Clinical trial NCT03738865
Conditions: Insulin Hypoglycemia Type 1 Diabetes Mellitus Severe Hypoglycemia
Keywords: glucagon hypoglycemia
Sponsor: Xeris Pharmaceuticals
Start date: 2018-09-27; Completion date: 2019-04-02
Enrollment: 132 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a multi-center, randomized, controlled, single-blind, two-way crossover efficacy and safety study in subjects with Type 1 diabetes mellitus. The study involves two daytime clinical research center (CRC) visits with random assignment to receive G-Pen glucagon 1 mg during one period and Novo Glucagon 1 mg during the other. Each daytime visit is preceded by an overnight stay in the CRC. In the morning of the inpatient study visit, the subject is brought into a state of severe hypoglycemia through IV administration of regular insulin diluted in normal saline. After a hypoglycemic state with plasma glucose \< 54 mg/dL (3 mmol/L) is verified, the subject is administered a dose of G-Pen or Novo Glucagon via subcutaneous injection. Plasma glucose levels are monitored for up to 180 minutes post-dosing, with a value of \>70.0 mg/dL (3.89 mmol/L) or an increase of \> 20 mg/dL (\>1.11 mmol/L) within 30 minutes of glucagon administration indicating a positive response. After 3 hours, the subject is given a meal and discharged when medically stable. After a wash-out period of 7 to 28 days, subjects return to the CRC, and the procedures are repeated with each subject crossed over to the other treatment. A follow-up visit as a safety check is conducted 2-7 days following administration of the final dose of study drug.

Detailed description:

Arms: arm 1: 1 mg G-Pen at the first treatment visit followed by 1 mg Novo Glucagon at the second treatment visit arm 2: 1 mg Novo Glucagon at the first treatment visit followed by 1 mg G-Pen at the second treatment visit
Interventions: intervention 1: G-Pen intervention 2: Novo Glucagon
Intervention descriptions: intervention 1: 1 mg subcutaneous injection of G-Pen (glucagon injection) administered via auto-injector intervention 2: 1 mg subcutaneous injection of Novo Glucagon (glucagon injection)

Protocol documents:
Prot_000.pdf: 
Cover Page
1 
Xeris Pharmaceuticals, Inc. 
Confidential and Proprietary 
Protocol for: 
Study No. XSGP-304 
Title: G-Pen (glucagon injection) compared to Glucagen® HypoKit® (glucagon) for induced 
hypoglycemia rescue in adults with T1D: a Phase 3 multi-center, randomized, controlled, single 
blind, 2-way crossover study to evaluate efficacy and safety 
NCT03738865 
Document Date: 17 December 2018 


1. TITLE PAGE 
G-PEN (GLUCAGON INJECTION) 
PROTOCOL XSGP-304 
 
G-PEN (GLUCAGON INJECTION) COMPARED TO 
GLUCAGEN® HYPOKIT® (GLUCAGON) FOR INDUCED 
HYPOGLYCEMIA RESCUE IN ADULTS WITH T1D: A PHASE 
3 MULTI-CENTER, RANDOMIZED, CONTROLLED, SINGLE 
BLIND, 2-WAY CROSSOVER STUDY TO EVALUATE 
EFFICACY AND SAFETY 
 
 
 
 
 
 
 
 
 
Version 2.1 
17 December 2018 




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Investigator’s Agreement 
 
I have read the XSGP-304 protocol 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 
Sponsor’s Study Leader & 
primary contact 
Debby Powers 
Director, Clinical Programs 
dpowers@xerispharma.com 
844-445-5704 (direct)  
512-739-8665 (cell) 
Medical Monitor & 
24-hour emergency contact 
M. Khaled Junaidi, MD, 
Medical Director, Clinical 
Research 
kjunaidi@xerispharma.com  
312-517-1461 (direct) 
815-593-2218 (cell)  
Reporting of Investigational 
Product concerns, including 
device failures 
Xeris Medical Affairs 
Department 
safety304@xerispharma.com   
+1.630.915.5885 
+1.815.593.2218 
 


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2. 
SYNOPSIS 
Protocol Number: XSGP-304 
G-PEN (GLUCAGON INJECTION) COMPARED TO GLUCAGEN® HYPOKIT® 
(GLUCAGON) FOR INDUCED HYPOGLYCEMIA RESCUE IN ADULTS WITH T1D: A 
PHASE 3 MULTI-CENTER, RANDOMIZED, CONTROLLED, SINGLE BLIND, 2-WAY 
CROSSOVER STUDY TO EVALUATE EFFICACY AND SAFETY 
IND: 
115091 
EudraCT Number: 
2018-002661-19 
Project phase: 
Phase 3 
Compounds:   
Xeris G-Pen (glucagon injection)  
Novo GlucaGen® Hypokit® (glucagon for injection) 
Objectives: 
The primary objective of this study is to demonstrate that G-Pen 1 mg (test) is 
not inferior to GlucaGen Hypokit (glucagon, Novo Nordisk) 1 mg (reference), 
in Type 1 diabetic (T1D) subjects in a state of insulin-induced hypoglycemia.  
The secondary objective of this study is to evaluate the safety and tolerability of 
G-Pen 1 mg versus GlucaGen Hypokit 1 mg in the study population.  
Endpoints: 
The study objectives will be assessed by the comparison of the two study drugs 
for the following primary and secondary endpoints:  
Primary:  
For the primary endpoint, groups will be compared for rates of achieving a 
positive plasma glucose response, defined as either a plasma glucose 
concentration > 70 mg/dL (> 3.88 mmol/L) or an increase in plasma glucose 
concentration > 20 mg/dL (>1.11 mmol/L) within 30 minutes of study drug 
injection. 
Secondary:  
For the secondary endpoints, groups will be compared based on each of the 
following:  
1. Rate of achieving a plasma glucose concentration > 70 mg/dL 
(> 3.88 mmol/L) within 30 minutes from injection of study drug. 
2. Rate of achieving an increase in plasma glucose concentration 
> 20 mg/dL (>1.11 mmol/L) within 30 minutes from injection of 
study drug. 
3. Rates of positive symptomatic response, defined as relief of 
neuroglycopenic symptoms within 30 minutes from a decision to 
dose. 
4. Rates of positive treatment response, defined as exhibiting either 
a positive plasma glucose response or a positive symptomatic 
response. 
5. Time to a positive plasma glucose response from injection of 
study drug. 


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6. Time to administer study drug from a decision to dose. 
7. Pharmacodynamic (PD) characteristics of mean plasma glucose 
concentration (0 to 90 minutes post-dose), maximum observed 
concentration (Cmax), time to maximum observed concentration 
(tmax), area under the concentration versus time curve from time 0 
to 90 minutes (AUC(0-90)), and area under the concentration 
versus time curve from time 0 to 180 minutes (AUC(0-180)). 
8. Time to (a) initial relief and (b) complete resolution of autonomic 
and neuroglycopenic symptoms of hypoglycemia from a decision 
to dose.  
9. Time to resolution of the overall feeling of hypoglycemia from a 
decision to dose. 
10. Safety endpoints, including: adverse event (AE)/serious adverse 
event (SAE) rates, and changes in vital signs, laboratory 
variables, and physical exam/electrocardiogram (ECG) findings. 
11. Tolerability endpoints, including: Draize scale scores for 
injection site erythema and edema as assessed by the investigator, 
and injection site discomfort and duration as assessed by subject 
questionnaire responses. 
Study design:   
This is a multi-center, randomized, active-controlled, single-blind, two-way 
crossover efficacy and safety inpatient study in adult subjects with T1D.  The 
study will involve two daytime visits at a clinical research center (CRC) or 
comparable setting, scheduled 7 to 28 days apart.  Subjects will be randomly 
assigned to receive G-Pen glucagon 1 mg during one period and GlucaGen 
Hypokit 1 mg during the other period. 
Study location: 
Approximately 8 clinical research centers in North America and Europe. 
Study duration: 
The estimated duration of study participation for each individual subject is 
approximately 4 weeks. The estimated duration of the entire study is 8 months. 
Sample size: 
It is anticipated that approximately 200 subjects will be screened for this study 
to achieve 122 randomized subjects and a goal of 111 subjects who are 
evaluable for treatment both periods.   
Subjects: 
The study will include male and female subjects with T1D between the ages of 
18 and 75 years, inclusive, at Screening. 
Inclusion Criteria: 
1. Males and females diagnosed with T1D for at least 24 months.  Women of 
childbearing potential require a negative urine pregnancy test and must use 
medically accepted contraception throughout the study and for 7 days after 
the last dose of study drug.   
Nursing mothers will be allowed to participate in the study.  However, 
breast feeding during the inpatient study visits (Visits 2 and 3) and for 48 
hours after each dose of study drug is not allowed. 
2. Current usage of daily insulin treatment that includes having an assigned 
“correction factor” for managing hyperglycemia.  


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3. Age 18 to 75 years, inclusive. 
4. Random serum C-peptide concentration < 0.6 ng/mL. 
5. Willingness to follow all study procedures, including attending all clinic 
visits. 
6. Subject has provided informed consent as evidenced by a signed and dated 
informed consent form (ICF) completed before any trial-related activities 
occur. 
Exclusion Criteria: 
1. Pregnancy 
2. Glycated hemoglobin (HbA1c) > 10% at Screening.   
3. Body mass index (BMI) > 40 kg/m2.  
4. Renal insufficiency (serum creatinine greater than 3.0 mg/dL) or Stage 2 or 
greater kidney failure. 
5. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
equal to or greater than 3 times the upper limit of normal. 
6. Hepatic synthetic insufficiency as defined as a serum albumin of less than 
3.0 g/dL. 
7. Hematocrit < 30%. 
8. Blood pressure (BP) readings at Screening where systolic blood pressure 
(SBP) < 90 or > 150 mm Hg, and diastolic blood pressure (DBP) < 50 or 
> 100 mm Hg. 
9. Clinically significant ECG abnormalities. 
10. Use of total insulin dose per day > 2 U/kg. 
11. Inadequate venous access. 
12. Congestive heart failure, New York Heart Association (NYHA) class II, III 
or IV. 
13. History of myocardial infarction, unstable angina, or revascularization 
within the past 6 months. 
14. History of a cerebrovascular accident or with major neurological deficits. 
15. Active malignancy within 5 years from Screening, except basal cell or 
squamous cell skin cancers.  Any history of breast cancer or malignant 
melanoma will be exclusionary. 
16. Major surgical operation within 30 days prior to Screening.  
17. History of or current seizure disorder (other than with suspect or 
documented hypoglycemia). 
18. Current bleeding disorder, treatment with warfarin, or platelet count below 
50 × 109 per liter. 
19. History of pheochromocytoma or disorder with increased risk of 
pheochromocytoma (multiple endocrine neoplasia type 2 [MEN 2], 
neurofibromatosis, or Von Hippel-Lindau disease). 
20. History of insulinoma. 
21. History of allergies to glucagon or glucagon-like products, or any history of 
significant hypersensitivity to glucagon or any related products or to any of 
the excipients (dimethyl sulfoxide [DMSO] and trehalose) in the 
investigational formulation.  


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22. History of glycogen storage disease. 
23. Subject tests positive for human immunodeficiency virus [HIV], hepatitis C 
virus [HCV], or hepatitis B virus [HBV] infection (hepatitis B surface 
antigen positive [HBsAg+]) at Screening. 
24. Active substance or alcohol abuse (more than 21 drinks per week for male 
subjects or 14 drinks per week for female subject).  
25. Administration of glucagon within 7 days of Screening. 
26. Participation in other studies involving administration of an investigational 
drug or device within 30 days or 5 half-lives, whichever is longer, before 
Screening for the current study and during participation in the current study. 
27. Any other reason the Investigator deems exclusionary. 
Study Methods: 
Subjects will complete the screening procedures to determine eligibility up to 
30 days before enrollment into the treatment period and administration of study 
drug.  Subjects not meeting eligibility criteria may be rescreened 30-days after 
an initial screen failure.  A single re-screen is permitted, and this re-screen is 
only permissible if the reason for the prior screen failure was for laboratory 
measurements.  Blood for clinical laboratory tests can be redrawn after a 30-day 
wait; however, other screening procedures do NOT need to be repeated.  If the 
new clinical laboratory test results meet eligibility, the subject may be dosed. 
Otherwise, the subject is not eligible for dosing or further re-screening. 
The evening prior to each inpatient study visit, subjects with confirmed plasma 
glucose not greater than 350 mg/dL (19.44 mmol/L) will be admitted for an 
overnight stay between 6 and 8 pm.  Subjects will be provided a standardized 
dinner and will continue their usual insulin regimen per PI discretion.  At the 
Investigator’s discretion, subjects may receive a standardized snack before 
midnight the day before treatment. 
Subjects will be instructed to fast after midnight.  If site staffing allows for 
appropriate oversight, an intravenous (IV) catheter will be placed, and 
maintenance fluids will be administered.  Otherwise, the subject’s own infusion 
pump will be used overnight.  The subject’s plasma glucose will be monitored 
overnight, and glucose (IV or oral tablets) and/or insulin (IV or subcutaneous 
[SC]) will be administered as necessary to maintain plasma glucose within a 
recommended target range of 80 to 150 mg/dL (4.44 to 8.34 mmol/L). 
Overnight glucose measurements outside of this recommended range will not 
be considered protocol deviations.  At a minimum, glucose will be assessed by 
BGM or YSI (not CGM) at midnight, 3 am, and 6 am, with ±30 minutes for 
these measurements, which will be entered into the EDC. 
Subjects will continue to fast the morning of the procedure and an IV catheter 
for blood sampling will be inserted, ideally in the antecubital fossa of the arm.  
The hand used for blood sampling will be kept warm by use of a heated-hand 
box to increase blood flow and achieve “arterialized” samples.  Subjects will be 
kept supine and covered under a blanket to maintain warmth. 
The subject will be eligible to begin the baseline euglycemic steady state period 
when their plasma glucose is confirmed to be within the range of 70 to 
270 mg/dL (3.89 to 15.0 mmol/L).  IV insulin will be administered to maintain 
the plasma glucose within the range of 75 to 115 mg/dL (4.17 to 6.38 mmol/L) 
for 30 minutes.  If the plasma glucose has been maintained within the range of 
75 to 115 mg/dL (4.17 to 6.38 mmol/L) for at least 30 minutes, and the insulin 
infusion rate varies no more than ±20%, the induction procedure may 
commence. 


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Eligible subjects will enter a state of insulin-induced hypoglycemia in a gradual 
and controlled fashion, through a monitored, standardized induction protocol.   
During the baseline phase, plasma glucose measurements will be taken every 15 
minutes. During the induction phase, plasma glucose measurements will be 
taken every 10 minutes while glucose is > 80.0 mg/dL (> 4.44 mmol/L) and at 
5-minute intervals once plasma glucose is ≤ 80.0 mg/dL (≤ 4.44 mmol/L). 
Once the initial plasma glucose measurement < 54.0 mg/dL (< 2.78 mmol/L) is 
achieved, the IV insulin infusion will be returned to the rate established at the 
end of the baseline euglycemia steady state period. After 5 minutes, the IV 
insulin infusion will be stopped, and a confirmatory plasma glucose reading 
will be taken to determine whether a hypoglycemic steady state has been 
reached, which is defined as a plasma glucose value ≥ 42 mg/dL 
(≥ 2.33 mmol/L) and < 54 mg/dL (< 2.78 mmol/L) with an 8-minute linearly 
extrapolated value for plasma glucose ≥ 42 mg/dL (≥ 2.33 mmol/L). 
If the subject is not in a hypoglycemic steady state, plasma glucose should be 
rechecked at up to two subsequent 5-minute intervals.  If the second or third 
confirmatory glucose is ≥ 42 mg/dL (≥ 2.33 mmol/L) and < 54 mg/dL 
(< 2.78 mmol/L) with an 8-minute linearly extrapolated value for plasma 
glucose ≥ 42 mg/dL (≥ 2.33 mmol/L), the subject will be deemed to be within a 
hypoglycemic steady state. 
After the third confirmatory reading, if plasma glucose is < 42 mg/dL 
(<2.33 mmol/L), the procedure will be terminated, study glucagon will NOT be 
administered, and the visit will be rescheduled after a minimum 3-day wait.   
If plasma glucose is > 54 mg/dL (>2.78 mmol/L) at any of the 3 confirmatory 
readings, IV insulin will be restarted at the rate used prior to the initial plasma 
glucose < 54 mg/dL being obtained. 
When a state of stabilized insulin-induced hypoglycemia is verified, subjects 
will be administered the randomly assigned dose of either G-Pen glucagon 1 mg 
SC or GlucaGen Hypokit 1 mg SC to the abdomen, around the umbilicus at a 
90º angle to the skin.  
Study drug will not be prepared ahead of time.  Rather, preparation of glucagon 
for administration will begin once the confirmatory plasma glucose reading is 
obtained, i.e., upon a “decision to dose.” 
After administration of study drug, plasma glucose will be monitored at 5-
minutes intervals for 90 minutes, and afterwards every 30 minutes through 
180 minutes posttreatment. 
The induction procedure may elicit symptoms of hypoglycemia. Therefore, 
subjects will complete a questionnaire regarding hypoglycemia symptoms at the 
start of the hypoglycemia induction period and periodically through180 minutes 
posttreatment.   
After 180 minutes posttreatment, subjects will resume insulin pump therapy, if 
applicable, and will be given a meal.  Subject may be discharged after 180 
minutes posttreatment if their plasma glucose is > 100 mg/dL (5.56 mmol/L) 
and if medically stable.  At the Investigator’s discretion, subjects’ prescribed 
insulin regimen can be restarted, or the meal can be given sooner, but not earlier 
than 90 minutes post-glucagon treatment, to prevent hyperglycemia or rebound 
hypoglycemia. 
After a wash-out period of 7 to 28 days, subjects will return to the CRC and the 
study procedures will be repeated with each subject crossed over to the other 
treatment.  After study-related procedures are performed on each of the 
treatment days, subjects will be discharged.  A Follow-Up Visit will be 


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conducted 2 to 7 days after administration of the final dose of study drug as a 
safety check.  
Tolerability will be assessed by comparing AE reports between the G-Pen and 
GlucaGen Hypokit treatment groups.  In addition, at the end of each treatment 
period the subjects will complete questionnaires to assess injection site 
discomfort, and the Investigator will use a modified Draize scale to evaluate the 
injection sites after each administration. 
Data management 
and statistical 
analysis: 
Data will be entered into an electronic Case Report Form (eCRF) by the study 
site personnel.  Data will be monitored at on-site visits by Xeris personnel or by 
a contract research organization (CRO) delegated by Xeris.  A stand-alone 
Statistical Analysis Plan (SAP) will be written to detail all protocol specified 
analyses. The SAP will take precedence over the protocol. The primary 
endpoint will be analyzed using an exact test procedure based on the 
conditional distribution for a maximum clinically acceptable non-inferior 
margin of ≤5%.  
Sample Size 
Determination: 
For the primary analysis, a failure is recorded if the subject’s plasma glucose 
fails to reach a concentration >70 mg/dL (>3.88 mmol/L) and fails to increase 
by at least 20.0 mg/dL (1.11 mmol/L) within 30 minutes of the decision to 
administer the dose of glucagon.  The determination of a constant clinically 
non-inferior margin for the cure rate difference is generally difficult in practice 
for a number of reasons.  To alleviate this concern, it has been recommended to 
use an Odds Ratio of success rates for estimation because the corresponding 
clinically non-inferior margin on the difference scale is getting small when the 
underlying success rate becomes large and close to 1.  In this study, it is 
expected that the subject’s recovery (success rate) will be high and approaching 
100%.  Since this is a cross-over design and each subject will serve as his/her 
control, power is improved.  
The sample size was derived for 80% power of detecting non-inferiority with 
respect to the Odds Ratio of subject recovery rates at an alpha of 0.025 under a 
cross-over design. Based on an underlying Odds Ratio of 1.0, and failure rates 
of 0.2 versus 0.25, 111 subjects are required for the study. With an anticipated 
10% drop-out rate, the total sample size for the study is 122 randomized 
subjects. 
 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............11 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................16 
5. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................19 
5.1. 
Primary Objective .......................................................................................................19 
5.2. 
Secondary Objective ...................................................................................................19 
5.3. 
Endpoints ....................................................................................................................19 
5.3.1. 
Primary Endpoint ........................................................................................................19 
5.3.2. 
Secondary Endpoints ..................................................................................................19 
6. 
BACKGROUND AND RATIONALE .......................................................................21 
6.1. 
Indication ....................................................................................................................21 
6.1.1. 
Background .................................................................................................................21 
6.1.2. 
Rationale .....................................................................................................................22 
6.2. 
Non-Clinical Pharmacology and Toxicology Experience with Glucagon .................22 
6.2.1. 
Nonclinical Pharmacology and Toxicology of Xeris G-Pen (glucagon 
injection) Investigational Non-Aqueous, Synthetic Glucagon ...................................23 
6.3. 
Description and Composition of Drug Product ..........................................................23 
6.4. 
Clinical Experience with Glucagon ............................................................................23 
7. 
STUDY DESIGN .......................................................................................................26 
7.1. 
Study Overview ..........................................................................................................26 
7.2. 
Hypoglycemia Induction Procedure and Justification ................................................28 
7.3. 
Interruption and Termination of Dosing .....................................................................33 
8. 
ELIGIBILITY CRITERIA AND STUDY ENROLLMENT .....................................34 
8.1. 
Inclusion Criteria ........................................................................................................34 
8.2. 
Exclusion Criteria .......................................................................................................34 
8.3. 
Randomization ............................................................................................................35 
8.4. 
Subject Numbers .........................................................................................................36 
9. 
STUDY TREATMENTS............................................................................................37 
9.1. 
Allocation to Treatment ..............................................................................................37 


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9.2. 
Blinding ......................................................................................................................37 
9.3. 
Drug Supplies .............................................................................................................37 
9.3.1. 
Drug Product Formulation and Packaging .................................................................37 
9.3.2. 
GlucaGen Hypokit for Injection .................................................................................38 
9.3.3. 
Preparation, Dispensing and Administration ..............................................................38 
9.3.4. 
Drug Storage and Drug Accountability ......................................................................38 
9.4. 
Concomitant Medications ...........................................................................................39 
10. 
STUDY PROCEDURES ............................................................................................40 
10.1. 
Visit 1 – Screening (Day -30 to -3) ............................................................................40 
10.2. 
Treatment and Follow-Up Phase ................................................................................41 
10.2.1. 
Visit 2 – Treatment 1 (Day -1 and Day 1) ..................................................................41 
10.2.1.1. 
Day -1 .........................................................................................................................41 
10.2.1.2. 
Day 1 ...........................................................................................................................42 
10.2.2. 
Visit 3 – Treatment 2 (Day 7-28) ...............................................................................46 
10.2.3. 
Visit 4 – Follow-Up (Day 9-35) .................................................................................46 
10.3. 
Subject Withdrawal ....................................................................................................46 
11. 
ASSESSMENTS.........................................................................................................50 
11.1. 
Blood Volume .............................................................................................................50 
11.2. 
Clinical Laboratory Tests ...........................................................................................51 
11.3. 
Electrocardiogram (12-lead ECG) ..............................................................................52 
11.4. 
Blood Pressure and Heart Rate ...................................................................................53 
12. 
SAFETY AND ADVERSE EVENT (AE) REPORTING..........................................54 
12.1. 
Definition of an Adverse Event ..................................................................................54 
12.2. 
Reporting Adverse Events ..........................................................................................54 
12.3. 
Reporting Period .........................................................................................................55 
12.4. 
Serious Adverse Events ..............................................................................................55 
12.5. 
Severity Assessment ...................................................................................................55 
12.6. 
Causality Assessment .................................................................................................56 
12.7. 
Withdrawal Due to Adverse Events ...........................................................................56 
12.8. 
Eliciting Adverse Event Information and Reporting ..................................................56 
12.9. 
Serious Adverse Event Reporting Requirements .......................................................56 
12.10. 
Non-Serious Adverse Event Reporting Requirements ...............................................57 
12.11. 
AE Reporting Requirements to Regulatory Authorities .............................................57 


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12.12. 
Pregnancy ...................................................................................................................57 
12.13. 
Subject Monitoring .....................................................................................................57 
13. 
DATA ANALYSIS AND STATISTICAL METHODS ............................................59 
13.1. 
General Approach .......................................................................................................59 
13.2. 
Sample Size Calculation .............................................................................................59 
13.3. 
Primary Endpoint ........................................................................................................59 
13.4. 
Secondary Endpoints ..................................................................................................60 
13.4.1. 
Pharmacodynamic Analyses .......................................................................................60 
13.4.2. 
Hypoglycemia Symptoms ...........................................................................................61 
13.4.3. 
Glucagon Preparation Time ........................................................................................61 
13.5. 
Safety Analysis ...........................................................................................................61 
13.5.1. 
Adverse Events ...........................................................................................................61 
13.5.2. 
Laboratory Safety Assessments ..................................................................................62 
13.5.3. 
Physical examination ..................................................................................................62 
13.5.4. 
Vital signs and body weight .......................................................................................62 
13.5.5. 
ECG ............................................................................................................................62 
13.5.6. 
Local Tolerability .......................................................................................................63 
13.6. 
Subgroup Analysis ......................................................................................................63 
13.7. 
Demographics and Baseline Characteristics ...............................................................63 
14. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................64 
15. 
DATA HANDLING, RECORD KEEPING, MONITORING AND AUDITS ..........65 
15.1. 
Case Report Forms/Electronic Data Record ...............................................................65 
15.2. 
Record Retention ........................................................................................................65 
15.3. 
Monitoring ..................................................................................................................66 
15.4. 
Audits and Inspections ................................................................................................66 
16. 
ETHICAL CONSIDERATIONS................................................................................67 
16.1. 
Conduct .......................................................................................................................67 
16.2. 
Institutional Review Board and Ethics Committee ....................................................67 
16.3. 
Subject Information and Consent ...............................................................................67 
16.4. 
Subject Recruitment ....................................................................................................68 
16.5. 
Reporting of Safety Issues and Serious Breaches of the Protocol ..............................68 
17. 
PROCEDURES FOR MODIFYING THE PROTOCOL OR 
TERMINATING THE STUDY .................................................................................69 


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17.1. 
Protocol Modifications and Deviations ......................................................................69 
17.2. 
Study Termination ......................................................................................................69 
18. 
REFERENCES ...........................................................................................................70 
APPENDICES ...............................................................................................................................72 
APPENDIX 1. HYPOGLYCEMIA SYMPTOM QUESTIONNAIRE ......................................72 
APPENDIX 2. INJECTION SITE DISCOMFORT ASSESSMENT .........................................73 
APPENDIX 3. DRAIZE SCALE ................................................................................................75 
APPENDIX 4. GOLD SCALE ...................................................................................................76 
APPENDIX 5. SUBJECT STUDY DRUG ASSIGNMENT QUESTIONNAIRE.....................77 
 


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LIST OF TABLES 
Table 1 
Emergency Contact Information ...................................................................................4 
Table 2 
Abbreviations and Specialist Terms ...........................................................................16 
Table 3 
Randomized Treatment Sequence ..............................................................................28 
Table 4 
Insulin Dose Adjustments ...........................................................................................32 
Table 5 
Schedule of Assessments ............................................................................................48 
Table 6 
Frequency and Volume of Blood Collections ............................................................50 
Table 7 
Clinical and Safety Related Laboratory Tests ............................................................51 
Table 8 
Conversion Table for Plasma Glucose Values ...........................................................52 
Table 9 
AE Severity Assessment .............................................................................................55 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2 
Abbreviations and Specialist Terms 
Abbreviation  
Definition 
AE 
adverse event 
ADA 
American Diabetes Association 
AI 
Auto-injector 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration versus time curve 
AUC(0-90) 
area under the concentration versus time curve from time 0 to 90 minutes 
AUC(0-180) 
area under the concentration versus time curve from time 0 to 180 minutes 
AUC(0-240) 
area under the concentration versus time curve from time 0 to 240 minutes 
BE 
bioequivalence 
β-hCG 
beta-human chorionic gonadotrophin 
BMI 
body mass index 
BP 
blood pressure 
CDC 
United States Center for Disease Control 
CFR 
Code of Federal Regulations 
Cmax 
maximum observed concentration 
CRF 
Case Report Form 
CRC 
clinical research center 
CRO 
contract research organization 
DBP 
diastolic blood pressure 
DMSO 
dimethyl sulfoxide 
ECG 
electrocardiogram 
EC50 
concentration at which a 50% effect is observed 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EMA 
European Medicines Agency 
EU 
European Union 
FDA 
United States Food and Drug Administration 
GCP 
Good Clinical Practice 


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Abbreviation  
Definition 
GEK 
glucagon emergency kits 
GLP-1 
glucagon-like peptide-1 
GLP-2 
glucagon-like peptide-2 
GMP 
Good Manufacturing Practice 
HbA1c 
glycated hemoglobin 
HBsAg(+) 
hepatitis B surface antigen (positive) 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HCVab 
hepatitis C virus antibody 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
human immunodeficiency virus 
HIVab 
human immunodeficiency virus antibody 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ID 
identification 
IEC 
Independent Ethics Committee 
IFU 
instructions for use 
IM 
intramuscular 
IND 
Investigational New Drug Application 
IP 
investigational product 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IUD 
intra-uterine device 
IV 
Intravenous(ly) 
IWRS 
Interactive Web-based Randomization System 
LSLV 
last subject last visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEN 2 
multiple endocrine neoplasia type 2 
min 
minute 
NDA 
New Drug Application 
NYHA 
New York Heart Association 
OTC 
over the counter 


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Abbreviation  
Definition 
PD 
pharmacodynamic(s) 
PFS 
prefilled syringe 
PK 
pharmacokinetic(s) 
PP 
per-protocol 
PT 
preferred term 
QA 
Quality Assurance 
RBC 
red blood cells 
rDNA 
recombinant deoxyribonucleic acid 
RLD 
reference listed drug 
RTU 
ready-to-use 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
systolic blood pressure 
SC 
Subcutaneous(ly) 
SmPC 
Summary of Product Characteristics 
SOC 
system organ class 
SOP 
standard operating procedures 
TEAE 
treatment-emergent adverse event 
THC 
tetrahydrocannabinol 
tmax 
time to maximum observed concentration 
T1D 
type 1 diabetes mellitus/type 1 diabetic 
T2D 
type 2 diabetes mellitus/type 2 diabetic 
U.K. 
United Kingdom 
US 
United States  
USP 
United States pharmacopeia 
VAS 
visual analog scale 
WBC 
white blood cells 
Xeris 
Xeris Pharmaceuticals, Inc. 
YSI 
Yellow Springs Instruments 
 


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5. 
STUDY OBJECTIVES AND ENDPOINTS 
5.1. 
Primary Objective 
The primary objective of this study is to demonstrate that G-Pen 1 mg (test) is not inferior to GlucaGen 
Hypokit 1 mg (reference), in Type 1 diabetic (T1D) subjects in a state of insulin-induced hypoglycemia.  
5.2. 
Secondary Objective 
The secondary objective of this study is to evaluate the safety and tolerability of G-Pen 1 mg versus 
GlucaGen Hypokit 1 mg in the study population. 
5.3. 
Endpoints 
5.3.1. 
Primary Endpoint 
For the primary endpoint, groups will be compared for rates of achieving a positive plasma 
glucose response, defined as either a plasma glucose concentration > 70 mg/dL (> 3.88 mmol/L) 
or an increase in plasma glucose concentration > 20 mg/dL (> 1.11 mmol/L) within 30 minutes 
of study drug injection.  
5.3.2. 
Secondary Endpoints 
For the secondary endpoints, treatment groups will be compared based on each of the following: 
1. Rate of achieving a plasma glucose concentration > 70 mg/dL (> 3.88 mmol/L) within 30 minutes 
from injection of study drug. 
2. Rate of achieving an increase in plasma glucose concentration > 20 mg/dL (>1.11 mmol/L) 
within 30 minutes from injection of study drug. 
3. Rates of positive symptomatic response, defined as relief of neuroglycopenic symptoms within 30 
minutes from a decision to dose. 
4. Rates of positive treatment response, defined as exhibiting either a positive plasma glucose 
response or a positive symptomatic response. 
5. Time to a positive plasma glucose response from injection of study drug. 
6. Time to administer study drug from a decision to dose. 
7. Pharmacodynamic (PD) characteristics of mean plasma glucose concentration (0 to 90 minutes 
post-dose), maximum observed concentration (Cmax), time to maximum observed concentration 
(tmax), area under the concentration versus time curve from time 0 to 90 minutes (AUC(0-90)), and 
area under the concentration versus time curve from time 0 to 180 minutes (AUC(0-180)). 
8. Time to (a) initial relief and (b) complete resolution of autonomic and neuroglycopenic symptoms 
of hypoglycemia from a decision to dose.  
9. Time to resolution of the overall feeling of hypoglycemia from a decision to dose. 
10. Safety endpoints, including: adverse event (AE)/serious adverse event (SAE) rates, and changes 
in vital signs, laboratory variables, and physical exam/electrocardiogram (ECG) findings. 


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11. Tolerability endpoints, including: Draize scale scores for injection site erythema and edema as 
assessed by the investigator, and injection site discomfort and duration as assessed by subject 
questionnaire responses. 


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6. 
BACKGROUND AND RATIONALE 
6.1. 
Indication 
The proposed indication is for the treatment of severe hypoglycemia. 
6.1.1. 
Background 
The investigational product is glucagon.  Glucagon is a 29 amino-acid polypeptide with a 
molecular weight of 3485 Daltons.  The peptide is secreted by the alpha cells of the islets of 
Langerhan’s in the pancreas, and functions as an anti-hypoglycemic agent and a gastrointestinal 
motility inhibitor.  A single glucagon gene encodes a larger proglucagon biosynthetic precursor 
in mammals.  Tissue-specific processing of proglucagon gives rise to glucagon, and to glicentin, 
oxyntomodulin, glucagon-like peptide-1 (GLP-1), and glucagon-like peptide-2 (GLP-2).  As a 
natural (non-steroid) hormone synthesized in the pancreatic islet cells, it binds to glucagon 
receptors in the liver, causing liver cells to convert glycogen polymers into glucose molecules.  
The cloned glucagon receptor encodes a 485 amino acid protein with a predicted molecular 
weight of 54,962 Daltons [Jelinek], which signals through both adenylate cyclase and 
intracellular calcium with a concentration at which a 50% effect is observed (EC50) of ~ 1 nM 
[Wakelam].   
Historically glucagon is being used as rescue therapy for severe hypoglycemia.  One of the main 
complications of diabetes treatment with insulin is the emergence of hypoglycemia, and the 
absolute or relative excess of therapeutic insulin is the determinant of risk.  Hypoglycemia in 
diabetes is defined by the American Diabetes Association (ADA) as “all episodes of abnormally 
low plasma glucose concentration that expose the individual to potential harm” [ADA], and 
presents as diaphoresis, pallor, nausea, palpitations, tremors, and anxiety.  If hypoglycemia 
becomes severe, symptoms may then include confusion, abnormal behavior, blurred vision, 
psychomotor abnormalities, loss of consciousness, seizures, and coma [DCCT/EDIC) Study 
Research Group].  Recent reports have found that from 6% to 10% of deaths of patients with 
type 1 diabetes mellitus (T1D) are attributable to hypoglycemia [Skrivarhaug, U.K. 
Hypoglycaemia Study Group].  The ADA Workgroup recommends that patients with drug-
treated diabetes (insulin secretagogue or insulin) become concerned about developing 
hypoglycemia at a plasma glucose concentration of ≤70 mg/dL (3.9 mmol/L) [ADA]. 
Therapy with insulin causes hypoglycemia during the course of established T1D, and 
progressively more frequently over time in type 2 diabetes mellitus (T2D).  The U.K. 
Hypoglycemia Study Group reported an incidence of 110 severe hypoglycemic episodes per 
100 patient-years in patients with T1D treated with insulin for < 5 years, and an incidence of 320 
episodes per 100 patient-years in those with T1D treated for > 15 years [U.K. Hypoglycaemia 
Study Group].  Type 1 diabetics suffer an average of two symptomatic hypoglycemic events per 
week, and a severe, temporarily disabling event approximately once a year [McLeod].  Insulin-
using T2D typically have several hypoglycemic episodes in a given year, one to two of these 
being severe episodes.  There are currently approximately 1.4 million T1D patients and 
3.8 million insulin-using T2D patients in the United States (US), as reported by the US Center 
for Disease Control [CDC].  On average, the total insulin-using patient population experiences 
about 3 million severe hypoglycemic events per year.   


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The ADA recommends that all insulin- and sulfonylurea-using diabetics carry glucagon 
emergency kits (GEKs) and use glucagon as first line therapy in the event of a severe 
hypoglycemic event [ADA].  However, a recent survey indicates that only approximately 30% of 
the insulin-using diabetic patients carry GEKs [Close Concerns].  The current standard of care 
for severe hypoglycemia is an injection of glucagon.  Administration of glucagon with current 
products (i.e. Lilly Glucagon for Injection, and Novo GlucaGen®) is a 9-step process including 
assembly of the kit, aqueous reconstitution of the powdered glucagon, and manual administration 
of the dose [Glucagon, Novo GlucaGen].   
6.1.2. 
Rationale 
Patients with diabetes frequently develop defective regulatory responses to hypoglycemia 
associated with reduced or absent glucagon responses.  This is an important clinical problem, as 
current diabetes management with intensive insulin regimens usually increases the risk and 
frequency of severe hypoglycemic events that may require therapeutic intervention. 
In response to the unmet medical need for a simple and ready-to-use (RTU) glucagon for 
episodes of severe hypoglycemia, Xeris Pharmaceuticals, Inc. (Xeris) is developing a glucagon 
rescue pen referred to as “G-Pen”, which utilizes Xeris’ biocompatible, non-aqueous 
peptide/protein reformulation technology.  This technology has enabled Xeris to create a 
concentrated, low volume, stable glucagon formulation, pre-mixed and pre-loaded into a 
prefilled syringe and auto-injector pen.  This creates a product with a number of advantageous 
features, which include the following:  a RTU treatment with no reconstitution required; precise 
and rapid dosing; a hidden needle; enhanced portability and availability due to room-temperature 
stability, providing a superior alternative to currently marketed treatments. 
6.2. 
Non-Clinical Pharmacology and Toxicology Experience with 
Glucagon 
Native glucagon for injection (bovine, porcine origin) was approved for use in humans in 1960 
[FDA CDER #1].  The 29-amino acid sequence of pancreatic glucagon is identical in humans, 
cows, pigs, dogs, and rats, and is also conserved in biosynthetic versions of glucagon [Eistrup].  
Glucagon for injection (recombinant deoxyribonucleic acid [rDNA] origin) was approved in 
1998 and is currently the drug substance identified in two approved New Drug Applications 
(NDAs) ([NDA 20-928] and [NDA 20-918]).  Complete NDA-required pharmacology and 
toxicology data have been reviewed and accepted by the United States Food and Drug 
Administration (FDA), as described in Lilly Glucagon (glucagon for injection) and Novo 
GlucaGen (glucagon for injection) labeling [Glucagon, Novo GlucaGen]. Novo GlucaGen 
Hypokit 1 mg is sold in the U.K. and European Union (EU) under marketing authorization 
PL 04668/0027, and pharmacology and toxicology information have been submitted to and 
accepted by European Medicines Agency (EMA) [Novo Hypokit]. 
As Xeris G-Pen drug product is produced by solid-phase peptide synthesis (SPPS), which also 
conserves the glucagon peptide sequence, the rDNA glucagon information is pertinent to the 
development of G-Pen for the treatment of severe hypoglycemia.  A summary of this information 
can be found in current G-Pen Investigator’s Brochure, which is provided to each Investigator 
participating in this study. 


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6.2.1. 
Nonclinical Pharmacology and Toxicology of Xeris G-Pen (glucagon injection) 
Investigational Non-Aqueous, Synthetic Glucagon 
Information on the nonclinical pharmacology, pharmacokinetics (PK), and toxicology of G-Pen 
(glucagon injection) is provided in the current G-Pen Investigator’s Brochure.  
6.3. 
Description and Composition of Drug Product 
Synthetic glucagon is the drug substance in G-Pen.  Glucagon current Good Manufacturing 
Practice (GMP) grade drug product is manufactured, packaged and released by Bachem AG 
(Bubendorf, Switzerland), conforms with United States pharmacopeia (USP) standards and has a 
Type II Drug Master File filed with the FDA.  G-Pen is a sterile subcutaneous (SC) injectable 
non-aqueous formulation of glucagon for treatment of severe hypoglycemia.  G-Pen delivers 
1 mg of glucagon, with trehalose and dimethyl sulfoxide (DMSO) as excipients.  The drug 
product is stored at controlled room temperature (20 to 25°C [68° to 77°F]) prior to use.   
G-Pen is supplied in a 1 mL long Crystal Zenith® pre-filled cyclic olefin polymer syringe with 
Flurotec® coated plunger.  The pre-filled syringe is loaded into a Molly® single-use, disposable 
auto-injector from SHL Group, and is packaged in a sealed poly/foil pouch. 
6.4. 
Clinical Experience with Glucagon 
Glucagon has a long history of medical use in the US and EU and is currently marketed by Eli 
Lilly & Co. in the US and Canada as Glucagon (Glucagon Injection [rDNA origin]), and by 
Novo Nordisk in the US, Canada, and EU as GlucaGen® HypoKit®, both reference listed drugs 
(RLD) at a dose of 1 mg per injection for treatment of severe hypoglycemia.  Glucagon has a 
rapid onset of action and an extremely short half-life, and its safety, efficacy, and clinical 
pharmacology have been well established since it was first approved for use in humans in 1960 
[FDA CDER #2]. 
Xeris has completed eight clinical studies using G-Pen, which include the following:  A Phase 1 
bioequivalence study of G-Pen auto-injector (Configuration A) and G-Pen manual syringe 
(Configuration B), 4 Phase 2 exploratory studies, a Phase 3 study in pediatric subjects with T1D, 
and 2 Phase 3 studies in adults with T1D.   
Phase 1 Study XSGP-101 was a randomized, open-label, two-way crossover bioequivalence 
(BE) and safety study in healthy subjects.  The study involved two treatment visits scheduled 
3 to 7 days apart.  Subjects were randomly assigned to a treatment sequence to receive G-Pen 
glucagon 1 mg SC via Configuration A (auto-injector [AI]) or Configuration B (prefilled syringe 
[PFS]).  Both configurations were administered to the abdomen around the umbilicus.  Each 
treatment visit was preceded by an overnight stay in the clinical study center.  PK analyses 
performed on plasma glucagon area under the concentration versus time curve from time 0 to 
240 minutes (AUC(0-240)) and maximum observed concentration (Cmax) in healthy subjects 
administered Xeris glucagon 1 mg SC in the abdomen via Configuration A and Configuration B 
satisfied the bioequivalence (BE) test criterion and established PK bioequivalence.  
Pharmacodynamic (PD) analyses performed on plasma glucose AUC(0-240), Cmax, and time to 
maximum observed concentration (tmax) in healthy subjects administered Xeris glucagon 1 mg 
SC in the abdomen via Configuration A and Configuration B satisfied the BE test criterion and 
established PD bioequivalence.  Overall, Configuration A and Configuration B administrations 


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were generally safe and well tolerated; safety findings were generally similar between the two 
administration groups. 
Phase 2 safety/efficacy Study XSGP-201 demonstrated that a 1 mg SC injection of Glucagon 
RTU was therapeutically equivalent to Lilly Glucagon for Injection 1 mg, when administered to 
healthy subjects.  There were no serious adverse events (SAEs) and adverse events (AEs) were 
generally mild in nature and similar to the known effects of rescue doses of glucagon.  The most 
commonly reported AE was injection site pain, the incidence of which was significantly higher 
in the Xeris 0.5 mg and Xeris 1 mg groups compared with the Lilly Glucagon 1 mg group.  
However, edema and erythema at the injection site occurred infrequently and did not vary 
significantly with treatment.   
Phase 2 Study XSGP-202 was an open-label crossover study in adult T1D subjects that explored 
the use of Glucagon RTU at doses of 0.5 and 1 mg in the treatment of insulin-induced 
hypoglycemia.  All subjects had a positive response with complete resolution of symptoms by 30 
minutes after injection for both treatments.  AEs were generally mild and corresponded to known 
effects of rescue doses of glucagon.  A single episode of vasovagal syncope was observed 
approximately 2 ¼ hours after treatment, which the investigator deemed to meet the definition of 
an SAE as an important medical event.  The attending investigator felt this event was attributable 
at least in part to the study procedures, which included a post-study meal that was consumed 
about 90 minutes after treatment.  There were no other clinically significant safety findings I this 
study. 
Phase 2 Study XSGO-201evaluated micro-doses of Glucagon RTU administered with an 
OmniPod® infusion pump and equivalent doses of reconstituted GlucaGen in T1D subjects.  
Micro-doses of Glucagon RTU (0.3 to 2.0 μg/kg) demonstrated comparable PK and efficacy to 
GlucaGen as discrete SC infusions with an OmniPod pump.  All treatments were well tolerated, 
no SAEs were observed with either product and AEs were generally of mild severity.  Well-
defined erythema and edema were the two most common adverse events and they occurred more 
frequently with Glucagon RTU.  Most observations of edema and erythema were mild and 
transient. 
Phase 2 Study XSMP-202 compared the safety and efficacy of oral glucose tablets to mini-doses 
(0.15 and 0.3 mg) of Xeris Glucagon RTU SC administered to T1D subjects as 
treatment/prevention of mild to moderate hypoglycemia.  A total of 20 subjects between the ages 
of 18 and 64 years were randomized in this 3-week, 2-period cross-over study with a 3-week 
follow-up period during which subjects had free choice of using either Glucagon RTU or glucose 
tablets to treat/prevent hypoglycemia.  Glucagon RTU successfully treated mild-to-moderate 
hypoglycemia and may be a useful alternative to treatment with oral carbohydrate.  All 
treatments were well tolerated, no SAEs were observed and AEs were generally of mild severity 
and consisted primarily of pain or tingling at the injection site.  Observations of edema and 
erythema were generally mild and transient.  Nausea occurred only at the higher dose of 0.3 mg, in 
one-third of the subjects. 
Phase 3 Study XSGP-301 was a non-inferiority, randomized, single-blind, 2-way crossover 
comparative efficacy and safety trial in adult subjects with T1D.  The study demonstrated that G-
Pen 1 mg SC was comparable to Lilly Glucagon via an intent-to-treat analysis.  The study 
demonstrated that administration of G-Pen and Lilly Glucagon either increased plasma glucose 
≥ 20 mg/dL at 30 minutes post-injection or resulted in a plasma glucose > 70 mg/dL within 30 


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minutes post-injection.  Symptomatic relief of hypoglycemia after glucagon injections was 
similar for G—Pen compared with Lilly Glucagon, based on the trends observed across average 
hypoglycemia symptom questionnaire scores.  Symptom scores did not differ significantly 
between treatment groups for average autonomic, neuroglycopenic, or overall symptoms.  As 
expected for both Glucagon RTU and Lilly glucagon, as plasma glucose levels increased, mean 
hypoglycemia symptom scores decreased with peak symptom relief occurring approximately 
30 minutes post injection.  G-Pen injections to the abdomen around the umbilicus demonstrated 
faster absorption when compared to injections to the outer arm and outer leg.  Both G-Pen and 
Lilly Glucagon were generally safe and well tolerated and safety findings were generally similar 
between the two treatment groups.  The most common treatment-emergent adverse event 
(TEAE) was nausea, which was reported more frequently for subjects after G-Pen treatment 
compared with Lilly Glucagon.  
Phase 3 Study XSGP-303 was a non-inferiority, randomized, single-blind, 2-way crossover 
comparative efficacy and safety study in adult subjects with T1D.  The study demonstrated that 
G-Pen 1 mg SC was non-inferior to Lilly Glucagon via an intent-to-treat analysis.  Overall, this 
study further supports the conclusion that G-Pen 1 mg SC reverses severe hypoglycemia in a 
reliable manner that is comparable to Lilly Glucagon 1 mg; and confirmed the results for 
Symptomatic relief of hypoglycemia after glucagon injection reported in Study XSGP-301.  Both 
G-Pen and Lilly Glucagon treatments were generally safe and well tolerated and safety findings 
were generally similar between the two treatment groups.  There were no SAEs or severe AEs 
reported in either treatment group.  The most common TEAE was nausea, which was reported 
more frequently in subjects administered G-Pen compared to Lilly Glucagon. 
Phase 3 Study XSGP-302 was an efficacy and safety study in pediatric subjects with T1D that 
evaluated PK and PD.  The study included subjects age 2 to < 18 years administered G-Pen 
0.5 mg, with subjects age 12 to < 18 years also receiving G-Pen 1 mg after a wash-out period.  
Statistically significant increases from baseline in mean plasma glucose were observed in each 
age category (p<0.001 for all groups) at 30 minutes after administration of G-Pen. Based on the 
results of the XSGP-201 study, the transition to the adult dose of G-Pen (0.5 mg to 1 mg) is 
recommended at 40 to 45 kg, corresponding to the average weight at approximately 12 years of 
age.  Age categories were generally similar with respect to  in mean plasma glucose area under 
the concentration vs time curve from time 0 to 90 minutes (AUC(0-90)), Cmax, and tmax.  Overall, 
G-Pen was generally safe and well tolerated in each of the 3 pediatric age groups.  There were no 
AEs leading to discontinuation and no SAEs were reported in this study.  Nausea and vomiting 
were the most commonly reported treatment-emergent adverse events (TEAEs) in this study and 
were expected for subjects receiving glucagon.  While the incidences of injection site discomfort, 
erythema, and edema were relatively high (at 10 and 30 minutes post G-Pen administration), pain 
and modified Draize Scale scores were at the low end of the assessment scales. 
 


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7. 
STUDY DESIGN 
7.1. 
Study Overview 
This is a multi-center, randomized, active-controlled, single-blind, two-way crossover efficacy 
and safety in-patient study in subjects with T1D.  The study involves two clinical research center 
(CRC) visits scheduled 7 to 28 days apart.  Subjects will be randomly assigned to a treatment 
sequence for which they will receive G-Pen glucagon 1 mg during one period and GlucaGen 
Hypokit 1 mg during the other.  Each daytime visit will be preceded by an overnight stay in the 
CRC.  Subjects will complete the screening procedures up to 30 days before randomization to 
determine their eligibility before enrollment into the treatment phase.  Subjects not meeting 
eligibility criteria may be rescreened after a 30-day wait. 
During the evening prior to each in-patient study visit, subjects will be admitted for an overnight 
stay between 6 and 8 pm.  At the Investigator’s discretion, plasma glucose may be assessed 
periodically during the overnight stay via CGM, Yellow Springs Instruments (YSI) model 2300 
or 2900 or an FDA/CE/Health Canada cleared blood glucose meter (hereafter, simply “glucose 
meter”).  Subjects will be asked to refrain from consuming alcohol during the day prior to the 
overnight stay.  Upon arrival in the evening, plasma glucose will be measured by a blood glucose 
meter and confirmed to be ≤ 350 mg/dL (≤ 19.44 mmol/L), or the visit will be rescheduled. 
At the CRC, subjects will receive a standardized dinner meal as per the usual practices of the 
clinical site.  Subjects should complete dinner before 9 pm.  Subjects should follow their usual, 
prescribed insulin regimen at dinner time under the supervision of a study nurse, and will 
continue their usual, prescribed insulin regimen until midnight per PI discretion. 
Subjects will be instructed to fast starting at midnight, at which point an intravenous (IV) 
catheter will be placed, and maintenance fluids will be administered.  Overnight, blood glucose 
will be confirmed by YSI. BGM or CGM as necessary; these data will be maintained in the 
source documents only.  At a minimum, blood glucose will be assessed by BGM/YSI (not CGM) 
at midnight, 3 am, and 6 am, with ±30 minutes for these measurements, which will be entered 
into the EDC.  
After midnight, the Investigator should optimize plasma glucose within a target range of 80 to 
150 mg/dL (4.44 to 8.33 mmol/L) through the administration of IV/SC insulin and/or IV/oral 
glucose.  If operational considerations at a site preclude IV administration of insulin overnight, 
no catheter will be placed, and oral glucose tablets and the subject’s own insulin infusion pump 
will be used to optimize blood glucose within a target range of 80 to 150 mg/dL (4.44 to 8.33 
mmol/L).  This range is considered a target only, and values outside of this range will not be 
considered protocol deviations.   
In the morning of the inpatient study visit, each subject’s plasma glucose will be measured and 
verified to be within the range of 70 to 270 mg/dL (3.89 to 15.0 mmol/L) to confirm their 
eligibility for continuation to the insulin induction procedure.  If this criterion is not met, the visit 
will be rescheduled after a minimum 3 day wait. 
Subjects will continue to fast during the morning of the procedure and another IV catheter for 
blood sampling will be inserted in their contralateral arm. Ideally, the sampling IV catheter 
should be placed in a vein within the antecubital fossa.  The hand used for blood sampling will 
be kept warm by use of a heated-hand box to increase blood flow to achieve “arterialized” 


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samples.  The subject will be kept supine and the abdomen and torso will be covered under a 
blanket to maintain warmth.  
The baseline euglycemic steady state period will begin when the plasma glucose is confirmed to 
be within the range of 70 to 270 mg/dL (3.89 to 15.0 mmol/L).  IV insulin will be administered 
to maintain the plasma glucose concentration within the range of 75 to 115 mg/dL (4.17 to 
6.83 mmol/L) for 30 minutes. If the plasma glucose has been maintained within the range of 
75 to 115 mg/dL (4.17 to 6.83 mmol/L) for at least 30 minutes and the insulin infusion rate 
varies no more than ±20%, the induction procedure may commence.  
During the induction procedure, the subject will enter a state of hypoglycemia through the 
administration of regular insulin diluted in normal saline (see Section 7.2), within a controlled 
and monitored setting.  Use of the insulin dose adjustment algorithm will be facilitated by real 
time data capture, allowing Sponsor personnel to monitor the induction procedures virtually in 
real time. 
The combination of one or more IV bolus doses of insulin along with continuous IV infusion of 
insulin will be used to gradually decrease a subject’s plasma glucose to a target < 54.0 mg/dL 
(< 3 mmol/L).  As per Section 11.2, all plasma glucose levels will be based on the average of two 
readings taken via YSI glucose analyzer at each time point.  Plasma glucose measurements will 
be taken every 10±5 minutes while glucose is > 65.0 mg/dL (> 3.61 mmol/L) and every 
5±2 minutes once plasma glucose is ≤ 65.0 mg/dL (≤ 3.61 mmol/L). 
Once the initial plasma glucose measurement < 54.0 mg/dL (< 3 mmol/L) is achieved, the IV 
insulin infusion will be returned to the rate established at the end of the baseline euglycemia 
steady state period. After 5 minutes, the IV insulin infusion will be stopped, and up to three 
confirmatory plasma glucose readings will be taken at subsequent 5-minute intervals to 
determine whether a hypoglycemic steady state has been reached, which is defined as a 
confirmatory plasma glucose value ≥ 42 mg/dL (≥ 2.33 mmol/L) and < 54 mg/dL (< 3 mmol/L) 
with an 8-minute linearly extrapolated value for plasma glucose ≥ 42 mg/dL (≥ 2.33 mmol/L). 
If a hypoglycemic steady state is not documented after any of three confirmatory readings, and 
plasma glucose is < 42 mg/dL (<2.33 mmol/L) after the third confirmatory reading, the 
procedure will be terminated, study glucagon will NOT be administered, and the visit will be 
rescheduled after a minimum 3-day wait.  At the Investigator’s discretion, the subject should be 
treated with IV glucose or oral carbohydrates, it should be verified that the subject achieved a 
euglycemic state and is medically stable prior to discharge. 
If plasma glucose is > 54 mg/dL (>3 mmol/L) at any of the 3 confirmatory readings, IV insulin 
will be restarted at the 120% of the rate used prior to the initial plasma glucose < 54 mg/dL being 
obtained. 
If a hypoglycemic state is verified by either the first, second, or third confirmatory reading, the 
subject will be eligible to receive either G-Pen or GlucaGen Hypokit in one of the randomized 
treatment sequences shown in Table 3.  The time of the Investigator’s “decision to dose” will be 
documented. 


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Table 3 
Randomized Treatment Sequence 
Treatment Sequence 
Dose 1 
Dose 2 
1 
G-Pen 1 mg 
Novo GlucaGen Hypokit 1 mg 
2 
Novo GlucaGen Hypokit 1 mg 
G-Pen 1 mg 
Plasma glucose levels will be monitored for 180 minutes post-dosing.  It is believed that plasma 
glucose < 54 mg/dL (< 3 mmol/L) will be low enough to generate neuroglycopenic and 
autonomic symptoms in most subjects, yet high enough (i.e., > 42 mg/dL [> 2.33 mmol/L)]) to 
avoid the impairment of consciousness.  Consequently, subjects will complete a questionnaire 
about symptoms of hypoglycemia [Nermoen] during the hypoglycemia induction phase, and for 
180 minutes after treatment with glucagon. 
After a wash-out period of 7 to 28 days, subjects will return to the CRC and the procedure will 
be repeated with each subject crossed over to the other treatment.  
After study-related procedures are performed on each of the treatment days (see Table 5), 
subjects will be discharged after consuming a meal as per each site’s usual practice.  A follow-up 
visit as a safety check will be conducted 2 to 7 days after administration of the final dose of 
study drug.   
The last subject last visit (LSLV) for each site is defined as the date the last subject completes 
the Follow-Up Visit (Visit 4), with the understanding that final review by the Investigator may 
be delayed a few days to allow for receipt of final lab results.  The end of the trial is the date of 
the LSLV for the last site. 
7.2. 
Hypoglycemia Induction Procedure and Justification 
The most commonly used hypoglycemia insulin induction method cited in the literature 
[Nermoen] involves constant insulin infusion rates many-fold above normal basal infusion rates.  
As hepatic glucose production is determined by the glucagon to insulin ratio, this procedure may 
not create realistic circumstances for evaluating the effectiveness of glucagon in raising blood 
glucose.  A predecessor study (XSGP-301), therefore, utilized a comparatively lower rate of 
insulin infusion at 1 to 2 times the normal basal rate, combined with push of an IV bolus dose of 
insulin derived from the subject’s own self-reported glucose correction factor.  About 30% of the 
procedures performed in Study XSGP-301 resulted in plasma glucose < 40 mg/dL 
(< 2.22 mmol/L).  To get more precision in achieving a steady state of plasma glucose below 
50 mg/dL (2.78 mmol/L), individual procedure data from the Study XSGP-301 were fitted to a 
model of insulin action allowing identification of opportunities for algorithm enhancements.  The 
algorithm was modified accordingly and tested in the model of the procedures representing a 
broad spectrum of subjects, including the two extremes of insulin sensitivity that were associated 
with low plasma glucose in Study XSGP-303. The algorithm was further refined for use in the 
current study based on experiences in the XSGP-303 trial.  
Hypoglycemia Induction Procedure 
The evening before treatments subjects will be admitted to the CRC and follow the procedures 
described in Table 5.  


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Baseline Euglycemic Steady State 
Prior to starting the hypoglycemia induction procedure, the subject must have stable plasma 
glucose for at least 30 minutes at 95±20 mg/dL (75 to 115 mg/dL [4.17 to 6.38 mmol/L]) and a 
stable IV insulin infusion rate varying no more than ±20% during which plasma glucose must be 
measured at least every 15±2 minutes. 
Induction Start 
For the induction, the starting plasma glucose level will be determined as the average of the last 
three YSI measurements taken during the baseline steady state period (i.e., start of baseline, next 
after 15 minutes, end of baseline after 30-minute baseline confirmation period).  The following 
procedures will then be performed: 
1. Subjects will continue the IV insulin infusion at the final rate of the baseline euglycemic 
steady state.  
2. Subjects then will be given an initial IV bolus push dose of regular insulin diluted in 
saline: 
a. The dose will be calculated as 75% of the dose estimated to reduce plasma glucose 
from the subject’s starting plasma glucose level to 54 mg/dL (3 mmol/L) based on the 
subject’s self-reported glucose correction factor.  This dose will be referred to as “1 
bolus (i.e., full bolus dose)” subsequently.  The Investigator may use discretion to 
decrease the amount of the calculated bolus dose based upon the subject’s insulin 
sensitivity factor.  However, the Investigator is not allowed to increase the amount of 
the bolus dose. 
b. Plasma glucose will be measured every 5 to 10 minutes, depending on the current 
plasma glucose value (see Table 4). 
c. The first insulin adjustment will be made no earlier than 20 minutes after the initial 
bolus but will otherwise follow the directions for insulin adjustments shown in 
Table 4. 
The Investigator may override the insulin dosing algorithm at their discretion. Note: investigator 
does not have discretion to give bolus doses once plasma glucose is 65 mg/dL (3.3 mmol/L) or 
less (see numbers 3.b.i and 4.b.i below). 
When plasma glucose is > 80 mg/dL (> 4.44 mmol/L), insulin adjustments should not be made 
more frequently than every 10 minutes. When plasma glucose is ≤ 80 mg/dL (≤ 4.44 mmol/L), 
the minimum time between adjustments to decrease, terminate or re-start insulin is either 10 or 5 
minutes, as indicated in Table 4. 
1. While plasma glucose is > 80 mg/dL (> 4.4 mM/L): 
a. Measure plasma glucose every 10 minutes. 
b. When 10 minutes have passed from the last insulin dose adjustment: 
i. Bolus: If the rate of plasma glucose decrease is < 0.15 mg/dL∙min (< 0.01 
mM/min), then an additional 1 bolus (full bolus dose) should be 
administered. 


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ii. Infusion Rate: If the rate of plasma glucose decrease is < 0.5 mg/dL∙min 
(< 0.03 mM/min), then the insulin infusion rate should be increased by 
20%. 
2. While plasma glucose is 66 to 80 mg/dL (3.66-4.4 mM/L): 
a. Measure plasma glucose every 5 minutes. 
b. When 10 minutes have passed from the last insulin dose adjustment: 
i. Bolus: If the rate of plasma glucose decrease is < 0.15 mg/dL∙min 
(< 0.01 mM/min), then an additional 1/2 bolus (half-bolus dose) should be 
administered. 
ii. Infusion Rate:  
1) If the rate of plasma glucose decrease is < 0.33 mg/dL∙min 
(< 0.02 mM/min), then the insulin infusion rate should be 
increased by 20%. 
2) If the rate of plasma glucose decrease is > 0.5 mg/dL∙min 
(> 0.03 mM/min), then the insulin infusion rate should be 
decreased by 20%. 
3. While plasma glucose is 61 to 65 mg/dL (3.39 to 3.61 mM):  
a. Measure plasma glucose at least every 5 minutes. 
b. When 10 minutes have passed from the last insulin dose adjustment: 
i. Bolus: not allowed. 
ii. Infusion Rate: 
1) If the rate of plasma glucose decrease is < 0.25 mg/dL∙min 
(< 0.01 mM/min), then the insulin infusion rate should be 
increased by 20%. 
2) If the rate of plasma glucose decrease is > 0.33 mg/dL∙min 
(> 0.02 mM/min), then the insulin infusion rate should be 
decreased by 20%. 
4. While plasma glucose is 54 to 60 mg/dL (3 to 3.33 mM):  
a. Measure plasma glucose at least every 5 minutes. 
b. When 10 minutes have passed from last insulin adjustment: 
i. Bolus: not allowed. 
ii. Infusion Rate: 
1) If the rate of plasma glucose decrease is < 0.15 mg/dL∙min 
(< 0.008 mM/min), then the insulin infusion rate should be:  
a. Increased by 20%, or 


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b. Set at 120% of the previous rate if the infusion was 
previously set at the baseline rate or decreased by 50%. 
Note: This escalation in rate can be performed every 
5 minutes until the rate of decrease is > 0.15 mg/dL∙hr 
(> 0.008 mM/hr) 
3) If the rate of plasma glucose decrease is greater than 0.25 up to 
0.33 mg/dL∙min (>0.014 - 0.02 mM/min), then the insulin infusion 
rate should be decreased 20%. 
4) If the rate of plasma glucose decrease is greater than 0.33 up to 
0.50 mg/dL∙min (>0.002 - 0.03 mM/min), then the insulin infusion 
rate should be decreased 50%. 
5) If the rate of plasma glucose decrease is > 0.5 mg/dL∙min 
(> 0.03 mM/min), then the insulin infusion rate should be stopped.  
After 5 minutes, the insulin infusion should be restarted at the rate 
used at the end of the baseline period.  
5. If the plasma glucose is < 54 mg/dL (< 3 mM), then the IV insulin infusion should be 
returned to the baseline insulin infusion rate used at the end of the baseline period for 
5 minutes, and then stopped. 
Induction Termination 
At any time, the induction procedure may be terminated at the Investigator’s discretion.  If the 
procedure is terminated, appropriate measures (oral or IV glucose) will be administered at the 
Investigator’s discretion.  If a subject exhibits signs of coma or convulsions, a IV bolus dose of  
dextrose will be given per standard of practice.  Signs and symptoms should be monitored, and if 
the subject’s condition fails to improve in a timely manner, additional dextrose or other medical 
interventions may be given at the Investigator’s discretion. 
Note: Study glucagon should NOT be administered as hypoglycemia rescue in this context. 
Euglycemia will be confirmed and the subject should be medically stabilized per Investigator 
discretion before being released.  The treatment visits should be rescheduled after a minimum 
3-day wait. 
If an SAE occurs during hypoglycemia induction, the procedure will end, and IV insulin will be 
safely withdrawn.  Causality should be fully assessed by both the Investigator and the Sponsor. 
Note: subjects will undergo a maximum of 4 hypoglycemia inductions in this study to achieve 
two successful procedures. 
 


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Table 4 
Insulin Dose Adjustments 
Plasma Glucose 
Measurement 
Interval 
(minutes) 
Target Rate  
of Plasma Glucose 
Decrease 
Insulin Bolus Criteria 
Insulin Basal Rate Adjustment Criteria 
(mg/dL) 
(mmol/L) 
> 80 
> 4.44 
10  
> 0.5 mg/(dL∙min) 
(> 0.03 mM/min) 
If plasma glucose ↓ < 0.15 
mg/(dL∙min) (< 0.01 mM/min); 
give 1 bolus 
If plasma glucose ↓ < 0.5 mg/dL∙min (< 0.03 mM/min),  
↑ 20% (10 min) 
66-80 
3.66-4.44 
5 
0.33-0.5 
mg/(dL∙min) 
(0.02-0.03 mM/min) 
If plasma glucose ↓ < 0.15 
mg/(dL∙min)  
(<0.01 mM/min); give ½ bolus 
If plasma glucose ↓ < 0.33 mg/dL∙min (< 0.02 mM/min),  
↑ 20% (10 min) 
If plasma glucose ↓ > 0.5 mg/dL∙min (> 0.03 mM/min), 
↓ 20% (10 min) 
61-65 
3.39-3.61 
5  
0.25-0.33 
mg/(dL∙min) 
(0.014-0.02 
mM/min) 
Not allowed 
If plasma glucose ↓ < 0.25 mg/dL∙min (< 0.01 mM/min), 
↑ 20% (10 min) 
If plasma glucose ↓ > 0.33 mg/dL∙min (> 0.02 mM/min), 
↓ 20% (10 min) 
54-60 
3-3.33 
5  
0.15-0.25 
mg/(dL∙min) 
(0.008-0.014 
mM/min) 
 
Not allowed 
If plasma glucose ↓ < 0.15 mg/dL∙min (<0.008 mM/min),  
↑ 20% (10 min); or  
If insulin infusion rate was previously set to baseline or the 
insulin infusion rate was ↓ by 50%, then set new insulin 
infusion rate at 120% of the prior rate (5 min) 
Note: This escalation in rate can be performed every 
5 minutes until the rate of decrease is > 0.15 mg/dL∙hr 
(> 0.008 mM/hr) 
If plasma glucose ↓ >0.25 up to 0.33 mg/dL∙min (>0.014-
0.02 mM/min), ↓ insulin infusion rate 20% (10 min) 
If plasma glucose ↓ >0.33-0.50 mg/dL∙min (>0.02 up to 0.03 
mM/min), ↓ insulin infusion rate 50% (5 min) 
If plasma glucose ↓ > 0.5 mg/dL∙min (>0.03 mM/min),  
 Stop infusion;  
then set insulin infusion rate to baseline level (5 min)   
< 54 
< 3 
5  
0 
Not allowed 
Set to baseline level for 5 minutes, then Stop 
↓=decrease, ↑=increase, min=minutes. [Note: if the plasma glucose decline is within the target range, keep the insulin infusion constant] 


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7.3. 
Interruption and Termination of Dosing 
As described in Section 7.1 , administration of study glucagon is only permitted if a subject 
meets the criteria for a hypoglycemic steady state. Administration of study glucagon to a subject 
not in a hypoglycemic steady state will be deemed a major protocol violation. 
At 30 minutes post-glucagon administration, if a subject fails to achieve an increase of plasma 
glucose of at least 20 mg/dL (1.11 mmol/L), appropriate measures (oral or IV glucose) will be 
taken at the Investigator’s discretion. 
Post-administration of study glucagon, if a subject exhibits signs of coma or convulsions, a IV 
bolus dose of dextrose will be given per standard of practice.  Signs and symptoms should be 
monitored, and if the subject’s condition fails to improve in a timely manner, additional dextrose 
or other medical interventions may be given at the Investigator’s discretion. 
Note: A second dose of study glucagon should NOT be administered as hypoglycemia 
rescue in this context. 
Euglycemia will be confirmed and the subject should be medically stabilized per Investigator 
discretion before being released.  If applicable, completion of a subsequent treatment visit will be 
at the discretion of the Investigator in consultation with the Medical Monitor.   


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8. 
ELIGIBILITY CRITERIA AND STUDY ENROLLMENT 
Subject eligibility should be reviewed and documented by an appropriately qualified member of 
the Investigator’s study team before a subject is included in the study.  Subjects must meet the 
following inclusion and exclusion criteria to be eligible for enrollment into the study. 
8.1. 
Inclusion Criteria 
1. Males and females diagnosed with T1D for at least 24 months.  Women of childbearing 
potential require a negative urine pregnancy test and must use medically accepted 
contraception throughout the study and for 7 days after the last dose of study drug.   
Nursing mothers will be allowed to participate in the study.  However, breast feeding 
during the inpatient study visits (Visits 2 and 3) and for 48 hours after each dose of study 
drug is not allowed. 
2. Current usage of daily insulin treatment that includes having an assigned “correction 
factor” for managing hyperglycemia.  
3. Age 18 to 75 years, inclusive. 
4. Random serum C-peptide concentration < 0.6 ng/mL. 
5. Willingness to follow all study procedures, including attending all clinic visits. 
6. Subject has provided informed consent as evidenced by a signed and dated informed 
consent form (ICF) completed before any trial-related activities occur. 
8.2. 
Exclusion Criteria 
1. Pregnancy 
2. Glycated hemoglobin (HbA1c) > 10% at Screening.   
3. Body mass index (BMI) > 40 kg/m2.  
4. Renal insufficiency (serum creatinine greater than 3.0 mg/dL) or Stage 2 or greater 
kidney failure. 
5. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) equal to or 
greater than 3 times the upper limit of normal. 
6. Hepatic synthetic insufficiency as defined as a serum albumin of less than 3.0 g/dL. 
7. Hematocrit < 30%. 
8. Blood pressure (BP) readings at Screening where systolic blood pressure (SBP) < 90 or 
> 150 mm Hg, and diastolic blood pressure (DBP) < 50 or > 100 mm Hg. 
9. Clinically significant electrocardiogram (ECG) abnormalities. 
10. Use of total insulin dose per day > 2 U/kg. 
11. Inadequate venous access. 
12. Congestive heart failure, New York Heart Association (NYHA) class II, III or IV. 


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13. History of myocardial infarction, unstable angina, or revascularization within the past 6 
months. 
14. History of a cerebrovascular accident or with major neurological deficits. 
15. Active malignancy within 5 years from Screening, except basal cell or squamous cell skin 
cancers.  Any history of breast cancer or malignant melanoma will be exclusionary. 
16. Major surgical operation within 30 days prior to Screening.  
17. History of or current seizure disorder (other than with suspect or documented 
hypoglycemia). 
18. Current bleeding disorder, treatment with warfarin, or platelet count below 50 × 109 per 
liter. 
19. History of pheochromocytoma or disorder with increased risk of pheochromocytoma 
(multiple endocrine neoplasia type 2 [MEN 2], neurofibromatosis, or Von Hippel-Lindau 
disease). 
20. History of insulinoma. 
21. History of allergies to glucagon or glucagon-like products, or any history of significant 
hypersensitivity to glucagon or any related products or to any of the excipients (DMSO 
and trehalose) in the investigational formulation.  
22. History of glycogen storage disease. 
23. Subject tests positive for human immunodeficiency virus [HIV], hepatitis C virus [HCV], 
or hepatitis B virus [HBV] infection (hepatitis B surface antigen positive [HBsAg+]) at 
Screening. 
24. Active substance or alcohol abuse (more than 21 drinks per week for male subjects or 14 
drinks per week for female subject).  
25. Administration of glucagon within 7 days of Screening. 
26. Participation in other studies involving administration of an investigational drug or 
device within 30 days or 5 half-lives, whichever is longer, before Screening for the 
current study and during participation in the current study. 
27. Any other reason the Investigator deems exclusionary. 
8.3. 
Randomization  
Subjects who meet all eligibility criteria, who reach the baseline euglycemia steady state, and 
who the Investigator deems appropriate to begin the induction procedure (see Section 10.2) at the 
first treatment visit will be randomized for the study.  The randomization schedule will be 
produced by the Study statistician a priori for loading and implementing in the Interactive Web-
based Randomization System (IWRS).  Using a permuted random block assignment, stratified by 
site, subjects will be randomly assigned to receive either Treatment Sequence 1 (G-Pen → 
GlucaGen Hypokit) or Treatment Sequence 2 (GlucaGen Hypokit → G-Pen).  


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Once a subject has been randomized, information regarding the glucagon (G-Pen or GlucaGen 
Hypokit) to be administered to the subject at each of the treatment visits will be viewable by 
study staff in the Dose Administration form in the electronic data capture (EDC) system.   
8.4. 
Subject Numbers  
Subjects will be screened, and if eligible, enrolled and eventually randomized for the study.  All 
screened subjects will be entered in the EDC.  As each subject is added to the EDC system, they 
will be assigned a Screening number, which will consist of a unique 2-digit site code (starting 
with 01) and a unique 2-digit sequential number (starting with 01 at each site) indicating the 
sequence at which the subject was screened for eligibility.  This Screening number will remain 
with the subject through enrollment and randomization, and will be considered their Subject 
identification (ID) if randomized into the study.  
Subjects will be eligible for rescreening.  Once laboratory results are obtained and a final 
determination of eligibility is made, subjects will be contacted to schedule the first treatment 
visit.  While immediate re-testing of laboratory results is not allowed, subjects failing to meet 
laboratory-based eligibility criteria may be rescreened for laboratory-based eligibility after a 
30 day wait.  If this occurs, the subject will maintain the same Screening number, but will have 
all eligibility reviewed and reconfirmed prior to enrollment. 
 


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9. 
STUDY TREATMENTS 
9.1. 
Allocation to Treatment 
Subjects will be randomly assigned to one of the two treatment sequences to receive the blinded 
study drug (see Table 3).  A total of 122 subjects will be randomized, with a goal of having an 
approximately equal number of subjects randomized to each of the two treatment sequences.  If 
there are subjects who are enrolled, but fail to be randomized, compensatory enrollment may be 
utilized to achieve at least 122 subjects who are randomized for the study.  Once a subject is 
randomized, the subject will be analyzed for the study.  Each subject will receive a single SC 
injection to the abdomen around the umbilicus on each of the two treatment days, with a period 
of 7 to 28 days between treatment 1 and treatment 2.   
9.2. 
Blinding 
For this study, the subject but not the Investigator will be blinded (single-blind design).  The 
G-Pen 1 mg device makes a series of two audible clicks when the dose is administered.  To help 
ensure blinding, the subject will wear headphones that play music to mask sound during dosing 
procedures.  The subject’s ability to see the injection equipment and procedure will be obstructed 
by use of a blindfold placed prior to dosing.  The subject will be instructed not to talk with the 
study staff about their impression of which product he/she received at a visit until the end of the 
second treatment sequence.  At which time, the subject will be asked to guess what their first 
treatment was, and what their second treatment was from the choices of “Xeris Glucagon, G-Pen, 
administered by auto-injector” or “Comparator Glucagon, GlucaGen Hypokit, administered by 
needle and syringe”.  The subject’s responses will be recorded in the electronic Case Report 
Form (eCRF) for the Subject Study Drug Assignment Questionnaire (see Appendix 5).  
In the event that a subject is inadvertently unblinded during one or both of the treatment 
sequences, the investigator will note the event as a protocol violation, and the subject will be 
allowed to continue further study treatments as per the protocol.   
9.3. 
Drug Supplies 
9.3.1. 
Drug Product Formulation and Packaging 
Xeris G-Pen is a non-aqueous, injectable liquid formulation of glucagon.  The G-Pen drug 
product consists of 1 mg synthetic glucagon peptide dissolved in a primary DMSO solvent, with 
trehalose added as a stabilizing excipient.  G-Pen drug product is filled into West 
Pharmaceutical’s 1 mL long Crystal Zenith® cyclic olefin polymer (plastic) pre-filled syringe 
with a Flurotec® coated plunger.  The pre-filled syringe is loaded into an SHL Molly® single-use, 
disposable auto-injector, and packaged in a sealed poly/foil pouch.  The drug product is stored at 
controlled room temperature (20 to 25°C [68° to 77°F]) prior to use. 
The G-Pen drug product is manufactured under current GMP by Pyramid Laboratories, Inc. 
(Costa Mesa, CA), and packaged under current GMP by SHL Group (Deerfield Beach, FL), both 
contract manufacturers for Xeris. 


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9.3.2. 
GlucaGen Hypokit for Injection 
GlucaGen Hypokit (Novo Nordisk) will be purchased commercially and provided by Xeris.  The 
glucagon will be stored at the CRC pharmacy according to labeled storage conditions. 
9.3.3. 
Preparation, Dispensing and Administration 
G-Pen will be supplied as 0.2 mL of non-aqueous solution in a plastic Crystal Zenith 1 mL long 
syringe loaded into a Molly disposable AI.  Subcutaneous administration will be performed by a 
qualified CRC staff member who has read the written Instructions for Use provided by Xeris.  
In the case of GlucaGen Hypokit, a new vial of lyophilized glucagon will be fully reconstituted 
immediately prior to abdominal administration using 1 mL of sterile diluent provided in the 
commercial kit as per the GlucaGen Hypokit Summary of Product Characteristics (SmPC) and 
Prescribing Instructions [Novo Hypokit].  
Study drug will be administered according to the randomization schedule accessed in the EDC 
system (see 8.3).  Randomization will occur at the start of the induction procedure, or about 2 to 
3 hours prior to administration of study drug.  When the Investigator believes the hypoglycemia 
induction procedure is approximately 1 hour from completion, a member of the study team will 
deliver the correct investigational product (IP) for the visit to the clinic area, making sure to 
maintain subject blinding. 
The study drugs will not be prepared ahead of time.  Instead, preparation of the investigational 
product (IP) (i.e., re-constitution of GlucaGen Hypokit) will begin after the confirmatory plasma 
glucose reading is obtained, indicating that a hypoglycemic steady state has been achieved, i.e., 
upon a “decision to dose.” 
G-Pen is being developed for SC injection.  The marketed comparator is labeled for both SC and 
intramuscular (IM) injection.  Both products will be administered via the SC route to the 
abdomen, around the umbilicus. 
The G-Pen auto-injector is made to be pressed against the skin perpendicularly (i.e., at a 90° 
angle) to the injection site.  The injection technique for G-Pen will follow printed instructions for 
use (IFU) provided by Xeris. 
For GlucaGen Hypokit, the skin should be pinched to avoid an IM injection.  The needle will be 
inserted into the loose tissue under the injection site at a 90° angle and the product injected 
smoothly over 1 to 3 seconds.  Following injection, light pressure should be applied to the 
injection site, as the needle is withdrawn. 
Prior to administration of the study drugs, the intended injection site should be sterilized with an 
alcohol wipe and examined to ensure it has a normal appearance and is free from signs of 
inflammation or injury.  The site staff will document the administration act (i.e. location, study 
product/dose) in the Vision EDC system. 
9.3.4. 
Drug Storage and Drug Accountability 
Unless notified otherwise by the Sponsor, all supplied G-Pen auto-injectors and GlucaGen 
Hypokit kits are to be stored at controlled room temperature (20°C to 25°C [68° to 77°F]). 
Excursions between 15° and 30° C (59° and 86 °F) that are experienced in pharmacies, hospitals, 


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and warehouses, and during shipping are allowed. Drug solution should be clear and of a water-
like consistency at time of use. 
The Investigator or an approved member of the study staff will ensure that the study drugs are 
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 in an on-going basis by the monitor.  Any deviations in the storage 
conditions must be documented (including minimum and maximum temperature excursion as 
well as 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. 
After administration, used vials of GlucaGen Hypokit should be returned to the kit and stored for 
accountability, while the syringe is disposed as per each site’s standard practice.  Used G-Pens 
should be returned to the foil pouch, which will be sealed with tape, and stored for 
accountability.  Any devices that fail to function should be handled in a similar manner, but they 
should also be identified on the pouch label as a failure.  Disposal of the study products should 
occur away from the subject in a manner that ensures blinding.  
The Investigator must maintain adequate records documenting the receipt, use, loss or other 
disposition of the investigational drug products and supplies.  Unused G-Pens and Novo 
GlucaGen Hypokits will be returned to Xeris.  Used G-Pen auto-injectors will be returned to 
Xeris after accountability is performed during site close-out.  Used GlucaGen Hypokits and other 
used supplies, will be destroyed according to local regulation and applicable Xeris standard 
operating procedures (SOPs), following accountability by Xeris or its designee. 
9.4. 
Concomitant Medications 
All subjects must be questioned about concomitant medications at each visit.  Medications taken 
within 4 weeks before Day 1 will be documented in the eCRF.  Any changes to a subject’s 
concomitant medication regimen after the first treatment on Day 1 will also be documented in 
the eCRF. 
Except for those medications (e.g., warfarin) listed under the exclusion criteria (see Section 8.2) 
and other current investigational agents which are absolutely proscribed, there are no 
medications that are specifically prohibited during participation in the study.  Subjects should be 
on a stable dose of all concomitant medications for at least 30 days prior to Screening, and they 
will be encouraged to avoid making changes to their concomitant medication regimen during 
participation in the study.  In addition, Investigators are encouraged to avoid adding to or 
changing a subject’s medications during study participation unless deemed medically necessary.  


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10. 
STUDY PROCEDURES 
A schedule of assessments for this study is provided below in Table 5.  
10.1. 
Visit 1 – Screening (Day -30 to -3) 
Subjects will be screened to confirm they meet the inclusion/exclusion criteria for the study.  
Prior to completing any screening activities, the Investigator or study team member will obtain 
informed consent from each subject in accordance with the procedures described in Section 16.3.  
A copy of the consent/authorization form will be given each subject.  The original will be kept 
by the site for the source document. 
Subjects will be instructed to complete a Screening Visit at least 3 days (to allow for receipt of 
blood test results), and no more than 30 days prior to the anticipated date of the first Treatment 
Visit (Day 1).  The following evaluations will be completed during the Screening Visit to 
confirm subjects meet eligibility criteria for this study: 
1. Assessment of inclusion/exclusion criteria by a study investigator, including a review of 
the subject’s medical history and medications. 
2. Recording of the subject’s insulin correction factor (i.e., the reduction in blood glucose in 
mg/dL per 1 unit of insulin taken).  
3. Measurement of height and weight (no shoes, lightly clothed). 
4. Physical examination, excluding breast, pelvic, and genitourinary exams. 
5. Performance of a 12-lead ECG after the subject has completed a 5-minute supine rest. 
6. Assessment of vital signs, including measurement of BP, after a 5-minute seated rest. 
7. Urine drug screen. Note: At the Investigator’s discretion, subjects with a positive result 
will be allowed to participate if the subject reports use of a concomitant medication that 
explains the result (e.g., positive urine test for opiates in a subject reporting use of cough 
syrup containing Dextromethorphan).  
8. Urine pregnancy test for women of childbearing potential and discussion about study 
requirements regarding contraception. 
9. If applicable, a discussion about study requirements regarding breast feeding. 
10. Collection of venous blood for the following tests as outlined in the Schedule of 
Activities: hemoglobin A1C, c-peptide, complete blood count (without differential), 
metabolic set (including creatinine, liver set, and electrolytes), and screening for HIV, 
HBV and HCV (Table 7).  
11. Gold scale for hypoglycemia unawareness (Appendix 4).  Note: this is being collected for 
informational purposes only; no scores are considered exclusionary. 
Once laboratory results are obtained and a final determination of eligibility is made, subjects will 
be contacted to schedule the first treatment visit.  While immediate re-testing of laboratory 
results is not allowed, subjects failing to meet laboratory-based eligibility criteria may be 
rescreened after a 30-day wait.  A single re-screening is permitted, and this re-screening is only 
permissible if the reason for the prior screen failure was for laboratory measurements.  Blood for 


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clinical laboratory tests can be redrawn after a 30-day wait; however, other screening procedures 
do NOT need to be repeated.  If the new clinical laboratory test results meet eligibility, the 
subject may be dosed. Otherwise, the subject is not eligible for dosing or further re-screening. 
10.2. 
Treatment and Follow-Up Phase 
Subjects will be instructed to eat normal meals during the day but to refrain from alcohol, and to 
follow their usual insulin regimen prior to their evening clinic arrival.  Subjects will be instructed 
to arrive at the clinic between 6 and 8 pm on Day -1, having not had dinner.  
10.2.1. 
Visit 2 – Treatment 1 (Day -1 and Day 1) 
The following procedures will be carried out at Visit 2. 
10.2.1.1. Day -1 
Clinic Arrival  
1. Plasma glucose (via glucose meter) will be assessed.  If the result is > 350.0 mg/dL 
(19.44 mmol/L), no further procedures should be performed, and the visit should be 
rescheduled after a minimum 24-hour wait. 
2. The subject will be questioned regarding any changes in concomitant medications will be 
documented in the eCRF, and it will be confirmed that the subject is not receiving a 
medication that is exclusionary. 
3. Women of childbearing potential will receive a urine pregnancy test, which must be 
negative before further participation is allowed. 
If it has been more than 30 days since Visit 1 (i.e., the visit is occurring outside of the 
allowed time window), venous blood will be collected for a repeat of baseline 
hematology and serum chemistry assessments.  However, the visit may continue based on 
qualification at the Screening visit. 
Note: At check-in for Visit 3, venous blood will be collected for a repeat of hematology 
and serum chemistry assessments as baseline for the first dose of study glucagon.  
4. Full vital signs will be assessed after a 5-minute seated rest.  It will be confirmed that the 
subject continues to meet eligibility requirements for SBP and DBP.  Other assessments 
of vital signs will be made during the visit as specified in the footnotes to Table 5. 
Evening Meal in Clinic  
1. A standardized healthy meal will be provided to the subject (see Section 7.1) with a goal 
of completion by 9 pm.   
2. The subject should follow their normal prescribed regimen for insulin per PI discretion, 
including meal-time correction, until midnight. 


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10.2.1.2. Day 1 
Overnight Monitoring (starting at approximately midnight)  
1. Subjects will be instructed to fast, taking nothing but water and oral glucose tablets if 
necessary, starting at approximately midnight and will be monitored for compliance by 
the CRC staff. 
2. An IV catheter will be placed in one arm, maintenance fluids will be started, and the 
subject’s insulin pump will be discontinued, if applicable.  If use of an overnight IV is not 
possible due to site staffing considerations, use of the subject’s own insulin infusion 
pump or SC insulin will be used overnight.  
3. Plasma glucose will be monitored overnight by CGM, YSI or glucose meter; these data 
will be kept in the source documents.  At a minimum, glucose will be assessed by BGM 
or YSI (not CGM) at midnight, 3 am, and 6 am; these data will be entered into the EDC. 
IV glucose or oral glucose tablets will be given and/or insulin will be administered by IV 
or infusion pump as necessary to optimize achieving plasma glucose within a target range 
of 80 to 150 mg/dL (4.44 to 8.33 mmol/L).  If the glucose is outside the recommended 
target range, it will not be considered a protocol deviation.  
4. Ideally, about 1 hour prior to the start of the Morning Procedures outlined below, subjects 
will be transitioned from SC to IV administration of insulin; any use of IV glucose will 
be discontinued. 
5. If the subject has plasma glucose < 270 mg/dL (< 15.0 mmol/L) in the morning as 
measured by YSI, then the subject will be eligible to begin the Morning Procedures. 
Morning Procedures (starting at approximately 6 am)  
1. In the morning, plasma glucose (via YSI) will be assessed, and if > 270.0 mg/dL 
(> 15.0 mmol/L), the visit will be rescheduled after a minimum 3-day wait.  Otherwise, 
the subject will be administered IV insulin to induce a baseline euglycemic steady state. 
2. If not already placed, an IV catheter will be placed for administration of insulin and 
maintenance fluids. 
3. A second IV catheter will be placed for blood sampling, ideally located in a vein within 
the antecubital fossa. 
The hand used for blood sampling will be kept warm by use of a heated-hand box to increase 
blood flow and achieve “arterialized” samples.  Note: The subjects will remain non-caloric 
fasting the morning of the procedure. 
Baseline Euglycemic Steady State (early morning) 
Prior to starting the hypoglycemia induction procedure, the subject must have stable plasma 
glucose for at least 30 minutes at 95±20 mg/dL (75 to 115 mg/dL [4.17 to 6.38 mmol/L]) at a 
stable IV insulin infusion rate varying no more than ±20% during which plasma glucose must be 
measured at least every 15 minutes. 


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Hypoglycemia Induction Procedure (following baseline euglycemic steady state) 
Induction Start   
For the induction, the starting plasma glucose level will be determined as the average of 
3 measurements taken over the final 30 minutes of the baseline euglycemic steady state period. 
The following procedures will then be performed: 
1. Subjects will continue the IV insulin infusion at the final rate of the euglycemic steady 
state. 
2. Subjects will be given an initial IV bolus push dose of regular insulin diluted in saline: 
a. The dose will be calculated as 75% of the dose estimated to reduce plasma glucose 
from the subject’s starting plasma glucose level to 54 mg/dL (3.0 mmol/L) based on 
the subject’s self-reported glucose correction factor.  This dose will be referred to as 
“1 bolus (full bolus dose)” subsequently. 
b. Plasma glucose will be measured no less frequently than every 10 minutes. 
The first insulin adjustment will be no earlier than 20 minutes after the initial bolus but will 
otherwise follow the directions for insulin adjustments shown in Section 7.2 (see also Table 4). 
Insulin Dose Adjustments   
Insulin dose adjustments will be performed as outlined in Section 7.2 (see also Table 4). 
Randomization 
Once the initial bolus dose of insulin has had time to take effect and the subjects is observed to 
be in a controlled rate of glucose decline, which will generally occur at approximately 30 to 
60 minutes after the beginning of the induction period, the subject will be randomly assigned to 
receive either G-Pen or GlucaGen Hypokit in one of the treatment sequences shown in Table 3.  
Confirmation of Hypoglycemic Steady State 
Once the initial plasma glucose measurement < 54.0 mg/dL (< 3 mmol/L) is achieved, the IV 
insulin infusion will be returned to the rate established at the end of the baseline euglycemia 
steady state period. After 5 minutes, the IV insulin infusion will be stopped, and up to 3 
confirmatory plasma glucose readings will be taken at subsequent 5-minute intervals to 
determine whether a hypoglycemic steady state has been reached. 
A hypoglycemic steady state is defined as a confirmatory plasma glucose value ≥ 42 mg/dL 
(≥ 2.33 mmol/L) and < 54 mg/dL (< 3 mmol/L), and an 8-minute linearly extrapolated future 
plasma glucose value ≥ 42 mg/dL (≥ 2.33 mmol/L). 
To determine whether a hypoglycemic steady state has been achieved, confirmatory plasma 
glucose measurements will be taken as necessary at 5, 10 and 15 minutes after an initial plasma 
glucose < 54 mg/dL (<3 mmol/L). Depending on the outcome, the following procedures will be 
followed. 
1. If any of the confirmatory measurements meets the criteria for hypoglycemic steady state, 
the subject will be eligible to receive study glucagon, and further confirmatory plasma 
glucose measurement are not required. 


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2. If the final confirmatory plasma glucose value is < 42 mg/dL (< 2.33 mmol/L), the 
procedure will be terminated, study glucagon will NOT be administered, and the visit 
will be rescheduled after a minimum 3-day wait.  At the Investigator’s discretion, the 
subject should be treated with IV glucose or oral carbohydrates, it should be verified that 
the subject achieved a euglycemic state and is medially stable prior to discharge. 
3. If any of the confirmatory plasma glucose measurements are > 54 mg/dL (> 3 mmol/L), 
then the IV insulin infusion will be re-started, and insulin adjustments will be made as per 
the induction procedure described above (see Table 4). Once another initial plasma < 54 
mg/dL (< 3 mmol/L) is obtained, the sequence of up to 3 confirmatory plasma glucose 
readings will repeated. 
Note: If a subject fails to achieve a hypoglycemic steady state within 60 minutes of the first 
plasma glucose measurement < 54 mg/dL (< 3 mmol/L), the procedure will be terminated, and 
the visit re-scheduled after a minimum 3-day wait. 
Decision to Dose   
If the subject is deemed to be within a hypoglycemic steady state, then the subject is ready to be 
dosed with study drug (decision to dose).  At this time, the subject will be eligible to receive the 
randomized study drug. 
Preparation and Administration of Study Drug 
1. Once the induction procedure has begun and glucose < 54 mg/dL (< 3 mmol/L) is 
predicted to occur within approximately 1 hour, the study staff member who will be 
performing the study drug injection should be notified that the induction procedure is 
reaching conclusion.  At this time the study staff member will bring the appropriate 
unopened test article (pouched G-Pen or Novo GlucaGen Hypokit kit) to the bedside, as 
assigned by the EDC system.  
2. Once the hypoglycemic steady state is confirmed, the Investigator will confirm that it is 
appropriate to administer study drug to the subject.  The clock time of this “Decision to 
Dose” will be captured in the source documents. 
3. At this point, the subject will receive the blindfold and headphones with music playing to 
maintain the blind. 
4. The treatment administrator will then open the study drug container (kit or pouch) and 
begin preparation of the glucagon for administration following the applicable IFU.  An 
Investigator should verify that the contents of the vial of lyophilized GlucaGen Hypokit 
have been fully reconstituted prior to administration. 
5. Subcutaneous administration of the study drug will be made to the abdomen around the 
umbilicus as per Section 9.3.3.  Clock time of study drug administration will be recorded 
in the source documents.  After study drug injection, the study product will be disposed 
in a location away from the subject in a manner that maintains the blind.  After disposal, 
the blindfold and headphones will be removed from the subject.  
6. Following study drug administration, plasma glucose will be measured every 
5±2 minutes through 90 minutes, and every 30±2 minutes thereafter through 180 minutes 
post-dosing.  


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7. At 180 minutes post-dosing, the subject will resume insulin therapy and be given a meal 
as per the standard practice at each site.  The subject can be discharged from the clinic if 
their plasma glucose is >100 mg/dL (> 5.55 mmol/L) and the subject is deemed 
medically stable.  
8. After study drug administration and before 180 minutes post-dosing, if rising glucose 
levels are observed and if deemed medically necessary, insulin therapy or other medical 
intervention may be initiated by the Investigator.  
a. Such intervention is not recommended to occur before 90 minutes post-dosing of 
study drug.  
b. Plasma glucose data and assessments of neuroglycopenic symptoms will be censored 
after the time of intervention, per the statistical analysis plan.   
c. These interventions (such as insulin, carbohydrates, or a meal) prior to 180 minutes 
post study drug administration should be captured in the source documents, and 
further glucose measurements may be performed at the discretion of the Investigator. 
Hypoglycemia Symptom Assessments 
Subjects will complete a questionnaire regarding severity of hypoglycemia symptoms 
(Appendix 1) at the following time points: 
1. Just before the IV bolus push dose of insulin is given at the start of the hypoglycemia 
induction procedure (baseline), 
2. Every time blood is drawn for evaluation of plasma glucose concentration during the 
induction procedure, 
3. Just before study drug is administered,  
4. Every 5±2 minutes after glucagon is administered until 90 minutes post-dosing, and 
every 30 minutes (coinciding with plasma glucose measurements) between 90 and 180 
minutes post study drug administration.  
Local Tolerability and Adverse Events 
Local tolerability and AEs will be assessed as follows: 
1. Subjects will complete a Visual Analog scale (VAS) questionnaire regarding injection 
site discomfort (Appendix 2) at 30±5, 90±5, and 180±5 minutes after injection of study 
drug. 
2. Subjects will complete an Injection Site Discomfort Description and Duration 
Questionnaire at 30±5 minutes post-dosing.  If discomfort is ongoing at 30 minutes post-
dosing, the questionnaire will be updated before the subject leaves the clinic to document 
the final duration.  
3. The Investigator will use the modified Draize scales (Appendix 3) to assess erythema and 
edema formation at the injection site at 30±5, 90±5, and 180±5 minutes after injection of 
study drug.  If any scores remain > 1 at the 180-minute evaluation, the subject may leave 
the clinic but will be instructed to contact a study staff member if the condition fails to 
resolve.  The CRC will make every attempt to ensure that the same investigator will 
assess the injection sites on the subject, during both treatment visits. 


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Note:  Even if the plasma glucose measurements have been stopped after 90 minutes, the 
Draize scale assessments should continue to 180 minutes post study drug injection.  
4. AEs reported by the subject or observed by an Investigator during the visit will be 
recorded in the eCRF. 
10.2.2. 
Visit 3 – Treatment 2 (Day 7-28) 
The subject will return to the CRC 7 to 28 days after the first Treatment Visit.  The procedures 
that will be repeated at Visit 3 are described in Section 10.2.1.  Note that venous blood will be 
collected for a repeat of baseline hematology and serum chemistry assessments at Visit 3.  At 
Visit 3, the subject will cross over to receive the other study drug, which will be administered at 
the time of Decision to Dose, so that each subject will have received one dose of G-Pen and one 
dose of GlucaGen Hypokit during the study.  At the end of Visit 3, the subject will be asked to 
guess what their first treatment was, and what their second treatment was from the choices of 
“Xeris Glucagon, G-Pen, administered by auto-injector” or “Comparator Glucagon, GlucaGen 
Hypokit, administered by needle and syringe”.  The subject’s responses will be recorded in the 
eCRF for the Subject Study Drug Assignment Questionnaire (see Appendix 5). 
10.2.3. 
Visit 4 – Follow-Up (Day 9-35) 
The subject will attend a Follow-Up Visit within 2 to 7 days after completing the final dosing 
visit or premature discontinuation.  This visit will include the following assessments: 
1. Review of changes in concomitant medications. 
2. Physical examination, excluding breast, pelvic and genitourinary exams.  To include 
review of injection sites to document any residual inflammation, pain or induration. 
3. Body weight (no shoes, lightly clothed). 
4. 12-lead ECG after 5-minute supine rest. 
5. Vital signs after 5-minute seated rest. 
6. Urine pregnancy test (females of child-bearing potential only). 
7. Blood draws for complete metabolic count and complete blood count.  
8. Solicitation of AEs by asking the subjects to respond to a non-leading question such as 
“how do you feel?” 
In case of any premature discontinuation from the study, the subject will, if possible, be 
scheduled for a final follow-up visit. 
10.3. 
Subject Withdrawal 
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the Investigator or Sponsor for safety, behavioral, or 
administrative reasons.   
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject to determine the reason(s) why the subject failed to return for the scheduled visit, and to 
reschedule the missed visit.  This includes contacting subjects, family members, or emergency 


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contacts via email and telephone.  If such efforts fail, a certified letter should be sent to the 
subject’s last known address requesting they contact study CRC. 
In all circumstances, every effort should be made to document subject outcome, per the follow-
up.  Information regarding the reason for not completing the study will be recorded in the eCRF.  
The Investigator should inquire about the reason for withdrawal, request that the subject return 
for a Final Visit, and further follow-up with the subject regarding any unresolved AEs.  It will be 
documented whether or not each subject completed the study.  Any subject who receives at least 
one treatment dose of study drug will be included in the safety analysis.  
If a decision by the Investigator or Sponsor is made to withdraw a subject, a Final Visit should 
be scheduled soon after the decision to withdraw is made.  The subject will be asked to return to 
site for the assessments described in Section 10.2.3.  
If the subject withdraws from the study and also withdraws consent, no further evaluations 
should be performed, and no additional data should be collected.  The Sponsor may retain and 
continue to use any data collected before such withdrawal of consent.   


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Table 5 
Schedule of Assessments 
Assessment 
Visit 1 
Screening 
Visit 2 
Treatment 1 
Visit 3 
Treatment 2 
Visit 4 
Follow-up 
Day -30 
to -3 
Check-in: Day -1  
Dose 1: Day 1 
Target1 
Check-in: Day 7 
Dose 2: Day 8 
(Dose 1 + 7-28 days) 
Target1 
Day 10-15 
(Dose 2 + 2-7 days) 
Informed consent 
x 
— 
— 
— 
Medical history and demographics 
x 
— 
— 
— 
Inclusion/exclusion review 
x 
— 
— 
— 
Concomitant medications 
x 
x 
x 
x 
Height, weight, and physical exam2 
x 
— 
— 
x 
12-lead ECG 
x 
— 
— 
x 
Vital signs 3 
x 
x3 
x3 
x 
Urine pregnancy test 
x 
x 
x 
x 
Urine drug screen 
x 
— 
— 
— 
Hematology & clinical chemistry 
x 
(x) 
x 
x 
HbA1c and C-peptide 
x 
— 
— 
— 
HIV, HCV and HBV 
x 
— 
— 
— 
Gold scale for hypoglycemia 
unawareness 
x 
 
 
 
Evening admission, dinner meal 
— 
x 
x 
— 
Overnight fast and glucose 
monitoring from midnight  
— 
x 
x 
— 
Hypoglycemia induction and 
confirmation of steady state 
— 
x 
x 
— 
Randomization 
— 
x 
— 
— 
Administration of study medication  
— 
x 
x 
— 
Hypoglycemia Symptom 
questionnaire 
— 
x 
x 
— 
Injection site discomfort scales 
— 
x 
x 
— 


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Assessment 
Visit 1 
Screening 
Visit 2 
Treatment 1 
Visit 3 
Treatment 2 
Visit 4 
Follow-up 
Day -30 
to -3 
Check-in: Day -1  
Dose 1: Day 1 
Target1 
Check-in: Day 7 
Dose 2: Day 8 
(Dose 1 + 7-28 days) 
Target1 
Day 10-15 
(Dose 2 + 2-7 days) 
Draize scales for erythema/edema 
— 
x 
x 
— 
Venous plasma glucose (PD)4 
— 
X5 
X5 
— 
Review AE(s) 
— 
x 
x 
x 
Subject Study Drug Assignment 
Questionnaire 
— 
— 
x 
— 
AE=adverse events, BP=blood pressure, ECG= electrocardiogram, HbA1c=glycated hemoglobin, HBV=hepatitis 
B virus, HCV=hepatitis C virus, HIV=human immunodeficiency virus, PD=pharmacodynamic, (X)=repeat if the 
visit is occurring outside of the allowed time window (i.e., more than 28 or 30 days have passed since the prior 
visit), YSI= Yellow Springs Instruments. 
1 Visit 3 should begin (i.e., admission to the CRC between 6 and 8 pm the day before treatment) 7 to 28 days after 
Visit 2; Visit 4 should occur 2 to 7 days after Visit 3. 
2 Excluding breast, pelvic and genitourinary exams. Note: height assessment is not required at Visit 4. 
3 Temperature, respiration, heart rate and BP (after >5 min seated rest) will be performed at all visits. 
Additionally, at visits 2 and 3, heart rate and BP will be repeated immediately prior to, and at 30, 60, 120, and 
180 minutes post-dosing, with ±5 minutes for all procedures. 
4 Via rapid glucose analyzer (YSI 2300 or 2900) before and during hypoglycemia induction, and every 5 minutes 
post study drug dose through 90 minutes, with ±2 minutes for all collections, and at 120, 150 and 180 minutes 
with ±5 minutes for collections. 
5 If plasma glucose is > 350.0 mg/dL (>19.44 mmol/L) upon clinic arrival or if the plasma glucose the morning 
after the overnight stay is > 270.0 mg/dL (> 15.0 mmol/L) the visit should be rescheduled. 
 


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11. 
ASSESSMENTS 
Every effort should be made to ensure that the required tests and procedures are completed as 
described.  However, it is anticipated that there may be circumstances outside the control of the 
Investigator, who will take all steps necessary to ensure the safety and well-being of the subject.  
When a protocol-required test cannot be performed, the Investigator will document the reason(s) 
and any corrective and preventive actions taken to ensure that study processes are adhered to as 
soon as possible.  The study team and the Sponsor will be informed of these incidents in a timely 
manner. 
For all blood and urine collections, an effort should be made to obtain these samples at roughly 
the same time of day (i.e., morning or afternoon) across all visits as well as at the time periods 
specified in the Schedule of Assessments (Table 5).  In addition, visits to the site must occur 
within the pre-defined windows outlined in this protocol; otherwise, they will be considered 
protocol deviations.  
11.1. 
Blood Volume 
There will be approximately 50 PD blood samples of approximately 2 mL drawn at each 
Treatment Visit for a total of about 100 mL of blood per visit.  The two treatment visits will be 
7 to 28 days apart.  There will be 10.5 mL blood samples drawn at Screening, Visit 3 and at the 
Follow-up Visit for analysis of a clinical chemistry panel and hematology, with an additional 
10.5 mL blood sample drawn at Screening for eligibility determination (HbA1c, C-peptide, and 
Serology).  A total of approximately 250 mL of blood will be drawn over the duration of the 
study (Table 6). 
Table 6 
Frequency and Volume of Blood Collections 
Sample Type 
Sample 
Volume 
(mL) 
Number of Sampling Times 
Total 
Volume 
(mL) 
Screening 
Visit 1 
Treatment 
Visits 2 & 3 
Follow-Up 
Visit 4 
Clinical Chemistry 
7.5 
1 
1-2a 
1 
22.5-30 
Hematology 
3 
1 
1-2a  
1 
9-12 
HbA1c 
3 
1 
- 
- 
3 
C-peptide 
2.5 
1 
- 
- 
2.5 
Serology 
5 
1 
- 
- 
5 
PD1 
2 
- 
~50/visit 
- 
200 
Total 
- 
- 
- 
- 
242-252.5 
HbA1c=glycated hemoglobin, PD=pharmacodynamic, (a)perform at V3, perform at V2 only if the visit is 
occurring outside of the allowed time window (i.e., more than 30 days have passed since the prior visit), 
1 Plasma glucose measurements (1 to 2 mL each) at bedside via rapid glucose analyzer. 


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11.2. 
Clinical Laboratory Tests 
The tests outlined in Table 7 will be performed at the specified time points described in the 
Schedule of Activities.   
Table 7 
Clinical and Safety Related Laboratory Tests 
Hematology 
Chemistry 
Urine 
Laboratory 
WBC count 
RBC count 
Hemoglobin 
Hematocrit 
Platelet count 
Glucose 
Creatinine 
Na+ 
K+ 
Ca++ 
Albumin 
Alkaline Phosphatase 
AST 
ALT 
β-hCG1 
Drug screen2 
HbA1c 
C-peptide 
HIVab 
HCVab 
HbsAg 
ALT=alanine aminotransferase, AST=aspartate aminotransferase, β-hCG=beta-human chorionic gonadotrophin, 
HbA1c=glycated hemoglobin, HbsAg=hepatitis B surface antigen, HCVab=hepatitis C virus antibody, 
HIVab=human immunodeficiency virus antibody, RBC=red blood cell, WBC=white blood cell. 
1 Female participants of childbearing potential require a negative pregnancy test at Screening and prior to dosing 
for each of the 2 Treatment Visits. Pregnancy testing will be repeated as the Follow-up visit for safety reasons. 
2 Drug screening performed at Screening will include: cocaine, THC, opiates, amphetamines, methamphetamine, 
and phencyclidine. Analytes other than those listed above may be included in the test kits provided to the sites. 
Investigator will exercise discretion in allowing or excluding a subject from study participation based on a 
positive test for one of these analytes if the subject reports use of a concomitant medication that explains the 
result (e.g., positive urine test for opiates in a subject reporting use of cough syrup containing 
Dextromethorphan).. Except as noted below, continuation in the study requires all tests to be negative. 
A central laboratory will be utilized for analysis of all blood analyses except for rapid plasma 
glucose measurements made during treatment visits.  A procedures manual will be provided to 
each site by the central laboratory.  This manual will cover procedures for the collection, 
processing and shipping of blood samples, and normal ranges for the central laboratory.  
The central laboratory will provide sites with all supplies needed for collection, processing and 
shipping of all blood samples, as well as point-of-care urine pregnancy tests and rapid urine drug 
screen kits. 
If a subject tests positive for a drug of abuse, the subject will normally be excluded from further 
study participation.  However, if a subject reports use of a concomitant medication (prescription 
or over the counter [OTC]) that provides a reasonable explanation for a positive result (other 
than THC), the subject may be allowed to participate in the study at the Investigator’s discretion.  
If the subject is not able to provide a reasonable explanation but still refutes a positive finding, a 
urine sample will be sent to the central laboratory for confirmation.  The result of this 
confirmatory test will be considered definitive.  The remainder of the Screening visit should still 
be completed in this case. 
During treatment visits, plasma glucose concentrations will be measured using a bedside YSI 
rapid glucose analyzer model 2300 or 2900.  At each time point specified in Section 10, the 
results of both the black and white leads to one decimal place will be recorded in the source 


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documents, with the average of the two values rounded up to the nearest one decimal place 
accepted as the plasma glucose level for the time point as per the following examples. 
Example #1: black lead=50.1 and white lead=49.8 
 
Calculation: 50.1+49.8=99.9/2=49.95=50.0 mg/dL recorded result 
Example #2: black lead=74.4 and white lead=74.5 
 
Calculation: 74.4+74.5=148.9/2=74.45=74.5 mg/dL recorded result 
The glucose analyzer will be set to auto-calibrate following the standard practice at each site.  
Before each subject visit, performance checks will be made as per the standard practice at each 
site, and sites will maintain a log of these results. 
The EDC system implemented for this study will allow entry of plasma glucose values in either 
mg/dL or mmol/L.  For reference, both units are provided in the written description and 
summary (Table 4) of the insulin dose adjustment algorithm.  For reference, Table 8 provides a 
conversion chart for key values of plasma glucose referenced throughout the protocol. 
Table 8 
Conversion Table for Plasma Glucose Values 
mg/dL 
mmol/L 
42.0 
2.33 
43.0 
2.39 
49.9 
2.77 
50.0 
2.78 
54.0 
3.00 
60.0 
3.33 
61.0 
3.39 
65.0 
3.61 
66.0 
3.66 
70.0 
3.89 
75.0 
4.17 
80.0 
4.44 
85.0 
4.72 
100 
5.55 
115.0 
6.38 
150.0 
8.33 
270.0 
15.0 
350.0 
19.44 
11.3. 
Electrocardiogram (12-lead ECG) 
Single, supine 12-lead ECGs will be obtained at the pre-defined time-points outlined in the 
Schedule of Assessments (Table 5) as follows: 
• 12-lead ECGs should be performed after the subject has rested quietly for at least 
5 minutes in a supine position. 


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• 12-lead ECGs should be obtained before assessment of BP and heart rate, and prior to 
blood collections. 
11.4. 
Blood Pressure and Heart Rate 
The BP and heart rate will be measured at the times specified in the Schedule of Assessments 
(Table 5).  Additional or changes to collection times, or collection of BP and heart rate using 
automated devices is permitted, as necessary, to ensure appropriate subject safety. 
BP and heart rate will be measured in the seated position with the subject’s arm supported at the 
level of the heart and recorded to the nearest mm Hg. The subject should be rested for at least 
5 minutes before the BP is obtained.  Measurements of both the BP and heart rate must be taken 
at least 2 minutes apart and recorded in the eCRF.  


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12. 
SAFETY AND ADVERSE EVENT (AE) REPORTING 
12.1. 
Definition of an Adverse Event 
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and which is not necessarily required to have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign, symptom, or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.  Examples of AEs include: 
• Abnormal test findings. 
• Clinically significant symptoms and signs. 
• Changes in physical examination findings which are untoward and deemed clinically 
significant by the Investigator. 
• Allergy/hypersensitivity. 
The criteria for determining whether an abnormal objective test finding may be reported as an 
AE are as follows: 
• Test result is associated with accompanying symptoms. 
• Test result requires additional diagnostic testing or medical/surgical intervention. 
• Test result leads to a change in study dosing or discontinuation from the study. 
significant additional concomitant drug treatment or other treatment. 
• Test result is considered to be an AE by the Investigator or Sponsor. 
Repeat of a test based on an abnormal result in the absence of the above conditions does not 
constitute an AE.  Any abnormal test result determined to be an error does not require reporting 
as an AE. 
A TEAE is an AE that either commenced following initiation of study treatment or was present 
prior to study treatment but increased in frequency or severity following initiation of study 
treatment. 
Standard medical terminology should be used in describing AEs.  Informal descriptions should 
be avoided. 
12.2. 
Reporting Adverse Events 
All observed or volunteered AEs regardless of treatment sequence or suspected causal 
relationship to the study treatment will be reported with two exceptions.  Since it is being 
experimentally induced in this study, hypoglycemia will not be considered an AE in this study 
unless the event meets one of the definitions of a SAE (see Section 12.4).  Injection site reactions 
will not be considered an AE unless a skin reaction or pain requires medical intervention.   
For all AEs, the Investigator must pursue and attempt to obtain information adequate to 
determine the outcome of the AE and to assess whether it meets the FDA criteria for 
classification as an SAE, requiring immediate notification to Xeris.   


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For all AEs, follow-up by the Investigator is required until the event resolves or stabilizes at a 
level acceptable to the Investigator to consider it resolved. For unresolved AEs to be considered 
stable, the Xeris Medical Monitor must concur with that assessment. 
As part of ongoing safety reviews conducted by the Sponsor, any non-SAE that is determined to 
be serious (according to the FDA definitions of an SAE) will be reported by the Sponsor as an 
SAE.  To assist in the determination of case seriousness, further information may be requested 
from the Investigator to provide clarity and understanding of the event in the context of the 
clinical study. 
12.3. 
Reporting Period 
For all AEs, the reporting period to Xeris begins from the subject providing informed consent, 
through the Follow-up Visit.  All adverse events will be followed until resolution or the subject 
is medically stable. 
12.4. 
Serious Adverse Events 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death, 
• Is life-threatening, 
• Requires in-patient hospitalization or prolongation of existing hospitalization, 
• Results in persistent or significant disability/incapacity, or 
• Is a congenital anomaly/birth defect. 
Medical and scientific judgment should be exercised in determining whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above.  These should 
also usually be considered serious.  Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm or blood dyscrasias or convulsions which 
do not result in hospitalization. 
12.5. 
Severity Assessment 
On the AE eCRF, the Investigator will use the adjectives “mild,” “moderate,” or “severe” to 
describe the maximum intensity of the AE.  These intensity grades are defined as follows in 
Table 9. 
Table 9 
AE Severity Assessment 
Mild 
Does not interfere with subject’s usual function. 
Moderate 
Interferes to some extent (<50%) with subject’s usual function. 
Severe 
Interferes significantly (≥50%) with subject’s usual function. 
The terms “serious” and “severe” are not synonymous.  The term “severe” is often used to 
describe the intensity (severity) of a specific event.  The event itself, however, may be of 
relatively minor medical significance.  This is not the same as “serious,” which is based on 


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subject/event outcome or action criteria.  Accordingly, a severe event is not necessarily a serious 
event. 
12.6. 
Causality Assessment 
The Investigator will answer “yes” or “no” to the following question when assessing causality 
between an adverse event to the study drug, where an answer of “yes” designates the event as 
related to study drug and a “no” designates the event as not related to study drug: “Is there a 
reasonable possibility that the drug caused the event?” A ‘‘reasonable possibility’’ means that 
there is evidence to suggest a causal relationship between the drug and the adverse event.  The 
Investigator’s assessment of causality must be provided for all AEs.  The Investigator must 
record the causal relationship in the eCRF, as appropriate, and report such an assessment in 
accordance with the serious adverse event reporting requirements, if applicable (Section 12.9).   
12.7. 
Withdrawal Due to Adverse Events 
Withdrawal due to AE should be distinguished from withdrawal due to insufficient response and 
recorded on the appropriate eCRF.  When a subject withdraws due to an SAE, the SAE must be 
reported in accordance with the reporting requirements (see Section 12.9). 
12.8. 
Eliciting Adverse Event Information and Reporting 
The Investigator is to report all directly observed AEs and all AEs spontaneously reported by the 
study subject.  Each study subject will be questioned about AEs.  Each AE is to be assessed to 
determine if it meets the criteria for SAEs.  If an SAE occurs, expedited reporting will follow the 
provisions of Section 12.9. 
12.9. 
Serious Adverse Event Reporting Requirements 
If an SAE occurs, Xeris is to be notified within 24 hours of awareness of the event by the 
Investigator.  In particular, if the SAE is fatal or life-threatening, notification to Xeris must be 
made immediately, irrespective of the extent of available AE information.  This time frame also 
applies to follow-up on previously forwarded SAE reports. 
In the rare event that the Investigator does not become aware of the occurrence of an SAE 
immediately (e.g., a study subject initially seeks treatment elsewhere), the Investigator is to 
report the event within 24 hours after learning of the event and document the time of first 
awareness of the AE.   
A death occurring during the study, during the per-protocol follow-up period, or within 30 days 
after stopping treatment with test drug must be reported to Xeris or its designee(s) immediately, 
whether or not it is considered treatment-related.  Initial SAE reports must be followed by 
detailed descriptions.  These should include copies of hospital case records and other documents 
when requested.  Telephone and e-mail reports must be confirmed promptly either by facsimile 
or by overnight courier or mail. 
Under 21 Code of Federal Regulations (CFR) 312.32(c), Xeris or its designee(s) is required to 
notify the FDA and all participating Investigators in an Investigational New Drug Application 
(IND) safety report (i.e., 7- or 15-day expedited report) of potentially serious risks from clinical 


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trials or any other source as soon as possible, but no later than 15 calendar days after the safety 
information is received and a determination is made that the information qualifies for reporting. 
12.10. 
Non-Serious Adverse Event Reporting Requirements 
All AEs will be reported on the AE page(s) of the eCRF.  AEs should be reported using concise 
medical terminology on the eCRFs as well as on the form for collection of the SAE information. 
12.11. 
AE Reporting Requirements to Regulatory Authorities 
AE reporting by the Sponsor, including suspected serious unexpected adverse reactions, will be 
carried out in accordance with applicable regulations. 
The Investigator must notify the Institutional Review Board (IRB)/Independent Ethics 
Committee (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 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 or its designee. 
12.12. 
Pregnancy 
The active pharmaceutical product in Xeris G-Pen is glucagon, which is in Pregnancy 
Category B.  Female subjects of child bearing potential will be tested (rapid, urine) for 
pregnancy at the Screening Visit.  Any subject found to be pregnant at the Screening Visit 
(Visit 1) will not be enrolled in the treatment phase.  At both Treatment Visits and at the Follow-
Up Visit (i.e., Visits 2, 3 and 4), pregnancy testing will be repeated.  Any subject who is found to 
be pregnant at one of the Treatment Visits will be withdrawn from the study immediately and no 
further study treatments will be given.  Pregnancy at the follow-up visit will be noted, but the 
visit will be completed.  Any pregnancy in a subject who received at least one dose of study drug 
will be followed until resolution (i.e., birth or voluntary or spontaneous termination of the 
pregnancy).  Any pregnancy outcome that meets the criteria for an SAE will be reported as an 
SAE. 
12.13. 
Subject Monitoring 
Subjects will be monitored for AEs throughout the study by the study unit staff.  The principal 
Investigator or designated sub-Investigator will be on site for drug administration and until 
3 hours after administration of study drug to the last subject.  The principal Investigator or 
designated sub-Investigator will also be on call for the remainder of the treatment visit.  If 
necessary, a physician, either at the study site or in a nearby hospital, will administer treatment 
for any AEs. 
Safety parameters, including laboratory results and ECGs, will be assessed by the principal 
Investigator or his delegate using the site’s criteria for clinical laboratory and ECG acceptance 
ranges as suggested guidelines in making the medical assessment. 


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Scheduled safety measurements will be repeated according to appropriate SOPs or upon request 
from a physician.  Any abnormal repeated measurement will be evaluated by a physician and 
repeated if judged necessary.  Further action may be taken on the physician’s request. 
Subjects will be advised to notify their health care professionals (e.g., physician, dentist, and/or 
pharmacist) that they are participating in a clinical research study of a drug called synthetic 
Glucagon Injection before taking any medicines or undergoing any medical procedure. 


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13. 
DATA ANALYSIS AND STATISTICAL METHODS 
13.1. 
General Approach 
Detailed methodology for descriptive and inferential statistical analyses of the data collected in 
the XSGP-304 study will be documented in the statistical analysis plan (SAP).  The SAP will be 
prepared by the Sponsor’s contract research organization (CRO) and agreed upon by the 
Sponsor.  The SAP will be finalized and approved by signature and dates prior to locking the 
database.  Additional graphical representations of the results may be produced after review of the 
data (post hoc).  The SAP will take precedence over the protocol.  The primary objective of the 
study is to test whether G-Pen is no worse than the GlucaGen Hypokit for injection in terms of 
hypoglycemia relief.  Any major modifications of the definition of the Primary Endpoint or 
analysis will be reflected in a protocol amendment. 
13.2. 
Sample Size Calculation 
For the primary endpoint analysis, a failure is recorded if the subject’s plasma glucose fails to 
reach a concentration >70 mg/dL (>3.88 mmol/L) and fails to increase by at least 20.0 mg/dL 
(1.11 mmol/L) within 30 minutes of the decision to administer the dose of glucagon.  The 
determination of a constant clinically non-inferior margin for the cure rate difference is generally 
difficult in practice for a number of reasons.  To alleviate this concern, it has been recommended 
to use an Odds Ratio of cure rates because the corresponding clinically non-inferior margin on 
the difference scale is getting small when the underlying cure rate becomes large and close to 1 
[Lui and Chang(a)]. In this study, it is expected that the recovery (cure rate) will be high and 
approaching 100%. Since this is a cross-over design and each subject will serve as his/her 
control, power is improved.  
The sample size was derived for 80% power of detecting non-inferiority with respect to the Odds 
Ratio of subject recovery rates at an alpha of 0.025 under a cross-over design [Lui and Chang(b)] 
Based on an underlying Odds Ratio of 1.0, and rates of 0.20 versus 0.25, 111 subjects are 
required for the study. With an anticipated 10% drop-out rate, the total sample size for the study 
is 122 randomized subjects. 
13.3. 
Primary Endpoint 
The primary endpoint comparison will be performed using both the Intention to Treat (ITT) and 
the per-protocol (PP) populations.  The evaluable set for the PP population will be defined as all 
randomized subjects who, during both study periods, successfully complete the insulin induction 
procedure, fulfill the criteria for having achieved a hypoglycemic steady state, and successfully 
receive a dose of both study drugs (G-Pen followed by GlucaGen Hypokit, or GlucaGen Hypokit 
followed by G-Pen).  For analysis of the primary endpoint, a failure for the study treatment 
(G Pen or GlucaGen Hypokit) will be recorded if the increase in plasma glucose remains 
< 20 mg/dL (< 1.11 mmol/L) throughout the 0- to 30-minute period from injection of study drug, 
while a success is defined as an increase in plasma glucose ≥ 20 mg/dL (≥ 1.11 mmol/L) in 
subjects from a state of insulin-induced hypoglycemia within the 0- to 30-minute period from 
injection of study drug.  


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Non-inferiority will be established based on the calculated 95% confidence interval for the 
difference in failure rates between G-Pen and GlucaGen Hypokit.  Non-inferiority will be 
declared if the upper limit of the 95% confidence interval for the difference in failure rates is 
≤ 5%; where the absolute failure rate of G-Pen treatment is ≤ 5%.  
13.4. 
Secondary Endpoints 
The following secondary endpoints will be assessed: 
1. Rate of achieving a positive plasma glucose response, defined as either a plasma glucose 
concentration > 70 mg/dL (> 3.88 mmol/L) or an increase in plasma glucose 
concentration > 20 mg/dL (>1.11 mmol/L) within 30 minutes from injection of study 
drug. 
2. Rates of positive symptomatic response, defined as relief of neuroglycopenic symptoms 
30 minutes from a decision to dose. 
3. Rates of positive treatment response, defined as exhibiting either a positive plasma 
glucose response or a positive symptomatic response. 
4. Time to a positive plasma glucose response from injection of study drug. 
5. Time to administer study drug from time to a decision to dose. 
6. PD characteristics of mean plasma glucose concentration (0 to 90 minutes post-dose), 
Cmax, tmax, AUC(0-90), and area under the concentration versus time curve from time 0 to 
180 minutes (AUC(0-180)). 
7. Time to (a) initial relief and (b) complete resolution of autonomic and neuroglycopenic 
symptoms of hypoglycemia from a decision to dose.  
8. Time to resolution of the overall feeling of hypoglycemia from a decision to dose. 
9. Safety endpoints, including: AE/ SAE rates, and changes in vital signs, laboratory 
variables, and physical exam/ECG findings. 
10. Tolerability endpoints measured at 30, 90, and 180 minutes post-dosing, including: 
Draize scale scores for injection site erythema and edema as assessed by the investigator, 
and injection site discomfort and duration as assessed by subject questionnaire responses. 
13.4.1. 
Pharmacodynamic Analyses 
The PD endpoints will be derived from the individual glucose profiles. 
Pharmacodynamic characteristics, including: plasma glucose area under the concentration versus 
time curve (AUC), Cmax, and tmax, time to achieve a ≥ 20.0 mg/dL (≥ 1.11 mmol/L) increase from 
glucose nadir, and time to reach ≥ 70.0 mg/dL (≥ 3.89mmol/L), will be compared between the 
treatment groups from time of glucagon administration.  Comparison between the treatment 
groups will be performed using a mixed model with treatment, period and sequence as terms. 


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13.4.2. 
Hypoglycemia Symptoms 
Symptom relief will be analyzed as aggregate scores for the four autonomic symptoms, four 
neuroglycopenic symptoms, and 8 total (autonomic and neuroglycopenic) symptoms (see 
Appendix 1).  
For analysis, “relief” will be defined as a return to a score no more than one unit above baseline 
symptoms during the euglycemic baseline period. 
The time to the minimal score post baseline will be described and compared between the 
treatment groups using a mixed model with treatment, period and sequence as terms.  Similarly, 
the time to first reporting of “no” for the overall hypoglycemia question (“Do you currently feel 
hypoglycemic?”) will be described and compared between the groups. 
13.4.3. 
Glucagon Preparation Time 
The time between “decision to dose” and time of study drug administration to the abdomen 
around the umbilicus will be measured and called the glucagon preparation time.  This time 
measurement will be used for analysis of study end points.  The total preparation time required to 
inject to the abdomen around the umbilicus from a decision to treat will be compared between 
the treatment groups, as measured between the “time of decision to dose” and “time of study 
drug administration.” 
13.5. 
Safety Analysis 
All safety analyses will be performed using the safety population, namely those subjects 
receiving at least one dose of the study drug. 
The following variables will be compared between the treatment groups for safety purposes: 
• AEs and SAEs 
• Laboratory safety variables (Screening to Final Visit) 
• Physical examination (Screening to Final Visit) 
• Vital signs 
• Body weight (Screening to Final Visit) 
• ECG (Screening to Final Visit) 
• Local tolerability, including: 
o Subjective injection site discomfort as reported by subjects using a 100-mm visual 
analog scale (VAS) and ordinal pain scales (Appendix 2). 
o Erythema and or edema formation at site of injection assessed using the Draize 
scale (Appendix 3). 
13.5.1. 
Adverse Events 
All verbatim AE terms will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and summarized by system organ class (SOC), preferred term (PT), and study drug.  
AE collection will begin from the time of informed consent.  Listings of all AEs (including non-


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TEAEs), SAEs, and TEAEs leading to study drug discontinuation will be provided by treatment 
group, site, subject, verbatim term, MedDRA SOC and PT, start and end dates, seriousness flag, 
severity, relationship to study drug, action taken with study treatment, frequency, and outcome. 
AEs will be summarized overall by the number and percentage of subjects who experienced at 
least 1 AE of the following categories in each treatment group: any AE, any TEAE, any drug 
related TEAE (defined as possibly, probably, or definitely related to study drug), any severe or 
life-threatening 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 treatment group will be 
tabulated by SOC and PT; by SOC, PT, and severity (mild, moderate, and severe/life-
threatening/death); and by SOC, PT, and relationship (unrelated [defined as unrelated or unlikely 
related to study drug] or related [defined as possibly, probably, or definitely related] to study 
drug).  
For all analyses of TEAEs, if the same AE (based on PT) was reported for the same subject more 
than once, then the AE will be counted only once for that PT and at the highest severity and 
strongest relationship to study drug.  
The numbers and percentages of subjects reporting an SAE or reporting a TEAE leading to 
premature discontinuation of study drug in each treatment group will be summarized by SOC 
and PT. 
Subjects will be analyzed for safety according to the study treatment received. 
13.5.2. 
Laboratory Safety Assessments 
Laboratory values (biochemistry and hematology) will be flagged if outside the normal range 
and a listing of clinically significant abnormal values will be presented.  Laboratory assessments 
will be summarized at Screening and at the Follow-up Visit.  Significant deviations/changes 
from the Screening Visit to the Final Visit will be documented as AEs if the Investigator judges 
them to be clinically significant. 
13.5.3. 
Physical examination 
Subjects with any findings in the physical examination evaluation at Screening will be listed.  
Changes to physical examination from Screening to end of study will be recorded as AEs if the 
Investigator judges them to be clinically significant. 
13.5.4. 
Vital signs and body weight 
Vital signs and body weight will be summarized by descriptive statistics.  Significant changes 
from pre- to post-dosing at treatment visits or from the Screening Visit to the Final Visit will be 
documented as AEs if the Investigator judges them to be clinically significant.  
13.5.5. 
ECG 
Any clinically significant ECG changes will be recorded and followed as appropriate.  The 
Investigator’s evaluations will be summarized in a data listing. 


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Significant deviations/changes from the Screening Visit to the Final Visit will be documented as 
AEs if the Investigator judges them to be clinically significant. 
13.5.6. 
Local Tolerability 
The incidence of any injection site discomfort (score > 0 on the ordinal rating scale) will be 
analyzed descriptively.  The incidences of erythema and edema will be analyzed in a similar 
manner.  Descriptive statistics (only) will be provided for time of onset and duration (of 
discomfort) and discomfort description (i.e., pain, irritation, itching, etc.).  Mean VAS scores 
will be compared between the treatments. 
13.6. 
Subgroup Analysis 
Analysis of subgroups is not planned or powered for this study.  Any subpopulations analyzed 
will be described in the SAP. 
13.7. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized for all subjects overall and by 
treatment.  Summary statistics (e.g., number of subjects, mean and standard deviation, median 
and range) will be generated for all continuous variables (i.e., age and weight,) and the number 
and percentage of subjects within each category will be presented for all categorical variables 
(i.e., gender, race, ethnicity,). 


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14. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Quality assurance and quality control systems will be implemented and maintained with 
Standard Operating Procedures by the Sponsor, as appropriate, to ensure that this clinical study is 
conducted and data are generated, documented (recorded), and reported in compliance with the 
protocol, International Conference on Harmonisation (ICH) E6 Good Clinical Practice (GCP): 
Consolidated Guidance, and the applicable regulatory requirements. 
This study will be monitored by the Sponsor in accordance with GCP, and may be audited or 
reviewed by an independent Quality Assurance (QA) department, IRB/EC, and/or regulatory 
authorities.  This implies that monitors and auditors/inspectors will have the right to inspect the 
study sites at any time during and/or after completion of the study and will have direct access to 
data/source documents, including the subject’s file.  By participating in this study, Investigators 
agree to this requirement. 
Measures will be undertaken to protect the confidentiality of records that could identify subjects, 
respecting the privacy and confidentiality rules in accordance with applicable regulatory 
requirements. 


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15. 
DATA HANDLING, RECORD KEEPING, MONITORING AND 
AUDITS 
15.1. 
Case Report Forms/Electronic Data Record 
Data collection is the responsibility of the clinical study staff under the supervision of the 
Investigator.  During the study, the Investigator will maintain complete and accurate 
documentation for the study. 
As defined in the ICH Guidelines for GCP (E6(R2)), Section 1.52, source documents may 
include:  original documents, data, and records (e.g., hospital records, clinical and office charts, 
laboratory notes, memoranda, participant’s diaries or evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate and complete, microfiches, photographic negatives, microfilm or 
magnetic media, x-rays, participant files, and records kept at the pharmacy, at the laboratories, 
and at medico-technical departments involved in the clinical study). 
As used in this protocol, the term eCRF is understood to refer to an electronic data record.  An 
eCRF is required and should be completed for each individual subject.  The completed original 
eCRFs are the property of Xeris and should not be made available in any form to third parties, 
except for authorized representatives of Xeris or appropriate regulatory authorities, without 
written permission from Xeris.  
Completion of eCRFs will be accomplished using a 21 CFR Part 11 compliant web-based EDC 
system. Sites will use existing computers to enter all other study-related data into the EDC 
system.  
The Investigator has the responsibility for the collection and reporting of all clinical, safety and 
laboratory data entered on the eCRFs and any other data collection forms (source documents) 
and ensuring that these are accurate, authentic, attributable, complete, consistent, legible, 
contemporaneous, enduring and available when required.  The eCRFs must be signed by the 
Investigator or by an authorized study staff member to attest that the data contained in the eCRFs 
is true.  Any corrections to entries made in the eCRFs or source documents must be dated, 
initialed and explained (if necessary), and should not obscure the original entry. 
In most cases, the source documents are the hospital’s or physician’s subject chart.  In these 
cases, data collected on the eCRFs must match the data in those charts.  In some cases, the eCRF, 
or part of the eCRF, may also serve as source documents.  In these cases, a document should be 
available at the Investigator’s site as well as at Xeris and clearly identify those data that will be 
recorded in the eCRF, and for which the eCRF will stand as the source document. Queries 
generated by Data Management will be sent to the study site for resolution.  The Investigator is 
responsible for the review and approval of all responses to eCRF queries. 
15.2. 
Record Retention 
To enable evaluations and/or audits from regulatory authorities or Xeris, the Investigator agrees 
to keep records, including the identity of all participating subjects (sufficient information to link 
records, e.g., eCRFs and hospital records), all original signed informed consent documents, 
copies of all eCRFs, safety reporting forms, source documents, and detailed records of treatment 


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disposition, and adequate documentation of relevant correspondence (e.g., letters, meeting 
minutes, telephone calls reports).  The records should be retained by the Investigator according 
to the ICH, local regulations, or as specified in the Clinical Study Agreement, whichever is 
longer.  The Investigator must obtain written permission from Xeris before disposing of any 
records, even if retention requirements have been met. 
15.3. 
Monitoring 
Monitoring and auditing procedures developed by Xeris and/or its designee will be implemented 
to ensure compliance with FDA and ICH GCP guidelines. 
The Xeris designated representative (the monitor or auditor) will contact the Investigator and 
conduct regular visits to the clinical site.  The monitor will be expected and allowed to verify the 
Investigator’s qualifications, to inspect clinical site facilities, and to inspect study records, 
including proof of IRB/IEC review, with the stipulation that subject confidentiality will be 
maintained in accordance with regional, local, and federal regulations (including Health 
Insurance Portability and Accountability Act of 1996 [HIPAA] requirements).  The monitor will 
also be responsible for confirming adherence to the study protocol, inspecting eCRFs and source 
documents, and ensuring the integrity of the data.  Electronic CRFs will be checked for accuracy, 
completeness, and clarity and will be cross-checked for consistency with source documents, 
including laboratory test reports and other subject records.  Instances of missing or 
uninterpretable data will be resolved in coordination with the Investigator.  
The monitor/auditor will also investigate any questions concerning adherence to regulatory 
requirements.  Any administrative concerns will be clarified and followed.  The monitor will 
maintain contact with the site through frequent direct communications with the study site by 
e-mail, telephone, facsimile, and postal mail.  The Investigator and all other site personnel agree 
to cooperate fully with the monitor and will work in good faith with the monitor to resolve all 
questions raised, and difficulties detected by the monitor. 
15.4. 
Audits and Inspections 
The Investigator understands that regulatory authorities, the IRB/IEC, and/or Xeris or their 
designees have the right to access all eCRFs, source documents, and other study documentation 
for on-site audit or inspection and will retain this right from the start of the study to at least 
2 years after the last approval of a marketing application or for at least 2 years after clinical 
development of the study drug for the indication being studied has been discontinued.  The 
Investigator is required to guarantee access to these documents and to cooperate with and support 
such audits and inspections. 


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16. 
ETHICAL CONSIDERATIONS 
16.1. 
Conduct 
This study will be conducted in compliance with the current version of Declaration of Helsinki, 
ICH E6, local and regional ethical and regulatory requirements, including the Federal Food, 
Drug and Cosmetic Act, U.S. applicable CFR (title 21), any IRB/IEC requirements relative to 
clinical studies.   
Should a conflict arise, the Investigator will follow whichever law or guideline affords the 
greater protection to the individual subject.  The Investigator will also ensure thorough 
familiarity with the appropriate administration and potential risks of administration of the study 
drug, as described in this protocol and the G-Pen Investigator’s Brochure, prior to the initiation 
of the study. 
16.2. 
Institutional Review Board and Ethics Committee 
The IRB/IEC must be a properly constituted board or committee operating in accordance with 
21 CFR Part 56, “Institutional Review Boards.”  This protocol, any protocol amendments, the 
associated informed consent forms, and the informed consent procedures must be submitted to 
the IRB/IEC for review and approved before the enrollment of any subject into the study.  Study 
drug may not be shipped to the Investigator until Xeris has received a copy of the letter or 
certificate of approval from the IRB/IEC for the protocol and any protocol amendments. 
All types of subject recruitment or advertising information must be submitted to Xeris or its 
designee and to the IRB/IEC for review and approval prior to implementation.  IRB approval of 
any protocol amendments must be received before any of the changes outlined in the 
amendments are put into effect, except when the amendment has been enacted to eliminate a 
potential hazard to study subjects.  In such cases, the chair of the IRB/IEC should be notified 
immediately, and the amendment forwarded to the IRB/IEC for review and approval. 
It is the responsibility of the Investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, e.g., 
recruitment advertisements from the IRB/IEC.  All correspondence with the IRB/IEC should be 
retained in the Investigator File.  Copies of IRB/IEC approvals should be forwarded to Xeris. 
16.3. 
Subject Information and Consent 
All parties will ensure protection of subject personal data and will not include subject names on 
any Sponsor forms, reports, publications, or in any other disclosures.  Subject names, address, 
date of birth and other identifiable data will be replaced by a numerical code consisting of a 
numbering system provided by Xeris to de-identify the study subject.  In the case of data 
transfer, Xeris will maintain confidentiality and protection of subject personal data. 
The informed consent document used in this study, and any changes made during the course of 
the study, must be prospectively approved by both the IRB/IEC and Xeris before use.  The 
Investigator must ensure that each study subject is fully informed about the nature and objectives 
of the study and possible risks associated with participation.  The Investigator, or a study staff 
member designated by the Investigator, will obtain written informed consent from each subject 
before any study-specific activity is performed.  The Investigator will retain the original of each 


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subject’s signed ICF.  Receipt of written informed consent will be documented in each subject’s 
or potential subject’s eCRF.  The signed informed consent document must remain on file at the 
study site and be available for verification by the study monitors at all times. 
16.4. 
Subject Recruitment 
All types of subject recruitment or advertising information must be submitted to Xeris or its 
designee and to the IRB/IEC for review and approval prior to implementation.  Advertisements 
approved by the IRB/IEC may be used as recruitment procedures. 
16.5. 
Reporting of Safety Issues and Serious Breaches of the Protocol 
In the event of any prohibition or restriction imposed (i.e., clinical hold), or if the Investigator is 
aware of any new information which might influence the evaluation of the benefits and risks of 
the investigational product, Xeris should be notified immediately.  In addition, the Investigator 
will inform Xeris immediately of any urgent safety measures taken by the Investigator to protect 
study subjects against any immediate hazard, and of any serious breaches of this protocol. 


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17. 
PROCEDURES FOR MODIFYING THE PROTOCOL OR 
TERMINATING THE STUDY 
17.1. 
Protocol Modifications and Deviations 
The principal Investigator must sign this protocol and its amendments (if any) before initiating 
the study at a particular site.  The Investigator will make all reasonable efforts to comply with the 
written protocol.  Protocol modifications to ongoing studies that affect the safety of subjects or 
that alter the scope of the investigation, the scientific quality of the study, the experimental 
design, dosing, study assessments, the number of subjects exposed to test drug, or subject 
selection criteria must be made only after consultation between Xeris and the Investigator.  All 
protocol modifications must be reviewed and approved by the IRB/IEC before the revised 
protocol can be implemented.  Emergency revisions that eliminate an apparent hazard to subjects 
do not require preapproval by the IRB/IEC.  However, the IRB/IEC must be notified in writing 
as soon as possible after the modification has been made.  A copy of this communication must be 
forwarded to Xeris.  All departures from the protocol must be fully documented in the source 
documents and the eCRFs of the subjects involved. Protocol deviations will be tracked in an 
electronic system implemented by the Sponsor or designated representative. 
17.2. 
Study Termination 
The study may be prematurely terminated at any time because of a regulatory authority decision, 
change in opinion of the IRB/IEC, safety problems resulting in subject deaths, or at the 
discretion of Xeris or the principal Investigator.   
Circumstances that may warrant premature study termination include, but are not limited, to the 
following: 
• Determination of unexpected, significant, or unacceptable risk to subjects, 
• Failure to enter subjects at an acceptable rate, 
• Insufficient adherence to the requirements of the protocol, 
• Insufficient provision of complete and evaluable data, or 
• Plans to modify, suspend, or discontinue development of the study drug. 
If the study is prematurely terminated or discontinued, Xeris will promptly notify the 
Investigators and document the reason for study termination.  Specific procedures for 
termination will be arranged by the Sponsor in coordination with the Investigators.  After 
notification, the Investigators must contact all participating subjects within 7 days.  All study 
materials must be collected and all eCRFs completed to the greatest extent possible, and all study 
materials must be returned to Xeris or its designee within an additional 28 days. 


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18. 
REFERENCES 
1. American Diabetes Association (ADA) Workgroup on Hypoglycemia: Defining and 
reporting hypoglycemia in diabetes. Diabetes Care 28:1245–1249, 2005  
2. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions 
and Complications (DCCT/EDIC) Study Research Group: Long-term effect of diabetes 
and its treatment on cognitive function. N Engl J Med 356:1842–1852, 2007.  
3. Skrivarhaug T, Bangstad H-J, Stene LC, Sandvik L, Hanssen KF, Joner G: Long-term 
mortality in a nationwide cohort of childhood-onset type 1 diabetic patients in Norway. 
Diabetologia 49:298 –305, 2006.  
4. U.K. Hypoglycaemia Study Group: Risk of hypoglycaemia in types 1 and 2 diabetes: 
effects of treatment modalities and their duration. Diabetologia 50:1140 –1147, 2007. 
5. McLeod KM, Hepburn DA, Frier BM. Frequency and morbidity of severe 
hypoglycaemia in insulin-treated diabetic patients. Diabet. Med. 1993. 10: 238-245. 
6. Centers for Disease Control (CDC) and Prevention. National diabetes fact sheet: national 
estimates and general information on diabetes and prediabetes in the United States, 2011. 
Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease 
Control and Prevention, 2011 
7. Close Concerns, Inc.  Market Survey (2,808 respondents).  2010.  
8. Glucagon for injection Prescribing Information.  Eli Lilly and Company, revised July 
2018 
9. GlucaGen ® (glucagon) for injection Prescribing Information.  Novo Nordisk, Inc. revised 
July 2018.  
10. GlucaGen® Hypokit 1 mg Summary of Product Characteristics. Novo Nordisk, Inc. 
revised February 2015. https://www.medicines.org.uk/emc/product/1289/smpc 
11. Jelinek LJ, Lok S, Rosenberg GB, Smith RA, Grant FJ, Biggs S, Bensch PA, Kuijper JL, 
Sheppard PO, Sprecher CA, et al.  Expression cloning and signaling properties of the rat 
glucagon receptor. Science. 1993 Mar 12; 259(5101): 1614-6.  
12. Wakelam MJ, Murphy GJ, Hruby VJ, Houslay MD.  Activation of two signal-
transduction systems in hepatocytes by glucagon.  Nature. 1986 Sep 4-10; 323(6083): 68-
71.  
13. FDA CDER #1.  Glucagon (glucagon hydrochloride).  NDA No. 01-2122.  Eli Lilly and 
Company, Indianapolis, IN, November 14, 1960. 
14. Eistrup, C., Hjortkjæ, R. K., Pickersgill, N., Virgo, D. M. and Woolley, A. P. A. H. 
(1993), Glucagon Produced by Recombinant DNA Technology: Repeated Dose Toxicity 
Studies, Intravenous Administration to CD Rats and Beagle Dogs for Four Weeks. 
Pharmacology & Toxicology, 73: 103–108. 
15. FDA CDER #2.  rDNA Glucagon for Injection, Pharmacology and Toxicology Review.  
NDA No. 20-928.  Eli Lilly and Company, Indianapolis, IN, April 16, 1998. 


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16. Nermoen I, Jorde R, Sager G, Sundsfjord J and Birkeland K. Effects of Exercise on 
Hypoglycaemic Responses in Insulin-Dependent Diabetes Mellitus. Diabetes & 
Metabolism. 1998. 24: 131-6. 
17. Lui and Chang, Test non-inferiority (and equivalence) based on the odds ratio under a 
simple crossover trial, Statistics in Medicine, published online 12 January 2011 in Wiley 
Online Library. 
18. Lui and Chang, Exact sample-size determination in testing non-inferiority under a simple 
crossover trial, Pharmaceutical Statistics, published online 10 January 2012 in Wiley 
Online Library. 


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APPENDICES 
APPENDIX 1. HYPOGLYCEMIA SYMPTOM QUESTIONNAIRE 
Investigative Site Instructions: The subject should complete the Hypoglycemia Symptom 
Questionnaire at the following time points: 
• Just before the IV bolus push dose of insulin is given at the start of the hypoglycemia 
induction procedure. 
• Every time blood is drawn for evaluation of plasma glucose concentration during the 
induction procedure. 
•  Just before study drug is administered. 
• Every 5±2 minutes after glucagon is administered until 90 minutes post-dosing. (Data 
will be collected 18 times). 
• Every 30±5 minutes (coinciding with plasma glucose measurements) between 90 and 
180 minutes post study drug dosing (90 minutes, 120 minutes, and 180 minutes). 
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 rate the current intensity (severity) of each of the following 
symptoms on a scale of 1-6, with a minimum score of “1” meaning the symptom was absent and 
a maximum score of “6” meaning the symptom was severe. For the final question, please answer 
“yes” or “no.” 
Neuroglycopenic Symptoms 
Severity Score (1-6) 
Dizziness 
 
Blurred vision 
 
Difficulty in thinking 
 
Faintness 
 
Autonomic Symptoms 
Severity Score (1-6) 
Sweating 
 
Tremor 
 
Palpitations 
 
Feeling of nervousness 
 
Overall Assessment of Hypoglycemia 
Yes/No 
Do you currently feel hypoglycemic? 
 


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APPENDIX 2. INJECTION SITE DISCOMFORT ASSESSMENT 
Visual Analog Scale (VAS) for Injection Site Discomfort 
Investigative Site Instructions: The subject should complete the 100-mm Visual Analog Scale 
(VAS) for Injection Site Discomfort at 30±5 and 90±5 minutes after injection of study drug, and 
again at 180±5 minutes after injection of study drug. The 180-minute evaluation after injection 
of study drug is still required even if glucose monitoring ends at an earlier timepoint.  The 
subject will complete the VAS by drawing a single vertical line through the scale 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 time point, 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 
point on the VAS corresponding to their level of discomfort, and study staff will enter a vertical 
line at that point. Documentation will be provided on each completed questionnaire as to who 
completed the form. 
Please verify the length of the VAS line to be 100-mm before providing it to the subject. 
Subject Instructions: Ignoring any pain from insertion of the needle, please draw a single vertical 
line through the scale below that corresponds to the intensity (severity) of any discomfort you are 
feeling right now at the study drug injection site. 
Discomfort could include stinging, burning, tingling, throbbing or pain. The further to the right 
you make your vertical mark, indicates the more intense discomfort you are feeling. 
You should normally draw a straight line across the scale to indicate your current level of 
discomfort. However, if you are currently feeling no discomfort, you should circle the vertical 
line on the left end of scale (above the word “no”). If you are currently feeling the worst 
discomfort possible, you should circle the vertical line on the right end of the scale. 
 
 ├                                                                                    ┤ 
No Discomfort 
 
 
 
 
 
 
 
 
Worst Possible Discomfort 
 


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Injection Site Discomfort Description and Duration Questionnaire 
Study Personnel Instructions:  Question 1a should be completed by the subject at 30±5 minutes 
after injection of study drug.  Any subject reporting discomfort other than “none,” should 
complete Question 1b at the same time.  All subjects should also answer Question 1c at the end 
of the visit (180 ±5 mins post-injection).  The goal is for the subject to report the qualitative 
nature and duration of discomfort, if any, associated with injection of study drug, ignoring any 
transient pain associated with needle insertion. 
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 question 1a and, if applicable to you, questions 1b and 1c. In 
answering these questions, you should ignore any pain from insertion of the needle. 
1a. How would you describe any discomfort you felt from the study drug? (Check all that apply): 
______None (Please ignore question 1b.) 
______Pain (e.g., throbbing, soreness, muscle ache) 
______Itching 
______Tingling, twitching or numbness 
______Irritation (e.g., burning, stinging) 
 
Other or additional comments:_____________________________________________________ 
 
1b. About how long did the discomfort last after the injection? (Check one): 
_____Less than 1 minute 
_____1-2 minutes 
_____3-5 minutes 
_____6-9 minutes 
_____at least 10 minutes (Please complete question 1c before leaving the clinic.) 
 
1c. In total, how long did the discomfort last after the injection? (Please enter a number below): 
 
_____ Minutes 
 


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APPENDIX 3. DRAIZE SCALE 
• 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. 
• The injection site should be examined for formation of both erythema and edema and 
results recorded in the Case Report Form.  Evaluations of the injection site should be 
performed at 30±5 and 90±5 minutes after injection of study drug, and again at the 
end of the treatment visit at 180±5 minutes after injection of study drug. The 180-
minute evaluation is still required even if glucose monitoring ends at an earlier 
timepoint. 
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 
Well defined erythema 
2 
Well defined edema 
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 
 


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APPENDIX 4. GOLD SCALE 
Hypoglycemia Awareness 
Study Personnel Instructions:  The following question should be answered by the subject at the 
Screening visit. This score is being collected for information purposes only; there are no scores 
that are considered exclusionary. 
 
Subject Instructions: Please respond to the following question using the scale of 1-7 below. A 
minimum score of “1” indicates that you are always aware of an onset of hypoglycemia. A 
maximum score of “7” indicates that you are never aware of an onset of hypoglycemia.  
 
To what extent are you aware of the onset of hypoglycemia? 
 
 
 
Your score: _____ 
 
 
 
 
Never 
 


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APPENDIX 5. SUBJECT STUDY DRUG ASSIGNMENT 
QUESTIONNAIRE 
 
Study Personnel Instructions:  The subject will be instructed not to talk with the study staff about 
their impression of which product he/she received until the end of the second treatment visit.  
Before leaving the clinic at the end of Visit 3, the subject should complete the questions below to 
indicate which study treatment they believe they received at each visit.  Please ensure that the 
subject checks only one box for each question and does not select each treatment more than 
once.  If the subject indicates they do not know, please ask them to make a guess. 
Subject Instructions: Please respond to the following questions by picking only one of the two 
choices per question.  
1a. Which study drug do you believe you received during your first treatment visit, which 
occurred before today’s visit. (Check one): 
 
Xeris Glucagon, G-Pen, administered by auto-injector  
 
 
Comparator Glucagon, GlucaGen Hypokit, administered by needle and syringe  
 
1b. Which study drug do you believe you received during your second treatment visit, which 
happened today. (Check one): 
 
Xeris Glucagon, G-Pen, administered by auto-injector  
 
 
 
Comparator Glucagon, GlucaGen Hypokit, administered by needle and syringe    
 
 
 
 

SAP_001.pdf: 
Cover Page
1 
Xeris Pharmaceuticals, Inc. 
Confidential and Proprietary 
Statistical Analysis Plan for: 
Study No. XSGP-304 
Title: G-Pen (glucagon injection) compared to Glucagen® HypoKit® (glucagon) for induced 
hypoglycemia rescue in adults with T1D: a Phase 3 multi-center, randomized, controlled, single 
blind, 2-way crossover study to evaluate efficacy and safety 
NCT03738865 
Document Date: 4 April 2019 


 
Protocol Number: XSGP-304 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Prepared for: 
Xeris Pharmaceuticals 
 
Version 1.0 
Date: 04 April 2019 
 
 
Study Biostatistician 
EmpiriStat, Inc. 
 
___________________________________ Date: __________ 
 
 
Medical 
Xeris Pharmaceuticals 
___________________________________ Date: __________ 
 
Clinical 
Xeris Pharmaceuticals 
___________________________________ Date: __________ 
 
Regulatory 
Xeris Pharmaceuticals 
___________________________________ Date: __________ 
 
Biostatistics 
Xeris Pharmaceuticals 
___________________________________ Date: __________ 
 
 
 
 
 
 
G-PEN (GLUCAGON INJECTION) COMPARED TO GLUCAGEN® HYPOKIT® 
(GLUCAGON) FOR INDUCED HYPOGLYCEMIA RESCUE IN ADULTS WITH T1D: 
A PHASE 3 MULTI-CENTER, RANDOMIZED, CONTROLLED, SINGLE BLIND, 2-
WAY CROSSOVER STUDY TO EVALUATE EFFICACY AND SAFETY 


Xeris Pharmaceuticals, Inc.                                                                                                                                              Private and Confidential 
Statistical Analysis Plan                                                                                                                                                     XSGP-304 
Version 1.0                                                                                                                                                                         04 April 2019 
 
Page 2 of 34 
 
 
TABLE OF CONTENTS 
PAGE 
 
TABLE OF CONTENTS ......................................................................................................... 2 
1 
LIST OF ABBREVIATIONS ................................................................................. 4 
2 
INTRODUCTION ................................................................................................... 5 
3 
STUDY OBJECTIVES AND ENDPOINTS .......................................................... 5 
3.1 
Primary Objective.................................................................................................... 5 
3.2 
Secondary Objectives .............................................................................................. 5 
3.3 
Endpoints ................................................................................................................. 5 
3.3.1 
Primary Endpoint .................................................................................................... 5 
3.3.2 
Secondary Endpoints ............................................................................................... 5 
4 
STUDY DESIGN .................................................................................................... 6 
4.1 
General Design ........................................................................................................ 6 
4.2 
Sample Size Determination ..................................................................................... 8 
4.3 
Randomization......................................................................................................... 8 
4.4 
Unblinding ............................................................................................................... 8 
4.5 
Changes in the Conduct of the Study ...................................................................... 9 
5 
STATISTICAL AND ANALYTICAL PROCEDURES ........................................ 9 
5.1 
Analysis Populations and Treatment Groups .......................................................... 9 
5.1.1 
Intent-to-Treat Population (ITT) ............................................................................. 9 
5.1.2 
Modified Intent-to-Treat Population (mITT) .......................................................... 9 
5.1.3 
Per-Protocol Population (PP) .................................................................................. 9 
5.1.4 
Safety Population .................................................................................................... 9 
5.1.5 
Treatment groups ..................................................................................................... 9 
5.2 
Reference Dates, Analysis Periods, Analysis Visits, and Baseline ....................... 10 
5.3 
Analysis Variables ................................................................................................. 14 
5.3.1 
Subject’s Disposition and Analysis Sets ............................................................... 14 
5.3.2 
Demographics and Baseline Characteristics ......................................................... 14 
5.3.3 
Medical History ..................................................................................................... 14 
5.3.4 
Pregnancy and Childbearing Potential .................................................................. 15 
5.3.5 
Prior and Concomitant Medications ...................................................................... 15 
5.3.6 
Efficacy Variables ................................................................................................. 16 
5.3.6.1 
Primary Endpoint .................................................................................................. 16 
5.3.6.2 
Secondary Endpoints ............................................................................................. 16 
5.3.6.3 
Safety Variables .................................................................................................... 19 
6 
STATISTICAL METHODS ................................................................................. 22 
6.1 
General Considerations ......................................................................................... 22 
6.1.1 
General guideline for descriptive summaries ........................................................ 22 


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Statistical Analysis Plan                                                                                                                                                     XSGP-304 
Version 1.0                                                                                                                                                                         04 April 2019 
 
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6.2 
Euglycemic Baseline ............................................................................................. 23 
6.3 
Hypoglycemic Baseline ......................................................................................... 23 
6.4 
General guideline for define the protocol time ..................................................... 23 
6.5 
Analysis of Primary Endpoints ............................................................................. 24 
6.6 
Secondary Endpoints ............................................................................................. 24 
6.6.1 
Binary Responses .................................................................................................. 24 
6.6.2 
Pharmacodynamics Analyses ................................................................................ 24 
6.6.3 
Neuroglycopenic, Autonomic, and Total Symptom scores ................................... 25 
6.6.4 
Time-to-Event Analyses ........................................................................................ 25 
6.6.5 
Study Drug Assignment Questionnaire ................................................................. 25 
6.7 
Subgroup Analysis ................................................................................................ 25 
6.8 
Interim Analysis .................................................................................................... 26 
7 
DATA HANDLING CONVENTIONS ................................................................ 26 
7.1 
Missing Data.......................................................................................................... 26 
7.2 
Repeated and Unscheduled Visits ......................................................................... 26 
7.3 
Conversion of Plasma Glucose Values ................................................................. 26 
8 
PLANNED LISTINGS, TABLES AND FIGURES ............................................. 26 
9 
SOFTWARE REQUIREMENTS.......................................................................... 26 
10 
DEVIATIONS FROM PLANNED ANALYSIS .................................................. 26 
APPENDIX 1: LIST OF TABLES, LISTINGS AND FIGURES ......................................... 27 
APPENDIX 2: CODE FRAGMENTS................................................................................... 34 
Risk difference test for binary response................................................................................. 34 
Mixed model .......................................................................................................................... 34 
Time-to-Event ........................................................................................................................ 34 
Study Drug Assignment ......................................................................................................... 34 
 


Xeris Pharmaceuticals, Inc.                                                                                                                                              Private and Confidential 
Statistical Analysis Plan                                                                                                                                                     XSGP-304 
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1 LIST OF ABBREVIATIONS 
Abbreviation or special 
term 
Explanation 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
BP 
Blood Pressure 
Cmax 
Maximum Plasma Concentration 
ECG 
Electrocardiogram 
GCP 
Good Clinical Practice 
CRO 
Contract Research Organization 
HbA1c 
Glycated hemoglobin 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HR 
Heart Rate 
ICF 
Informed Consent Form 
IB 
Investigator’s Brochure 
MedDRA 
Medical Dictionary for Regulatory Activities 
QTN 
Quartesian LLC 
PD 
Pharmacodynamics 
PGR 
Positive Glucose Response 
SAE 
Serious Adverse Event 
Tmax 
Time to Maximum Plasma Concentration 
T1D 
Type 1 Diabetes Mellitus 
VAS 
Visual Analog Scale 
WHO 
World Health Organization 
 


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2 INTRODUCTION 
This documentation describes the planned data analyses for clinical trial XSGP-304 
sponsored by Xeris Pharmaceuticals, Inc. 
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different these differences will be identified. If additional 
analyses are required to supplement objectives described in the SAP, they may be performed 
and will be identified in the Clinical Study Report (CSR). 
3 STUDY OBJECTIVES AND ENDPOINTS 
3.1 Primary Objective 
The primary objective of this study is to demonstrate that G-Pen 1 mg (test) is not inferior to 
GlucaGen Hypokit 1 mg (reference), in Type 1 diabetic (T1D) subjects in a state of insulin-
induced hypoglycemia. 
3.2 Secondary Objective 
The secondary objective of this study is to evaluate the safety and tolerability of G-Pen 1 mg 
versus GlucaGen Hypokit 1 mg in the study population. 
3.3 Endpoints 
3.3.1 Primary Endpoint 
For the primary endpoint, groups will be compared for rates of achieving a positive plasma 
glucose response (PGR), defined as either a plasma glucose concentration > 70 mg/dL (> 
3.88 mmol/L) or an increase in plasma glucose concentration > 20 mg/dL (> 1.11 mmol/L), 
within 30 minutes of study drug injection. 
3.3.2 Secondary Endpoints 
For the secondary endpoints, treatment groups will be compared based on each of the 
following:  
1. Rate of achieving a plasma glucose concentration > 70 mg/dL (> 3.88 mmol/L) within 
30 minutes from injection of study drug.  
2. Rate of achieving an increase in plasma glucose concentration > 20 mg/dL 
(> 1.11 mmol/L) within 30 minutes from injection of study drug.  
3. Rates of positive symptomatic response, defined as relief of neuroglycopenic 
symptoms within 30 minutes from a decision to dose.  
4. Rates of positive treatment response, defined as exhibiting either a positive plasma 
glucose response (within 30 minutes from injection of study drug) or a positive 
symptomatic response (within 30 minutes from a decision to dose).  
5. Time to a positive plasma glucose response from injection of study drug.  
6. Time to administer study drug from a decision to dose.  


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7. Pharmacodynamic (PD) characteristics of mean plasma glucose concentration (0 to 90 
minutes post-dose), maximum observed concentration (Cmax), time to maximum 
observed concentration (Tmax), area under the concentration versus time curve from 
time 0 to 90 minutes (AUC0-90), and area under the concentration versus time curve 
from time 0 to 180 minutes (AUC0-180).  
8. Time to (a) initial relief and (b) complete resolution of autonomic and 
neuroglycopenic symptoms of hypoglycemia from a decision to dose.  
9. Time to resolution of the overall feeling of hypoglycemia from a decision to dose.  
10. Safety endpoints, including adverse event (AE)/serious adverse event (SAE) rates, 
and changes in vital signs, laboratory variables, and physical exam/electrocardiogram 
(ECG) findings.  
11. Tolerability endpoints, including: Draize scale scores for injection site erythema and 
edema as assessed by the investigator, and injection site discomfort and duration as 
assessed by subject questionnaire responses. 
4 STUDY DESIGN 
4.1 General Design 
This is a non-inferiority, multi-center, randomized, active-controlled, single-blind, two-way 
crossover efficacy and safety in-patient study in subjects with Type 1 diabetes mellitus. 
Subjects will be randomized to one of two treatment sequences below and will receive one 
dose within each treatment period separated by a washout period. 
Table 1:  Randomized Treatment Sequence 
 
Treatment 
Sequence 
Treatment 1 
Treatment 2 
1 
G-Pen 1 mg 
GlucaGen Hypokit 1 mg 
2 
GlucaGen Hypokit 1 mg 
G-Pen 1 mg 
In each period subjects will be confined to clinic at Day -1 before dosing, will undergo the 
following procedures and will be discharged at Day 1. 
Day -1: Clinic arrival, assessments specified by protocol, evening meal in clinic. 
Day 1:  
• Overnight monitoring (starting approximately at midnight) and Morning 
Procedures (starting at approximately 6 AM).  
Subjects will be monitored by glucose and will be given glucose and/or insulin to 
optimize plasma glucose levels. In the morning, plasma glucose (via YSI) will be 
assessed, and if > 270.0 mg/dL (> 15.0 mmol/L), the visit will be rescheduled after a 
minimum 3-day wait. Otherwise, the subject will be administered IV insulin to induce a 
baseline euglycemic steady state. 
• Baseline Euglycemic Steady State (early morning).  


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Prior to starting the hypoglycemia induction procedure, the subject must have stable 
plasma glucose for at least 30 minutes at 95±20 mg/dL (75 to 115 mg/dL [4.17 to 6.38 
mmol/L]) at a stable IV insulin infusion rate varying no more than ±20% during which 
plasma glucose must be measured at least every 15±2 minutes (i.e., at least 
3 consecutive values in the target range at 0, 15, and 30 minutes).  
The starting plasma glucose level (SG) will be determined as the average of the last 
3 measurements taken over the final 30 minutes of the baseline euglycemic steady state 
period. 
• Hypoglycemia Induction Procedure (following baseline euglycemic steady state). 
Hypoglycemia will be induced by adding an initial IV bolus push dose of regular 
insulin diluted in normal saline until and further insulin dose adjustments specified in 
the protocol. 
Initial IV bolus push dose will be calculated as 75% of the dose estimated to reduce 
plasma glucose from the subject’s starting plasma glucose level (SG) to desired glucose 
level 54 mg/dL (3.0 mmol/L) based on the subject’s self-reported glucose correction 
factor. This dose will be referred to as “first bolus (full bolus dose)” (BD1) 
subsequently: 
BD1 (mg/dL) = [(SG – 54 mg/dL) / Correction factor)] x 0.75. 
• Randomization. Once the initial bolus dose of insulin has had time to take effect and 
the subject is observed to be in a controlled rate of glucose decline, the subject will be 
randomly assigned to one of the treatment sequences shown in Table 1. 
• Confirmation of Hypoglycemic Steady State. Once the initial plasma glucose 
measurement < 54.0 mg/dL (< 3 mmol/L) is achieved, the IV insulin infusion will be 
returned to the rate established at the end of the baseline euglycemia steady state 
period. After 5 minutes, the IV insulin infusion will be stopped, and up to 3 
confirmatory plasma glucose readings will be taken at subsequent 5-minute intervals to 
determine whether a hypoglycemic steady state has been reached. 
A hypoglycemic steady state is defined as a confirmatory plasma glucose value ≥ 42 
mg/dL (≥ 2.33 mmol/L) and < 54 mg/dL (< 3 mmol/L), and an 8-minute linearly 
extrapolated future plasma glucose value ≥ 42 mg/dL (≥ 2.33 mmol/L). 
• Decision to Dose. Once the hypoglycemic steady state is confirmed, the Investigator 
will confirm that it is appropriate to administer study drug to the subject. The clock 
time of this “Decision to Dose” will be captured in the source documents. Decision to 
dose time is entered on the Induction CRF for each visit and will be used in the 
analysis. 
• Preparation and Administration of Study Drug. Following a decision to dose, 
subjects were administered a subcutaneous injection around the umbilicus with either 1 
mg GlucaGen Hypokit or 1 mg G-Pen. 
• Post-dose assessments. Blood glucose levels will be monitored for up to 180 minutes 
post-dosing. Subjects will also complete a questionnaire about symptoms of 
hypoglycemia during the hypoglycemia induction phase and for up to 180 minutes after 
treatment with glucagon. 
Plasma glucose levels and assessments of neuroglycopenic symptoms will be censored 
after the time of drug administration.  This censoring is applicable only if the insulin is 


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restarted prior to the 180 minutes timepoint as per the following language in the 
protocol: 
“After study drug administration and before 180 minutes post-dosing, if rising glucose 
levels are observed and if deemed medically necessary, insulin therapy or other medical 
intervention may be initiated by the Investigator. 
a. Such intervention is not recommended to occur before 90 minutes post-dosing of 
study drug. 
b. Plasma glucose data and assessments of neuroglycopenic symptoms will be censored 
after the time of intervention, per the statistical analysis plan. 
c These interventions (such as insulin, carbohydrates, or a meal) prior to 180 minutes 
post study drug administration should be captured in the source documents, and further 
glucose measurements may be performed at the discretion of the Investigator.” 
The specific hypoglycemia induction procedures and justification, and rules for interruption 
and termination of dosing are specified in the protocol. 
4.2 Sample Size Determination 
For the primary objective, a failure is recorded if the subject’s plasma glucose fails to rise 
above 70.0 mg/dL (3.88 mmol/L) and fails to increase by at least 20.0 mg/dL (1.11 mmol/L) 
within 30 minutes of the decision to administer the dose of glucagon. 
In this study, it is expected that the recovery (cure rate) will be high and approaching 100%. 
Since this is a cross-over design and each subject will serve as his/her control, power is 
improved. 
The sample size was derived for 80% power of detecting non-inferiority with respect to the 
Odds Ratio of subject recovery rates at an alpha of 0.025 under a cross-over design. Based on 
an underlying Odds Ratio of 1.0, and rates of 0.20 versus 0.25, 111 subjects are required for 
the study. With an anticipated 10% drop-out rate, the total sample size for the study is 122 
randomized subjects. 
If there are subjects who are enrolled, but fail to be randomized, compensatory enrollment 
may be utilized to achieve at least 122 subjects who are randomized for the study. Once a 
subject is randomized, the subject will be analyzed for the study. 
4.3 Randomization 
Subjects who meet all eligibility criteria, who reach the baseline euglycemia steady state, and 
who the Investigator deems appropriate to begin the induction procedure at the first treatment 
visit will be randomized for the study.  
The randomization schedule will be produced by the Study statistician a priori for loading 
and implementing in the Interactive Web-based Randomization System (IWRS). Using a 
permuted random block assignment, stratified by site, subjects will be randomly assigned to 
receive either Treatment Sequence 1 (G-Pen → GlucaGen Hypokit) or Treatment Sequence 2 
(GlucaGen Hypokit → G-Pen).   
4.4 Unblinding 
This is a single-blind study. Only the subjects are blinded for treatment. The investigator and 
clinical staff will be aware of the treatment. Thus, there is no unblinding requirements needed 
for the study. 


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In the event that a subject is inadvertently unblinded during one or both of the treatment 
sequences, the investigator will note the event as a protocol violation, and the subject will be 
allowed to continue further study treatments as per the protocol. 
At the end of the study, the subjects will be asked to guess what their first treatment was, and 
what their second treatment was from the choices of “Xeris Glucagon, G-Pen, administered 
by auto-injector” or “Comparator Glucagon, GlucaGen Hypokit, administered by needle and 
syringe”.  The subject’s responses will be recorded in the electronic Case Report Form 
(eCRF) for the Subject Study Drug Assignment Questionnaire. 
4.5 Changes in the Conduct of the Study 
There were no changes in the conduct of the study at the time of preparing this statistical 
analysis plan. 
5 STATISTICAL AND ANALYTICAL PROCEDURES 
5.1 Analysis Populations and Treatment Groups 
The following populations will be considered for the study: 
5.1.1 Intent-to-Treat Population (ITT) 
The Intent-to-Treat (ITT) population is defined as all subjects randomized. A subject’s 
randomized treatment will be used for analysis regardless of the actual treatment received. 
ITT population will be used for all summaries except safety/tolerability and disposition 
(where Enrolled population will be used). Primary endpoint comparison and secondary 
efficacy analysis will be performed for ITT, mITT and PP populations. 
5.1.2 Modified Intent-to-Treat Population (mITT) 
The Modified Intent-to-Treat (mITT) population is defined as all ITT subjects and received at 
least one dose of study drug. The actual treatment received will be used for analysis. 
5.1.3 Per-Protocol Population (PP) 
The Per-Protocol (PP) population is defined as all randomized patients who during both study 
periods successfully receive a dose of both study drugs (G-Pen followed by GlucaGen 
Hypokit or GlucaGen Hypokit followed by G-Pen) and have no any major protocol 
deviations. The actual treatment received will be used for analysis. 
Primary endpoint comparison and secondary efficacy analyses will be performed for ITT, 
mITT and PP populations. 
5.1.4 Safety Population 
The safety population is defined as all subjects randomized that received at least one dose of 
study drug. The actual treatment received will be used for analysis. The safety population will 
be used for all safety analyses and endpoints. 
5.1.5 Treatment groups 
For summary statistics, subjects will be presented in two different ways, as applicable to the 
type of analysis: 
• by planned treatment sequence of randomized subjects (GlucaGen Hypokit – G-Pen 
and G-Pen – GlucaGen Hypokit). This presentation and analysis will be used optionally 


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for descriptive outputs, but generally will not be used for analysis of the primary 
objective. 
• by planned/actual treatment of subject in each treatment period (GlucaGen Hypokit and 
G-Pen). This presentation and analysis will be used for all primary and secondary 
endpoints, and optionally for descriptive outputs (disposition, demographics, etc.).  
Planned treatment will be used for ITT population analyses and actual treatment received (by 
Period) will be used for mITT, PP and Safety population analyses. 
5.2 Reference Dates, Analysis Periods, Analysis Visits, and Baseline 
There will be two treatment periods defined and analyzed, which starts from study drug 
administration and the associated clinical phases associated, related with the pre-dose study 
procedure:  
SCREENING/BASELINE, RUN-IN (1 and 2), TREATMENT PERIOD (1 and 2).  
• SCREENING/BASELINE: analysis phase starts with Informed Consent, includes 
Day -1 check-in before first drug administration. 
Baseline will be defined as the last assessment within this phase and used as the 
reference point for safety assessments across the study to each of the visits 
(laboratory data, ECG, physical examination, weight, temperature and respiratory 
rate). 
• PRE-TREATMENT PERIOD 1: analysis phase will be assigned only if subject 
failed to achieve hypoglycemic steady state and study drug was not administered at 
the first treatment visit. It will start from first overnight monitoring to last check-in 
before first drug administration inclusively. 
Baseline 1 will be defined as last assessment at Day -1 of Treatment 1 and will be 
used as the reference point for safety assessments within Treatment Period 1(HR 
and BP). 
• RUN-IN 1: analysis phase starts from Day 1 of Treatment 1 study procedures prior 
to first drug administration and continues until the first drug administration or study 
discontinuation, whichever comes first. 
• TREATMENT PERIOD 1: 
analysis 
phase/period 
starts 
from 
first 
drug 
administration to check-in of the next treatment visit  or study discontinuation, 
whichever comes first.  
• PRE-TREATMENT PERIOD 2: analysis phase will be assigned only if subject 
failed to achieve hypoglycemic steady state and the subject’s second study drug was 
not injected at the first treatment visit after the end of Treatment Period 1. The 
period will start from first overnight monitoring after the end of Treatment Period 1 
to last check-in before second drug administration inclusively. 
Baseline 2 will be defined as last assessment at Day -1 before Treatment 2 and used 
as reference point for safety assessments within Treatment Period 2 (HR and BP). 


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• RUN-IN 2: analysis phase starts from Day 1 of Treatment 2 study procedures prior 
to second drug administration and continues until the second drug administration or 
study discontinuation, whichever comes first. 
• TREATMENT PERIOD 2: analysis period/phase starts from second dose 
administration to the end of study.  
RUN-IN 1 and RUN-IN 2 analysis phases will include all interventions before dose 
injections, thereof: 
- 
EUGLYCEMIC BASELINE 1 / 2.  
The Euglycemic Baseline phase will be determined as time interval which starts 
from last 30 minutes of the baseline euglycemic steady state period, covering at 
least 3 scheduled consecutive plasma measurements in the target range at 0, 15, and 
30 minutes used to confirm euglycemic steady state; and stops just before 
hypoglycemia induction with IV bolus push dose.  
Euglycemic Baseline (1 and 2): to determine for the Hypoglycemia Symptoms 
Assessment scheduled at the end of this phase just before the IV bolus push dose of 
insulin, will serve as baseline to determine hypoglycemia symptoms relief and/or 
resolution within Treatment Period (1 and 2). If more than one assessment is  
performed in this time interval, then the last assessment of each hypoglycemia 
symptom or score will be selected for use as the baseline. 
- 
HYPOGLYCEMIA INDUCTION (1 and 2). During the induction procedure the 
subject will enter a state of hypoglycemia through the administration of regular 
insulin diluted in normal saline within a controlled and monitored setting. 
Hypoglycemic steady state (1 and 2):  for Treatment Period (1 and 2) is confirmed 
if: 
• penultimate plasma glucose measurement during hypoglycemia induction is 
< 54.0 mg/dL (< 2.78 mmol/L); 
• last plasma glucose measurement during hypoglycemia induction is ≥ 42 
mg/dL (≥2.33 mmol/L) and < 54 mg/dL (< 2.78 mmol/L); and 
• 8-minute linearly extrapolated value from two last measurements of plasma 
glucose is ≥ 42 mg/dL (≥ 2.33 mmol/L). 
Hypoglycemic Baseline (1 and 2). If the subject achieved hypoglycemic steady 
state then from the last of the last two plasma glucose readings during 
hypoglycemia induction to time of study drug administration will be defined as 
Hypoglycemic Baseline for the corresponding treatment period and will serve as 
baseline for the Primary Endpoint and Secondary Endpoints related to 
pharmacokinetic and pharmacodynamic characteristics within Treatment Period (1 
and 2). 
Assessments and Adverse Events with onset in TREATMENT PERIOD 1 or TREATMENT 
PERIOD 2 will be attributed to the actual treatment and analyzed respectively. Adverse 


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Events which started at RUN-IN (1 and 2) phase, will be treated as TEAE, but not attributed 
to forthcoming treatment. They will be attributed to the previous treatment period (or prior to 
first treatment administration and not categorized as treatment emergent). 
Visit 2 and Visit 3 will be differentiated to Day -1 and Day 1 according to protocol and 
schedule of assessments. Analysis periods, visits, and baseline are summarized in the table 
below. 


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Table 3 - Analysis Periods and Visits 
Analysis Phase/ 
Period 
Analysis Subperiod 
(optional) 
Analysis Visit 
Protocol Visit/ 
Period 
Baseline for 
period? 
SCREENING - 
BASELINE  
Screening 
Screening, 
Baseline* 
Visit 1 
Overall 
Check-In 1  
(CRC Admission) 
Treatment 1 Day -1, 
Baseline 1*/Baseline* 
Visit 2 
Period 1, 
Overall 
RUN-IN 1 
Overnight monitoring 
Treatment 1 Day 1 
Visit 2 
 
Euglycemic Baseline 1 
Treatment 1 Day 1, 
Euglycemic Baseline 1* 
Visit 2 
Period 1 
Hypoglycemia Induction 1 
 
Treatment 1 Day 1  
(pre-dose measurements), 
Hypoglycemic Baseline 1* 
Visit 2 
 
Period 1 
 
TREATMENT 
PERIOD 1 / 
TREATMENT 
PERIOD 1 
Post treatment 1 
measurements/  
CRC discharge 
Treatment 1 Day 1  
(post-dose measurements) 
Visit 2 
 
Outclinic 1 
 
 
 
Follow-Up (optionally) 
Follow-Up (optionally) 
 
 
Check-In 2  
(CRC Admission) 
Treatment 2 Day -1, 
Baseline 2* 
Visit 3 
Period 2 
RUN-IN 2 
Overnight monitoring 
Treatment 2 Day 1 
Visit 3 
 
Euglycemic Baseline 2 
Treatment 2 Day 1, 
Euglycemic Baseline 2* 
Visit 3 
Period 2 
Hypoglycemia Induction 2 
 
Treatment 2 Day 1  
(pre-dose measurements), 
Hypoglycemic Baseline 2* 
Visit 3 
 
Period 2 
TREATMENT 
PERIOD 2 / 
TREATMENT 
PERIOD 2 
Post treatment 2 
measurements/  
CRC discharge 
Treatment 2 Day 1 
(post-dose measurements) 
Visit 3 
 
Outclinic 2 
 
 
 
Follow-Up 
Follow-Up  
Visit 4 
 
* Derived visit. 


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5.3 Analysis Variables 
5.3.1 Subject’s Disposition and Analysis Sets 
Disposition will be summarized descriptively using counts and percentages for Enrolled 
Population by treatment sequence, and for the ITT Population by planned treatment. 
The number and percentage of subjects screened, screen failures, entered the study, 
randomized, and completed the study will be presented, together with number and percentage 
of subjects who prematurely discontinued from the study along with reasons for study 
discontinuation by treatment sequence and overall.  
A listing of the subject’s disposition status will be provided. The number of subjects in each 
analysis set will be summarized descriptively by treatment with counts and percentages. A 
listing of subject’s inclusion to analysis sets will be provided. A subject’s eligibility with 
inclusion/exclusion criteria completions or deviations will be listed.  
5.3.2 Demographics and Baseline Characteristics 
Demographic data will include gender (male, female), age, age group (>=18 to <65 and >=65 
years), race, ethnic origin and treatment group. 
Baseline characteristics will include: 
• body weight, height, BMI; 
• Gold Scale of Hypoglycemia Unawareness; 
• average correction factor per unit of insulin (mg/dL); 
• duration of Type 1 diabetes calculated in years. 
Subjects who: 
• were diagnosed with Type 1 diabetes by a health care practitioner; 
• were taking daily insulin treatment;  
• has assigned correction for managing their hypoglycemia, and average correction factor 
per unit of insulin (mg/dL) for subjects with assigned correction factor. 
Demographics and baseline characteristics will be summarized for all subjects overall and by 
treatment. Summary statistics (e.g., number of subjects, mean and standard deviation, median 
and range) will be generated for all continuous variables (i.e., age and weight,) and the 
number and percentage of subjects within each category will be presented for all categorical 
variables (i.e., gender, race, ethnicity,). The summary results will be based on the ITT 
population. 
5.3.3 Medical History 
Medical history will consist of two parts: 
1) General Medical History. This data will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA, latest version), listed and summarized with 
descriptive statistics by System Organ Class (SOC) and Preferred Term (PT). 
2) Diabetes History will include information about date of diagnosis of Type 1 Diabetes 
diagnosis, current daily insulin treatment and correction factor for managing 
hypoglycemia. This data will be listed separately as part of demographics and baseline 
characteristics. 


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Duration of T1D in years will be calculated using date of informed consent and date of 
diagnosis as integer part of  
[<Date of Informed Consent> - <Date of Diagnosis> + 1]/365.25. 
If day of diagnosis is unknown, then day will be imputed as '01' (first day of the month). 
If month of diagnosis is unknown, then month will be imputed as '01' (Jan of year of 
diagnosis).  
Duration of T1D will be listed and analyzed with descriptive statistics as Baseline 
characteristics. 
5.3.4 Pregnancy and Childbearing Potential 
For female subjects, pregnancy test and/or childbearing potential will be listed. 
5.3.5 Prior and Concomitant Medications 
Medications will be coded with the latest version of the WHO drug dictionary, listed and 
presented by ATC Class 2 and Preferred Term. 
If a medication cannot be coded by WHO dictionary, it will be coded as “WHO Code Not 
Defined”. 
Each medication will be classified as prior, concomitant, or both. 
Any medication taken within 4 weeks before Day 1 will be considered as prior.  
Any medication taken on or after the drug administration (Day 1) will be considered as 
concomitant. 
In case when start/stop date is incomplete, or medication is ongoing, the following 
assumption will be made for Prior/Concomitant classification: 
- 
If there is reasonable possibility that medication was taken within 4 weeks (28 
days) before study drug administration, the medication will be considered as 
prior; 
- 
If there is no evidence that medication was taken before the drug administration, 
medication will not be classified as prior; 
- 
If there is reasonable possibility that medication was taken on or after study drug 
administration and there is no evidence that medication intake was stopped 
before first drug administration, then the medication will be classified as 
concomitant. 
If dates of medications are incomplete, missing, or medication is ongoing, the medication will 
be considered as concomitant if there is no evidence that the medication intake stopped 
before study treatment. The medication will be considered as prior if there is an evidence that 
medication intake started before the study treatment, and there is a possibility that medication 
intake started not earlier than 6 months before screening. 
Prior and Concomitant medication will be summarized and listed with ATC Class 2 and 
preferred term (PT) by treatment sequence and overall for the Safety population. 
Concomitant medication which started or changed with dosing/regimen after study drug 
administration, will be attributed to Treatment Period 1 or 2 by start date and analyzed 
descriptively by treatment received for the Safety population. 


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Patients may have more than one medication per ATC category and PT. At each level of 
patient summarization, a patient will be counted only once. 
5.3.6 Efficacy Variables 
The following efficacy variables will be utilized in the efficacy analyses. 
5.3.6.1 Primary Endpoint 
Positive Plasma Glucose Response 1 (PGR1) 
Positive Plasma Glucose Response 1 (PGR1) is defined as reaching a plasma glucose 
concentration ≥70 mg/dL (≥ 3.88 mmol/L) within 30 minutes of study drug injection (actual 
time).(The baseline plasma glucose is the blood glucose reading immediately before study 
drug dosing.) 
Positive Plasma Glucose Response 2 (PGR2) 
Positive Plasma Glucose Response 2 (PGR2) is defined as reaching an increase in plasma 
glucose concentration ≥ 20 mg/dL (≥ 1.11 mmol/L) within 30 minutes of study drug injection 
(actual time). 
Positive Plasma Glucose Response (PGR) 
For the primary endpoint, Positive Plasma Glucose Response (PGR) is defined as reaching 
Positive Plasma Glucose Response 1 (PGR1) or Positive Plasma Glucose Response 2 
(PGR2).  
For the primary endpoint, treatment groups will be compared for rates of achieving a positive 
plasma glucose response. The comparison will be performed using Intention to Treat (ITT), 
Modified Intent-to-Treat (mITT) and the Per-Protocol (PP) populations. Risk difference in 
rates of failing to achieve Positive Plasma Glucose Response (PGR) will be assessed for G-
Pen versus GlucaGen Hypokit used as reference and the associated 95% CIs presented.  
5.3.6.2 Secondary Endpoints 
5.3.6.2.1 Pharmacodynamic (PD) Parameters 
The PD endpoints will be derived from the individual glucose profiles. Pharmacodynamic 
characteristics, including:  
• AUC0-90 and AUC0-180 : plasma glucose area under the concentration versus 
time curve for 90 and 180 mins from glucagon administration; 
• Cmax: Maximum concentration of glucose in plasma; 
• Tmax:  time (in mins) when Glucose Cmax is reached; 
The following rules will be used for incomplete data: 
• 
AUC: If there are missing data points before the last observed value, they will 
be extrapolated using the last two data points; 
• 
AUC: If there are missing data points after the last observed value, they will 
not be imputed, and the AUC will be treated as not defined; 
• 
If insulin starts after receiving glucagon, the glucose values post insulin start 
will be censored out and considered as missing.  This is also considered a major 
protocol deviation. 


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Comparison between the treatments will be performed using a mixed model with treatment, 
period and treatment*period as fixed factors and subject as a random factor.  
5.3.6.2.2 Hypoglycemia Symptom Mean Scores 
Symptoms of hypoglycemia are captured using the following questionnaire: 
Neuroglycopenic Symptoms 
Severity Score (1-6) 
Dizziness 
 
Blurred vision 
 
Difficulty in thinking 
 
Faintness 
 
Autonomic Symptoms 
Severity Score (1-6) 
Sweating 
 
Tremor 
 
Palpitations 
 
Feeling of nervousness 
 
Overall Assessment of Hypoglycemia 
Yes/No 
Do you currently feel hypoglycemic? 
 
The following three mean scores will be calculated for each subject at each of the 
measurement time points: 
1. Average Neuroglycopenic Symptom Score (ANS) : 
                           Dizziness + Blurred vision + Difficulty in thinking + Faintness 
4 
 
2. Average Autonomic Symptom Score (AAS): 
                              Sweating + Tremor + Palpitations + Feeling of nervousness  
4 
 
3. Average Total Symptom Score (ATS): 
                                                                   Sum of all symptoms 
8 
Overall Assessment of Hypoglycemia: 
• this will be treated as a categorical variable and analyzed with descriptive statistics by 
timepoints; 
• additional descriptive summary will be done for overall assessment of hypoglycemia as 
number and percentage of subjects who: answered “Yes” at baseline, answered “Yes” 
at baseline and never answered “No” post-baseline, answered “No” at baseline, 


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answered “No” at baseline and at least once answered “Yes” post-baseline. 
This parameter will be analyzed from a decision to dose. 
5.3.6.2.3 Time-to-Event Efficacy Endpoints  
Symptom relief will be analyzed as aggregate scores for the four autonomic symptoms, four 
neuroglycopenic symptoms, and 8 total (autonomic and neuroglycopenic) symptoms. 
Symptom relief of hypoglycemia is defined as a return to a score (ANS, AAS, and ATS) no 
more than one unit above euglycemic baseline (1 / 2). Only subjects with baseline score at 
least 2 or more (for ANS, AAS, or ATS) will be evaluable for this analysis. 
Complete resolution of hypoglycemia symptoms is defined as all symptoms in the domain 
(ANS, AAS, or ATS) have a score of 1 after receiving glucagon. 
The time to resolution of the overall feeling of hypoglycemia is defined as first reporting 
of “No” for the global hypoglycemia question. This will be calculated as the difference (in 
mins) between the actual time when the first “No” for “Overall Assessment of 
Hypoglycemia” is observed and the time to decision of glucagon dosing.  
Glucagon Preparation Time is defined as time to administer study drug from a decision to 
dose. 
The following timing parameters will be calculated for analysis:  
1. Time to a Positive Plasma Glucose Response (PGR) from injection of study drug. 
2. Glucagon Preparation Time. 
3. Time to symptom relief of autonomic and neuroglycopenic symptoms of 
hypoglycemia from a decision to dose. That include: 
• 
time to symptom relief of neuroglycopenic symptoms (ANS) from a decision 
to dose; 
• 
time to symptom relief of autonomic symptoms (AAS) from a decision to 
dose; 
• 
time to symptom relief of autonomic and neuroglycopenic symptoms (ATS) 
from a decision to dose; 
4. Time to complete resolution of autonomic and neuroglycopenic symptoms of 
hypoglycemia from a decision to dose. That include: 
• 
time to complete resolution of neuroglycopenic symptoms (ANS) from a 
decision to dose; 
• 
time to complete resolution of autonomic symptoms (AAS) from a decision 
to dose; 
• 
time to complete resolution of autonomic and neuroglycopenic symptoms 
(ATS) from a decision to dose;  
5. Time to minimal score of autonomic and neuroglycopenic symptoms of 
hypoglycemia from a decision to dose. That includes: 
• 
time to minimal score of neuroglycopenic symptoms (ANS) from a decision 
to dose; 


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• 
time to minimal score of autonomic symptoms (AAS) from a decision to 
dose; 
• 
time to minimal score of autonomic and neuroglycopenic symptoms (ATS) 
from a decision to dose;  
6. Time to resolution of the overall feeling of hypoglycemia from a decision to dose. 
The following rules will be applied: 
• 
only subjects who answered “Yes” at baseline will be evaluable for this analysis; 
•    in very rare cases, if subject answers “Yes” all the way to the last time point, 
the total time to the last assessment will be recorded. 
Actual Time will be used for calculations. 
5.3.6.2.4 Binary Responses 
For secondary response endpoints the following parameters will be defined: 
Positive Symptomatic Response 
Positive Symptomatic Response is defined as relief of neuroglycopenic symptoms 
(ANS) within 30 minutes from a decision to dose. 
Positive Treatment Response 
Positive Treatment Response is defined as exhibiting either a positive plasma glucose 
response (PGR) or a positive symptomatic response. 
The following secondary response endpoints will be assessed.  
1. Rate of failing to achieve a Positive Plasma Glucose Response 1 (PGR1). 
2. Rate of failing to achieve a Positive Plasma Glucose Response 2 (PGR2). 
3. Rate of failing to achieve a Positive Symptomatic Response. 
4. Rate of failing to achieve a Positive Treatment Response. 
For these secondary endpoints, analysis will be the same that for primary endpoint (PGR) 
described above in section 5.3.6.1. Actual time will be used for calculations. 
5.3.6.3 Safety Variables 
All Safety and Tolerability assessments will be performed using the Safety Population. 
5.3.6.3.1.1 Adverse Events (AE) 
All verbatim AE terms will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA, latest version) and summarized by System Organ Class (SOC) and Preferred 
Term (PT). AE collection will begin from the time of informed consent.  
Time periods for Adverse Events 
Adverse Events will be attributed to analysis phases and periods by time of onset. 
Treatment Emergent Adverse Events (TEAEs) will be defined as AEs not present prior to the 
start of study procedures, or AEs present before study medication that worsened after starting 
of study procedures at Day 1 prior to first dose administration. If a partially missing date or 
time of onset allows the possibility that an AE may be a TEAE it will be assumed that it is a 
TEAE.  


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TEAEs will be analyzed by treatment and in overall. TEAEs will be attributed to study 
treatment which was administered before the AE onset within the respective Treatment 
Period 1 or 2. 
Each TEAE will be attributed to Treatment Period 1 or 2. If TEAE started at the time of 
Day 1 Pre-dosing procedures of second dose, it will not be attributed to Treatment Period 1, 
but will be counted in the Overall TEAE summary. 
AEs will be summarized by treatment, period and in overall by the number and percentage of 
subjects who experienced at least one AE of the following categories in each treatment group: 
any AE, any AE from CRC admission to the time of induction, any AE from time of 
induction to treatment, any TEAE, any drug related TEAE, any severe or life-threatening 
TEAE, any serious TEAEs, any drug-related SAE, any SAE leading to death, any TEAE 
leading to study discontinuation, and any SAE leading to study discontinuation.  
AEs will be tabulated by SOC and PT in each category.  
TEAEs will be summarized by highest relationship to study drug (Not Related, Related) and 
maximum severity (Mild, Moderate, Severe). If severity of AE is missing, then the AE will 
be analyzed as 'Severe'. If relationship to study drug for the AE is unknown, then the TEAEs 
will be classified as Related, and non-TEAEs will be classified as Not Related.  
AEs will be analyzed for safety according to the study treatment received in corresponding 
treatment period and overall. All AEs will be summarized by actual treatment sequence, 
treatment period (Treatment Period 1 / Treatment Period 2) and overall.  Subjects will be 
counted only once in the Overall analysis. 
Listings of all AEs, SAEs, and TEAEs leading to study drug discontinuation will be provided 
with treatment group, site, subject, then in chronological order displaying treatment period, 
verbatim term, MedDRA SOC and PT, start and end dates, seriousness flag and category, 
severity, relationship to study drug, action taken, contributing factors, and outcome. 
5.3.6.3.2 Laboratory safety assessments 
Laboratory values (chemistry and hematology) will be flagged if outside the normal range 
and a listing of clinically significant abnormal values will be presented.  
Normality ranges and evaluation should be consistent across the study. 
Laboratory measurements will be summarized with descriptive statistics for actual value and 
change from baseline.  
Baseline will be defined as last assessment before the first dose administration. Summaries 
will be presented by actual treatment received. 
5.3.6.3.3 Physical Examination 
Subjects with any findings in the physical examination evaluation at Screening will be listed.   
5.3.6.3.4 Body Weight 
Body weight and change from baseline to end of study will be summarized with descriptive 
statistics. Baseline is defined as last assessment before first drug administration. 
5.3.6.3.5 Vital signs  
Vital signs (temperature, respiration, heart rate and BP after >5 mins seated rest) will be 
summarized for actual values and change from baseline with descriptive statistics by 
scheduled timepoints.  


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Temperature and respiration will be analysed by treatment sequence and by actual treatment 
received with baseline defined as last assessment before first drug administration.  
Change from baseline will be assessed within period only. Summaries will be presented by 
treatment sequence and by actual treatment received. 
5.3.6.3.6 Electrocardiogram (ECG) 
ECG assessment and Investigator’s evaluations will be displayed in a data listing.  
5.3.6.3.7 Local Tolerability 
Summaries for tolerability will be presented by treatment and tabulated by scheduled 
timepoints. Worst post-baseline cases or scores will be determined for each subject and 
analyzed, which will include all scheduled and unscheduled assessments, if any. 
5.3.6.3.7.1 Injection Site Discomfort 
The incidence of any injection site discomfort reported by the subject will be analysed 
descriptively with counts and percentages for all scheduled time points. 
- 
None  
- 
Any injection site discomfort (including ‘Other’);  
- 
Pain;  
- 
Itching;  
- 
Tingling, twitching or numbness;  
- 
Irritation.  
The following descriptive statistics will be provided for all timing variables for subjects 
reporting at least one injection site discomfort: 
- 
Counts and percentages of time of onset from study drug injection (0-<1 min, 1-2 mins, 
3-5 mins, 6-9 mins, >=10 mins); 
- 
Total duration of discomfort will be analysed with descriptive statistics for continuous 
variables. 
 
5.3.6.3.7.2 Draize Scale (Erythema and Edema) 
The incidence of erythema and edema will be analysed descriptively with counts and 
percentages by scheduled timepoints, worst post-baseline score, and by the categories 
indicated below: 
Erythema Formation 
Edema Formation 
Description 
Score Description 
Score 
No erythema 
0 
No edema 
0 
Erythema 
1-4 
Edema 
1-4 
Very slight erythema: Barely perceptible 
1 
Very slight edema: Barely perceptible 
1 
Well defined erythema 
2 
Well defined edema 
2 
Moderate erythema 
3 
Moderate edema: raised approx. 1mm 
3 
Severe erythema: Beet redness to slight 
eschar formation 
4 
Severe edema: raised more than 1mm and 
beyond exposure area 
4 
Subject will be counted only once per actual treatment and timepoint and once for worst 
post-baseline score or erythema/edema occurrence. 
 


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5.3.6.3.7.3 VAS 
VAS is reported using a 100-mm scale. 
 
 
VAS scores will be summarized by all timepoints and worst post-baseline score. 
Mean VAS scores will be compared between the treatments. Comparison between the 
treatments will be performed using a mixed model with treatment, period and 
treatment*period as fixed factors and subject as a random factor. This analysis will be 
performed on the Safety population. 
6 STATISTICAL METHODS 
6.1 General Considerations  
The statistical analyses will be performed using SAS Version 9.4 (or higher). All tables, 
figures and listings will be produced in landscape format. 
Data will be presented at each scheduled timepoint (nominal time), where applicable. 
However, time-related endpoints (time to event) will be summarized using actual time.  
For actual time, two reference points will be used: (a) decision to dose and/or (b) injection of 
study drug, which are specified in the primary and secondary endpoint analyses.  
The total number of subjects in the study group (N) under the stated population will be 
displayed in the header of summary tables. 
All study data will be included in the study data listings. Listings will be displayed by subject 
in chronological order, if not stated otherwise. 
For tabulated safety summaries, only the scheduled timepoints will be included in the 
summary tables. Unscheduled assessments will be listed and used for evaluation of worst 
post-baseline value in categorical assessments, where applicable. 
Sample codes and calculations for the efficacy analysis are provided in Appendix 2: Code 
Fragments. Actual code or procedure usage can differ from these samples, based on the 
model and conditions that correspond to those pre-specified in the SAP. Additional analysis 
may be performed for the cases not specified in SAP and will be described in CSR. 
6.1.1 General guideline for descriptive summaries 
For continuous variables, mean, median, standard deviation, minimum and maximum will 
be presented for each treatment group and category.  
Additionally, coefficient of variation, geometric mean and geometric coefficient of 
variation will be calculated for: Cmax,, AUC0-90  and AUC0-180. 
For categorical variables, count and percent of subjects/counts in each treatment group 
and category will be presented. Percentages will be based on number of subjects with non-
missing values, if not specified otherwise. 


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6.2 Euglycemic Baseline 
Prior to starting the hypoglycemia induction procedure, the subject must have stable plasma 
glucose for at least 30 minutes at 95 ± 20 mg/dL (75 to 115 mg/dL [4.17 to 6.38 mmol/L]) at 
a stable IV insulin infusion rate varying no more than ±20% during which plasma glucose 
must be measured at least every 15 ± 2 minutes (i.e., at least 3 consecutive values in the 
target range at 0, 15, and 30 minutes).   
For Hypoglycemia Symptoms Assessment scheduled at the end of the Euglycemic Baseline 
phase just before the IV bolus push dose of insulin, will serve as baseline to determine 
hypoglycemia symptoms relief and/or resolution. If more than one assessment performed in 
this time interval, then the last assessment of each hypoglycemia symptom or score will be 
selected for baseline. 
6.3 Hypoglycemic Baseline 
Hypoglycemic steady state is defined as a confirmatory plasma glucose value ≥ 42 mg/dL 
(≥ 2.33 mmol/L) and < 54 mg/dL (< 3 mmol/L), and an 8-minute linearly extrapolated future 
plasma glucose value ≥ 42 mg/dL (≥ 2.33 mmol/L). 
To determine whether a hypoglycemic steady state has been achieved, confirmatory plasma 
glucose measurements will be taken as necessary at 5, 10 and 15 minutes after an initial 
plasma glucose < 54 mg/dL (< 3 mmol/L). Depending on the outcome, the following 
procedures will be followed. 
1. If any of the confirmatory measurements meets the criteria for hypoglycemic steady 
state, the subject will be eligible to receive study glucagon, and further confirmatory 
plasma glucose measurement are not required. 
2. If the final confirmatory plasma glucose value is < 42 mg/dL (< 2.33 mmol/L), the 
procedure will be terminated, study glucagon will NOT be administered, and the visit 
will be rescheduled after a minimum 3-day wait. At the Investigator’s discretion, the 
subject should be treated with IV glucose or oral carbohydrates, it should be verified 
that the subject achieved a euglycemic state and is medially stable prior to discharge. 
3. If any of the confirmatory plasma glucose measurements are > 54 mg/dL 
(> 3 mmol/L), then the IV insulin infusion will be re-started, and insulin adjustments 
will be made as per the induction procedure. Once another initial plasma < 54 mg/dL 
(< 3 mmol/L) is obtained, the sequence of up to 3 confirmatory plasma glucose 
readings will repeated. 
If the subject achieved hypoglycemic steady state their linearly extrapolated plasma glucose 
value from the last two readings of hypoglycemia induction to time of study drug 
administration will be defined as Hypoglycemic Baseline for corresponding treatment period 
and will serve as baseline for the Primary Endpoint and Secondary Endpoints related to 
pharmacokinetic and pharmacodynamic characteristics within Treatment Period 1 / 2. 
6.4 General guideline for define the protocol time 
Protocol time is needed to find the 30-minute glucose value as well as to generate most 
of the glucose or hypoglycemia score curves. 
Protocol time will be developed based on the following procedures: 
• Protocol time zero will be based on either receiving glucagon or decision to dose: 
o 
Receiving glucagon: T0 = actual time stamp of glucagon injection 
o 
Decision to dose: T0 = actual time stamp when dose decision is made 


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• Subsequent protocol times are calculated by the following minutes plus T0 
(receiving glucagon): 
o 5, 10,15,20,25,30,35,40,45,50,55,60,65,70,75,80,85,90; 
o 120,150, and180. 
• For any continuous (number) variable, the value at the protocol time will be 
determined by linear interpolation between the two adjacent time points. 
• For any categorical (text) variable, the value at the protocol time will be 
determined using the nearest value: 
o Protocol time 5 – 85: -2 minute to +3 minute; 
o Protocol time 90: -2 minute to 15 minute; 
o Protocol time 120, 150, 180: -15 minute to +15 minute; 
o If multiple values are attributed to a single protocol time, then the last 
value will be used. 
Several analyses will be conducted using both the protocol time based on study drug 
administration and the one based on decision to dose. These analyses will be noted in 
each of the corresponding sections. 
6.5 Analysis of Primary Endpoint 
The primary endpoint analysis will be based on the risk difference in rates of failing to 
achieve Positive Plasma Glucose Response (PGR) of G-Pen versus GlucaGen Hypokit and 
a 95% CI will be calculated. Non-inferiority will be declared if the upper limit of the 95% 
confidence interval for the difference in failure rates is ≤ 5%; where the absolute failure 
rate of G-Pen treatment is ≤ 5%. This analysis will be repeated for ITT, mITT and PP 
populations. 
Subjects who are missing the primary endpoint for a study treatment will be considered as 
having a failure in the primary analysis for that treatment administration.  This imputation 
will be conducted for both the ITT and the mITT populations. If a subject received the 
same two treatment administrations for both periods (Period 1 and Period 2), only the visit 
with the planned treatment received will be included in the primary analysis and the subject 
will be considered a failure in the primary analysis for the for unreceived treatment 
administration (ITT, mITT). For all other analyses, data will be included for only the 
planned treatment received in those analyses. 
A sensitivity analysis will be performed for where all missing data will be considered a 
success and the same analysis as above completed. 
6.6 Secondary Endpoints 
6.6.1 Binary Responses 
The same test as described in the previous section 6.5, will be applied to each of the binary 
responses (no sensitivity analyses will be performed). 
Note that all these analyses will be repeated for ITT, mITT and PP population.  
6.6.2 Pharmacodynamics Analyses 
All PD parameters will be presented descriptively. 


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A mixed model with treatment, period and treatment*period as fixed factors and subject as 
a random factor will be applied to compare the least square mean differences. Log 
transformation will be applied if skewness is observed. Unstructured covariance matrix will 
be used for the covariance matrix unless the model failed. In such case, structured 
covariance matrix will be selected based on the one given the smallest AIC (Akaike 
Information). 
P-value for the difference test and 95% confidence for non-inferior test will be reported. 
Additionally, mean glucose curve from 0 to 180 minutes post receiving glucagon will be 
presented graphically for each treatment. For this group of figures, the protocol defined 
time will be used. The mean glucose curve during hypoglycemia induction time will also 
be presented for each treatment. Since there is no protocol time for hypoglycemia induction 
stage, the mean glucose will be summarized for every 5 minutes based on the glucagon 
injection time. 
This will be conducted based on the mITT population only. 
6.6.3 Neuroglycopenic, Autonomic, and Total Symptom scores 
The average Neuroglycopenic, Autonomic and Total Symptom scores (ANS, AAS, and 
ATS) will be summarized descriptively at each of the protocol defined time points for each 
treatment group. A LOCF imputation will be used for post-baseline assessments to 90 
minutes inclusively. Additionally, this will also be presented graphically. 
Analysis will be conducted for the mITT population only and will use time from decision to 
dose. 
6.6.4 Time-to-Event Analyses  
All the Time-to-Event Efficacy parameters will be presented descriptively. 
A survival analysis will be conducted for comparing the difference between treatments. 
Survival curves will be provided to compare both treatments graphically. Two-sided log-rank 
p-value for the difference will be reported.  
This analysis will be repeated for ITT, mITT and PP population. 
6.6.5 Study Drug Assignment Questionnaire 
After study procedures at Visit 3, the subject will be asked to guess what their first treatment 
was, and what their second treatment was from the choices of “Xeris Glucagon, G-Pen, 
administered by auto-injector”, and “Comparator Glucagon, GlucaGen Hypokit, administered 
by needle and syringe”.  
This data will be analyzed descriptively with counts and percentages by treatment. 
Percentage of guessing will be compared against 50% using binomial proportion for each 
treatment. 
This will be conducted based on the PP population only. 
6.7 Subgroup Analysis 
Analysis of subgroups will not be performed in this study. 


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6.8 Interim Analysis 
Interim analysis will not be performed in this study. 
7 DATA HANDLING CONVENTIONS 
7.1 Missing Data 
Unless specified in any of the previous sections, no other missing data will be imputed. 
7.2 Repeated and Unscheduled Visits 
Unless specified in any of the previous sections, the principle of ‘last observation priority’ 
will be used to handle the situation of a repeated visit. Worst post-baseline assessments will 
be defined using all visits, including unscheduled.  
7.3 Conversion of Plasma Glucose Values 
For measurements of plasma glucose standard units will be considered as mg/dL. All 
measurements in mmol/L will be converted into mg/dL with next rule applied: 
 
1 mmol/L = 18.0182 mg/dL 
8 PLANNED LISTINGS, TABLES AND FIGURES 
Please see the Appendix 1.  
Note: this is the planned Table of Contents. Based on the actual data, table numbers, table 
names and structures may change. 
9 SOFTWARE REQUIREMENTS 
SAS – Version 9.4 or higher.  
WinNonlin - Professional Version 5.2 or higher. 
Excel - Microsoft Excel 2007 or higher. 
10 DEVIATIONS FROM PLANNED ANALYSIS 
For timing parameters mixed model analysis was replaced by time-to-event analysis. 


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APPENDIX 1: LIST OF TABLES, LISTINGS AND FIGURES 
Tables 
Number 
Title 
14.1.1.1 
Summary of Patient Disposition (All Enrolled Patients) 
14.1.1.2 
Summary of Patient Disposition by Treatment (Intent-to-Treat Population) 
14.1.1.3 
Summary of Analysis Populations (All Randomized Patients) 
14.1.2 
Summary of Demographic and Baseline Characteristics (Intent-to-Treat 
Population) 
14.1.3.1.1 
Summary of Vital Signs – Blood Pressure and Heart Rate by Treatment 
(Safety Population) 
14.1.3.1.2 
Summary of Vital Signs – Blood Pressure and Heart Rate by Treatment 
Sequence (Safety Population) 
14.1.3.2.1 
Summary of Vital Signs – Weight, Respiratory Rate and Temperature by 
Treatment (Safety Population) 
14.1.3.2.2 
Summary of Vital Signs – Weight, Respiratory Rate and Temperature by 
Treatment Sequence (Safety Population) 
14.1.4 
Summary of Treatment Exposure (Intent-to-Treat Population) 
14.1.5 
Summary of Medical History (All Randomized Patients) 
14.2.1.1.1.1 
Summary of Patients Having Positive Plasma Glucose Response by 
Treatment (Intent-to-Treat Population) 
14.2.1.1.1.2 
Summary of Patients Having Positive Plasma Glucose Response by 
Treatment (Modified Intent-to-Treat Population) 
14.2.1.1.1.3 
Summary of Patients Having Positive Plasma Glucose Response by 
Treatment (Per-Protocol Population) 
14.2.1.1.2.1 
Summary of Patients Having Positive Plasma Glucose Response 1 by 
Treatment (Intent-to-Treat Population) 
14.2.1.1.2.2 
Summary of Patients Having Positive Plasma Glucose Response 1 by 
Treatment (Modified Intent-to-Treat Population) 
14.2.1.1.2.3 
Summary of Patients Having Positive Plasma Glucose Response 1 by 
Treatment (Per-Protocol Population) 
14.2.1.1.3.1 
Summary of Patients Having Positive Plasma Glucose Response 2 by 
Treatment (Intent-to-Treat Population) 
14.2.1.1.3.2 
Summary of Patients Having Positive Plasma Glucose Response 2 by 
Treatment (Modified Intent-to-Treat Population) 
14.2.1.1.3.3 
Summary of Patients Having Positive Plasma Glucose Response 2 by 
Treatment (Per-Protocol Population) 
14.2.1.1.4.1 
Summary of Patients Having Positive Symptomatic Response by 
Treatment (Intent-to-Treat Population) 
14.2.1.1.4.2 
Summary of Patients Having Positive Symptomatic Response by 
Treatment (Modified Intent-to-Treat Population) 
14.2.1.1.4.3 
Summary of Patients Having Positive Symptomatic Response by 
Treatment (Per-Protocol Population) 
14.2.1.1.5.1 
Summary of Patients Having Positive Treatment Response by Treatment 
(Intent-to-Treat Population) 
 


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Tables 
Number 
Title 
14.2.1.1.5.2 
Summary of Patients Having Positive Treatment Response by Treatment 
(Modified Intent-to-Treat Population) 
14.2.1.1.5.3 
Summary of Patients Having Positive Treatment Response by Treatment 
(Per-Protocol Population) 
14.2.1.2.1 
Summary of Plasma Glucose Cmax (mg/dL) by Treatment (Modified 
Intent-to-Treat Population)  
14.2.1.2.2 
Summary of Plasma Glucose Tmax (min) by Treatment (Modified Intent-
to-Treat Population)  
14.2.1.2.3 
Summary of Plasma Glucose AUC0-90 (min*mg/dL) by Treatment 
(Modified Intent-to-Treat Population)  
14.2.1.2.4 
Summary of Plasma Glucose AUC0-180 (min*mg/dL) by Treatment 
(Modified Intent-to-Treat Population)  
14.2.1.2.5.1 
Summary of Time (minutes) to First Positive Plasma Glucose Response 
After Study Drug Injection by Treatment (Intent-to-Treat Population) 
14.2.1.2.5.2 
Summary of Time (minutes) to First Positive Plasma Glucose Response 
After Study Drug Injection by Treatment (Modified Intent-to-Treat 
Population) 
14.2.1.2.5.3 
Summary of Time (minutes) to First Positive Plasma Glucose Response 
After Study Drug Injection by Treatment (Per-Protocol Population) 
14.2.1.3.1 
Summary of Average Neuroglycopenic Scores, Average Autonomic 
Scores and Average Total Scores by Treatment and Time Point (Modified 
Intent-to-Treat Population) 
14.2.1.3.2.1 
Summary of Time (min) to Symptom Relief (Neuroglycopenic, 
Autonomic and Total) After Decision to Dose by Treatment (Intent-to-
Treat Population) 
14.2.1.3.2.2 
Summary of Time (min) to Symptom Relief (Neuroglycopenic, 
Autonomic and Total) After Decision to Dose by Treatment (Modified 
Intent-to-Treat Population) 
14.2.1.3.2.3 
Summary of Time (min) to Symptom Relief (Neuroglycopenic, 
Autonomic and Total) After Decision to Dose by Treatment (Per-Protocol 
Population) 
14.2.1.3.3.1 
Summary of Time (min) to Complete Resolution (Neuroglycopenic, 
Autonomic and Total) After Decision to Dose by Treatment (Intent-to-
Treat Population) 
14.2.1.3.3.2 
Summary of Time (min) to Complete Resolution (Neuroglycopenic, 
Autonomic and Total) After Decision to Dose by Treatment (Modified 
Intent-to-Treat Population) 
14.2.1.3.3.3 
Summary of Time (min) to Complete Resolution (Neuroglycopenic, 
Autonomic and Total) After Decision to Dose by Treatment (Per-Protocol 
Population) 
14.2.1.3.4.1 
Summary of Time (min) to Resolution of the Overall Feeling of 
Hypoglycemia After Decision to Dose by Treatment (Intent-to-Treat 
Population) 
14.2.1.3.4.2 
Summary of Time (min) to Resolution of the Overall Feeling of 
Hypoglycemia After Decision to Dose by Treatment (Modified Intent-to-
Treat Population) 
 


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Tables 
Number 
Title 
14.2.1.3.4.3 
Summary of Time (min) to Resolution of the Overall Feeling of 
Hypoglycemia After Decision to Dose by Treatment (Per-Protocol 
Population) 
14.2.1.3.5.1 
Summary of Time (min) to the Minimal Score Post Baseline 
(Neuroglycopenic, Autonomic and Total) After Decision to Dose by 
Treatment (Intent-to-Treat Population) 
14.2.1.3.5.2 
Summary of Time (min) to the Minimal Score Post Baseline 
(Neuroglycopenic, Autonomic and Total) After Decision to Dose by 
Treatment (Modified Intent-to-Treat Population) 
14.2.1.3.5.3 
Summary of Time (min) to the Minimal Score Post Baseline 
(Neuroglycopenic, Autonomic and Total) After Decision to Dose by 
Treatment (Per-Protocol Population) 
14.2.1.4.1 
Summary of Glucagon Preparation Time (min) by Treatment (Intent-to-
Treat Population) 
14.2.1.4.2 
Summary of Glucagon Preparation Time (min) by Treatment (Modified 
Intent-to-Treat Population) 
14.2.1.4.3 
Summary of Glucagon Preparation Time (min) by Treatment (Per-Protocol 
Population) 
14.2.1.5 
Summary of Study Drug Assignment Questionnaire by Period and by 
Treatment (Per-Protocol Population) 
14.2.2.1.1 
Non-inferiority Analysis of Positive Plasma Glucose Response by 
Treatment (All Enrolled Patients) 
14.2.2.1.2 
Non-inferiority Analysis of Positive Plasma Glucose Response 1 by 
Treatment (All Enrolled Patients) 
14.2.2.1.3 
Non-inferiority Analysis of Positive Plasma Glucose Response 2 by 
Treatment (All Enrolled Patients) 
14.2.2.1.4 
Non-inferiority Analysis of Positive Symptomatic Response by Treatment 
(All Enrolled Patients) 
14.2.2.1.5 
Non-inferiority Analysis of Positive Treatment Response by Treatment 
(All Enrolled Patients) 
14.2.2.2.1 
Non-inferiority Analysis of Plasma Glucose Cmax (mg/dL) by Treatment 
(Intent-to-Treat Population) 
14.2.2.2.2 
Non-inferiority Analysis of Plasma Glucose Tmax (min) by Treatment 
(Intent-to-Treat Population) 
14.2.2.2.3 
Non-inferiority Analysis of Plasma Glucose AUC0-90 (min*mg/dL) by 
Treatment (Intent-to-Treat Population) 
14.2.2.2.4 
Non-inferiority Analysis of Plasma Glucose AUC0-180 (min*mg/dL) by 
Treatment (Intent-to-Treat Population) 
14.2.2.2.5 
Non-inferiority Analysis of Time (min) to First Positive Plasma Glucose 
Response After Study Drug Injection by Population and by Treatment (All 
Enrolled Patients) 
14.2.2.3.1 
Non-inferiority Analysis of Time (min) to Symptom Relief 
(Neuroglycopenic, Autonomic and Total) After Decision to Dose by 
Population and by Treatment (All Enrolled Patients) 
14.2.2.3.2 
Non-inferiority Analysis of Time (min) to Complete Resolution 
(Neuroglycopenic, Autonomic and Total) After Decision to Dose by 
Population and by Treatment (All Enrolled Patients) 


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Statistical Analysis Plan                                                                                                                                                     XSGP-304 
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Tables 
Number 
Title 
14.2.2.3.3 
Non-inferiority Analysis of Time (min) to Resolution of the Overall 
Feeling of Hypoglycemia After Decision to Dose by Population and by 
Treatment (All Enrolled Patients) 
14.2.2.3.4 
Non-inferiority Analysis of Time (min) to the Minimal Post Baseline 
Score After Decision to Dose by Population and by Treatment (All 
Enrolled Patients) 
14.2.2.4 
Non-inferiority Analysis of Glucagon Preparation Time (min) by 
Population and by Treatment (All Enrolled Patients) 
14.2.2.5.1 
Non-inferiority Analysis of Study Drug Assignment Questionnaire by 
Treatment (Per-Protocol Population) 
14.2.2.5.2 
Non-inferiority Analysis of Mean Visual Analog Scale (VAS) (Intent-to-
Treat Population) 
14.3.1.1 
Overview of Adverse Events (Safety Population) 
14.3.1.2.1 
Summary of Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term and by Treatment (Safety Population) 
14.3.1.2.2 
Summary of Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term, Period and by Treatment Sequence (Safety Population) 
14.3.1.3.1 
Summary of Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term, Severity and by Treatment (Safety Population) 
14.3.1.3.2 
Summary of Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term, Severity, Period and by Treatment Sequence (Safety 
Population) 
14.3.1.4.1 
Summary of Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term, Relationship to Study Drug and by Treatment (Safety 
Population) 
14.3.1.4.2 
Summary of Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term, Relationship, Period to Study Drug and by Treatment 
Sequence (Safety Population) 
14.3.1.5.1 
Summary of Serious Adverse Events Leading to Study Discontinuation by 
System Organ Class, Preferred Term and by Treatment (Safety 
Population) 
14.3.1.5.2 
Summary of Serious Adverse Events Leading to Study Discontinuation by 
System Organ Class, Preferred Term, Period and by Treatment Sequence 
(Safety Population) 
14.3.1.6.1 
Summary of Treatment-Emergent Adverse Events Leading to Study 
Discontinuation by System Organ Class, Preferred Term and by Treatment 
(Safety Population) 
14.3.1.6.2 
Summary of Treatment-Emergent Adverse Events Leading to Study 
Discontinuation by System Organ Class, Preferred Term, Period and by 
Treatment Sequence (Safety Population) 
14.3.2.1 
Listing of Deaths (Safety Population) 
14.3.2.2 
Listing of Serious Adverse Events (Safety Population) 
14.3.2.3 
Listing of Treatment-Emergent Adverse Events Leading to Study 
Discontinuation (Safety Population) 
14.3.4.1.1 
Summary of Clinical Chemistry Results (Safety Population) 
14.3.4.1.2 
Summary of Clinical Hematology Results (Safety Population) 
 


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Tables 
Number 
Title 
14.3.4.3 
Incidence of Abnormal Laboratory Findings (Safety Population) 
14.3.5.1 
Summary of Local Tolerability – Subjective Injection Site Discomfort 
from VAS (Safety Population) 
14.3.5.2 
Summary of Local Tolerability – Subjective Injection Site Discomfort 
from Ordinal Pain Scales (Safety Population) 
14.3.5.3 
Summary of Local Tolerability – Draize Scale (Safety Population) 
14.3.6.1.1 
Summary of Prior Medications by Treatment (Safety Population) 
14.3.6.1.2 
Summary of Prior Medications by Treatment Sequence (Safety 
Population) 
14.3.6.2.1 
Summary of Concomitant Medications by Treatment (Safety Population) 
14.3.6.2.2 
Summary of Concomitant Medications by Treatment Sequence (Safety 
Population) 
Listings 
Number 
Title 
16.1.7 
Listing of Randomization (Intent-to-Treat Population) 
16.2.1.1 
Listing of Patient Disposition (All Patients) 
16.2.1.2 
Listing of Screen Failure and Inclusion / Exclusion Criteria Assessment 
(All Patients) 
16.2.2.1 
Listing of Protocol Deviations (All Patients) 
16.2.2.2 
Listing of Major Protocol Deviations (All Patients) 
16.2.4.1 
Listing of Patient Demographic and Baseline Characteristics (Safety 
Population) 
16.2.4.2 
Listing of Medical History (Safety Population) 
16.2.4.3.1 
Listing of Prior Medications (Safety Population) 
16.2.4.3.2 
Listing of Concomitant Medications (Intent-to-Treat Population) 
16.2.5.1 
Listing of Study Drug Administration (Intent-to-Treat Population) 
16.2.5.2 
Listing of Euglycemic Baseline and Hypoglycemia Induction (All 
Randomized Patients) 
16.2.6.1.1 
Listing of Dose Monitoring – Plasma Glucose (Intent-to-Treat Population) 
16.2.6.1.2 
Listing of Dose Monitoring – Pharmacodynamic Parameters (Intent-to-
Treat Population) 
16.2.6.2.1 
Listing of Hypoglycemia Symptom Questionnaire (Intent-to-Treat 
Population) 
16.2.6.2.2 
Listing of Average Neuroglycopenic Scores, Average Autonomic Scores 
and Average Total Scores (Intent-to-Treat Population) 
16.2.6.3.1 
Listing of Time to Symptom Relief (Intent-to-Treat Population) 
16.2.6.3.2 
Listing of Time to Complete Resolution (Intent-to-Treat Population) 
16.2.6.3.3 
Listing of Time to Resolution of the Overall Feeling of Hypoglycemia 
(Intent-to-Treat Population) 
16.2.6.3.4 
Listing of Time to the Minimal Post Baseline Score (Intent-to-Treat 
Population) 
16.2.6.4.1 
Listing of Positive Plasma Glucose Response (Intent-to-Treat Population) 
16.2.6.4.2 
Listing of Positive Plasma Glucose Response 1 (Intent-to-Treat 
Population) 
16.2.6.4.3 
Listing of Positive Plasma Glucose Response 2 (Intent-to-Treat 
Population) 
16.2.6.4.4 
Listing of Positive Symptomatic Response (Intent-to-Treat Population) 


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Listings 
Title 
16.2.6.4.5 
Listing of Positive Treatment Response (Intent-to-Treat Population) 
16.2.6.4.6 
Listing of Glucagon Preparation Time (Intent-to-Treat Population) 
16.2.6.5 
Listing of Study Drug Assignment Questionnaire (Intent-to-Treat 
Population) 
16.2.7 
Listing of Adverse Events (All Patients) 
16.2.8.1 
Listing of Laboratory Results: Chemistry (Safety Population) 
16.2.8.2 
Listing of Laboratory Results: Hematology (Safety Population) 
16.2.8.3 
Listing of Urine Pregnancy Test Results (Safety Population) 
16.2.8.4 
Listing of Urine Drug Screen Results (Safety Population) 
16.2.9.1 
Listing of Injection Site Discomfort – Visual Analog Scale (VAS) (Intent-
to-Treat Population) 
16.2.9.2 
Listing of Injection Site Discomfort – Injection Site Discomfort 
Description and Duration Questionnaire (Intent-to-Treat Population) 
16.2.9.3 
Listing of Injection Site Discomfort – Draize Scale (Intent-to-Treat 
Population) 
16.2.10.1 
Listing of Vital Signs - Blood Pressure and Heart Rate (Safety Population) 
16.2.10.2 
Listing of Vital Signs - Height, Weight, Respiratory Rate and Temperature 
(Safety Population) 
16.2.11 
Listing of Physical Examinations (Safety Population) 
16.2.12 
Listing of ECG Findings (Safety Population) 
16.2.13 
Comments (All Patients) 
Figures 
Number 
Title 
14.2.1.1 
Individual Plasma Glucose Concentration by Time and Treatment – Linear 
Scale (Intent-to-Treat Population) 
14.2.1.2 
Individual Plasma Glucose Concentration by Time and Treatment – Semi-
Log Scale (Intent-to-Treat Population) 
14.2.2.1 
Mean (+/- SE) Plasma Glucose Concentration by Time and Treatment – 
Linear Scale (Intent-to-Treat Population) 
14.2.2.2 
Mean (+/- SE) Plasma Glucose Concentration by Time and Treatment – 
Semi-Log Scale (Intent-to-Treat Population) 
14.2.3.1.1 
Individual Average Autonomic Score, Average Neuroglycopenic Score 
and Average Total Score by Time and Treatment – Linear Scale (Intent-to-
Treat Population) 
14.2.3.1.2 
Individual Average Autonomic Score, Average Neuroglycopenic Score 
and Average Total Score by Time and Treatment – Semi-Log Scale 
(Intent-to-Treat Population) 
14.2.3.2.1 
Mean (+/- SE) Average Autonomic Score, Average Neuroglycopenic 
Score and Average Total Score by Time and Treatment – Linear Scale 
(Intent-to-Treat Population) 
14.2.3.2.2 
Mean (+/- SE) Average Autonomic Score, Average Neuroglycopenic 
Score and Average Total Score by Time and Treatment – Semi-Log Scale 
(Intent-to-Treat Population) 
14.2.4.1 
Individual Subject Plasma Glucose Concentration and Insulin Induction 
Profile by Time and Treatment (Intent-to-Treat Population) 
14.2.4.2 
Mean Plasma Glucose Concentration and Hypoglycemia Symptom Score 
Profiles by Time and Treatment (Intent-to-Treat Population) 


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Figures 
Number 
Title 
14.2.5.1.1 
Survival Curves of Time (min) to First Positive Plasma Glucose Response 
After Study Drug Injection by Period and by Treatment (Intent-to-Treat 
Population) 
14.2.5.1.2 
Survival Curves of Time (min) to First Positive Plasma Glucose Response 
After Study Drug Injection by Period and by Treatment (Per-Protocol 
Population) 
14.2.5.2.1 
Survival Curves of Time (min) to Symptom Relief (Neuroglycopenic, 
Autonomic and Total) After Decision to Dose by Period and by Treatment 
(Intent-to-Treat Population) 
14.2.5.2.2 
Survival Curves of Time (min) to Symptom Relief (Neuroglycopenic, 
Autonomic and Total) After Decision to Dose by Period and by Treatment 
(Per-Protocol Population) 
14.2.5.3.1 
Survival Curves of Time (min) to Complete Resolution (Neuroglycopenic, 
Autonomic and Total) After Decision to Dose by Period and by Treatment 
(Intent-to-Treat Population) 
14.2.5.3.2 
Survival Curves of Time (min) to Complete Resolution (Neuroglycopenic, 
Autonomic and Total) After Decision to Dose by Period and by Treatment 
(Per-Protocol Population) 
14.2.5.4.1 
Survival Curves of Time (min) to Resolution of the Overall Feeling of 
Hypoglycemia After Decision to Dose by Period and by Treatment (Intent-
to-Treat Population) 
14.2.5.4.2 
Survival Curves of Time (min) to Resolution of the Overall Feeling of 
Hypoglycemia After Decision to Dose by Period and by Treatment (Per-
Protocol Population) 
14.2.5.5.1 
Survival Curves of Time (min) to the Minimal Score Post Baseline 
(Neuroglycopenic, Autonomic and Total) After Decision to Dose by 
Period and by Treatment (Intent-to-Treat Population) 
14.2.5.5.2 
Survival Curves of Time (min) to the Minimal Score Post Baseline 
(Neuroglycopenic, Autonomic and Total) After Decision to Dose by 
Period and by Treatment (Per-Protocol Population) 
14.2.5.6.1 
Survival Curves of Glucagon Preparation Time (min) by Period and by 
Treatment (Intent-to-Treat Population) 
14.2.5.6.2 
Survival Curves of Glucagon Preparation Time (min) by Period and by 
Treatment (Per-Protocol Population) 


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Statistical Analysis Plan                                                                                                                                                     XSGP-304 
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APPENDIX 2: CODE FRAGMENTS 
Risk difference test for binary response 
Proc Freq data = <Data> order=data; 
      weight Count / ZEROS; 
      tables <Treatment>*<Response> / riskdiff; 
      output out = <Out> riskdiff; 
run; 
Mixed model 
ods output lsmeans(match_all) = <Out_LSmean>  
           Diffs(match_all) = <Out_Diffs>;  
Proc Mixed data=<Data>; 
      class <Treatment> <Period> <Subject>; 
      model <Value> = <Treatment> <Period> <Treatment>*<Period>; 
      random <Subject> / Type = un; 
      lsmeans <Treatment> / cl DIFF; 
run;  
Time-to-Event 
ods output means=<Out_Means> HomTests=<Out_Test>; 
proc lifetest data=<Data>; 
      time <Time>; 
      strata <Treatment>; 
run; 
Study Drug Assignment 
proc freq data=<Data>; 
      tables <Treatment>/ BINOMIAL (p=0.50) alpha=0.05; 
      output out=<Out> Binominal; 
      weight count; 
run;