothyroidism [Laurent et al, 2018; Winther et al, 2016; Colucci et al, 
2013]. 
Regardless of etiology, inadequate thyroid hormone that manifests clinically should be treated, 
i.e., thyroid hormone replacement. Treatment is often chronic, most commonly lifelong. The goal 
of replacement therapy is restoration of the euthyroid state, with reversal of the clinical 
manifestations of hypothyroidism. In most developed countries, replacement most commonly 
consists of levothyroxine monotherapy and in most guidelines, TSH is currently recommended 
as the sole biomarker of replacement adequacy. 
5.2. 
Existing Parenteral Replacement 
Oral and IV levothyroxine products have exhibited acceptable safety profiles and have been in 
use for many decades. Currently, there are no approved levothyroxine products indicated for SC 
administration for the treatment of hypothyroidism. The extremely low water solubility of 
levothyroxine (approximately 0.1 mg/mL) has hindered the development of ready-to-use 
aqueous commercial formulations. Approved use of lyophilized powders of levothyroxine for 
reconstitution as aqueous IV formulations in myxedema coma are also used off-label as 
intramuscular (IM) and SC injections. However, such use requires large injection volumes, and 
the formulation is pharmaceutically unstable, rendering such use unsuitable for a broad patient 
application. 
5.3. 
Limitations with Levothyroxine Administered Orally 
Levothyroxine is a drug with a narrow therapeutic index [Vita et al, 2014]. It has been reported, 
however, that nearly 40% of patients undergoing treatment with levothyroxine are either over- or 
under-treated [Laurent et al, 2018] due to factors that include but are not limited to drug 
formulation, drug-food interaction, drug-drug interaction, adherence, gastrointestinal (GI) 
malabsorption, and other preexisting medical conditions. Levothyroxine absorption issues are 
frequently based on concurrent absorption of interfering substances in the digestive tract [Skelin 
et al, 2017]. When co-administered with a standard test breakfast, levothyroxine absorption is 
impaired about 40% [Hennessey, 2017]; oral levothyroxine sodium labeling recommends 
avoidance of food around the time of dosing.  
Because of these limitations, there is an unmet need for levothyroxine formulations that 
circumvents the GI tract and the need for daily drug administration. 
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5.4. 
XP-8121 for Subcutaneous Injection 
XP-8121 is a ready-to-use, liquid formulation of levothyroxine sodium intended for SC 
administration once-weekly. XP-8121 is made possible via use of XeriSol™ formulation 
technology that uses dimethyl sulfoxide (DMSO) as an excipient. The toxicology, pharmacology, 
and metabolic properties of DMSO have been studied extensively. DMSO possesses a low 
degree of toxicity to humans via oral and parenteral routes [McKim et al, 2008]. Notably, 
DMSO, at a similar concentration as used in XP-8121, is used in a concentrated, liquid-stable 
formulation of glucagon [Gvoke®; Xeris Pharmaceuticals, 2021] approved for the treatment of 
severe hypoglycemia in pediatric and adult patients with diabetes ages 2 years and above.  
Toxicology data for the XeriSol formulation were obtained as part of a 26-week SC toxicity and 
toxicokinetic study supporting Gvoke (Report 8394785, data on file). In male and female rats, no 
adverse clinical findings or safety signals were observed. The incidence of injection site 
reactions (minimal to marked erosion/ulcer; minimal to moderate mixed cell inflammation, 
hemorrhage, exudate, epithelial hyperplasia, and/or fibrosis; and minimal to slight thrombus) 
were comparable among animals administered XeriSol vehicle or active XeriSol glucagon. All 
XeriSol glucagon-related clinical observations were considered non-adverse as they did not 
affect the overall health of the animals and were reversible during recovery phase.  
5.4.1. 
Clinical Experience 
Xeris has recently completed 2 Phase 1 XP-8121 clinical trials. Study XP-8121-101 was 
designed to evaluate the safety, PK, and absolute and relative bioavailability of levothyroxine 
sodium after a single SC dose of XP-8121 300 μg compared to reference IV and PO formulations 
of levothyroxine sodium of the same dose in 30 healthy adult subjects (mean age of 28.5 years, 
73% male). Study XP-8121-108 was a single-center, randomized, open-label, crossover study to 
evaluate XP-8121 in 60 healthy subjects (mean age of 40.4 years, 42% male) designed to 
characterize the absorption and elimination kinetics of XP-8121 600 μg, 1200 μg, and 1500 μg 
following SC administration in healthy volunteers. The study evaluated dose proportionality 
across the potential range of clinical doses and the relative bioavailability of XP-8121 600 μg SC 
versus levothyroxine 600 μg PO. Results are described briefly below. 
5.4.1.1. 
Study XP-8121-101 
A single SC dose of XP-8121 was well-tolerated in healthy volunteers with reported TEAEs 
similar in incidence and severity across arms. Overall, TEAEs were mild to moderate in severity, 
self-limited, and required no intervention. No deaths or other serious adverse events (SAEs) were 
reported, and no subject was withdrawn due to TEAE. Headache (30% of subjects) and catheter 
site pain (13% of subjects) were the only TEAEs reported for more than 10% of subjects overall. 
Headache was the sole TEAE assessed as related to study drug that was reported for more than 
10% of subjects overall. Headache is an adverse reaction listed in approved product labels of IV 
and oral levothyroxine [Abbott Laboratories, 2001; AbbVie Inc, 2018]. 
Within each study arm, the most frequently reported TEAEs were: 
• For PO levothyroxine, headache (10.7% of subjects), catheter site pain (7.1%), and 
oropharyngeal pain (7.1%). 
• For IV levothyroxine, headache (7.1%), catheter site pain (7.1%), and infusion site erythema 
(7.1%). 
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• For XP-8121, headache (22.2%), nausea (7.4%), and injection site reaction (7.4% of 
subjects). 
With respect to other safety findings, there was no evidence of mean population changes during 
the study and, while a few individual results changed across the normal range boundaries, none 
was found to be of clinical significance. 
Interpretation of the PK results is limited to estimations for Cmax, Tmax, and AUC across the 
sample collection period (0 - 312 hr), as the 300-µg doses did not allow estimation of baseline-
corrected levothyroxine elimination-phase PK parameters (inadequate for determining the 
elimination constant and half-life).  
• Absorption of XP-8121 was slower; median Tmax approximately 30 hr slower than either IV 
or PO;  
• Cmax mean for XP-8121 was reduced compared to IV or PO; mean values 
27.6 (±15.74) ng/mL, 70.4 (±37.72) ng/mL and 32.8 (±23.18) ng/mL, respectively;  
• AUC means for XP-8121 compared to IV and PO were lower across the early portion of the 
assessment period [area under the drug concentration-time curve from time 0 to 12 hr 
(AUC0-12hr), area under the drug concentration-time curve from time 0 to 24 hr (AUC0-24hr), 
and area under the drug concentration-time curve from time 0 to 48 hr (AUC0-48hr)], 
indicating slower absorption of XP-8121 as compared to the other routes of administration;  
• Comparable AUC values were obtained between XP-8121 and oral levothyroxine for area 
under the drug concentration-time curve from time 0 to 144 hr (AUC0-144hr), while the Area 
under the drug concentration-time curve from time 0 to 312 hr (AUC0-312hr) was slightly 
greater for XP-8121. All values for AUC levothyroxine IV were greater than those of either 
XP-8121 or oral.  
5.4.1.2. 
Study XP-8121-108 
5.4.1.2.1. Safety 
In Study XP-8121-108, single SC doses of XP-8121 600 μg, 1200 μg, and 1500 μg were 
well-tolerated in healthy volunteers with reported TEAEs similar in incidence and severity across 
study arms. Overall, TEAEs were mild to moderate in severity and self-limited. No deaths or 
other SAEs were reported, and no subjects were withdrawn due to TEAE.  
Overall, TEAEs reported in more than 2 subjects were constipation (10/60; 16.7%), dermatitis 
contact (10/60 subjects; 16.7%), headache (5/60; 8.3%) and pruritis (4/30; 13.3%).  
With respect to other safety findings, there was no evidence of clinically relevant mean 
population changes during the study and, while a few individual results changed across the 
normal range boundaries, none was found to be of clinical significance. No clinically significant 
mean changes from baseline were observed in any safety assessment. Importantly, with respect 
to electrocardiogram (ECG) findings, there were no observations of any major cardiovascular 
manifestation (e.g., atrial fibrillation, tachycardia, myocardial ischemia, arrhythmias) that have 
been associated with levothyroxine overdosage. Two subjects reported telemetry-related adverse 
event (AE) findings that were considered related to study drug (atrial tachycardia following 
treatment with XP-8121 600 μg SC and ventricular extrasystoles with XP-8121 1500 μg SC). 
Both events were considered mild in severity and resolved prior to end of study. No AEs were 
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reported in the subject with the highest reported Cmax value after administration of XP-8121 
1500 μg. 
Overall, there were no notable differences in the safety results between doses of XP-8121 nor 
between XP-8121 and Synthroid 600 μg PO. 
5.4.1.2.2. Pharmacokinetics 
Baseline-adjusted plasma levothyroxine levels analyzed by noncompartmental analysis showed 
that subjects receiving XP-8121 SC have slower absorption, lower peak plasma concentration, 
and higher extended exposure of levothyroxine compared to Synthroid PO at the comparable 
dose of 600 μg. Peak levothyroxine exposure, as measured by mean Cmax was highest for 
subjects receiving levothyroxine 600 μg PO and was 55% lower at 600 μg XP-8121 SC, 22% 
lower at 1200 μg XP-8121 SC, and 1% lower at 1500 μg XP-8121 SC. 
While plasma levothyroxine exposure over 72 hr as measured by mean area under the drug 
concentration-time curve from time 0 to 72 hr (AUC0-72) was higher for Synthroid PO than 
XP-8121 at comparable doses of 600 μg, exposure was approximately 35% higher for XP-8121 
with respect to mean AUC0-last. The relationship of XP-8121 dose and PK parameters (AUC0-last 
and Cmax) was assessed with a power model. The 95% confidence intervals (CIs) for the slope of 
the model are (0.78, 1.32) for AUC0-last and (0.67, 1.06) for Cmax, respectively. Both 95% CIs 
contain 1, indicating dose proportionality. 
A PPK model estimated that an XP-8121 SC weekly dose equivalent to 4 times a daily Synthroid 
PO dose will provide similar exposure (AUC) to thyroxine.  
5.5. 
Current Study (XP-8121-120) Design and Dose Range Rationale 
Following the above-described studies in healthy volunteers, Xeris received guidance from Food 
and Drug Administration (FDA) on a proposed registration path for XP-8121. The current study 
was designed, incorporating FDA guidance, to provide information on weekly use of XP-8121 in 
stably treated subjects with hypothyroidism. The goals of the study are to determine safe starting 
doses, safe and feasible titration schedules, and the effective dose range of XP-8121, wherein 
effectiveness is determined by maintenance of normalized TSH. The dose conversion target was 
considered the primary objective and serves as the basis for hypothesis testing and sample size 
determination. Pharmacokinetics will also be characterized in a subset of subjects to determine 
any differences from modeled chronic PK using data from healthy volunteers. The findings from 
this study will inform a future clinical efficacy and safety demonstration. 
This is a non-randomized, open-label, single arm, self-controlled study (i.e., subjects serve as 
their own controls based on baseline assessment of thyroid function). The design is appropriate 
because replacement of deficient T4 with levothyroxine is necessary and sufficient to treat 
hypothyroidism. A comparator is not necessary for an initial assessment of the ability of SC 
administered levothyroxine to maintain normalized TSH in stably treated subjects, as efficacy is 
not being established by this study. Blinding is not necessary since all subjects receive active 
therapy and there is no comparator. Furthermore, the primary outcome measure, TSH, is 
objective, and compliance (adherence) with therapy will be assessed.  
The XP-8121 initiation dose will correspond to 50% of the target weekly dose of XP-8121 SC, 
which is defined, per study hypothesis, as the baseline daily oral levothyroxine dose (in μg) 
multiplied by 4, rounded up to the nearest 50 μg. The lowest initiation dose to be studied is 
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100 μg. The highest dose to be studied is 1500 μg weekly, selected based on the known safety 
and toxicity profile of levothyroxine, published use of oral levothyroxine as a weekly dose 
regimen, and the observed and expected PK profile of XP-8121. This dose is not expected to 
result in overdosage using the proposed biweekly titration-to-target scheme with careful safety 
monitoring as described below. 
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6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Objectives 
6.1.1. 
Primary Objective 
• To assess the safety and tolerability of XP-8121 after once-weekly SC injections in 
adult subjects with hypothyroidism  
• To determine a target dose conversion factor from stably dosed oral levothyroxine to 
XP-8121 in patients with hypothyroidism 
6.1.2. 
Secondary Objectives 
• To determine a dose range of XP-8121 capable of maintaining normalized TSH 
following a switch from stable replacement therapy with oral levothyroxine 
• To evaluate a safe initiation dose of XP-8121 based on the prior stable dose of oral 
levothyroxine 
• To evaluate a safe titration scheme for dosing XP-8121 to TSH target 
6.1.3. 
Exploratory Objectives 
• To characterize the dynamics of thyroid hormones and TSH in blood during and after 
titration (ie, Titration and Maintenance Periods) with XP-8121 
• To characterize the PK of plasma thyroid hormones following multiple once-weekly 
XP-8121 SC injections in adult subjects with hypothyroidism 
• To compare patient treatment satisfaction between daily oral levothyroxine and 
once-weekly XP-8121 SC injections 
 
 
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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design and Plan 
This is a non-randomized, open-label, single arm, self-controlled study of XP-8121 to determine 
a target dose conversion factor from stably dosed oral levothyroxine to XP-8121 in patients with 
hypothyroidism and to assess the safety and tolerability of XP-8121 after once-weekly SC 
injections.  
This study includes the following periods: Screening, Titration Period, and Maintenance Period. 
The study will conclude with an End of Maintenance or Early Termination (ET) Visit. Subjects 
will be maintained on a stable dose of XP-8121 for a total of 6 weeks; subjects are required to be 
on a stable dose of XP-8121 for the last 2 weeks of the Titration Period, enter the Maintenance 
Period on the same dose, and continue at the same dose during the 4-week duration of the 
Maintenance Period. 
Screening will be performed within 28 days of the planned start of the Titration Period. Subjects 
will be required to be on a stable dose of oral levothyroxine (Synthroid or an FDA-approved 
generic equivalent), or in the PK substudy, Synthroid only, for at least 3 months prior to 
Screening. Subjects will also be required to have a normal TSH documented during Screening 
via the central laboratory (study reference range: 0.47 to 4.68 μIU/mL) and for at least 3 months 
prior to Screening according to local laboratory reference ranges.   
The XP-8121 initiation dose will correspond to 50% of the target weekly dose of XP-8121 SC 
(in μg), which is calculated as the current daily oral levothyroxine dose (in μg) multiplied by 4, 
rounded up to the nearest 50 μg.  
During the Titration Period, subjects will come into the clinic once a week for 2 through up to 
8 weeks, as applicable, for dosing administration. Based on free thyroxine (fT4) levels, XP-8121 
will be titrated biweekly (every other week) by intervals of 25% of the target dose. TSH and T4 
(free and total) will be checked weekly. A safety check will be completed 72 hr after the initial 
dose and each escalation during the Titration Period. If fT4 exceeds the upper limit of normal 
during titration, the XP-8121 dosage will be lowered and held at the previously tolerated dose.  
Once subjects have completed the Titration Period, they will continue at the same dose of 
XP-8121 in the Maintenance Period for 4 weeks, returning to the Clinical Research Unit (CRU) 
on a weekly basis for dosing. An End of Maintenance Visit will be performed at Day 29 (1 week 
after the last XP-8121 dose). Subjects not achieving an adequate fT4 at ≤125% of the target dose 
or the maximum weekly dose of 1500 μg may also continue into the Maintenance Period at the 
discretion of the Investigator and after conferring with the Medical Monitor. Titration details are 
outlined in Appendix A.  
During Week 4 of the Maintenance Period, a subgroup of subjects (~12) who have been on a 
stable dose of Synthroid for at least 3 months prior to Screening and who have maintained 
adequate trough fT4 and total T4 levels will participate in a PK substudy. Subjects will be 
housed in the CRU for 9 days and 8 nights to undergo PK sample collections at specified 
timepoints as outlined in Table 5. 
After completing the Maintenance Period, subjects will complete the study with the End of 
Maintenance Visit and will subsequently restart their previous daily levothyroxine PO dose that 
they were taking before the study. AEs that are ongoing at the End of Maintenance Visit will be 
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During the Titration Period, XP-8121 will be titrated based on individual response to therapy 
(using blood fT4 trough concentration as a fast-response marker) at intervals no more frequent 
than every other week and in dosage increments corresponding to 25% of the target dose, up to a 
maximum of 125% of the target dose or 1500 µg (whichever is lower).  
Operationally, each week subjects will return to the CRU for dosing and to have trough fT4 
concentrations measured. Based on the fT4 concentration, the Titration Period will proceed as 
follows: 
• If fT4 concentration is below or within normal range (study reference range: 0.78 to 
1.42 ng/dL), and no signs/symptoms of thyroid hormones excess are present, the dose of 
XP-8121 SC will be increased by 25% of the target dose (eg, if fT4 concentration levels 
drawn at Week 2 of Titration Period are confirmed to be within the normal range at Week 
3 of Titration Period, XP-8121 will be increased to 75% of the target weekly XP-8121 SC 
dose). If a drug-related AE is reported or if overdosage is a concern, the Investigator 
should consult with the Medical Monitor before up-titrating.   
• If fT4 is in the normal range with presence of signs/symptoms of thyroid excess, then 
XP-8121 titration will occur at the discretion of the Investigator and in discussion with 
the Medical Monitor.  
− Signs/symptoms of thyroid excess have differing dynamics (ie, start and worsen at 
varying time and rates) and are non-specific when assessed individually. Therefore, 
clinical judgment is needed to interpret them in the scenario of acute response to 
changes in the replacement levothyroxine dose using XP-8121. Investigators should 
determine whether solicited symptom(s) or observed sign(s) warrant a presumptive 
determination of thyroid excess (or intolerance of replacement therapy). Such 
determination should be made conservatively, considering the potential impact of the 
signs/symptoms on the subject well-being during the subsequent Maintenance Period 
(See Appendix B for a list of positive signs/symptoms of thyroid excess).  
• If fT4 concentration exceeds the upper limit of normal (regardless of signs/symptoms of 
thyroid hormones excess), then XP-8121 titration will end, and the XP-8121 dosage will 
be lowered and held at the highest previously tolerated dose for the remainder of the 
study. 
Once subjects have completed the Titration Period, they will continue at the same dose of 
XP-8121 in the Maintenance Period for 4 weeks (see Appendix A for details on titration 
algorithm). 
7.4.3. 
Maintenance Period 
Subjects will remain on the dose of XP-8121 used at the end of the Titration Period.  
If, during Maintenance Period, biochemical hyperthyroidism is present, as evidenced by elevated 
trough fT4 and/or low TSH, the Investigator may reduce the weekly dose of XP-8121 SC by one 
dose level (ie, 25% of the target dose) and maintain the lowered dose throughout the remainder 
of the study as tolerated. If multiple signs/symptoms of thyroid excess are present without 
definitive biochemical evidence of hyperthyroidism, the Investigator should confer with the 
Medical Monitor. If the Investigator and Medical Monitor agree to a XP-8121 dose reduction, 
the dose should be reduced by one dose level and held at the lowered dose for the remainder of 
the study, as tolerated. 
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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Inclusion Criteria 
To be eligible, a subject must meet all the following inclusion criteria: 
1. Provide written informed consent.  
2. Male or female between the ages of 18 and 65 years (inclusive) at Screening, with chronic 
hypothyroidism and on a stable dose of oral levothyroxine (Synthroid or an FDA-approved 
generic equivalent to Synthroid) or, if in the PK substudy, Synthroid only for at least 
3 months.  
3. TSH within the normal range at Screening (study reference range: 0.47 to 4.68 μIU/mL) and 
at least 3 months prior to Screening (documented by local laboratory).  
4. Free T4 within the normal range at Screening (study reference range: 0.78 to 1.42 ng/dL).  
5. Women of childbearing potential (WOCBP) must have a negative urine pregnancy test at 
Screening and agree to use medically accepted contraception (except for contraceptives 
containing estrogen for PK substudy subjects only), or abstinence throughout the study.  
6. Body Mass Index (BMI) 18 to 40 kg/m² at Screening.  
7. Average triplicate blood pressure (BP) reading for systolic BP >90 mmHg and <150 mmHg 
and diastolic BP >40 mmHg and <100 mmHg at Screening.  
8. Average triplicate resting heart rate/pulse >40 beats per minute (bpm) or <100 bpm at 
Screening.  
9. Agrees to return to the CRU for all study visits, and if a part of the substudy PK group, 
remain at the CRU to comply with all required study procedures. 
8.2. 
Subject Exclusion Criteria 
To be eligible a subject must not meet any of the following exclusion criteria: 
1. 
History of hypersensitivity to levothyroxine (any formulation).  
2. 
Current dose of oral levothyroxine, based on body weight >2 μg/kg/day. 
3. 
Current levothyroxine total daily dose either <50 μg or >375 μg.  
4. 
Current use of combined thyroid treatment (ie, Synthroid plus liothyronine or Synthroid plus 
Armour Thyroid) and/or any other levothyroxine aside from those used in the study. 
5. 
Has renal insufficiency (serum creatinine >3.0 mg/dL) or end-stage renal disease requiring 
renal replacement therapy. 
6. 
Has any diagnosed hepatic disease affecting liver functionality or serum ALT or AST 
>3 times the upper limit of normal (ULN) 
7. 
Has hepatic synthetic insufficiency (eg, serum albumin <3.0 g/dL). 
8. 
Has hematocrit of <33.5% for females and <38.7% for males. 
9. 
Has hemoglobin of <10.8 g/dL for females and <12.8 g/dL for males. 
10. Has clinically significant ECG abnormalities at Screening. 
11. Has congestive heart failure, New York Heart Association (NYHA) Class III or IV. 
12. Has history of myocardial infarction, unstable angina, or revascularization within 6 months 
prior to Screening. 
13. Has history of a cerebrovascular accident within 6 months prior to Screening with major 
neurological deficits. 
14. Has active malignancy within 5 years prior to Screening (except: basal cell or squamous cell 
skin cancers). 
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15. Has had major surgical operation within 60 days prior to Screening or planned surgical 
operation during the study. 
16. Has a current bleeding disorder or platelet count <50 ×109/L. 
17. Has donated blood or plasma within 7 days prior to Screening Visit or plans to donate 
within 7 days prior to Screening or during the study.  
18. Use of supplements containing biotin within 7 days prior to Screening and during the study.  
19. Participated in a clinical study within 30 days or 5 half-lives of the study drug prior to 
Screening.  
20. Current use or history of using anticoagulants 14 days prior to Screening. (Use of aspirin 
greater than 325 mg/day is excluded). 
21. Hemoglobin A1C (HbA1c) >8% at Screening.  
22. History of active substance or alcohol abuse within the 12 months prior to Screening. Abuse 
of alcohol defined as an average weekly intake of >21 units (1 unit is equivalent to a half 
pint of beer, 1 serving of hard liquor, or 1 glass of wine).  
23. Positive urine drug screen (except: if the results are positive for a benzodiazepine that is 
being taken as a prescribed concomitant medication, as defined and documented in 
accordance with the protocol). 
24. Positive blood screen for human immunodeficiency virus (HIV), hepatitis B surface antigen 
(HBsAg), or hepatitis C antibodies at Screening.  
25. Has a history of clinically significant or uncontrolled gastrointestinal, neurologic, 
hematologic, endocrine (with the exception of hypothyroidism), oncologic, pulmonary, 
immunologic, psychiatric, or cardiovascular disease, or any other condition which could 
jeopardize the safety of the subject or impact the validity of the study results,  
OR 
Any reason the Investigator or designee deems exclusionary.  
26. For PK substudy only: Use of any estrogen-containing compound within 14 days prior to 
Day 1 of the Titration Period and throughout the study.  
27. For PK substudy only: On medical examination (at Screening) by the Investigator or 
designee, has inadequate or difficult venous access that may jeopardize the quality or timing 
of the PK samples. 
8.3. 
Duration of Subject Participation 
Subject participation in this study will last for up to approximately 16 weeks (~4 months).  
8.4. 
Subject Withdrawal Criteria 
Subjects may withdraw their consent to participate in the study at any time. If a subject 
withdraws consent, the date and reason for consent withdrawal should be documented. Wherever 
possible, the tests and evaluations described for the Early Termination Visit in Section 11.4 
should be performed for all subjects who discontinue prior to the completion of the study. 
Subject data, including the results of sample testing, will be included in the analysis up to the 
date of the withdrawal of consent. The reason for withdrawal must be specified on the 
appropriate electronic case report form (eCRF), including further specification if the category of 
‘Other’ is selected. 
Individual subjects will be advised verbally and in the written informed consent form (ICF) that 
they have the right to withdraw from the study at any time. The Investigator or sponsor may 
discontinue a subject from the study in the event of an intercurrent illness, adverse event, death, 
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positive pregnancy test at any time during the study, other reasons concerning the health or well-
being of the subject, or in the case of lack of cooperation, non-compliance, protocol deviations, 
or other administrative reasons. In addition, potential reasons for early termination from the 
study include: 
• Inability to achieve an adequate replacement dosage 
• Inability to achieve a tolerable replacement dosage 
If a subject is withdrawn from the study, a replacement subject will not be enrolled 
(Section 7.2.1). 
8.5. 
Study Termination 
This study may be suspended or prematurely terminated by Xeris.  Reasons for this may include 
the benefit risk assessment of participating in the study, practical reasons, or for regulatory or 
medical reasons (including slow enrolment). Written notification, documenting the reason for 
study suspension or termination, will be provided by the suspending or terminating party. If the 
study is prematurely terminated or suspended, the PI will promptly inform the IRB and will 
provide the reason(s) for the termination or suspension. 
8.6. 
Lifestyle Considerations 
8.6.1. 
Contraception 
For WOCBP (ie, women who are not postmenopausal or who have not had bilateral 
oophorectomy or hysterectomy), there is a requirement for a negative urine pregnancy test at all 
assessment timepoints and for agreement to use medically accepted contraception (eg, 
non-hormonal or estrogen- or progestin-containing hormonal intrauterine device, surgical 
sterilization of the partner, physical barrier with spermicide for at least 14 days prior to first 
dosing and throughout the study, bilateral tubal ligation or salpingectomy) or abstinence from 
heterosexual intercourse for at least 28 days prior to first dosing and throughout the study. Note: 
estrogen-containing compounds are exclusionary for subjects entering the PK substudy. A 
female subject who becomes sexually active during the course of the study must agree to use a 
physical barrier method (eg, condom, diaphragm) with spermicide from the time of the start of 
sexual activity and throughout the study.  
8.6.2. 
Other Restrictions 
8.6.2.1. 
Alcohol Consumption  
For only those subjects participating in the PK substudy, subjects must agree to abstain from 
alcohol intake from 48 hr before study drug administration on Day 22 of the Maintenance Period 
until the end of the inpatient period (Maintenance Day 29). 
8.6.2.2. 
Fasting  
Subjects will be required to fast from all food and drink except water for at least 10 hrs prior to 
the collection of blood when a glucose evaluation is planned. Fasting will not be required for 
other safety laboratory testing or when a safety recheck is deemed necessary and glucose 
assessment is not included. 
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9. 
TREATMENT OF SUBJECTS 
9.1. 
Description of Study Drug 
9.1.1. 
XP-8121 
XP-8121 is supplied as a sterile, nonpyrogenic, preservative-free, liquid for injection of 
levothyroxine sodium 10 mg/mL packaged in single-use glass vials. XP-8121 will be 
administered using a sterile-packaged, 0.3 mL CovidienTM (now Cardinal HealthTM) MonojectTM 
Insulin Syringe. XP-8121 is manufactured using XeriSol formulation technology that includes 
DMSO, trehalose, mannitol, and sulfuric acid. 
Further details relating to preparation, storage, and administration of XP-8121 will be provided 
in the Pharmacy Manual. 
9.2. 
Concomitant Medications 
Medication (eg, prescription drugs, over the counter (OTC) drugs, vaccines, topical medications, 
herbal remedies) used by a subject from 30 days or 5 half-lives (whichever is the longer) before 
Screening and for the duration of the study will be recorded on the subject’s eCRF, including the 
medication name, total daily dose, route, frequency of dosing, and indication for use.  
9.2.1. 
Prohibited Medications 
The following medications are prohibited: 
• Administration of an investigational product in another trial within 30 days prior to the 
Screening, or five half-lives, whichever is longer. 
• Use of any levothyroxine (other than XP-8121) or any combined thyroid hormone 
preparation (eg, Synthroid plus liothyronine or Synthroid plus Armour Thyroid) and/or any 
other non-approved oral thyroid replacement.  
• Use of any estrogen-containing compound within 14 days prior to Day 1 of the Titration 
Period and throughout the study (subjects in PK substudy only). 
• Use of any supplements containing biotin within 7 days prior to Screening and during the 
study. 
• Use or history of using anticoagulants 14 days prior to Screening.  
• Use of aspirin greater than 325 mg/day prior to Screening and during the study. 
9.3. 
Treatment Compliance 
All doses of XP-8121 will be administered at the CRU. Study drug administration during 
Titration and Maintenance Periods will be recorded on the drug accountability log. 
9.4. 
Randomization and Blinding 
This is an open-label, non-randomized study. 
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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
The Sponsor will supply XP-8121 to the investigational site. The XP-8121 provided for this 
study will be manufactured under current Good Manufacturing Practices (cGMP) and will be 
suitable for human use.  
10.2. 
Study Drug Packaging and Labeling 
XP-8121 is supplied as a sterile, nonpyrogenic, preservative-free, liquid for injection as 
levothyroxine at 10 mg/mL. The formulation is a clear, colorless-to-yellow solution packaged in 
single-use glass vials. The Sponsor is responsible for the preparation and labeling of XP-8121, 
and for providing details such as batch numbers, safety, and stability data. 
XP-8121 will be labeled in accordance with applicable regulatory requirements and will be 
shipped under temperature monitored conditions at a temperature of 2 °C to 8 °C (35-46 °F). 
10.3. 
Study Drug Storage 
The Investigator or an approved member of the study staff will ensure that study drug is stored in 
a secure area under recommended storage conditions and in accordance with applicable 
regulatory requirements. 
The site will maintain appropriate documentation of continuous storage conditions, and these 
records will be monitored on an ongoing basis by the monitor. Any deviations in the storage 
condition must be documented (including minimum and maximum temperature excursions as 
well as an estimate of total duration of storage outside the recommended storage conditions). 
Such deviations must be communicated to the Sponsor as soon as identified by the site with an 
appropriate course of action taken, regarding the future use of the study drugs, upon consultation 
with Xeris. 
The Investigator must maintain adequate records documenting the receipt, use, loss, or other 
disposition of the investigational drug product.  
Further details are provided in the Pharmacy Manual. 
10.3.1. 
XP-8121 Storage 
Vials containing XP-8121 should be stored at 2 °C to 8 °C (35-46 °F).  
10.4. 
Study Drug Preparation 
Procedures relating to study drug preparation and dispensing are outlined in the Pharmacy 
Manual. 
10.5. 
Administration and Dose 
Subjects will receive single doses of XP-8121 on a weekly basis (every 7 days). The time of the 
weekly XP-8121 dose administration will remain consistent throughout the study and will occur 
within ±2 hours of the time of the XP-8121 SC initiation dose. The SC injections of the XP-8121 
will be performed within the periumbilical region of the abdomen.  
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The Investigator and/or delegate is responsible for the education of study staff as to the correct 
timing and procedure for administration of the study drug. Further details are provided in the 
Pharmacy Manual. 
10.6. 
Study Drug Accountability 
A record will be maintained by the investigational site that will account for all dispensing and 
return of any used and unused study drug. At the end of the study, the study drug will be 
reconciled, and a copy of the record will be included in the Trial Master File (TMF). 
10.7. 
Study Drug Handling and Disposal 
On completion of the study, any study drug surplus will be destroyed, in accordance with the 
procedures of the investigational site and following receipt of written approval from the Sponsor 
unless otherwise specified. Documented evidence of the destruction of any surplus study drug 
will be included in the TMF. If no supplies remain, this will be documented in the accountability 
record. 
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11. 
STUDY SCHEDULE 
A Schedule of Assessments is provided in Table 2. See Table 3 for a table of timing window 
allowances for T4 and TSH sampling, ECG collections and vital sign measurements.  
This study includes the following periods: Screening, Titration Period, and Maintenance Period. 
The study will conclude with an End of Maintenance Visit or, if applicable, the ET Visit. 
11.1. 
Screening (Day -28 to Day -1) 
Prior to enrolling and before performance of any procedures, potential subjects will arrive at the 
CRU for Screening, at which time they will be provided with complete information about the 
study assessments and procedures. They will also be provided with an ICF, be given time to 
review it and will be encouraged to discuss questions with the site staff prior to being asked to 
sign. 
After the ICF is signed, Screening assessments will be carried out as follows: 
• Review of inclusion and exclusion criteria 
• Review of concomitant medications and medical history which should include adequate 
historical data on the etiology of hypothyroidism and prior treatments (e.g., prior surgeries 
and radiation therapies, including radioactive iodine)  
• Complete physical examination (See Section 12.8.2 for details) 
• Measurement of height and weight (See Section 12.8.3  for details) 
• Calculation of BMI (weight (kg) / [height (m)]2) (See Section 12.8.3  for details) 
• 12-lead ECG (See Section 12.8.5 for details) 
• Vital sign measurements (See Section 12.8.4 for details) 
• Serology sample collection (hepatitis C virus (HCV), HBsAg, & HIV) 
• Clinical safety laboratory testing (hematology, chemistry, and urinalysis). See Section 12.8.7 
for details. See Section 8.6.2.2 for fasting requirements. 
• Free and total T4 and TSH measurements 
• Urine drug screen (See Section 12.8.8 for details) 
• Urine pregnancy test (WOCBP only) (See Section 12.8.9 for details) 
During the Screening Period, subjects will continue their prescribed daily dose of oral 
levothyroxine.  
At Screening, subjects must have TSH and fT4 clinical laboratory values within the normal 
range (study reference range for TSH and fT4 are 0.47 to 4.68 μIU/mL and 0.78 to 1.42 ng/dL, 
respectively). (Note: TSH is also required to be within the normal range for at least 3 months 
prior to Screening [documented by local laboratory].) 
If a potential subject does not meet the eligibility requirements described in the Section 8 on 
initial Screening, they may be eligible to re-screen only if their medical condition has changed 
and increases the likelihood that they would meet the study eligibility criteria. Such re-screenings 
will be exceptional circumstances, and all re-screenings require prior permission of the study 
Medical Monitor before they begin. Repeating Screening visit laboratory assessments for clinical 
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safety (with Medical Monitor approval) and repeating a Screening test (eg, fT4 and/or TSH) that 
has been found to be technically flawed will not be considered re-screening. 
Note: AEs and changes in medications will be recorded from the time of informed consent. 
Repeat urine drug screens will be permitted for suspected false positive results. A repeat of the 
Screening visit laboratory assessments for clinical safety (hematology, chemistry, and urinalysis) 
may be permitted after consultation with the Medical Monitor. 
11.2. 
Titration Period 
The XP-8121 initiation dose will correspond to 50% of the target weekly dose of XP-8121 SC 
(in μg), which is calculated as the current daily oral levothyroxine dose (in μg) multiplied by 4 
and rounded up to the nearest 50 μg.  
XP-8121 will be titrated biweekly, as needed, by intervals of 25% of the target dose, up to a 
maximum of 125% of the target or 1500 μg (whichever is lower). Titration algorithm details are 
outlined in Appendix A. See Section 7.4, Dose Adjustment Criteria, for further details. 
The following procedures will be conducted once a week for 2 up to 8 weeks as applicable or 
unless otherwise noted: 
• Abbreviated physical examination (See Section 12.8.2 for details) 
• Vital sign measurements (See Section 12.8.4 for details) 
• Free and total T4 and TSH measurements  
• Urine pregnancy test (WOCBP only) will be done every 2 weeks (ie, Weeks 1, 3, 5 and 7) 
during this period (See Section 12.8.9 for details) 
• XP-8121 administration (See Section 10.5) 
• Modified Draize Scale to be completed 30 (±5) minutes after each XP-8121 injection. If the 
Draize score is >1 at 30 minutes, the subject will be discharged, and a follow up visit will be 
scheduled at 24 (±3) hrs post-dose to allow the Investigator or designee to complete an 
assessment of the injection site using the Modified Draize Scale. See Appendix E for details. 
• Injection Site Discomfort Evaluations to be completed (See Appendix C): Numeric Rating 
Scale for Injection Site Discomfort to be done 10 (±2) minutes after injection as well as 
Injection Site Discomfort Description and Duration Questionnaire completed 10 (±2) minutes 
after each XP-8121 injection. 
• Treatment Satisfaction Questionnaire for Medication (TSQM-9) to be completed during the 
first visit of the Titration Period prior to XP-8121 administration.  
• Review of AEs and changes in concomitant medication 
Following the initial XP-8121 dose and any up-titrations, subjects will be required to return for 
an outpatient visit 72 hr (±1) day. The following procedures will be conducted: 
•  Abbreviated physical examination (See Section 12.8.2 for details) 
• 12-lead ECG (See Section 12.8.5 for details) 
• Vital sign measurements (See Section 12.8.4 for details) 
• Free and total T4 and TSH measurements 
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• Review of AEs and changes in concomitant medication 
11.3. 
 Maintenance Period 
Once subjects have completed the Titration Period, they will continue at the same dose of 
XP-8121 in the Maintenance Period for 4 weeks. All subjects will return to the CRU weekly for 
dosing before having an End of Maintenance Visit. 
The following procedures will be conducted once a week for 4 weeks (Day 1, Day 8, Day 15, 
and Day 22), as applicable, unless specified differently below: 
• Clinical safety laboratory testing (hematology, chemistry, and urinalysis) on Day 1 (Week 1 
Maintenance Period). See Section 12.8.7 for details. See Section 8.6.2.2 for fasting 
requirements.  
• Free and total T4 and TSH measurements every week 
• Urine pregnancy test (WOCBP only) on Day 1 (Week 1 Maintenance Period) (See 
Section 12.8.9 for details) 
• XP-8121 administration (See Section 10.5) 
• Modified Draize Scale to be completed 30 (±5) minutes after each XP-8121 injection. If the 
Draize score is >1 at 30 minutes, the subject will be discharged, and a follow up visit will be 
scheduled at 24 (±3) hr post-dose to allow the Investigator or designee to complete an 
assessment of the injection site using the Modified Draize Scale. See Appendix E for details.  
• Injection Site Discomfort Evaluations to be completed (see Appendix C): Numeric Rating 
Scale for Injection Site Discomfort to be done 10 (±2) minutes after injection as well as 
Injection Site Discomfort Description and Duration Questionnaire completed 10 (±2) minutes 
after each XP-8121 injection.  
• TSQM-9 questionnaire to be completed on Maintenance Day 22 after last administration of 
XP-8121.  
• Review of AEs and changes in concomitant medication 
11.3.1. 
 XP-8121 Pharmacokinetic Substudy 
During Week 4 of the Maintenance Period, a subgroup of subjects (~12) who have been on 
Synthroid for at least 3 months prior to Screening and who have maintained adequate trough T4 
(free and total) concentration levels (study reference ranges: 0.78 to 1.42 ng/dL and 5.53 to 
10.96 μg/dL, respectively) in the Maintenance Phase will participate in a PK substudy. Subjects 
will be housed in the CRU for 9 days and 8 nights to undergo PK sample collections at specified 
timepoints as outlined in Table 5.  
Subjects will be admitted to the CRU on Maintenance Day 21 (day prior to XP-8121 
administration and initiation of PK sampling) and discharged from the CRU on Maintenance 
Day 29 (168 hr PK sample). During the inpatient period, subjects are to be fed standardized 
meals according to the clinic schedule. In addition to PK sample collections at the specified 
timepoints noted below, all procedures required for Maintenance Day 22 and Maintenance 
Day 29 are to be completed per protocol. There are no additional procedures required during the 
inpatient period.  
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Venous blood samples (approximately 5 mL) will be collected for the determination of plasma 
T4 and T3 concentrations. 
Table 5 outlines the PK sampling timepoints. The actual collection time of each sample must be 
recorded in the source data documentation and in the eCRF. The PK sample on Day 29 should be 
drawn before administration of previous oral levothyroxine. A deviation will be recorded if the 
collection time falls outside of the allowed time windows. Instructions for the collection and 
handling of the PK samples will be provided.  The samples will be analyzed utilizing a validated 
assay of appropriate sensitivity and specificity. 
Table 5: 
Pharmacokinetic Sample Timepoints 
XP-8121 Pharmacokinetic Sampling 
Day 22: Predose  
within 10 minutes of dosing 
Day 22: 1, 6, 12, and 18 hr post dose 
±5 minutes for 1-hour timepoint; ±10 minutes for 6, 12, 
and 18 hr timepoints 
Days 23-29: 24,36,48,60,72,84,96,108, 
120,144 and 168 hr post Day 22 dose 
±10 minutes 
11.3.2. 
End of Maintenance Visit  
An End of Maintenance Visit will be performed on Maintenance Day 29, 1 week after the last 
XP-8121 dose. At the End of Maintenance Visit, the following procedures will be conducted: 
• Complete physical examination (See Section 12.8.2 for details) 
• Weight (See Section 12.8.3  for details) 
• 12-lead ECG (See Section 12.8.5 for details) 
• Vital sign measurements (See Section 12.8.4 for details) 
• Clinical safety laboratory testing (hematology, chemistry, and urinalysis). See Section 12.8.7 
for details. See Section 8.6.2.2 for fasting requirements. 
• Free and total T4 and TSH measurements 
• Urine pregnancy test (WOCBP only) (See Section 12.8.9 for details) 
• Restart previously prescribed daily oral levothyroxine medication 
• Subject Preference Survey (Appendix D) 
• Review of AEs and changes in concomitant medication. AEs that are ongoing at the End of 
Maintenance Visit will be recorded on the CRF and followed until resolution or maximally 
up to 14 days after the End of Maintenance.  
11.4. 
Early Termination Visit 
An ET Visit will be performed 14 (±2) days after the last dose of XP-8121. Subjects who 
withdraw prematurely from the study will be encouraged to complete an ET Visit to assess 
safety.  
The following procedures will be conducted at the Early Termination Visit: 
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• Complete physical examination (See Section 12.8.2 for details) 
• Weight (See Section 12.8.3 for details) 
• 12-lead ECG (See Section 12.8.5 for details) 
• Vital sign measurements (See Section 12.8.4 for details) 
• Clinical safety laboratory testing (hematology, chemistry, and urinalysis). See Section 12.8.7 
for details. See Section 8.6.2.2 for fasting requirements. 
• Free and total T4 and TSH measurements 
• Urine pregnancy test (WOCBP only) – if urine pregnancy test result is positive, a serum 
pregnancy test must be conducted to confirm results. 
• Subject Preference Survey (Appendix D) 
• Review of AEs and changes in concomitant medication.  AEs that are ongoing at the ET 
Visit will be recorded on the CRF and followed until resolution or maximally up to 14 days 
after the ET Visit. 
11.5. 
Order of Procedures 
When applicable, all procedures are to be performed pre-dose except for the Modified Draize 
Scale and Injection Site Discomfort Evaluations, unless otherwise stated. Where possible, 
assessments should be conducted in order of least invasive to most invasive. When ECGs, vital 
signs measurement, and/or blood draws are required at the same visit, they should be performed 
in the aforementioned order. 
Note that at Screening only, the order of ECGs, vital signs, and blood draw procedures are 
allowed to vary. 
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12. 
ASSESSMENT OF SAFETY 
Safety assessments include evaluations of AEs/SAEs, physical examinations, vital sign 
measurements, clinical safety laboratory evaluations, ECGs, and injection site assessments. 
Safety assessments will be performed at specified timepoints as defined in Table 2 and Table 3. 
All spontaneously volunteered and enquired for, as well as observed AEs, will be recorded in the 
subject’s source documentation and the eCRF.  Additional unscheduled safety assessments may 
be performed at other times if deemed necessary by the Investigator. 
12.1. 
Adverse and Serious Adverse Events 
12.1.1. 
Definition of Adverse Events 
12.1.1.1. Adverse Event  
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered casually related to the product. In clinical studies, an AE can include 
an undesirable medical condition occurring at any time, including baseline or washout periods, 
even if no study treatment has been administered. 
12.1.1.2. Serious Adverse Event 
A SAE is an AE occurring during any study period and at any dose of the study drug that fulfils 
one or more of the following: 
• Results in death 
• It is immediately life-threatening 
• It requires in-patient hospitalization or prolongation of existing hospitalization 
• It results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
• It is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above. 
All SAEs that occur after any patient/subject has been enrolled, before treatment, during 
treatment, or within 14 days following the cessation of treatment, whether or not they are related 
to the study, must be recorded on forms provided by Xeris. 
12.1.1.3. Other Adverse Event (OAE) 
OAEs will be identified by the Drug Safety Physician and if applicable also by the Clinical Study 
Team Physician during the evaluation of safety data for the Clinical Study Report (CSR). 
Significant AEs of particular clinical importance, other than SAEs and those AEs leading to 
discontinuation of the patient/subject from the study, will be classified as OAEs. For each OAE, 
a narrative may be written and included in CSR. 
12.2. 
Relationship to Study Drug 
An Investigator who is qualified in medicine must make the determination of relationship to the 
study drug for each AE (Unrelated, Possibly Related, Probably Related or Definitely Related). 
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The Investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the study drug. If no valid reason exists for 
suggesting a relationship, then the AE should be classified as “unrelated.” If there is any valid 
reason, even if undetermined, for suspecting a possible cause-and-effect relationship between the 
study drug and the occurrence of the AE, then the AE should be considered “related.” 
If the relationship between the AE/SAE and the study drug is determined to be “possible” or 
“probable” the event will be considered to be related to the study drug for the purposes of 
expedited regulatory reporting. 
12.3. 
Recording Adverse Events 
Adverse events spontaneously reported by the patient/subject and/or in response to an open 
question from the study personnel or revealed by observation will be recorded during the study at 
the investigational site. Clinically significant changes in laboratory values, BP, and heart 
rate/pulse also need to be reported as AEs. Disease -related events will be recorded as AEs if the 
events occur with greater frequency, severity or duration than expected.  Information about AEs 
will be collected from the signing of consent form and followed until resolution or maximally up 
to 14 days after the End of Maintenance. Serious Adverse Event information will be collected 
from time of consent and followed until resolution. The AE term should be reported in standard 
medical terminology when possible. For each AE, the Investigator will evaluate and report the 
onset (date and time), resolution (date and time), intensity, causality, action taken, serious 
outcome (if applicable), and whether or not it caused the patient to discontinue the study. 
Intensity will be assessed according to the following scale: 
• Mild (awareness of sign or symptom, but easily tolerated) 
• Moderate (discomfort sufficient to cause interference with normal activities) 
• Severe (incapacitating, with inability to perform normal activities) 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria above. An AE of severe intensity may not be 
considered serious. 
Should a pregnancy occur, it must be reported within 24 hrs of the first awareness of the event 
and recorded on Xeris’ pregnancy form. Pregnancy in itself is not regarded as an AE unless there 
is a suspicion that a study drug may have interfered with the effectiveness of a contraceptive 
medication. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth, or 
congenital abnormality) must be followed up and documented even if the patient was 
discontinued from the study. 
All reports of congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages should 
also be reported and handled as SAEs. Elective abortions without complications should not be 
handled as AEs. 
12.4. 
Reporting Adverse Events 
Adverse events including SAEs will be reported for all subjects from the time of consent until 
the completion of the End of Maintenance Visit. AEs that are ongoing at the End of Maintenance 
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Visit will be recorded on the CRF and followed until resolution or maximally up to 14 days after 
the End of Maintenance Visit or ET Visit.  
Any SAEs considered possibly or probably related to the study drug and discovered by the 
Investigator at any time after the study should be reported. All SAEs must be reported to Xeris 
within 24 hr of the first awareness of the event. The Investigator must complete, sign and date 
the SAE pages, verify the accuracy of the information recorded on the SAE pages with the 
corresponding source documents, and send a copy to Xeris via email to both 
ClinicalPV@xerispharma.com and Xerispharma.pharmacovigilance@propharmagroup.com. 
Additional follow-up information, if required or available, should all be sent to Xeris via email to 
both ClinicalPV@xerispharma.com and Xerispharma.pharmacovigilance@propharmagroup.com 
within 24 hrs of receipt and this should be completed on a follow-up SAE form and placed with 
the original SAE information and kept with the appropriate section of the eCRF and/or study file.  
Xeris is responsible for notifying the relevant regulatory authorities of certain events. It is the 
Investigator’s responsibility to notify the Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) of all SAEs that occur at his or her site. Investigators will also be notified of all 
unexpected, serious, drug-related events (7/15 Day Safety Reports) that occur during the clinical 
trial. Each site is responsible for notifying its IRB or IEC of these additional SAEs. 
12.5. 
Adverse Event Reporting Requirements to Regulatory Authorities 
Adverse event reporting by the Sponsor, including suspected serious unexpected adverse 
reactions, will be carried out in accordance with applicable regulations. 
An Investigator must notify the IRB/IEC of the occurrence of any SAE, in writing, as soon as is 
practicable and in accordance with local regulations. A copy of this notification must be 
provided to Xeris Pharmaceuticals or its designee. 
In the event of an SAE that meets the criteria for expedited reporting, an SAE report will be 
prepared for submission to the FDA and any other applicable authorities by Xeris 
Pharmaceuticals or its designee. 
12.6. 
Clinical Laboratory Abnormalities and Other Abnormal 
Assessments Reported as Adverse Events and Serious Adverse 
Events 
Abnormal laboratory findings (eg, serum chemistry, hematology, and urinalysis) or other 
abnormal assessments (eg, ECG and vital signs) per se are not reported as AEs. However, those 
abnormal findings that are deemed clinically significant by the Investigator and/or delegate or 
are associated with signs/symptoms must be recorded as AEs if they meet the definition of an AE 
(and recorded/reported as an SAE if they meet the criteria of being serious) as previously 
described. Clinically significant abnormal laboratory or other clinically significant abnormal 
findings that are detected after consent or that are present at Screening and worsen after consent 
are included as AEs (and SAEs if serious). 
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12.7. 
Subject Monitoring 
Subjects will be monitored for AEs throughout the study by the CRU staff. The Investigator or 
designated sub-Investigator will be available during onsite drug administration. The Investigator 
or designated sub-Investigator will also be available (eg, “on call”) for the subject as needed.  
Subjects will be advised to notify their health care professionals (eg, physician, dentist, and/or 
pharmacist) that they are participating in a clinical research study before taking any medicines or 
undergoing any medical procedure. 
12.8. 
Other Safety Parameters 
12.8.1. 
Subject Blood Volumes to be Drawn Over the Course of the Study 
The approximate amount of blood drawn over the course of the study for each subject is 
presented below in Table 6 and Table 7. 
Table 6: 
Number and Volume of Blood Collections for Subjects Not Participating in 
Pharmacokinetic Substudy  
Sample Type 
Volume 
Per 
Sample 
(mL) 
Total Volume (mL) 
Screening 
Period 
Titration Period 
Maintenance Period 
ET 
Clinical Chemistry 
7.5 
7.5 
0 
15 
7.5 
Free and total T4 
2 
2 
6-24 
10 
2 
TSH 
3.5 
3.5 
10.5-42 
17.5 
3.5 
Hematology 
3 
3 
0 
6 
3 
Serology 
5 
5 
0 
0 
0 
Cumulative Sample Volume 
21 
21 
16.5-66 
48.5 
16 
 
 
Total Volume (mL) for Study through End of Maintenance Period:
 
86-135.5 
Abbreviations:  ET= Early termination; mL = milliliter; TSH = thyroid-stimulating hormone, T4 = thyroxine 
Table 7: 
Number and Total Volume of Blood Collections for Subjects Participating in 
Pharmacokinetic Substudy 
Sample Type 
Volume 
Per 
Sample 
(mL) 
Total Volume (mL) 
 
 
Screening 
Period 
Titration Period 
Maintenance Period 
ET 
Clinical Chemistry 
7.5 
7.5 
0 
15 
7.5 
Free and total T4 
2 
2 
6-24 
10 
2 
TSH 
3.5 
3.5 
10.5-42 
17.5 
3.5 
Hematology 
3 
3 
0 
6 
3 
Serology 
5 
5 
0 
0 
0 
Substudy PK 
4 
0 
0 
64 
0 
Cumulative Sample Volume 
25 
21 
16.5-66 
112.5 
16 
 
 
Total Volume (mL) for Study through End of Maintenance Period:
 
150-199.5  
Abbreviations:  ET= Early termination; mL = milliliter; PK = pharmacokinetic; TSH = thyroid-stimulating hormone, T4 = 
thyroxine 
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12.8.2. 
Physical Examination 
Complete and abbreviated physical examinations will be performed by the Investigator or 
appropriately trained, delegated designee at the timepoints specified in the Schedule of 
Assessments (Table 2). 
Complete physical examinations include general appearance, head, ears, eyes, nose, throat, 
dentition, thyroid, respiratory, cardiovascular, abdomen, skin, neurological, musculoskeletal, and 
lymph nodes. 
Abbreviated physical examinations include head, ears, eyes, nose, throat, respiratory, 
cardiovascular, abdomen, skin, musculoskeletal, and lymph nodes and any pertinent system 
based on any prior findings. 
12.8.3. 
Weight, Height, BMI 
Body height (centimeters) and body weight (kilograms) will be measured at Screening and will 
be used to calculate BMI (kg/m2). Body weight and height will be obtained with the subject’s 
shoes and jacket removed.  
12.8.4. 
Vital Sign Measurements 
Vital signs (systolic and diastolic BP, heart rate/pulse, respiratory rate, oral temperature) will be 
measured as described in the Schedule of Assessments (Table 2). Three readings of BP and heart 
rate/pulse should be taken at intervals of 1 to 2 minutes. The three readings of each will be 
recorded on the eCRF and assessed to determine eligibility for inclusion into the study and 
throughout the study (Section 8.1).  
Subjects should be resting for at least 10 minutes in a supine position prior to measurement of 
BP and heart rate/pulse. See Table 3 for timing window allowances with respect to measurement 
collection. Where possible, assessments should be conducted in order of least invasive to most 
invasive (See Section 11.5 for details). 
12.8.5. 
Electrocardiogram 
12-lead ECGs are to be performed prior to vital signs with subjects in a supine position at least 
10 minutes before the reading is taken. See Table 3 for timing window allowances with respect 
to measurement collection. 
All ECG tracings will be reviewed and assessed by the Investigator or designee.  All potentially 
clinically significant automated ECG readings should be repeated within 5 minutes of the 
reading.  If potentially clinically significant reading is confirmed, then the ECG will be sent to a 
local cardiologist for review. 
12.8.6. 
Local Tolerability 
Local tolerability will be assessed following SC injection as follows: 
• The Investigator/qualified designee will use the Modified Draize Scale (Appendix E) to 
assess erythema and edema formation at the injection site at 30±5 minutes after injection of 
XP-8121. Note: If the Draize score is >1 at 30 minutes, the subject will be discharged, and a 
follow up visit will be scheduled at 24 (±3) hrs after injection in order for the Investigator or 
designee to complete an assessment of the injection site using the Modified Draize Scale. 
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• To assess injection site discomfort, subjects will complete an 11-point Numeric Rating Scale 
(NRS) questionnaire and an Injection Site Discomfort Description and Duration 
Questionnaire 10 (±2) minutes after injection of XP-8121 (Appendix C).  
12.8.7. 
Clinical Safety Laboratory Assessments 
Safety laboratory tests will be performed at the timepoints specified in the Schedule of 
Assessments (Table 2). Additional laboratory tests may be performed at other times, if deemed 
necessary by the Investigator. A repeat of the Screening visit laboratory assessments for clinical 
safety (hematology, chemistry, and urinalysis) may be permitted after consultation with the 
Medical Monitor. 
The central laboratory will perform hematology, chemistry, and urinalysis tests. Blood and urine 
samples for hematology, chemistry, and urinalysis will be prepared using standard procedures. 
Laboratory panels are defined as listed in Table 8. 
Table 8: 
Clinical Safety Laboratory Tests 
Hematology 
Serum Chemistry 
Urinalysis (Dipstick) 
Virology 
• Erythrocytes (red 
blood cells [RBC]) 
• Hematocrit  
• Hemoglobin  
• Leukocytes with 
differential (including 
eosinophils, 
neutrophils, basophils, 
monocytes, 
lymphocytes, and 
reticulocytes)  
• Mean platelet volume  
• Platelets  
• ALT 
• Albumin  
• Alkaline phosphatase  
• AST 
• Bicarbonate 
• Calcium  
• Chloride  
• Creatine kinase 
• Creatinine 
• Globulin  
• Glucose (fasting laboratory 
assessments only) 
• HbA1c  
• Phosphate 
• Potassium 
• Sodium  
• Thyroid-stimulating hormone 
• T4 
• Total and direct bilirubin  
• Urate  
• Urea  
• Blood  
• Glucose 
• Ketones 
• Leukocytes  
• Nitrite  
• pH 
• Protein  
• Specific gravity  
• Total bilirubin  
• Urobilinogen  
• If abnormality is noted for 
protein, blood, nitrite or 
leukocyte esterase, a 
microscopic examination of 
RBC, white blood cell 
(WBC), bacteria, and casts 
will be performed 
• Hepatitis C 
• Hepatitis B 
• HIV 
Abnormalities in clinical laboratory tests that are considered clinically significant are to be 
recorded on the AE eCRF page. If laboratory values constitute part of an event that meets criteria 
defining it as serious, the event (and associated laboratory values) must be reported as an SAE 
(see Section 12.4). 
12.8.8. 
Urine Drug Screen 
A urine drug screen will be performed at Screening and will include the following: 
• Tetrahydrocannabinol 
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• Cocaine 
• Amphetamines 
• Barbiturates 
• Benzodiazepines 
• Opiates 
• Methadone 
• Methamphetamines 
• Ecstasy (3,4-Methylenedioxymethamphetamine [MDMA]) 
• Phencyclidine 
Repeat assessments may be performed in the event of a suspected false positive result.  
If the results are positive for a benzodiazepine that is being taken as a prescribed concomitant 
medication, as defined and documented in accordance with Section 9.2, then the assessment 
would not have to be repeated. 
12.8.9. 
Pregnancy Testing 
A urine pregnancy test is to be performed all timepoints specified in the Schedules of 
Assessments (Table 2). If a urine pregnancy test returns a positive result, a serum pregnancy test 
must be performed in order to confirm the result. If confirmed positive, subjects should be 
withdrawn and pregnancy reported to Sponsor within 24 hr. See Section 12.3 for reporting 
requirements for pregnancies. 
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13. 
STATISTICS 
Detailed methodology for PK descriptive and inferential statistical analyses of the data collected 
in this study will be documented in the Statistical Analysis Plan (SAP). This SAP will be used 
for both clinical parameters from the eCRF and the PK parameters derived from bioanalytical 
analysis data. Procedures outlined in the SAP will supersede protocol-specified statistical 
methods in the event of divergence. 
Descriptive statistics will be used to summarize clinical and laboratory data. Continuous data 
will be represented by n (number of subjects), mean, median, standard deviation (SD), and range. 
Categorical variables will be presented by number and percentage of subjects (n [%]). Additional 
details of the testing procedures not included here, including handling of missing data, will be 
described in the SAP. 
If not otherwise stated, baseline will be determined by the last evaluable assessment prior to 
dosing in each period. Measurement of specific baseline values will be described in the SAP. 
13.1. 
Sample Size Determination  
Assuming a between-subject coefficient of variation of 0.5 and a within-subject, between 
measurements correlation of 0.5, a sample size of 38 subjects will have 80% power to reject the 
null hypothesis that the dose conversion factor is less than 3.2X or more than 5X, in favor of the 
alternative hypothesis that the dose conversion factor is between 3.2X and 5X (in another words, 
within 80% and 125% of the proposed 4X conversion factor derived from PPK modeling). For 
the exploratory endpoint of TSQM-9, assuming a SD of differences of 20, a sample size of 
34 subjects will have 80% power to detect a difference of 10 in means (domain scores range 
from 0 to 100) with a 5% two-sided significance level (α=0.05). Taking into consideration study 
non-completers and non-normalizers of TSH at study end, a total of 44 subjects will be enrolled.  
13.2. 
Subject Disposition 
The number of subjects enrolled, included in each analysis population, who complete the study, 
and who prematurely discontinue, along with reason for discontinuation will be summarized.  
13.3. 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized for all subjects. Summary statistics 
will be generated for continuous variables and the number and percentage of subjects within each 
category will be presented for categorical variables. 
13.4. 
Analysis Populations 
Safety Population: All subjects who receive at least 1 dose of XP-8121. 
Completer Population: All subjects who complete the Maintenance Period and exhibit 
normalized TSH throughout the Maintenance Period while on a stable dose for approximately 6 
weeks. 
PK Population: All safety population subjects who participate in the PK substudy, who do not 
have any major protocol deviations affecting the PK endpoints and for whom a sufficient number 
of samples is available to determine at least one PK parameter. 
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13.5. 
Study Endpoints 
13.5.1. 
Primary Endpoints 
• Safety endpoints collectively include incidence, frequency, severity, and relationship to study 
drug of TEAEs, including clinically significant vital sign measurements, safety laboratory 
test results, ECGs, and physical examinations  
• Tolerability assessments include Modified Draize Scale and Injection Site Discomfort 
questionnaires  
• Geometric mean ratio of the weekly dose of XP-8121 SC (in μg) to the daily dose of oral 
levothyroxine (aka dose conversion factor), where the XP-8121 dose corresponds to the 
administration immediately preceding collection of blood TSH used to determine 
normalization at the end of Maintenance Period 
13.5.1.1. Analysis of Primary Endpoint (Dose Conversion Factor) 
The final dose conversion factor will be assessed by comparing the ln-transformed final XP-8121 
SC dose (in μg) that maintains normalized TSH throughout the Maintenance Period to the 
ln-transformed daily oral levothyroxine dose (in μg) the subject was taking before the study, 
using a linear mixed effects model with treatment as fixed effects, and subject as random effect. 
Geometric LSMs, geometric mean ratios, and 90% CIs will be presented. This endpoint will be 
analyzed using the Completer population for subjects with primary hypothyroidism only. 
Additional sensitivity analyses that include subjects with secondary/tertiary hypothyroidism, 
subjects with dose adjustment, and/or subjects that maintain normal free T4 may be conducted. 
The details of the sensitivity analyses will be described in the SAP.  
Analysis of safety endpoints will be described in Section 13.7. 
13.5.2. 
Secondary Endpoints 
The secondary endpoints of the study are as follows: 
• Proportion of subjects enrolled with normalized TSH throughout the Maintenance Period 
• Proportion of subjects enrolled with normalized TSH at the end of Maintenance Period 
• Blood thyroid hormone concentrations (total thyroxine, fT4 and TSH) following the first 
dose of XP-8121 and after titration (ie, during the Titration and Maintenance Periods) 
13.5.2.1. Analysis of Secondary Endpoints 
Secondary endpoints will be analyzed for the safety population, for subjects with primary 
hypothyroidism only and for all subjects, if applicable. Subjects with normalized TSH 
throughout the Maintenance Period and at the end of Maintenance Period will be presented by 
number and percentage of subjects referenced to the safety population and the number of 
subjects entering the Maintenance Period, along with corresponding 95% CIs. TSH, total and 
free T4 measures following the first dose of XP-8121 will be summarized using descriptive 
statistics. Number and percentage of subjects with results outside the normal ranges will be 
tabulated. 
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13.5.3. 
Exploratory Endpoints 
• Observed values and changes from baseline values in thyroid hormones (total and fT4) and 
TSH during the Titration and Maintenance Periods  
• Pharmacokinetic profile of plasma thyroid hormones (T4 and T3 during the 168-hr PK period 
(PK substudy only):  
− Tmax 
− Cmax and Cmax normalized by dose (Cmax/Dose) 
− AUC0-168hr and AUC0-168hr normalized by dose (AUC0-168hr/Dose) 
− If supported by the data, the following additional parameters may be calculated: 
− Total apparent clearance (CL/F)  
• Comparison of the score of Convenience, Overall Satisfaction, and Effectiveness domain of 
the TSQM-9 between oral levothyroxine and once-weekly XP-8121 SC treatments  
• Summary of results from the Subject Preference Survey 
13.5.3.1. Analysis of Exploratory Endpoints 
All exploratory endpoints except for PK endpoints will be analyzed for the safety population, for 
subjects with primary hypothyroidism only and for all subjects, if applicable. TSH, total and free 
T4 measures and changes from baseline will be summarized by each protocol-specified 
timepoint using descriptive statistics. Analysis of PK endpoints will be described in Section 13.6. 
The analysis of the exploratory endpoint of TSQM-9 domain scores will be gated on results from 
the primary endpoint analysis. The three domain scores will be hierarchically analyzed to ensure 
control of the family-wise type I error rate at the 0.05 level, with the Convenience score first, 
Overall Satisfaction score second, and Effectiveness third. Hypothesis tests for the three domain 
scores will be based on null hypotheses that assume no difference between oral levothyroxine 
and once-weekly XP-8121 SC treatments. Each domain score will be compared between the two 
treatments using a paired t-test.  
Subject counts and percentages for each answer to each question from the Subject Preference 
Survey will also be presented.  
13.6. 
Pharmacokinetics 
Plasma PK parameters will be summarized for all subjects in the PK Population, using 
descriptive statistics (number of non-missing observations (N), arithmetic mean, SD, CV%, 
median, minimum, maximum, geometric mean, and geometric CV%).  
Total plasma concentration of thyroxine and triiodothyronine will be summarized by collection 
timepoint within the PK period for all subjects in the PK Population using descriptive statistics 
(N, arithmetic mean, SD, CV%, median, minimum, maximum, geometric mean, and geometric 
CV%).  
13.7. 
Safety and Tolerability 
All safety analyses will be performed using the Safety population. Safety data will be collected 
and summarized by study period (Titration Period, Maintenance Period). No formal hypotheses 
will be tested on safety data. 
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13.7.1. 
Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 25.0 or higher. Listings of all AEs, treatment-emergent SAEs, and TEAEs leading to 
study discontinuation will be provided by subject, study period, verbatim term, MedDRA System 
Organ Classification (SOC) and Preferred Term (PT), start and end dates, seriousness, severity, 
relationship to study drug, action taken with study treatment, and outcome.  
AEs will be summarized overall by the number and percentage of subjects who experienced at 
least one AE of the following categories in each study period: any AE, any TEAE, any 
drug-related TEAE, any severe TEAE, any serious TEAEs, any drug-related SAE, any SAE 
leading to death, any TEAE leading to premature discontinuation of study drug, and any SAE 
leading to premature study drug discontinuation. 
The number and percentage of subjects reporting a TEAE in each study period and overall (while 
taking XP-8121) will be tabulated by SOC and PT; by SOC, PT, and severity (mild, moderate, 
and severe); and by SOC, PT, and relationship to study drug. 
The number and percentage of subjects reporting an SAE or reporting a TEAE leading to 
premature discontinuation of study drug in each study period and overall will be summarized by 
SOC and PT. 
13.7.2. 
Laboratory Evaluations, Vital Sign Measurements, and Electrocardiograms 
Laboratory evaluations (including TSH), vital signs, and ECG assessments will be summarized 
by study period, and protocol-specified collection timepoint within each period using descriptive 
statistics. A summary of change from baseline at each protocol-specified timepoint will also be 
presented. 
Listings of clinically significant abnormal laboratory values will be presented. Individual 
laboratory results will be listed indicating values outside normal range. Vital signs and 
electrocardiogram results will be listed.  
13.7.3. 
Prior and Concomitant Medications 
Prior and concomitant medications will be mapped to a World Health Organization (WHO) drug 
classification using WHO Drug Dictionary (WHO-DD) and summarized for anatomical 
therapeutic chemical (ATC), and PT.  
Prior and concomitant medication will be summarized for all subjects. A listing of prior and 
concomitant medications will be provided for the safety population. 
13.7.4. 
Local Tolerability 
Local tolerability (incidence of injection site discomfort and erythema/edema) will be 
summarized by protocol-specified timepoint following SC injections of XP-8121. Specifically, 
subjective injection site discomfort as reported by the NRS and Discomfort Description and 
Duration Questionnaire will serve as the data basis. The incidence of any injection site 
discomfort (score >0 on the ordinal rating scale) will be analyzed descriptively. Descriptive 
statistics also will be provided for time of onset and duration (of discomfort), and discomfort 
description (i.e., pain, irritation, itching, etc.). 
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In addition, erythema and/or edema formation at the injection site will be assessed using the 
Modified Draize Scale. Counts and percentages of each category on the erythema/edema 
spectrum will be presented for each scheduled timepoint. 
13.7.5. 
Physical Examinations 
Findings on the physical examinations will be listed by subject, and abnormal findings will be 
flagged for clinical significance based on the investigator’s judgment. 
13.8. 
Other Assessments 
The following assessments will be listed by subject: 
• Medical history (coded using MedDRA) 
• Pregnancy test 
• Urine drug screen 
13.9. 
Statistical Issues 
13.9.1. 
Missing or Imputed Data 
No statistical adjustments for missing data will be conducted. 
13.9.2. 
Interim Analysis 
No interim analysis will be conducted. 
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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
Before an investigational site can enter a patient into the study, a representative of Xeris will 
visit the investigational study site to: 
• Determine the adequacy of the facilities 
• Discuss with the Investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of Xeris or its representatives. This will be 
documented in a Clinical Study Agreement between Xeris and the Investigator. 
During the study, a monitor from Xeris or representative will have regular contacts with the 
investigational site, for the following: 
• Provide information and support to the Investigator(s) 
• Confirm that facilities remain acceptable 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms, and that study drug accountability checks are 
being performed 
• Perform source data verification. This includes a comparison of the data in the case report 
forms with the patient’s medical records at the hospital or practice, and other records relevant 
to the study. This will require direct access to all original records for each patient (e.g., clinic 
charts). 
• Record and report any protocol deviations not previously sent to Xeris. 
• Confirm AEs and SAEs have been properly documented on CRFs and confirm any SAEs 
have been forwarded to Xeris and those SAEs that met criteria for reporting have been 
forwarded to the IRB. 
The monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice. 
The Medical Monitor will review each proposed subject prior to entering into the Titration 
Period of the study. The Investigator or designee will complete the Enrollment Authorization 
Request Form which will detail out the key eligibility criteria and submit to the medical monitor 
for review and approval.   
14.2. 
Audits and Inspections 
Authorized representatives of Xeris, a regulatory authority, an IRB or IEC may visit the site to 
perform audits or inspections, including source data verification. The purpose of a Xeris audit or 
inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, International Council for 
Harmonization Good Clinical Practice (GCP) guidelines, and any applicable regulatory 
requirements. The Investigator should contact Xeris and the IRB/IEC immediately if contacted 
by a regulatory agency about an inspection. 
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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with GCP and all applicable regulatory requirements, Xeris may conduct a 
quality assurance audit. Please see Section 14.2 for more details regarding the audit process. 
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16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB or IEC as appropriate. The Investigator must submit 
written approval to Xeris before he or she can enroll any patient/subject into the study. 
The Investigator is responsible for informing the IRB or IEC of any amendment to the protocol 
in accordance with local requirements. In addition, the IRB or IEC must approve all advertising 
used to recruit patients for the study. The protocol must be re-approved by the IRB or IEC upon 
receipt of amendments and annually, as local regulations require. 
The Investigator is also responsible for providing the IRB with reports of any reportable serious 
adverse drug reactions from any other study conducted with the study drug. Xeris will provide 
this information to the Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
16.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Council for Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)/GCP, 
applicable regulatory requirements and the Xeris’ policy on Bioethics. 
16.3. 
Written Informed Consent 
The Investigator(s) at each center will ensure that the patient is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study. Patients 
must also be notified that they are free to discontinue from the study at any time. The patient 
should be given the opportunity to ask questions and allowed time to consider the information 
provided. 
The patient’s signed and dated informed consent must be obtained before conducting any study 
procedures. 
The Investigator(s) must maintain the original, signed ICF. A copy of the signed ICF must be 
given to the patient. 
 
 
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17. 
DATA MANAGEMENT 
Electronic CRFs (eCRFs) will be employed for this study. Data will be entered into the eCRFs 
by the study site unless transmitted to Xeris or designee electronically (eg, laboratory data). 
Queries will be issued for any inconsistencies, omissions, and discrepancies and will be resolved 
by the appropriate parties. The PI or authorized designee will ensure that all information derived 
from the source documentation is consistent with the source information and accurately reflected 
in the CRF. By signing the eCRFs, the PI confirms that the information is complete and correct. 
All medical history conditions and AEs will be coded using MedDRA. Concomitant medications 
will be coded using the current WHO-DD. Data management details will be outlined in a 
separate data management plan. Following database lock, archive media will be created and 
forwarded to the clinical site, and the clinical database will be archived.   
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18. 
DATA HANDLING AND RECORDKEEPING 
18.1. 
Inspection of Records 
Xeris will be allowed to conduct site visits to the investigation facilities for the purpose of 
monitoring any aspect of the study. The Investigator agrees to allow the monitor to inspect the 
drug storage area, study drug stocks, drug accountability records, subject charts and study source 
documents, and other records relative to study conduct. 
18.2. 
Retention of Records 
The Investigator must maintain all documentation relating to the study for a period of 2 years 
after the last marketing application approval, or if not approved 2 years following the 
discontinuance of the test article for investigation. If it becomes necessary for Xeris or the 
Regulatory Authority to review any documentation relating to the study, the Investigator must 
permit access to such records. 
 
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19. 
PUBLICATION POLICY 
All data generated from this study are the property of Xeris and shall be held in strict confidence 
along with all information furnished by Xeris. Independent analyses and/or publication of these 
data by an Investigator or any member of his/her staff is not permitted without prior written 
consent of Xeris.  
Any formal presentation or publication of data from this trial will be considered as a joint 
publication by the Investigator(s) and appropriate Xeris personnel. Authorships will be 
determined chiefly by merit, with rights of final authorship decisions to be held by Xeris, unless 
superseded by an agreement stipulating otherwise. Factors determining merit will include active 
participation in study design and conduct, as well as interest and ability to participate 
meaningfully in analyzing or interpreting, writing, or presenting study results. The venue(s) 
selected for publication will be determined jointly by the publication authors. The first 
publication will be based on data from all study centers and analyzed as stipulated in the protocol 
and SAP. Investigators participating in multicenter studies agree not to present data gathered 
from one study center or a subset of centers before the first full publication, unless formally 
agreed by Xeris in advance. Written permission to Investigators to publish subset or secondary 
results will be contingent on prior review by Xeris of the proposed methodology and analytical 
plan. Any Investigator-led publication or presentation will provide for nondisclosure of Xeris 
confidential or proprietary information. In all cases, parties planning to publish data agree to 
submit all draft manuscripts or abstracts to Xeris and other relevant parties at least 60 days prior 
to publication submission. This will enable involved parties to protect proprietary information 
and to provide comments to authors.  
Further details on the publication process may be provided in individual contractual agreements 
signed by the Investigators and Xeris. 
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20. 
LIST OF REFERENCES 
Abbott Laboratories. Synthroid Levothyroxine Sodium Powder for Injection [Product 
Information] Available at http://www.pharmacistconnection.com/images/ch/synthroid/pi.pdf. 
2001. Accessed 12 July 2019. 
AbbVie Inc. SYNTHROID® (levothyroxine sodium tablets) [Package Insert] Available at 
https://www.rxabbvie.com/pdf/synthroid.pdf. 2018. Accessed 12 July 2019. 
Colucci P, Yue CS, Ducharme M, Benvenga S. A review of the pharmacokinetics of 
levothyroxine for the treatment of hypothyroidism. Eur Endocrinol. 2013;9(1):40-47. 
Downie WW, Leatham PA, Rhind VM, et al. Studies with pain rating scales. Ann Rheum Dis, 
1978; 37: 378-381. 
Draize JH, Woodard G, Calvery HO. Methods for the study of irritation and toxicity of 
substances applied topically to the skin and mucous membranes. Journal of Pharmacology and 
Experimental Therapeutics. November 1944;82(3):377-390. 
Guidance for Industry, Skin Irritation and Sensitization Testing of Generic Transdermal Drug 
Products. US Department of Health and Human Services Food and Drug Administration Center 
for Drug Evaluation and Research (CDER). December 1999. Appendix A. 
https://www.federalregister.gov/documents/2000/02/03/00-2299/guidance-for-industry-on-skin-
irritation-and-sensitization-testing-of-generic-transdermal-drug  
Hennessey JV. The emergence of levothyroxine as a treatment for hypothyroidism. Endocrine. 
2017;55(1):6-18. 
Laurent I, Tang S, Astere M, et al. Liquid L-thyroxine versus tablet L-thyroxine in patients on 
L-thyroxine replacement or suppressive therapy: a meta-analysis. Endocrine. 2018;61(1):28-35. 
McKim AS, Strub R. Dimethyl sulfoxide USP, PhEur in approved pharmaceutical products and 
medical devices. Pharm Tech. 2008;32(5):74-85. 
Skelin M, Lucijanic T, Amidzic Klaric D, et al. Factors affecting gastrointestinal absorption of 
levothyroxine: A review. Clin Ther. 2017;39(2):378-403. 
Vita R, Fallahi P, Antonelli A, Benvenga S. The administration of L-thyroxine as soft gel 
capsule or liquid solution. Expert Opin Drug Deliv. 2014;11(7):1103-1111. 
Winther KH, Cramon P, Watt T, et al. Disease-specific as well as generic quality of life is widely 
impacted in autoimmune hypothyroidism and improves during the first six months of 
levothyroxine therapy. PLoS One. 2016;11(6): e0156925. 
Xeris Pharmaceuticals, Inc. GVOKE® (glucagon injection, for subcutaneous use) [Package 
Insert] Available at Prescribing Information | Gvoke™ (glucagon injection). 2021. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212097Orig1s007lbl.pdf . Accessed 
27 December 2022. 
 
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21. 
APPENDICES 
 
 
 
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APPENDIX A. TITRATION ALGORITHM  
 
a. 
Corresponds to 50% of the target weekly dose of XP-8121 (in μg), which is calculated as the current daily oral 
levothyroxine dose (in μg) multipled by 4 rounded up to the nearest 50 μg. 
b. During the Titration Period, XP-8121 will be titrated based on individual response to therapy (using blood free 
T4 [fT4] trough concentration as a fast-response, interim biomarker of replacement adequacy) at intervals no 
more frequent than every other week and in dosage increments corresponding to 25% of the target dose, up to a 
maximum of 125% of the target dose or 1500 μg (whichever is lower). 
c. 
If a drug-related adverse event is reported or if overdosage is a concern, the Investigator should consult with the 
Medical Monitor before up-titrating. 
d. Dosing titration decsions should be made after conferring with the Medical Monitor. 
e. 
Once subjects have completed the Titration Period they will continue at the same dose and time of 
administration of XP-8121 in the Maintenance Period. 
Note: Subjects not achieving an adequate fT4 at ≤125% of the target dose or the maximum weekly dose of 1500 μg 
may also continue into the Maintenance Period at the discretion of the Investigator and after conferring with the 
Medical Monitor. 
 
 
  
 
 
 
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APPENDIX B. SIGNS AND SYMPTOMS OF HYPERTHYROIDISM 
This table includes an overview of the most common symptoms and signs for the diagnosis of 
hyperthyroidism. The presence of several of the following signs/symptoms may be indicative of 
hyperthyroidism and should be further investigated. 
Table 9: 
Signs/Symptoms of Indicative of Hyperthyroidism 
Heat intolerance 
Hyperkinesis 
Atrial fibrillation 
Excessive sweating 
Increased Appetite 
Decreased Weight 
Casual heart rate/pulse >90 bpm 
Palpitations 
Tiredness 
Nervousness 
Hot hands 
Shortness of breath 
Moist hands 
Tremor 
Increased frequency of bowel movements 
Urinary frequency and nocturia 
 
 
 
 
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APPENDIX C. INJECTION SITE DISCOMFORT ASSESSMENT 
Numeric Rating Scale for Injection Site Discomfort 
Investigative Site Instructions: The subject should complete the 11-point NRS for Injection 
Site Discomfort at 10 (±2) minutes after injection of study drug. The subject will complete the 
NRS by drawing a circle around the number corresponding to the perceived intensity (severity) 
of discomfort according to the instructions below. The goal is for the subject to report the 
amount of discomfort, if any, remaining at each timepoint, as opposed to reporting the transient 
pain associated with needle insertion. 
Note: If a subject is unable to physically complete the questionnaire, the subject will indicate the 
number on the NRS corresponding to their level of discomfort, and study staff will circle it. 
Documentation will be provided on each completed questionnaire as to who completed the form. 
Subject Instructions: Ignoring any pain from insertion of the needle, please draw a circle 
around the number on the scale below that corresponds to the intensity (severity) of any 
discomfort you are feeling right now at the study drug injection site. 
For example, if you are currently feeling no discomfort, you should circle the number “0” on the 
left end of scale. If you are currently feeling the worst discomfort possible, you should circle 
number “10” on the right end of the scale. 
 
 
 
 
 
 
Source:  Downie et al, 1978 
Injection Site Discomfort Description and Duration Questionnaire 
Study Personnel Instructions: Question 1 should be completed by the subject at 10 (± 2) minutes 
after study drug injection. If the answer to Question 1 is ‘Yes’ then complete the following: 
i. Questions 1a and 1b should be assessed at 10 (±) 2 minutes after study drug injection and, 
ii. Question 1c only should be assessed once discomfort has fully resolved.  
If the answer to Question 1 is ‘No’, then questions 1a, 1b, and 1c should not be assessed. 
The goal is for the subject to report if they had any discomfort and if there was discomfort, the 
qualitative nature and duration of discomfort associated with the delivery of study drug, ignoring 
any transient pain associated with injection of study drug. 
Note: If a subject is unable to physically complete the questionnaire, the subject will provide 
verbal responses, which will be recorded on the questionnaire by study staff. Documentation will 
be provided on each completed questionnaire as to who completed the form. 
Subject Instructions: Please answer the questions below. 
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1. Did you have any discomfort from the study drug administration? 
 _____ Yes ____ No 
If yes, 
1a. How would you describe any discomfort you felt from the study drug?  (Check all that 
apply): 
______Pain (e.g., throbbing, soreness, muscle ache) 
______Itching 
______Tingling, twitching or numbness 
______Irritation (e.g., burning, stinging) 
______Other (specify):  _____________________________________________________ 
1b. About how long after the study drug administration did the discomfort start?   
(Please enter a number) _____ minutes 
1c. In total, how long did the discomfort last?  (Please enter a number): _____ minutes 
Source: Downie et al, 1978 
 
 
 
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APPENDIX D. SUBJECT PREFERENCE SURVEY 
By participating in this study (XP-8121-120), you have now received thyroid replacement 
therapy in two different ways: 
1. A once-daily oral pill (e.g., Synthroid) that should be taken every day at the same time before 
breakfast with only water and on an empty stomach and then wait for at least 30 minutes 
before eating, drinking, or taking any other medications.  
2. A once-weekly injectable medication administered under the skin that can be taken at any 
time of day. 
Please think back to your participation in this study (XP-8121-120) and consider your life 
and what works best for you.  Think about the treatment itself, rather than the doctor’s 
office or study personnel.  There are no right or wrong answers. 
If you had the choice between these two medications for thyroid replacement therapy, 
which one would you choose? 
a. 
once-daily oral pill 
b. 
once-weekly injection 
c. 
no preference 
If you prefer one of the administration methods, how strong is the preference? 
a. Very strong 
b. Fairly strong 
c. Slightly strong 
d. Not very strong 
If you prefer one of the administration methods, what are the main reason(s) for your 
preference? Choose all that apply. 
a. Convenience 
b. Ease of administration 
c. Frequency of administration 
d. My level of compliance with therapy 
e. Confidence in my therapy 
f. Other 
 
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APPENDIX E. MODIFIED DRAIZE SCALE 
Draize Scales 
g. Study Personnel Instructions:  The Modified Draize Scale as shown in the table below will 
be used for physical examination/rating of abnormalities at the injection site. 
h. The injection site should be examined by the Investigator/qualified designee for formation of 
both erythema and edema and results recorded in the eCRF at the timepoint noted in the 
Schedule of Assessments. 
i. If the Draize score is >1 at 30 minutes, the subject will be discharged, and a follow up visit 
will be scheduled at 24 (±3) hrs post-dose to allow the Investigator or designee to complete 
an assessment of the injection site using the Modified Draize Scale.  
Erythema Formation 
Edema Formation 
Description 
Score 
Description 
Score 
No erythema 
0 
No edema 
0 
Very slight erythema 
Barely perceptible 
1 
Very slight edema 
Barely perceptible 
1 
Slight erythema 
(Edges of area well 
defined 
by definite raising) 
2 
Slight edema 
(Edges of area well 
defined 
by definite raising) 
2 
Moderate erythema 
3 
Moderate edema 
Raised approx. 1 mm 
3 
Severe erythema 
Beet redness to slight 
eschar formation 
4 
Severe edema 
Raised more than 1 mm 
and beyond exposure area 
4 
Source: FDA, 1999; Draize et al, 1944 
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APPENDIX F. SUMMARY OF PRIOR CHANGES TO PROTOCOL 
Rationale and Summary of Changes from Protocol Version 1.0 to Version 2.0 
This protocol was amended to update the minimum current daily dose of oral levothyroxine 
permitted for enrollment into the study to a level that would permit subjects to start at a dose of 
100 μg XP-8121. The minimum laboratory values for hematocrit and hemoglobin were also 
updated to reflect the lower limit of the normal range for the central laboratory being used for the 
study. In the preparation of this amendment, other minor updates were made and are included in 
the following table. 
Affected 
Sections/Tables 
Summary of Revisions Made 
Rationale 
General 
Minor formatting updates and 
clarifications. 
Updated wording to increase 
specificity of procedures and 
timing. 
Administrative update. 
Section 1 
Added new protocol version. 
Administrative update. 
Summary of 
Revisions 
Added description of changes 
made to the protocol with the 
amendment. 
Administrative update. 
Procedures in 
Case of 
Emergency 
Removed reference to direct phone 
number. 
Administrative update. 
Section 2 
Synopsis was updated to align with 
changes in main body of protocol. 
Administrative update. 
Table 2 
Removed study procedure for oral 
levothyroxine administration 
during Screening and at the End of 
Maintenance Visit. 
Oral levothyroxine administration is part of 
the eligibility assessments performed during 
the Screening Period and at the End of 
Maintenance it is a return to standard of 
care for the subject. 
Table 2 
Moved clinical safety laboratory 
assessment from the end of the 
Titration Period to the beginning 
of the Maintenance Period. 
Clarified timing of clinical safety laboratory 
assessment from the end of the Titration 
Period, as it is unknown at the time of the 
visit if it is the last visit in the Titration 
Period; therefore, the laboratory 
assessments for this need to be performed at 
the beginning of the Maintenance Period. 
Table 2 
Clarified timing of urine 
pregnancy test during Titration 
Period as Weeks 1, 3, 5 and 7. 
Administrative update. 
Table 2 
ECG footnote updated to include 
handling of potentially clinically 
significant ECG readings, as 
defined in Section 12.8.5. 
Administrative update. 
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Affected 
Sections/Tables 
Summary of Revisions Made 
Rationale 
Table 2 
Section 11.2 
Section 11.3 
Section 12.8.6 
Appendix E 
 
Clarified description of the 
assessment of the injection site, if 
required 24 (±3) hrs post-dose to 
be completed using the Modified 
Draize Scale. 
Administrative update 
Section 5.5 
Updated lowest dose of XP-8121 
administered to 100 μg. 
Updated the lowest dose to 100 μg to 
correspond to the initiation dose required 
for the lowest dose of oral levothyroxine. 
Section 5.5 
Updated lowest daily dose of oral 
levothyroxine permissible for 
enrollment to 50 μg. 
Updated to ensure that the lowest dose of 
oral levothyroxine aligned with the 
conversion criteria being applied for the 
minimum starting dose of XP-8121 (eg, 
4 times 50 μg, is 200 μg, and the 50% 
starting dose would be the minimum dose 
of 100 μg XP-8121). 
Section 8.2 
Exclusion Criteria #3 updated 
lowest dose of oral levothyroxine 
permissible for enrollment to 
50 μg. 
Updated to ensure that the lowest dose of 
oral levothyroxine aligned with the 
conversion criteria being applied for the 
minimum starting dose of XP-8121 (eg, 4 
times 50 μg, is 200 μg, and the 50% starting 
dose would be the minimum dose of 100 μg 
XP-8121). 
Section 8.2 
Exclusion Criteria #8 updated the 
minimum hematocrit level allowed 
for enrollment to 33.5% for 
females and 38.7% for males. 
Updated to align with the normal range for 
the central laboratory being used for the 
study. 
Section 8.2 
Exclusion Criteria #9 updated the 
minimum hemoglobin level 
allowed for enrollment to 
10.8 g/dL for females and 
12.8 g/dL for males. 
Updated to align with the normal range for 
the central laboratory being used for the 
study. 
Section 9.1 
Removed description of unit 
markings on syringe. 
Administrative update. 
Section 11.2 
Clarified timing of urine 
pregnancy test during Titration 
Period as Weeks 1, 3, 5 and 7. 
Removed clinical safety laboratory 
assessments from the end of the 
Titration Period. 
Administrative update. 
Section 11.3 
Added clinical safety laboratory 
assessments to the beginning of the 
Maintenance Period 
 
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Affected 
Sections/Tables 
Summary of Revisions Made 
Rationale 
Section 11.2.1 
 
Table 6 
 
Table 7 
Updated volume of blood drawn in 
the Titration and Maintenance 
Periods. 
Updated to align with the shift of clinical 
laboratory assessments from the end of the 
Titration Period to the beginning of the 
Maintenance Period, maximum total 
volume remained unchanged. 
Updated to clarify minimum volume 
requirements for minimum free and total T4 
sample collections. 
Appendix C 
Clarified question to align with the 
qualitative nature and duration of 
the potential discomfort associated 
with the delivery of study drug. 
Administrative clarification. 
 
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