Clinical trial NCT03439072
Conditions: Insulin Hypoglycemia Type 1 Diabetes Mellitus Severe Hypoglycemia
Keywords: glucagon hypoglycemia
Sponsor: Xeris Pharmaceuticals
Start date: 2018-01-23; Completion date: 2018-05-03
Enrollment: 81 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a non-inferiority, 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 Lilly 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 hypoglycemia through IV administration of regular insulin diluted in normal saline. After a hypoglycemic state with plasma glucose \< 50 mg/dL is verified, the subject is administered a dose of G-Pen or Lilly Glucagon via subcutaneous injection. Plasma glucose levels are monitored for up to 180 minutes post-dosing, with a value of \>70.0 mg/dL 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 procedure 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 Lilly Glucagon at the second treatment visit arm 2: 1 mg Lilly Glucagon at the first treatment visit followed by 1 mg G-Pen at the second treatment visit
Interventions: intervention 1: G-Pen intervention 2: Lilly 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 Lilly Glucagon (glucagon injection \[RNDA Origin\])

Protocol documents:
Prot_000.pdf: 
PROTOCOL XSGP-303 
 
G-PEN™ (GLUCAGON INJECTION) COMPARED TO LILLY 
GLUCAGON (GLUCAGON FOR INJECTION [RDNA ORIGIN]) 
FOR INDUCED HYPOGLYCEMIA RESCUE IN ADULTS WITH 
T1D: A PHASE 3B MULTI-CENTERED, RANDOMIZED, 
CONTROLLED, SINGLE BLIND, 2-WAY CROSSOVER STUDY 
TO EVALUATE EFFICACY AND SAFETY 
 
NCT03439072 
 
Document Date: January 29, 2018 
 
 


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1. TITLE PAGE 
G-PEN™ (GLUCAGON INJECTION) 
PROTOCOL XSGP-303 
 
G-PEN™ (GLUCAGON INJECTION) COMPARED TO LILLY 
GLUCAGON (GLUCAGON FOR INJECTION [RDNA ORIGIN]) 
FOR INDUCED HYPOGLYCEMIA RESCUE IN ADULTS WITH 
T1D: A PHASE 3B MULTI-CENTERED, RANDOMIZED, 
CONTROLLED, SINGLE BLIND, 2-WAY CROSSOVER STUDY 
TO EVALUATE EFFICACY AND SAFETY 
 
 
 
 
 
 
 
 
 
Version 1.2 
January 29, 2018 


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INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for G-Pen™ (glucagon injection).  I have 
read the XSGP-303 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 
Martin J. Cummins, 
VP, Drug Development 
mcummins@xerispharma.com 
512-498-2675 (direct)  
806-282-2120 (cell) 
Medical Monitor & 
24-hour emergency contact 
Dr. 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 
safety303@xerispharma.com   
+1.630.915.5885 
+1.815.593.2218 
 


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2. 
SYNOPSIS 
Protocol Number: XSGP-303 
G-PEN™ (GLUCAGON INJECTION) COMPARED TO LILLY GLUCAGON (GLUCAGON FOR 
INJECTION [RDNA ORIGIN]) FOR INDUCED HYPOGLYCEMIA RESCUE IN ADULTS WITH 
T1D: A PHASE 3B, MULTI-CENTER, RANDOMIZED, CONTROLLED, SINGLE-BLIND, 2-WAY 
CROSSOVER STUDY TO EVALUATE EFFICACY AND SAFETY. 
Principal 
Investigator:   
Each participating clinical site will nominate a physician who, based on 
training and experience, will serve as Principal Investigator for that site. 
IND: 
115091 
Project phase: 
Phase 3b 
Compound(s):   
G-Pen™ (glucagon injection)  
Lilly Glucagon for Injection (rDNA origin) 
Objectives: 
The primary objective of this study is to demonstrate the efficacy (return to 
plasma glucose >70.0 mg/dL) of G-Pen 1 mg (test) to be non-inferior to Lilly 
Glucagon 1 mg (reference), in Type 1 diabetic (T1D) subjects in a state of 
insulin-induced hypoglycemia. This will be assessed by the comparison of 
failure rates of plasma glucose to have a measured value > 70.0 mg/dL within 
30 minutes of administration of glucagon. 
The secondary objectives of this study are: 
1. To demonstrate the efficacy (either return to plasma glucose >70.0 mg/dL 
or an increase in plasma glucose ≥ 20 mg/dL within 30 minutes post study 
drug injection) of G-Pen 1 mg (test) to be non-inferior to Lilly Glucagon 1 
mg (reference), in T1D subjects in a state of insulin-induced 
hypoglycemia. 
2. To demonstrate the efficacy (return to plasma glucose >70.0 mg/dL or 
alleviation of all neuroglycopenic symptoms at 30 minutes post study drug 
injection) of G-Pen 1 mg (test) to be non-inferior to Lilly Glucagon 1 mg 
(reference), in T1D subjects in a state of insulin-induced hypoglycemia. 
3. To compare the pharmacodynamic characteristics of G-Pen 1 mg (test) 
versus Lilly Glucagon 1 mg (reference) in T1D subjects who are in a state 
of insulin-induced hypoglycemia. 
4. To compare G-Pen (test) and Lilly Glucagon (reference) with regards to 
hypoglycemia symptom relief. 
5. To compare G-Pen (test) and Lilly Glucagon (reference) with regards to 
the preparation time required to inject to the abdomen from a decision to 
treat. 


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6. To determine the safety and tolerability of G-Pen 1 mg (test) versus Lilly 
Glucagon 1 mg (reference) in T1D subjects in a state of induced 
hypoglycemia. 
Study design:   
This is a non-inferiority, multi-centered, randomized controlled, single-blind, 
two-way crossover efficacy and safety inpatient study in adult subjects with 
Type 1 diabetes mellitus (T1D).  The study will involve two daytime clinical 
research center (CRC, or comparable setting) visits 7-28 days apart, with 
random assignment to receive G-Pen™ glucagon 1 mg during one period and 
Lilly Glucagon 1 mg during the other. 
Study location: 
Approximately 6 clinical research centers in North America. 
Study duration: 
The estimated duration of study participation for individual subjects is 
approximately 4 weeks. The estimated duration of the entire study is 4 months. 
Sample size: 
Approximately 200 subjects are anticipated to be screened for this study to 
achieve the goal of 85 subjects randomized and minimally 75 subjects who are 
evaluable for both periods.   
Subjects: 
The study will include male and female subjects with T1D between the ages of 
18 and 75 years of age, inclusive, at Screening. 
Inclusion Criteria: 
1. Males and females diagnosed with type 1 diabetes mellitus for at least 24 
months. 
2. Current usage of daily insulin treatment that includes having an assigned 
“correction factor” for managing hyperglycemia.  
3. Age 18-75 years, inclusive. 
4. Random serum C-peptide concentration < 0.5 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/dated 
informed consent form completed before any trial-related activities occur. 
Exclusion Criteria: 
1. Pregnancy: For women of childbearing potential, there is a requirement for 
a negative urine pregnancy test and for agreement to use contraception 
throughout the study and for 7 days after the last dose of study glucagon. 
Acceptable contraception includes birth control pill / patch / vaginal ring, 
Depo-Provera, Norplant, an IUD, the double barrier method (the woman 
uses a diaphragm and spermicide and the man uses a condom), or 
abstinence. 
2. Breastfeeding: Nursing mothers will be allowed into the study. However, 
breast feeding during the during in-patient study visits (Visit 2 & Visit 3) 
and for 48 hours after each dose of study drug is not allowed.  
3. HbA1c >9.0% at Screening. 
4. BMI > 40 kg/m2.  
5. Renal insufficiency (serum creatinine greater than 3.0 mg/dL) or end-stage 
renal disease requiring renal replacement therapy. 
6. Serum ALT or AST equal to or greater than 3 times the upper limit of 
normal. 


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7. Hepatic synthetic insufficiency as defined as a serum albumin of less than 
3.0 g/dL. 
8. Hematocrit < 30%. 
9. BP readings at Screening where SBP <90 or >150 mm Hg, and DBP <50 
or >100 mm Hg. 
10. Clinically significant ECG abnormalities. 
11. Use of > 2.0 U/kg total insulin dose per day. 
12. Inadequate venous access. 
13. Congestive heart failure, NYHA class III or IV. 
14. History of myocardial infarction, unstable angina, or revascularization 
within the past 6 months. 
15. History of a cerebrovascular accident in past 6 months or with major 
neurological deficits. 
16. 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. 
17. Major surgical operation within 30 days prior to Screening.  
18. Current seizure disorder (other than with suspect or documented 
hypoglycemia). 
19. Current bleeding disorder, treatment with warfarin, or platelet count below 
50 x 109 per liter. 
20. History of pheochromocytoma or disorder with increased risk of 
pheochromocytoma (MEN 2, neurofibromatosis, or Von Hippel-Lindau 
disease). 
21. History of insulinoma. 
22. 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 & trehalose) in the investigational 
formulation.  
23. History of glycogen storage disease. 
24. Subject tests positive for HIV, HCV, or HBV infection (HBsAg+) at 
Screening. 
25. Active substance or alcohol abuse (more than 21 drinks/wk for males or 14 
drinks/wk for females). Subjects reporting active marijuana use or testing 
positive for tetrahydrocannabinol (THC) via rapid urine test will be 
allowed to participate in the study at the discretion of the Investigator. 
26. Administration of glucagon within 28 days of Screening. 
27. 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. 
28. Any other reason the Investigator deems exclusionary. 


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Study Methods: 
Subjects will complete the screening procedures up to 30 days before dosing to 
determine eligibility before enrollment to the treatment period. Subjects not 
meeting eligibility criteria can be rescreened after a 30-day wait. 
The evening prior to each inpatient study visit, subjects with confirmed blood 
glucose not greater than 350 mg/dL will be admitted for an overnight stay 
between 6 and 8 pm and a CGM will be placed at the discretion of the 
Investigator. At investigator discretion, the subject may visit the clinic up to 5 
days prior to the scheduled check-in for placement of the CGM. Subjects will 
be provided a standardized dinner and will continue their usual insulin 
regimen. At Investigator discretion, subjects may receive a standardized snack 
before midnight. 
Subjects will be instructed to fast after midnight. If site staffing allows for 
appropriate oversight, an intravenous catheter will be placed, and maintenance 
fluids administered. If not, the subject’s own infusion pump will be used 
overnight if applicable. The subject’s blood glucose will be monitored 
overnight, and glucose (IV or oral tablets) or insulin (IV or SC) will be 
administered as necessary to maintain blood glucose in a target range of 80-
150 mg/dL. 
In the morning of the inpatient study visit, the subject’s plasma glucose will be 
measured and verified to be not more than 270 mg/dL to be confirmed eligible 
for continuation into the insulin induction procedure. As another confirmation 
of eligibility for the induction procedure, overnight glucose data will be 
checked, and it will be verified that the subject did not have blood glucose < 
60 or greater than 270 mg/dL overnight.  
The subjects will continue fasting the morning of the procedure and will have 
an intravenous catheter for blood sampling inserted in 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. The subject 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 the plasma glucose is confirmed to be within range of 70-270 
mg/dL. IV insulin will be administered to maintain the plasma glucose within 
the range of 75-115 mg/dL for 30 minutes. If the plasma glucose has been 
maintained within the range of 75-115 mg/dL for at least 30 minutes, and the 
insulin infusion rate varies no more than +/- 20%, the induction procedure may 
commence. 
Eligible participants will enter a state of insulin-induced hypoglycemia in a 
gradual and controlled fashion, through a monitored, standardized induction 
protocol. Adherence to the protocol insulin dose adjustment algorithm will be 
facilitated by real time data entry on a pair of laptop computers. One will be 
for entry of glucose values as the measurements become available from the 
YSI glucose analyzer. The other laptop will display the induction procedure, 
glucose results, insulin bolus and insulin infusion rate data, and will provide 
information on glucose trajectory.  
Plasma glucose measurements will be taken every 10 minutes while glucose is 
>80.0 mg/dL and at 5-minute intervals once plasma glucose is ≤ 80.0 mg/dL. 
Once the initial plasma glucose measurement < 50.0 mg/dL is achieved, the IV 
insulin infusion will be stopped. A confirmatory plasma glucose reading will 
be taken 5 minutes later to confirm that a hypoglycemic steady state has been 


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reached, which is defined as two consecutive plasma glucose values between 
43.0 and 49.9 mg/dL and an 8-minute linearly extrapolated value for plasma 
glucose is ≥ 42.0 mg/dL. 
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 subcutaneously or Lilly glucagon 1 mg, via the subcutaneous route 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 the IP 
will begin once the confirmatory plasma glucose reading is obtained, i.e., upon 
a “decision to dose.” 
1. As an assessment of the preparation time, the time between the 
decision to dose and injection of the randomized study drug to the 
abdomen will be measured. 
2. Following dosing, the plasma glucose will be monitored every 5 
minutes until 90, and afterwards every 30 minutes until 180 minutes 
post-dosing. 
3. The induction procedure itself may elicit symptoms of hypoglycemia. 
Thus, subjects will complete a questionnaire regarding hypoglycemia 
symptoms at the start of the hypoglycemia induction period and 
periodically until either all symptoms abate or 180 minutes post-
dosing with glucagon.   
4 
After 180 minutes, the subject will resume insulin pump therapy, if 
applicable, and will be given a meal. The subject may be discharged 
after 180 mins with blood glucose > 100 mg/dL and if medically 
stable. At the Investigator’s discretion, the subject’s prescribed insulin 
regimen can be restarted, or the meal can be given sooner, but not 
earlier than 90 minutes post-glucagon, to prevent hyperglycemia or 
rebound hypoglycemia. 
After a wash-out period of 7 to 28 days, subjects will return to the clinic 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 
conducted 2-7 days following administration of the final dose as a safety 
check.  
Tolerability will be assessed by comparing adverse event reports between the 
G-pen and Lilly Glucagon groups. In addition, at the end of each treatment 
period the subjects will complete questionnaires concerning injection site 
discomfort, and an Investigator will use modified Draize scales to evaluate the 
injection sites following each administration. 
Data management 
and statistical 
analysis: 
Data will be entered into an electronic Case Report Form by site personnel. 
Data will be monitored at on-site visits by Xeris personnel or by a CRO acting 
as Xeris’ agent. The primary endpoint will be assessed in both the per protocol 
(PP) and intent-to-treat (ITT) populations. The evaluable set for the PP 
population will be defined as all randomized patients who, during both study 
periods, successfully complete the insulin induction procedure, and fulfill the 
criteria for having achieved a hypoglycemic steady state, and successfully 
receive a dose of both study drugs (G-Pen followed Lilly Glucagon, or Lilly 


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Glucagon followed by G-Pen). PP and ITT analysis will also be applied to all 
secondary endpoints of the study.  
Sample Size 
Determination: 
For the primary analysis, a failure is recorded if the subject’s plasma glucose 
fails to rise above 70.0 mg/dL within 30 minutes of the administration of the 
dose of glucagon. Using this criterion, a sample size of 85 randomized subjects 
yields probabilities of G-Pen acceptance of 87.7% if the population failure 
rates of G-Pen and control are not more than 2%.  
Subjects will be recruited at approximately 6 clinical sites with a goal of no 
single center accounting for > 20% of the total sample. 
 


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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 Objectives .................................................................................................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 ...................................22 
6.3. 
Description and Composition of Drug Product ..........................................................22 
6.4. 
Clinical Experience with Glucagon ............................................................................23 
7. 
STUDY DESIGN .......................................................................................................24 
7.1. 
Study Overview ..........................................................................................................24 
7.2. 
Hypoglycemia Induction Procedure and Justification ................................................26 
7.3. 
Interruption and Termination of Dosing .....................................................................30 
8. 
ELIGIBILITY CRITERIA AND STUDY ENROLLMENT .....................................31 
8.1. 
Inclusion Criteria ........................................................................................................31 
8.2. 
Exclusion Criteria .......................................................................................................31 
8.3. 
Randomization ............................................................................................................32 
8.4. 
Subject Numbers .........................................................................................................33 
9. 
STUDY TREATMENTS............................................................................................34 
9.1. 
Allocation to Treatment ..............................................................................................34 


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9.2. 
Blinding ......................................................................................................................34 
9.3. 
Drug Supplies .............................................................................................................34 
9.3.1. 
Drug Product Formulation and Packaging .................................................................34 
9.3.2. 
Lilly Glucagon for Injection .......................................................................................34 
9.3.3. 
Preparation, Dispensing and Administration ..............................................................34 
9.3.4. 
Drug Storage and Drug Accountability ......................................................................35 
9.4. 
Concomitant Medications ...........................................................................................36 
10. 
STUDY PROCEDURES ............................................................................................37 
10.1. 
Visit 1 - Screening (Day -30 to -3) .............................................................................37 
10.2. 
Treatment and Follow-Up Phase ................................................................................38 
10.2.1. 
Visit 2 - Treatment 1 (Day 0) .....................................................................................38 
10.2.2. 
Visit 3 - Treatment 2 (Day 7-28) ................................................................................43 
10.2.3. 
Visit 4 - Follow-Up (Day 9-35) ..................................................................................43 
10.3. 
Subject Withdrawal ....................................................................................................43 
11. 
ASSESSMENTS.........................................................................................................47 
11.1. 
Blood Volume .............................................................................................................47 
11.2. 
Clinical Laboratory Tests ...........................................................................................47 
11.3. 
Electrocardiogram (12-lead ECG) ..............................................................................49 
11.4. 
Blood Pressure and Heart Rate ...................................................................................50 
12. 
SAFETY AND ADVERSE EVENT (AE) REPORTING..........................................51 
12.1. 
Definition of an Adverse Event ..................................................................................51 
12.2. 
Reporting Adverse Events ..........................................................................................51 
12.3. 
Reporting Period .........................................................................................................52 
12.4. 
Serious Adverse Events ..............................................................................................52 
12.5. 
Severity Assessment ...................................................................................................52 
12.6. 
Causality Assessment .................................................................................................53 
12.7. 
Withdrawal Due to Adverse Events ...........................................................................53 
12.8. 
Eliciting Adverse Event Information and Reporting ..................................................53 
12.9. 
Serious Adverse Event Reporting Requirements .......................................................53 
12.10. 
Non-Serious Adverse Event Reporting Requirements ...............................................54 
12.11. 
AE Reporting Requirements to Regulatory Authorities .............................................54 
12.12. 
Pregnancy ...................................................................................................................54 
12.13. 
Subject Monitoring .....................................................................................................55 


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13. 
DATA ANALYSIS AND STATISTICAL METHODS ............................................56 
13.1. 
General Approach .......................................................................................................56 
13.2. 
Efficacy .......................................................................................................................56 
13.2.1. 
Primary Endpoint: .......................................................................................................56 
13.2.2. 
Sample Size Calculation: ............................................................................................57 
13.3. 
Secondary Endpoints ..................................................................................................57 
13.3.1. 
Binary Responses ........................................................................................................57 
13.3.2. 
Pharmacodynamic Analyses .......................................................................................58 
13.3.3. 
Hypoglycemia Symptoms:..........................................................................................58 
13.3.4. 
Glucagon Preparation Time: .......................................................................................58 
13.4. 
Safety Analysis ...........................................................................................................58 
13.4.1. 
Adverse Events ...........................................................................................................59 
13.4.2. 
Laboratory Safety Assessments ..................................................................................59 
13.4.3. 
Physical examination ..................................................................................................60 
13.4.4. 
Vital signs and body weight .......................................................................................60 
13.4.5. 
ECG ............................................................................................................................60 
13.4.6. 
Local Tolerability .......................................................................................................60 
13.5. 
Subgroup Analysis ......................................................................................................60 
13.6. 
Demographics and Baseline Characteristics ...............................................................60 
14. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................61 
15. 
DATA HANDLING, RECORD KEEPING, MONITORING AND AUDITS ..........62 
15.1. 
Case Report Forms/Electronic Data Record ...............................................................62 
15.2. 
Record Retention ........................................................................................................63 
15.3. 
Monitoring ..................................................................................................................63 
15.4. 
Audits and Inspections ................................................................................................63 
16. 
ETHICAL CONSIDERATIONS................................................................................64 
16.1. 
Conduct .......................................................................................................................64 
16.2. 
Institutional Review Board and Ethics Committee ....................................................64 
16.3. 
Subject Information and Consent ...............................................................................64 
16.4. 
Subject Recruitment ....................................................................................................65 
16.5. 
Reporting of Safety Issues and Serious Breaches of the Protocol ..............................65 
17. 
DEFINITION OF END OF TRIAL ...........................................................................66 


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18. 
PROCEDURES FOR MODIFYING THE PROTOCOL OR 
TERMINATING THE STUDY .................................................................................67 
18.1. 
Protocol Modifications and Deviations ......................................................................67 
18.2. 
Study Termination ......................................................................................................67 
19. 
PUBLICATION OF STUDY RESULTS ...................................................................68 
20. 
REFERENCES ...........................................................................................................69 
APPENDICES ...............................................................................................................................71 
APPENDIX 1. HYPOGLYCEMIA SYMPTOM QUESTIONNAIRE ......................................71 
APPENDIX 2. INJECTION SITE DISCOMFORT ASSESSMENT .........................................72 
APPENDIX 3. DRAIZE SCALE ................................................................................................74 
APPENDIX 4. GOLD SCALE ...................................................................................................75 
 


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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 ..............................................................................26 
Table 4: 
Insulin Dose Adjustments ...........................................................................................28 
Table 5: 
Schedule of Assessments ............................................................................................45 
Table 6: 
Frequency and Volume of Blood Collections ............................................................47 
Table 7: 
Clinical and Safety Related Laboratory Tests ............................................................48 
Table 8: 
Conversion Table for Plasma Glucose Values ...........................................................49 
Table 9: 
AE Severity Assessment .............................................................................................53 
 


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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 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
BP 
Blood Pressure 
CLIA 
Clinical Laboratory Improvement Act 
Cmax 
Maximum Plasma Concentration 
CRF 
Case Report Form 
CRC 
Clinical Research Center 
CRO 
Contract Research Organization 
DBP 
Diastolic Blood Pressure 
DMSO 
Dimethyl sulfoxide 
ECG 
Electrocardiogram 
GCP 
Good Clinical Practice 
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 
ICH 
International Conference on Harmonization 


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IEC 
Independent Ethics Committee 
Im 
Intramuscular 
IRB 
Institutional Review Board 
IUD 
Intra-uterine device 
Iv 
Intravenous 
Kg 
Kilogram 
L 
Liters 
LSLV 
Last Subject Last Visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligram 
min 
Minute 
mmHg 
Millimeters Mercury 
mM 
NOAEL 
PG 
Millimoles per Liter 
No Observed Adverse Effect Level 
Plasma Glucose 
PD 
Pharmacodynamics 
PK 
Pharmacokinetic 
RBC 
Red blood cells 
rDNA 
Recombinant 
RLD 
Reference Listed Drug 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
Sc 
Subcutaneous 
THC 
Tetrahydrocannabinol 
Tmax 
Time to Maximum Plasma Concentration 


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T1D 
Type 1 Diabetes Mellitus 
ULN 
Upper Limit of Normal 
VAS 
Visual Analog Scale 
WHO 
World Health Organization 
YSI 
Yellow Springs Instrument 


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5. 
STUDY OBJECTIVES AND ENDPOINTS 
5.1. 
Primary Objective 
The primary objective of this study is to demonstrate the efficacy (return to plasma glucose >70.0 mg/dL) 
of G-Pen 1 mg (test) to be non-inferior to Lilly Glucagon 1 mg (reference), in T1D subjects in a state of 
insulin-induced hypoglycemia. This will be assessed by the comparison of failure rates of plasma glucose 
to have a measured value > 70.0 mg/dL within 30 minutes of administration of glucagon. 
5.2. 
Secondary Objectives 
The secondary objectives of this study are: 
• To demonstrate the efficacy (either return to plasma glucose >70.0 mg/dL or an 
increase in plasma glucose ≥ 20 mg/dL within 30 minutes post study drug injection) 
of G-Pen 1 mg (test) to be non-inferior to Lilly Glucagon 1 mg (reference), in T1D 
subjects in a state of insulin-induced hypoglycemia. 
• To demonstrate the efficacy (return to plasma glucose >70.0 mg/dL or alleviation of 
all neuroglycopenic symptoms at 30 minutes post study drug injection) of G-Pen 1 
mg (test) to be non-inferior to Lilly Glucagon 1 mg (reference), in T1D subjects in a 
state of insulin-induced hypoglycemia. 
• To compare the pharmacodynamic characteristics of G-Pen 1 mg (test) versus Lilly 
Glucagon 1 mg (reference) in T1D subjects who are in a state of insulin-induced 
hypoglycemia. 
• To compare G-Pen (test) and Lilly Glucagon (reference) with regards to 
hypoglycemia symptom relief.  
• To compare G-Pen (test) and Lilly Glucagon (reference) with regards to the 
preparation time required to inject to the abdomen from a decision to treat. 
• To compare the safety and tolerability of G-Pen 1 mg (test) versus Lilly Glucagon 1 
mg (reference) in T1D subjects who are in a state of insulin-induced hypoglycemia. 
5.3. 
Endpoints 
5.3.1. 
Primary Endpoint 
Treatment success in this study will be based on a primary endpoint of an increase in plasma 
glucose concentration from below 50.0 mg/dL to greater than 70.0 mg/dL within 30 minutes 
after receiving glucagon. 
5.3.2. 
Secondary Endpoints 
The secondary endpoints for this study include: 
• Return of plasma glucose to > 70 mg/dL or clearance of all neuroglycopenic 
symptoms within 30 minutes after receiving glucagon. 


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• Return of plasma glucose to > 70 mg/dL or an increase in plasma glucose by 
≥20 mg/dL within 30 minutes after receiving glucagon. 
• Increase in plasma glucose by ≥ 20.0 mg/dL within 30 minutes after receiving 
glucagon. 
• Relief within 30 minutes after receiving glucagon of all neuroglycopenic symptoms 
present immediately after the decision to dose. 
• Pharmacodynamic characteristics, including: plasma glucose AUC, Cmax, and Tmax, 
time to achieve a 20.0 mg/dL increase, and time to reach >70.0 mg/dL will be 
compared between the treatment groups both from time of glucagon administration 
and from time of the decision to dose. 
• The total preparation time required to inject to the abdomen from a decision to treat 
will be compared between the treatment groups, as measured between the time of 
“decision to dose” and time of injection.  
• Hypoglycemia symptom relief as measured using the hypoglycemia symptom 
questionnaire (Appendix 1), from just after the decision to dose to 180 minutes post-
injection of glucagon.   
• Safety-related parameters including:  
o Change in Vital signs from just prior to dosing to 180 minutes post-injection of 
glucagon 
o Changes in physical exam findings from Screening to Follow-up. 
o Changes in ECG findings from Screening to Follow-up. 
o Change in standard safety laboratory parameters (e.g., hematology and serum 
chemistry) from Screening to Follow-up. 
o Incidence of adverse events (AEs) and serious adverse events (SAEs). 
o Subjective injection site discomfort as reported by subjects using a 100-mm VAS 
and other questionnaires (Appendix 2). 
o Erythema and/or edema formation at site of injection assessed by an Investigator 
using the modified Draize scale (see Appendix 3). 


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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, GLP-1, and 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 an 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 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 are attributable to hypoglycemia 
[Skrivarhaug, U.K. Hypoglycaemia Study Group].  The American Diabetes Association 
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 type 1 diabetes, and 
progressively more frequently over time in type 2 diabetes.  The U.K. Hypoglycemia Study 
Group reported an incidence of 110 severe hypoglycemic episodes per 100 patient-years in 
patients with type 1 diabetes treated with insulin for <5 years, and an incidence of 320 episodes 
per 100 patient-years in those with type 1 diabetes 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 type 2 diabetics typically have several hypoglycemic episodes in a given year, 1-2 of these 
being severe episodes.  There are currently approximately 1.4 million type 1 and 3.8 million 
insulin-using type 2 diabetics in the US alone [CDC].  On average, the total insulin-using patient 
population experiences about 3 million severe hypoglycemic events per year.   
The American Diabetes Association [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.  However, a recent survey indicates only about 30% of the 
insulin-using diabetics carry GEKs [Close Concerns].  The current standard of care for severe 


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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, 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 glucagon for episodes of 
severe hypoglycemia, Xeris Pharmaceuticals is developing a glucagon rescue pen called the 
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, including:  a ready-to-use 
treatment with no reconstitution required, precise and rapid dosing, a hidden needle, and 
enhanced portability and availability due to room-temperature stability, to provide 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 (rDNA origin) was approved in 1998, and is currently the drug substance 
identified in two approved NDAs ([NDA 20-928] and [NDA 20-918]).  Complete NDA-required 
pharmacology and toxicology data have been reviewed and accepted by the FDA, as described in 
Lilly Glucagon [rDNA origin] for injection and Novo GlucaGen® (glucagon [rDNA origin] for 
injection) labeling [Glucagon, Glucagen].  As Xeris’ 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 Xeris’ current Investigator’s 
Brochure, which will be provided to each Investigator participating in this study. 
6.2.1. 
Nonclinical Pharmacology and Toxicology of Xeris G-Pen™ (glucagon injection) 
Investigational Non-Aqueous, Synthetic Glucagon 
Information on the nonclinical pharmacology, pharmacokinetics, and toxicology of G-PenTM 
(glucagon injection) is provided in Xeris’ current Investigator’s Brochure.  
6.3. 
Description and Composition of Drug Product 
Synthetic glucagon is the drug substance in G-Pen.  Glucagon cGMP grade is manufactured, 
packaged and released by Bachem AG (Bubendorf, Switzerland), conforms with USP standards 
and has a Type II DMF filed with the FDA.  G-Pen is a sterile subcutaneous injectable non-


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aqueous formulation for treatment of severe hypoglycemia.  G-Pen delivers 1 mg of glucagon, 
with trehalose and DMSO as excipients.  The drug product is stored at controlled room 
temperature (20-25°C) prior to use.   
G-Pen is supplied in 1.0 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 is currently marketed by Eli Lilly & 
Co. as Glucagon (Glucagon Injection [rDNA origin]), and Novo Nordisk as GlucaGen® 
HypoKit®, both reference listed drugs (RLD) 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 [FDA CDER #2].  The FDA first approved glucagon 
for use in humans in 1960. 
On September 25, 2013, Xeris IND 115091 went into effect and Study No. XSGP-201 was 
completed in January 2014. This study examined safety, pharmacokinetics (PK), and efficacy of 
rescue doses (0.5 and 1.0 mg) of G-Pen as compared to Lilly Glucagon (1.0 mg) in healthy 
volunteers. Phase 3 studies in adult (XSGP-301) and pediatric (XSGP-302) subjects with type 1 
diabetes were completed in August and June 2017, respectively. The results of these studies as 
well as a summary of clinical pharmacology, published studies, post-market surveillance data, 
and immunogenicity of Lilly Glucagon are provided in Xeris’ current Investigator’s Brochure.   


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7. 
STUDY DESIGN 
7.1. 
Study Overview 
This is a non-inferiority, multi-centered, randomized, controlled, single-blind, two-way crossover 
efficacy and safety in-patient study in subjects with Type 1 diabetes mellitus (T1D).  The study 
involves two daytime clinical research center (CRC) visits 7-28 days apart, with random 
assignment to receive G-Pen™ glucagon 1 mg during one period and Lilly Glucagon 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 
eligibility before enrollment to the treatment phase.  Subjects not meeting eligibility criteria may 
be rescreened after a 30-day wait. 
The evening prior to each in-patient study visit, subjects will be admitted for an overnight stay 
between 6 and 8 pm and at Investigator discretion a continuous glucose monitor (CGM) 
(Dexcom® G4 to be provided by Xeris) will be placed. At investigator discretion, the subject 
may visit the clinic up to 5 days prior to the scheduled check-in for placement of the CGM. 
Instead of placing a CGM, at Investigator discretion, blood glucose will be assessed periodically 
during the overnight stay via YSI model 2300 or 2900 or an FDA/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 blood glucose meter and confirmed to be ≤ 350 mg/dL, or 
the visit will be rescheduled. 
In clinic, 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. 
Subjects will be instructed to fast starting at midnight, at which point an intravenous catheter will 
be placed, and maintenance fluids administered. Blood glucose will be confirmed by glucose 
meter as necessary to calibrate the CGM, and blood glucose will be monitored overnight by 
CGM.  At Investigator discretion, CGM glucose values may be confirmed by glucose meter or 
Yellow Springs Instrument (YSI) glucose analyzer.  
After midnight, the Investigator should optimize blood glucose within a target range of 80.0-
150.0 mg/dL through the administration of IV insulin and 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 or subcutaneous insulin will be used 
to optimize blood glucose within a target range of 80.0-150.0 mg/dL.  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, the subject’s plasma glucose will be measured and 
verified to be not more than 270 mg/dL to be confirmed eligible for continuation into the insulin 
induction procedure. As another confirmation of eligibility for the induction procedure, CGM 
data will be checked and it will be verified that the subject did not have blood glucose < 60 or 
greater than 270 mg/dL overnight. If either of these criteria is not met, the visit will be 
rescheduled after a minimum 7-day wait. 


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The subject will continue fasting the morning of the procedure, and will have another 
intravenous catheter for blood sampling inserted in the 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” samples.  The subject will be kept supine and the abdomen and torso covered 
under a blanket to maintain warmth.  
Baseline euglycemic steady state period will begin when the plasma glucose is confirmed to be 
within range of 70-270 mg/dL. IV insulin will be administered to maintain the plasma glucose 
within the range of 75-115 mg/dL for 30 minutes. If the plasma glucose has been maintained 
within the range of 75-115 mg/dL 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. Adherence to the insulin dose adjustment algorithm will be facilitated by 
real time data capture on a pair of laptop computers.  One laptop will be used for entry of glucose 
values as the measurements become available from the YSI glucose analyzer.  The other laptop 
will display the induction procedure, glucose values, insulin bolus doses, and insulin infusion 
rate data, and will provide guidance on appropriate insulin dosing changes based on the subject’s 
glucose trajectory.  The application will include a data entry form for the Investigator to either 
document concurrence or to provide reasoning for any deviations from the protocol algorithm.  
Both laptops will be connected via either wireless or hard-wired secure internet connection to 
each other as well as a central database, 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 <50.0 mg/dL.  
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 >80.0 mg/dL and every 5±2 minutes once plasma glucose is 
≤ 80.0 mg/dL. 
The IV insulin infusion may be stopped when the plasma glucose first reaches <50 mg/dL, or, as 
guided per the insulin dosing algorithm, when plasma glucose is > 50 mg/dL. Five minutes after 
this first plasma glucose <50 mg/dL, a confirmatory plasma glucose reading (plasma glucose 
<50.0 mg/dL) will be verified.  The Investigator will determine whether a hypoglycemic steady 
state has been achieved, which is defined as two consecutive plasma glucose values between 
43.0 and 49.9 mg/dL, and a linearly extrapolated 8-minute later glucose value ≥ 42.0 mg/dL. 
If plasma glucose is not in a steady state, the subject’s plasma glucose should be rechecked at a 
subsequent 5-minute interval.  If this second confirmatory glucose is > 42.0 mg/dL and a linearly 
extrapolated 8-minute later glucose value ≥ 42.0 mg/dL is obtained, the subject will be deemed 
to be within a hypoglycemic steady state. 
If the second confirmatory plasma glucose measurement is < 42.0 mg/dL, the subject should not 
be administered study glucagon, should be treated instead with IV glucose or oral carbohydrates 
at the Investigator’s discretion, verified to be euglycemic, and their visit rescheduled after a 
minimum 7-day wait.  


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After a hypoglycemic state is verified, the subject will be eligible to receive either G-Pen or Lilly 
Glucagon in one of the randomized treatment sequences shown in Table 3.  The time of this 
“decision to dose” on the part of the Investigator will be documented. 
Table 3: 
Randomized Treatment Sequence 
Group 
Dose 1 
Dose 2 
1 
G-Pen™ 1 mg 
Lilly 1 mg 
2 
Lilly 1 mg 
G-Pen™ 1 mg 
Plasma glucose levels will be monitored for 180 minutes post-dosing.  It is believed that blood 
glucose <50 mg/dL will be low enough to generate neuroglycopenic and autonomic symptoms in 
most subjects, yet high enough (i.e., > 40 mg/dL) 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 clinic 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, subjects will be 
discharged after receiving a meal as per each site’s usual practice.  A follow-up visit as a safety 
check will be conducted 2-7 days following administration of the final dose of study drug.   
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.  The predecessor study (XSGP-301), therefore, utilized a comparatively lower rate of 
insulin infusion at 1 to 2 times the normal basal rate, combined with intravenous push of a bolus 
dose of insulin derived from the subject’s own self-reported glucose correction factor.  About 
30% of the procedures performed in XSGP-301 study resulted in plasma glucose (PG) <40 
mg/dL. To achieve more precision in achieving a steady state of PG below 50 mg/dL, individual 
procedure data from the XSGP-301 study 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 PG in XSGP-303. 
Hypoglycemia Induction Procedure 
Subjects will be admitted the evening prior, provided a standardized meal, use their regularly 
prescribed evening insulin regimen, and fast overnight. During the fast, subjects will be provided 
maintenance IV fluids and their glucose optimized, if site staffing permits.  In morning of the 
procedure (prior to the baseline euglycemia steady state period), the subject’s plasma glucose 
will be verified to be not more than 270 mg/dL. CGM will be used to verify that subjects did not 
experience hypo- or hyperglycemia overnight (i.e., blood glucose < 60 mg/dl or > 270 mg/dl). 
During the baseline euglycemia steady state and hypoglycemia induction, subjects should be 


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hydrated using IV fluids. Once glucagon dosing has taken place, IV fluids may be discontinued 
at investigator discretion and replaced by oral intake of water. 
After the overnight stay, subjects will have a second catheter 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. 
Use of the heated-hand box will follow the manufacturer’s printed instruction sheet.   
Baseline Euglycemic Steady State 
Prior to starting the hypoglycemia induction procedure, the subject must have PG stable for at 
least 30 minutes at 95 +/- 20 mg/dL (75-115 mg/dL) and a stable IV insulin infusion rate varying 
no more than +/- 20% during which PG must be measured at least every 15 minutes.  
Induction Start   
For the induction, the starting plasma glucose level will be determined as the average of three 
YSI measurements taken over the final 30 minutes of the baseline steady state period.  The 
following procedures will then be undertaken: 
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 50 mg/dL based on the subject’s 
self-reported glucose correction factor.  This dose will be referred to as “1 bolus (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. PG will be measured every 5 to 10 minutes, depending on the current PG 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 at discretion override the insulin dosing algorithm, but must document the 
reason for this decision. 


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Table 4: 
Insulin Dose Adjustments 
PG 
(mg/dl) 
PG 
(mM) 
Measurement 
interval 
Target Rate of 
PG decrease 
Insulin Bolus Criteria 
Insulin Basal Rate Adjustment Criteria 
>80 
>4.4 
10 min. 
>30 mg/(dl*hr) 
(>1.67 mM/hr) 
If PG decrease < 9 mg/(dl*hr) 
(<0.5 mM/hr); give 1 bolus 
If PG decrease <30 mg/dl*hr (<1.67 mM/hr); 
increase 20% (15 min) 
61-80 
3.4-4.4 
5 min. 
30 mg/(dl*hr) 
(1.67 mM/hr) 
If PG decrease < 9 mg/(dl*hr) 
(<0.5 mM/hr); give 1/2 bolus 
If PG decrease <30 mg/dl*hr (<1.67 mM/hr); 
increase 20% (15 min) 
If PG decrease >60 mg/dl*hr (>3.33 mM/hr); 
decrease 25% (15 min) 
56-60 
3.1-3.3 
5 min. 
15 mg/(dl*hr) 
(0.83 mM/hr) 
Not allowed 
If PG decrease <9 mg/dl*hr (<0.5 mM/hr); 
increase 20% (10 min), or set at 120% of 
previous rate if previously stopped or 
decreased by 50% (5 min) 
If PG decrease >30 mg/dl*hr (>1.67 mM/hr); 
decrease 50% (5 min) 
If PG decrease >60 mg/dl*hr (>3.33 mM/hr); 
Stop (5 min) 
50-55 
2.8-3.1 
5 min. 
15 mg/(dl*hr) 
(0.83 mM/hr) 
Not allowed 
If PG decrease <9 mg/dl*hr (<0.5 mM/hr); 
increase 20% (10 min), or set at 120% of 
previous rate if previously stopped or 
decreased by 50% (5 min) 
If PG decrease >30 mg/dl*hr (>1.67 mM/hr); 
Stop (5 min) 
<50 
<2.8 
5 min. 
0 
Not allowed 
Stop 
Note: mM = mmol/l 
When PG is > 60 mg/dL, insulin adjustments should not be made more frequently than every 15 minutes. When PG is ≤60 mg/dL, the 
minimum time between adjustments to decrease, terminate or re-start insulin is either 10 or 5 minutes, as indicated in Table 4. 
 


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1. While PG is greater than 80 mg/dL (4.4 mM): 
a. Measure PG at least every 10 minutes. 
b. When 15 minutes have passed from the last insulin dose adjustment: 
i. If the rate of PG decrease is less than 30 mg/dl*hr (<1.67 mM/hr), then the 
insulin infusion rate should be increased by 20%. 
ii. If the rate of PG decrease is less than 9 mg/dl*hr (<0.5 mM/L*hr), then 
the insulin infusion rate should be increased by 20%, plus an additional 1 
bolus (full bolus dose) should be administered. 
2. While PG is 61-80 mg/dL (3.4 – 4.4 mM):  
a. Measure PG at least every 5 minutes. 
b. When 15 minutes have passed from the last insulin dose adjustment: 
i. If the rate of PG decrease is greater than 60 mg/dl*hr (>3.33 mM/hr), then 
the insulin infusion rate should be decreased by 25%. 
ii. If the rate of PG decrease is less than 30 mg/dl*hr (>1.67 mM/hr), then the 
insulin infusion rate should be increased by 20%. 
iii. If the rate of PG decrease is less than 9 mg/dl*hr (<0.5 mM/hr), then the 
insulin infusion rate should be increased by 20%, plus an additional 1/2 
bolus dose (one-half of the “1 bolus”) should be administered.  
3. While PG is 56-60 mg/dL (3.1 – 3.4 mM):  
a. Measure PG at least every 5 minutes. 
b. Bolus doses of insulin should not be given. 
c. When 5 minutes have passed from last insulin adjustment: 
i. If the rate of PG decrease is greater than 60 mg/dl*hr (>3.33 mM/hr), then 
stop the IV insulin infusion. 
ii. If the rate of PG decrease is greater than 30 mg/dl*hr (>1.67 mM/hr), then 
the insulin infusion rate should be decreased by 50%. 
iii. If the infusion was previously stopped or decreased by 50%, and the rate 
of PG decrease rate is less than 9 mg/dl*hr (<0.5 mM/hr), then the insulin 
infusion should be set at 120% of the previous rate.  
d. When 10 minutes have passed from the last insulin dose adjustment: 
i. If the rate of PG decrease rate is less than 9 mg/dl*hr (<0.5 mM/hr), then 
the insulin infusion rate should be increased by 20%.  
4. While PG is 50-55 mg/dL (2.8 – 3.1 mM): 
a. Measure PG at least every 5 minutes. 
b. Bolus doses of insulin should not be given 
c. When 5 minutes have passed from last insulin adjustment: 


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i. If the rate of PG decrease is greater than 30 mg/dl*hr (>1.67 mM/hr), the 
IV insulin infusion should be stopped. 
ii. If the infusion was previously stopped or decreased by 50%, and the rate 
of PG decrease rate is less than 9 mg/dl*hr (<0.5 mM/hr), then the insulin 
infusion should be set at 120% of the previous rate.  
d. When 10 minutes have passed from the last insulin dose adjustment: 
i. If the rate of PG decrease is less than 9 mg/dl*hr (<0.5 mM/hr), then the 
insulin infusion rate should be increased by 20%.  
5. If the PG is less than 50 mg/dL (<2.8 mM), then the IV insulin infusion should be 
stopped. 
7.3. 
Interruption and Termination of Dosing 
At any time during the induction procedure if there are two consecutive plasma glucose 
measurements taken 5 minutes apart that are < 42.0 mg/dL, the procedure will be terminated and 
appropriate measures (oral or IV glucose) will be taken at the Investigator’s discretion.  If a 
subject exhibits signs of coma or convulsions, a 25-mL IV bolus dose of 50% dextrose will be 
given in lieu of study drug.  Signs and symptoms should be monitored, and if the subject’s 
condition fails to improve in a timely fashion, additional dextrose or other medical intervention 
may be given at the discretion of the Investigator.  
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 7-
day wait. 
The study procedure will end for any SAE that occurs during the induction procedure.  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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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 type 1 diabetes mellitus for at least 24 months. 
2. Current usage of daily insulin treatment that includes having an assigned “correction 
factor” for managing hyperglycemia.  
3. Age 18-75 years, inclusive. 
4. Random serum C-peptide concentration < 0.5 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/dated informed consent 
form completed before any trial-related activities occur. 
8.2. 
Exclusion Criteria 
1. Pregnancy: For women of childbearing potential, there is a requirement for a negative 
urine pregnancy test and for agreement to use contraception throughout the study and for 
7 days after the last dose of study glucagon. Acceptable contraception includes birth 
control pill / patch / vaginal ring, Depo-Provera, Norplant, an IUD, the double barrier 
method (the woman uses a diaphragm and spermicide and the man uses a condom), or 
abstinence. 
2. Breastfeeding: Nursing mothers will be allowed into the study. However, breast feeding 
during the during inpatient study visits (Visit 2 & Visit 3) and for 48 hours after each 
dose of study drug is not allowed.  
3. HbA1c >9.0% at Screening. 
4. BMI > 40 kg/m2.  
5. Renal insufficiency (serum creatinine greater than 3.0 mg/dL) or end-stage renal disease. 
requiring renal replacement therapy. 
6. Serum ALT or AST equal to or greater than 3 times the upper limit of normal. 
7. Hepatic synthetic insufficiency as defined as a serum albumin of less than 3.0 g/dL. 
8. Hematocrit of less than or equal to 30%. 
9. BP readings at Screening where SBP <90 or >150 mm Hg, and DBP <50 or >100 mm 
Hg. 
10. Clinically significant ECG abnormalities. 
11. Use of > 2.0 U/kg total insulin dose per day. 
12. Inadequate venous access. 


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13. Congestive heart failure, NYHA class III or IV. 
14.  History of myocardial infarction, unstable angina, or revascularization within the past 6 
months. 
15. History of a cerebrovascular accident in past 6 months or with major neurological 
deficits. 
16. Active malignancy within 5 years from Screening, except basal cell or squamous cell skin 
cancers.  History of breast cancer or malignant melanoma will be exclusionary. 
17. Major surgical operation within 30 days prior to Screening.  
18. Current seizure disorder (other than with suspect or documented hypoglycemia). 
19. Current bleeding disorder, treatment with warfarin, or platelet count below 50 x 109 per 
liter. 
20. History of pheochromocytoma or disorder with increased risk of pheochromocytoma 
(MEN 2, neurofibromatosis, or Von Hippel-Lindau disease). 
21. History of insulinoma. 
22. 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 & 
trehalose) in the investigational formulation.  
23. History of glycogen storage disease. 
24. Subject tests positive for HIV, HCV or HBV infection (HBsAg+) at Screening. 
25. Active substance or alcohol abuse (more than 21 drinks/wk. for males or 14 drinks/wk. 
for females). Subjects reporting active marijuana use or testing positive for 
tetrahydrocannabinol (THC) via rapid urine test will be allowed to participate in the study 
at the discretion of the Investigator. 
26. Administration of glucagon within 28 days of Screening. 
27. 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. 
28. Any reason the Investigator deems exclusionary. 
8.3. 
Randomization  
Randomization will be carried out via the Vision™ electronic data capture (EDC) system, 
version 9.3. The just-in-time randomization algorithm is programmed as a calculation within the 
Vision software system. The calculation is triggered when 1) site staff complete the Eligibility 
form and the subject is found to be eligible based on the inclusion/exclusion answers, and 2) the 
user checks a box on the Randomization form indicating a decision to randomize. This triggers 
the randomization calculation that sets the treatment group on the Dose Administration form. 
When the calculation is triggered, Vision generates a treatment based on the remaining 
treatments left within the block. This randomization calculation uses the java cryptographically 
strong SecureRandom random number generator in the case that the treatment group is not 


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already determined by the previous assignments. The SecureRandom algorithm computes the 
SHA-1 hash over a true-random seed value concatenated with a 64-bit counter, which is 
incremented by 1 for each operation. From the 160-bit SHA-1 output, only 64 bits are used. As a 
result, there is no known computer analysis that is able to predict the next "toss" better than a 
random guess. 
Subjects meeting all eligibility criteria and the following additional requirements will be 
randomized 1:1 by site in simple blocks to receive G-Pen™ glucagon or Lilly glucagon injection 
at the first treatment visit. Randomization at the first treatment visit (i.e., Day 0) should happen 
following the overnight stay and after the baseline euglycemia steady state has been achieved 
and the Investigator deems it is appropriate to begin the induction procedure (see Section 10.2). 
A member of the study staff who has verified the above criteria have been met will randomize 
the subject using the Vision EDC system. Once a subject has been randomized, information 
regarding the glucagon (G-Pen or Lilly) 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 EDC system.   
8.4. 
Subject Numbers  
As each subject is added to the EDC system, they will be assigned a unique Screening number, 
which will consist of a unique 2-digit site code (starting with 01) and a 2-digit number (starting 
with 01 at each site) indicating the sequence at which the subject was screened for eligibility.  
Upon randomization on Treatment Day 0 (see 10.2.1), eligible subjects will be assigned a unique 
Subject ID number that will consist of the project number “XSGP-303,” the Screening number 
and a 3-digit number (starting with 001 at each site) indicating the sequence at which the subject 
was randomized for treatment.  For example, XSGP-303-05-10-007 would be the Subject ID 
assigned to the 10th subject screened and the 7th subject randomized at site number 5.   


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9. 
STUDY TREATMENTS 
9.1. 
Allocation to Treatment 
Subjects will be randomized to one of the two treatment groups to receive the appropriate 
sequence of blinded study medication (see Table 3).  A total of 85 subjects will be randomized, 
with a goal of an approximately equal number of subjects being randomized to each treatment at 
both visits.  If there are subjects who are randomized but fail to receive either study drug, 
compensatory enrollment may be utilized to achieve at least 85 subjects who receive at least one 
of the treatments.  Each subject will receive a single subcutaneous injection to the abdomen on 
each of the two (2) treatment days, with a period of 7-28 days between doses.   
9.2. 
Blinding 
For this study, the subject but not the Investigator will be blinded (single-blind design).   The 1 
mg G-Pen™ 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.  
Subjects for whom the treatment has been unblinded inadvertently will be noted, and allowed to 
continue further study treatments, as per protocol. The statistical analysis plan for the study will 
outline a separate subgroup analysis for these subjects.  
9.3. 
Drug Supplies 
9.3.1. 
Drug Product Formulation and Packaging 
G-Pen from Xeris Pharmaceuticals, Inc. 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 (20-25°C) prior to use. 
The G-Pen drug product is manufactured under cGMP by Pyramid Laboratories, Inc. (Costa 
Mesa, CA), and packaged under cGMP by SHL Group (Deerfield Beach, FL), both Xeris 
Pharmaceuticals’ contract manufacturers. 
9.3.2. 
Lilly Glucagon for Injection 
Lilly Glucagon will be purchased commercially and provided by Xeris.  The glucagon will be 
stored at the research 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 
(CZ) 1 mL long syringe loaded into a Molly™ disposable auto-injector.  


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Subcutaneous administration will be performed by a qualified site staff member who 
has read the written Instructions for Use provided by Xeris.  
• In the case of Lilly Glucagon, 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 label [Glucagon].  
Study medications 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 
2-3 hours prior to glucagon dosing. When the investigator believes the induction procedure is 
approximately 1 hour from completion, a member of the study team will deliver the correct IP 
for the visit to the clinic area, making sure to maintain blinding of the subject. 
The study drugs will not be prepared ahead of time.  Instead, preparation of the investigational 
product (IP) (i.e., re-constitution of Lilly Glucagon) will begin after the confirmatory plasma 
glucose reading is obtained that indicates that a hypoglycemic steady state has been achieved, 
i.e., upon a “decision to dose.” 
G-Pen™ is being developed for subcutaneous (SC) injection.  The marketed comparator is 
labeled for both SC and intramuscular (IM) injection.  Both products will be administered via the 
subcutaneous 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-
degree angle) to the injection site.  The injection technique for G-Pen will follow printed 
instructions for use (IFU) provided by Xeris. 
For Lilly Glucagon, 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 1-3 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 Lilly Glucagon 
kits are to be stored at controlled room temperature between 20°C to 25°C (68° to 77°F), and 
drug solution should be clear and of a water-like consistency at time of use. 
The Investigator or an approved study staff will ensure that the study medications 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 


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appropriate course of action taken regarding the future use of the study medications upon 
consultation with Xeris Pharmaceuticals. 
After administration, used vials of Lilly Glucagon 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 similarly, but 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 Lilly kits will 
be returned to Xeris.  Used G-Pen auto-injectors will be returned to Xeris after accountability is 
performed during site close-out.  Used Lilly kits and other used supplies, will be destroyed 
according to local regulation and applicable Xeris Pharmaceuticals SOPs, following 
accountability by Xeris Pharmaceuticals 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 0 will be documented in the case report form (CRF).  Any changes to 
a subject’s concomitant medication regimen after the first treatment on Day 0 will also be 
documented in the CRF. 
Except for those medications (e.g., warfarin) listed under the exclusion criteria (see Section 8.2) 
and other currently 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 participant’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 
- Subject Information and Consent.  A copy of the consent/authorization form will be given to 
the 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 0).  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 subject has completed a 10-minute supine rest. 
6. Assessment of vital signs, including measurement of BP, after a 5-minute seated rest. 
7. Urine drug screen. Note: At Investigator discretion, subjects with a positive result for 
drugs other than THC 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. 


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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, having not had dinner.  
10.2.1. 
Visit 2 - Treatment 1 (Day 0) 
The following procedures will be carried out at this visit. 
Clinic Arrival 
1. Blood glucose (via glucose meter) will be assessed. If the result is > 350.0 mg/dL, no 
further procedures should be performed, and the visit should be rescheduled after a 
minimum 24-hour wait. 
2. The subject will be questioned, any changes in concomitant medications will be 
documented in the CRF, 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. 
4. If it has been more than 30 days since Visit 1 (i.e., the visit is occurring out of 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.  
5. 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 footnote to Table 5. 
6. A continuous glucose monitor should be placed and allowed to calibrate according to site 
procedures, which will include the use of a glucose meter. At investigator discretion, the 
subject may visit the clinic up to 5 days prior to the scheduled check-in for placement of 
the CGM. 
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. The composition of the meal should be described in the source 
documents, and the approximate percentage of the meal consumed should be recorded in 
10% increments, etc.). 
2. The subject should follow their normal prescribed regimen for insulin, including meal-
time correction, until midnight. 
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 
site staff. 


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2. An intravenous catheter will be placed in one arm, maintenance fluids 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 subcutaneous insulin will be used overnight.  
3. Blood glucose will be monitored overnight by CGM, YSI or glucose meter. At 
Investigator discretion, CGM values may be confirmed by glucose meter or YSI. IV 
glucose or oral glucose tablets will be given and/or insulin will be administered by IV or 
infusion pump as necessary to optimize the blood glucose within a target range of 80-150 
mg/dL.  
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, and any use of IV glucose 
will be discontinued. 
5. Overnight, if a blood glucose of < 60 or > 270 mg/dL is confirmed, the visit will be 
rescheduled after a minimum 7-day wait. Otherwise, the subject will be eligible to begin 
the Morning Procedures. 
Note: After the overnight stay, data from the Sponsor-supplied CGM will be uploaded to the 
IMD EDC system, if applicable. Otherwise, the site’s source document for overnight YSI or 
BGM values will be scanned and uploaded to the Vision EDC system.  
Morning Procedures (starting at approximately 6 am) 
1. In the morning, plasma glucose (via YSI) will be assessed, and if > 270.0 mg/dL, the visit 
will be rescheduled after a minimum 7-day wait.  Otherwise, the subject will be 
administered IV insulin to induce a baseline euglycemic steady state. 
2. If applicable, the CGM will be discontinued at this point and all further glucose 
measurement will be assessed via YSI. 
3. If not already placed, an IV catheter will be placed for administration of insulin and 
maintenance fluids. 
4. 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 PG stable for at 
least 30 minutes at 95 +/- 20 mg/dL (75-115 mg/dl) at a stable IV insulin infusion rate varying 
no more than +/- 20% during which PG must have be measured at least every 15 minutes (i.e., at 
least 3 consecutive values in the target range at 0, 15 and 30 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 undertaken: 
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 50 mg/dL based on the subject’s 
self-reported glucose correction factor. This dose will be referred to as “1 bolus (full 
bolus dose)” subsequently. 
b. PG 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 
Randomization will be performed after the baseline stabilization period has been successfully 
completed and the Investigator deems it is appropriate to begin the induction procedure.  At this 
time, the subject will be randomized to receive either G-Pen or Lilly Glucagon in one of the 
treatment sequences shown in Table 3.  
Confirmation of Hypoglycemic Steady State.  
1. Once an initial plasma glucose measurement < 50.0 mg/dL is achieved, the IV insulin 
infusion will be stopped.  Note: The requirement is that the average of the readings from 
the two YSI leads be < 50.0 mg/dL, but it is not required that both readings be 
< 50.0 mg/dL. 
2. After a minimum of 5 minutes, a confirmatory plasma glucose measurement will be 
performed. 
a. If the confirmatory plasma glucose measurement is 43.0-49.9 mg/dL, the 
Investigator must confirm that a hypoglycemic steady state has been achieved as 
follows. A hypoglycemic steady state is defined as two consecutive plasma 
glucose values between 43.0 and 49.9 mg/dL, and the 8-minute linearly 
extrapolated future PG value is ≥ 42.0 mg/dL. 
i. If the extrapolated 8-minute PG value is ≥ 42.0 mg/dL, the subject is eligible 
for dosing with glucagon (see Decision to Dose, below). 
ii. 
If the extrapolated 8-minute PG value is < 42.0 mg/dL, re-check PG after 5 
minutes. If this subsequent PG measurement is ≥ 42.0 mg/dL and the 
extrapolated 8-minute PG value is ≥ 42.0 mg/dL, the subject is eligible for 
glucagon dosing (see Decision to Dose, below); otherwise, the treatment visit 
will be terminated (see item d, below).   


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b. If the confirmatory plasma glucose measurement is > 50.0 mg/dL, then the IV 
insulin infusion will be re-started, and insulin adjustments made as per the 
induction procedure described above (Table 4), and the sequence will be repeated 
until there are two consecutive plasma glucose readings between 43.0-49.9 
mg/dL. These two consecutive measurements should occur within 60 minutes of 
the initial plasma glucose measurement < 50.0 mg/dL. 
c. If the confirmatory plasma glucose measurement is < 43.0 mg/dL, then the 
subject’s plasma glucose should be rechecked after 5 minutes. If the subsequent 
PG is ≥ 42.0 mg/dL, then the subject may be deemed to be within a hypoglycemic 
steady state. 
d. If the subsequent plasma glucose reading is < 42.0 mg/dL, the treatment visit will 
be terminated. In this case: 
i. Study drug should NOT be given. 
ii. If appropriate, medical intervention to achieve euglycemia can be 
implemented at the Investigator’s discretion. The subject can leave the clinic 
after glucose is confirmed to be above 100 mg/dL and the subject is deemed 
medically stable by the Investigator.  
iii. The visit should be rescheduled after a 7-day minimum wash-out period.  
Decision to Dose   
If the subject is deemed to be within a hypoglycemic steady state, then the subject is ready to be 
dosed (decision to dose) with study drug.  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 < 50 mg/dL 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 staff member will bring the appropriate unopened test article (pouched G-
Pen or Lilly Glucagon 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 in 
order to maintain the blind. 
4. A stop watch will be started, and 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 Lilly Glucagon have been fully reconstituted prior to administration. 
5. Subcutaneous administration of the study drug will be made to the abdomen as per 
Section 9.3.3. Upon completion of the administration, the stop watch will be stopped and 
the elapsed time in minutes and seconds will be recorded in the source documents. After 
the study drug injection, the study product will be disposed in a location away from the 
patient in a manner that maintains the blind. After disposal, the blindfold and headphones 
will be removed from the subject.  


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6. Following study drug administration, plasma glucose will be measured every 5±2 
minutes until 90 minutes, and every 30±2 minutes thereafter until 180 minutes post-
dosing.  
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 
glucose >100 mg/dL 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 all symptoms have abated (i.e., all 
symptoms have score = 1) or 90 minutes post-dosing, whichever occurs first, and 
5. Every 30 minutes (coinciding with plasma glucose measurements) between 90-180 
minutes post study drug dosing, or until all symptoms have abated (i.e., all symptoms 
have score = 1).  
Local Tolerability and Adverse Events 
Local tolerability and adverse events will be assessed as follows: 
1. Subjects will complete a Visual Analog (VAS) questionnaire regarding injection site 
discomfort (Appendix 2) at 10±5 and 30±5 minutes post-dosing, and again at 180±5 
minutes post-dosing if VAS score reported at 30 minutes is > 0 mm. 
2. Subjects will complete an Injection Site Discomfort Description and Duration 
Questionnaire at 10±5 minutes post-dosing. If discomfort is ongoing at 10 minutes post-
dosing, the questionnaire will be updated before the subject leaves the clinic to document 
the final duration.  


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3. The Investigator will use the modified Draize scales (Appendix 3) to assess erythema and 
edema formation at the injection site at 10±5 and 30±5 minutes following administration.  
Any injection site with a score > 0 for either erythema or edema at 30 minutes post-
dosing will be re-evaluated for both at 180±5 minutes post-dosing. If any scores remain > 
1 at the 180-minute evaluation, the subject may leave the clinic but will be instructed to 
contact study staff if the condition fails to resolve. 
Note: Ideally, the same investigator will assess the injection sites on the subject, during 
both treatment visits. 
4. Adverse events reported by the subject or observed by an Investigator during the visit 
will be recorded in the CRF. 
10.2.2. 
Visit 3 - Treatment 2 (Day 7-28) 
The subject will return 7 to 28 days following the first treatment visit. The procedures to be 
repeated at this visit are as listed in Section 10.2.1. If it has been more than 28 days since Visit 2 
(i.e., the visit is occurring out of window), venous blood will be collected for a repeat of 
hematology and serum chemistry assessments. However, the visit may continue based on 
qualification at the Screening visit.  At Visit 3, the other study drug will be administered at the 
time of Decision to Dose, so that between the two dosing visits, each subject will have received 
both G-Pen once, and Lilly Glucagon once.   
10.2.3. 
Visit 4 - Follow-Up (Day 9-35) 
The subject will attend a follow-up visit within 2-7 days of 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 10-minute supine rest. 
5. Vital signs after 5-minute seated rest. 
6. Urine pregnancy test (females of child-bearing potential). 
7. Blood draws for complete metabolic count and complete blood count.  
8. Adverse event questioning by asking the subjects to respond to a non-leading question 
such as “how do you feel?” 
In case of any premature discontinuation of a subject 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.   


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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 via email and telephone, including 
family members or emergency contacts. If such efforts fail, a certified letter should be sent to the 
subject’s last known address requesting they contact study staff. 
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 CRF.  
The Investigator should inquire about the reason for withdrawal, request that the subject return 
for a final visit, and 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 medication 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 listed 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 
Visit 2 
Visit 3* 
Visit 4* 
Screening 
Day -30 to -3 
Treatment 1 
Day 0 
Treatment 2 
Day 7-28 
Follow-up 
Day 9-35 
Informed consent 
x 
— 
— 
— 
Medical History & Demographics 
x 
— 
— 
— 
Inclusion/exclusion review 
x 
— 
— 
— 
Concomitant medications 
x 
x 
x 
x 
Height, weight & physical exama 
x 
— 
— 
x 
12-lead ECG 
x 
— 
— 
x 
Vital signs b 
x 
xb 
xb 
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, CGM 
placement**, dinner meal 
— 
x 
x 
— 
Overnight fast and CGM 
monitoring from midnight  
— 
x 
x 
— 
Hypoglycemia induction & 
confirmation of steady state 
— 
x 
x 
— 
Randomization 
— 
x 
— 
— 
Administration of study medication  
— 
x 
x 
— 
Hypo. symptom questionnaire 
— 
x 
x 
— 
Injection site discomfort scales 
— 
x 
x 
— 


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Assessment 
Visit 1 
Visit 2 
Visit 3* 
Visit 4* 
Screening 
Day -30 to -3 
Treatment 1 
Day 0 
Treatment 2 
Day 7-28 
Follow-up 
Day 9-35 
Draize scales for erythema/edema 
— 
x 
x 
— 
Venous blood glucose (PD)d 
— 
xc 
xc 
— 
Review adverse events (AE) 
— 
x 
x 
x 
a  Excluding breast, pelvic and genitourinary exams. Note: height assessment is not required at Visit 4. 
b Temperature, respiration, HR and BP (after >5 min seated rest) will be performed at all visits. Additionally, at 
visits 2 and 3, HR and BP will be repeated immediately prior to, and at 30, 60, 120 and 180 minutes post-dosing, 
with ±5 minutes for all procedures. 
c If plasma glucose is > 350.0 mg/dL upon clinic arrival or if the plasma glucose the morning after the overnight 
stay is > 270.0 mg/dL the visit should be rescheduled. 
d 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.  
(X) = repeat if the visit is occurring out of window (i.e., more than 28 or 30 days have passed since the prior 
visit). 
*Visit 3 should occur 7-28 days following Visit 2, and Visit 4 should occur 2-7 days following Visit 3. 
**At investigator discretion, the subject may visit the clinic for CGM placement up to 5 days prior to the check-
in for treatment visits. 


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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 
fashion. 
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 Activities.  In addition, visits to the site must occur within the pre-
defined windows outlined in this protocol, otherwise they will be considered as protocol 
deviations.  
11.1. 
Blood Volume 
There will be approximately 40 PD samples of about 2 cc each drawn at each treatment visit for 
a total of about 80 cc of blood per visit. These two treatment visits will be 7 to 28 days apart. 
There will be a 10.5 cc sample at Screening and at the Follow-up Visit for a clinical chemistry 
panel and hematology, with an additional 10.5 cc sample at Screening for eligibility 
determination. A total of about 200 cc of blood will be drawn over the total study (Table 6). 
Table 6: 
Frequency and Volume of Blood Collections 
Sample Type 
Sample 
Volume 
(mL) 
Number of Sampling Times 
Total 
Volume 
(mL) 
Screening 
Treatment 
Visits 1-2 
Follow-Up 
Visit 
Clinical Chemistry 
7.5 
1 
(X) 
1 
15 
Hematology 
3 
1 
(X) 
1 
6 
HbA1c 
3 
1 
- 
- 
3 
C-peptide 
2.5 
1 
- 
- 
2.5 
Serology 
5 
1 
- 
- 
5 
Pharmacodynamicsa 
2 
- 
c. 40/visit 
- 
160 
Total 
2-7.5 
5 
c. 40/visit 
2 
191.5 
a Plasma glucose measurements (1-2 mL ea.) at bedside via rapid glucose analyzer. 
(X) Optional if visit occurs outside the prescribed window. 
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.   


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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/SGOT 
ALT/SGPT 
β-hCGa 
Drug screenb 
HbA1c 
C-peptide 
HIVab 
HCVab 
HBsAg 
a 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. 
b 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 of excluding a subject from study participation based on a positive 
test for one of these additional analytes. Except as noted below, continuation in the study requires all tests to be 
negative with the exception of THC, which will be noted, but will not be considered exclusionary.  
A central laboratory will be utilized for analysis of all blood variables with the exception of 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, along with the Clinical Laboratory 
Improvement Act (CLIA) certification 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 drugs other than THC, the subject will normally be excluded from 
further study participation. However, if a subject reports use of a concomitant medication 
(prescription or 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, PG levels 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 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 


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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. In the rest of the protocol, plasma glucose 
values are provided in mg/dL. 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 
2.34 
43.0 
2.39 
49.9 
2.77 
50.0 
2.78 
70.0 
3.89 
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 Activities as follows: 
• 12-lead ECGs should be performed after the subject has rested quietly for at least 10 
minutes in a supine position. 
• 12-lead ECGs should be obtained before assessment of BP and heart rate, and prior to 
blood collections. 


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11.4. 
Blood Pressure and Heart Rate 
The BP and heart rate will be measured at the times specified in the Schedule of Activities.  
Additional or changes to collection times, or collection of BP and heart rate using automated 
devices is permitted, as necessary, to ensure appropriate subject’s 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 mmHg. The subject should be rested for at least 5 
min. before the BP is obtained. Measurements of both the BP and heart rate must be taken at 
least 2 min. apart and recorded in the CRF.  


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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 treatment-emergent AE (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 group 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 an 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 Pharmaceuticals.   


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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-serious adverse event 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 Pharmaceuticals 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 at any dose which: 
• 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 case report forms (CRF), 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 below. 


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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 
subject/event outcome or action criteria.  Accordingly, a severe event is not necessarily a serious 
event. 
12.6. 
Causality Assessment 
The Investigator will use the following question when assessing causality between an adverse 
event to the study drug, where an affirmative answer designates the event as a suspected adverse 
reaction: “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 CRF, 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 CRF.  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 Pharmaceuticals 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 Pharmaceuticals 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 


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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 Pharmaceuticals 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 CFR 312.32(c), Xeris Pharmaceuticals or its designee(s) is required to notify FDA and 
all participating Investigators in an IND safety report (i.e., 7- or 15-day expedited report) of 
potentially serious risks from clinical 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 CRF.  AEs should be reported using concise 
medical terminology on the CRFs 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 IRB/Ethics Committee of the occurrence of any SAE, in 
writing, as soon as is practicable and in accordance with local regulations.  A copy of this 
notification must be provided to Xeris Pharmaceuticals or its designee. 
In the event of an SAE that meets the criteria for expedited reporting, an SAE report will be 
prepared for submission to the FDA and any other applicable authorities by Xeris 
Pharmaceuticals or its designee. 
12.12. 
Pregnancy 
The active pharmaceutical product in Xeris Pharmaceuticals’ G-Pen is Glucagon, which is in 
Pregnancy Category B.  Female subjects able to become pregnant 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 randomized to treatment. 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. 


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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. 
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-303 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. In addition to the SAP, other graphical representations of the results may be produced 
after review of the data (post hoc).  Any major modifications of the definition of the Primary 
Endpoint or analysis will be reflected in a protocol amendment. 
13.2. 
Efficacy 
This is a non-inferiority study in which the primary objective is to test whether the G-Pen is not 
unacceptably less efficacious in terms of hypoglycemia relief than the Lilly Glucagon for 
injection. 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 patients 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 Lilly Glucagon, or Lilly 
Glucagon followed by G-Pen). 
For analysis of the primary endpoint, a failure for the study treatment (G-Pen or Lilly Glucagon) 
will be recorded if plasma glucose remains ≤ 70.0 mg/dL throughout the 0-30-minute period 
from a drug administration, while a success is defined as a return to plasma glucose >70.0 mg/dL 
in subjects from a state of insulin-induced hypoglycemia within the 0-30-minute period from 
drug administration.  
The following scoring system for the primary endpoint will be applied to all subjects in the PP 
cohort.  If a G-Pen failure is observed, then the treatment failure score = 1; similarly, the Lilly 
Glucagon failure score = 1 if a control failure is observed. An observed plasma glucose rising 
above 70.0 mg/dL within 30 minutes study drug administration yields a failure score = 0, for 
either treatment. 
For the ITT cohort, the following scoring system will be applied for analysis of the primary 
endpoint: If a G-Pen failure is observed, then the treatment failure score = 1; similarly, the Lilly 
Glucagon failure score = 1 if a control failure is observed.  If the G-Pen treatment outcome is 
missing, then the treatment failure score = 0.2.  A missing control outcome yields a control 
failure score = 0.1.  An observed plasma glucose rising above 70.0 mg/dL within 30 minutes 
study drug administration yields a failure score = 0, for either treatment [Koch].   
Secondarily, analysis of the primary endpoint will be repeated with success/failure evaluated at a 
time point of 30 minutes from a decision to dose (see Section 10.2.1). For this analysis, the 30-
minute value will be determined by linear interpolation between the two adjacent time points.  
13.2.1. 
Primary Endpoint: 
The G-pen acceptance criterion will be based on the sample mean of the failure scores derived 
from each subject (treatment-control). If Dht is designated as the sample mean of the G-Pen 


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minus control failure difference, and SE is the estimated standard error of Dht (square root of the 
estimated G-Pen minus control variance divided by the sample size), then the G-Pen will be 
accepted provided:  
 
Dht + 2.8 SE ≤ 0.1.   
This criterion, including the value 2.8, came from Monte-Carlo simulations from selected 
scenarios where the population G-Pen failure rate exceeded the control rate by 0.1. Under these 
circumstances the rate of G-Pen acceptance was found to be within 0.025 using this criterion, 
with missing data rates within 15%.  This bound of 0.025 on the type 1 error rate was observed 
for control failure rates up to 5%.    Monte Carlo simulation rather than asymptotic normality is 
necessary because an observed failure from either G-Pen or control is expected to be low, less 
than 5%. 
13.2.2. 
Sample Size Calculation: 
Using the above criterion for the primary endpoint assumptions under scoring described above 
(Koch), a sample size of 85 randomized subjects yields probabilities of G-Pen acceptance of 
88% if the population failure rate differences of G-Pen and control are within 2%, and the rate of 
missing observations is within 5%.   
The power and type 1 error bounds were obtained from a simulation model using a 3x3 table of 
outcomes for G-Pen and control.  The three outcomes for each were Success, Failure, and 
Missing.  Probabilities were assigned to each of the 9 cells for determining the probability of G-
Pen acceptance, either the type 1 error probability or power depending on the scenario being 
simulated, with the missing outcome being stochastically independent of the Success and Failure 
outcome combinations.  Also, the failure score difference, G-Pen minus control, was assigned to 
each of the nine cells.  To simulate one replicate of the study, 85 independent draws were made 
from the multinomial distribution determined by the probabilities from the 9 cells, and the 
sample mean with its estimated standard error were computed.  The G-pen acceptance criterion 
was applied and either a 0 (G-pen failed) or 1 (G-pen accepted) was recorded.  This was repeated 
10,000 times to obtain the estimated probability of G-pen acceptance under the conditions 
defined by the cell probabilities. The simulations were performed using R version 3.1.2 (2014-
10-31). 
It is expected that randomization of 85 subjects will achieve at least 75 evaluable subjects for PP 
analysis at approximately 6 clinical sites with a goal of no single center accounting for > 20% of 
the total randomization. Screening and enrollment will continue until at least 85 randomized 
subjects have received at least one dose of study drug (see Section 9.1). 
13.3. 
Secondary Endpoints 
All secondary endpoints will be assessed in both the ITT and PP analysis populations. 
13.3.1. 
Binary Responses 
The following secondary response endpoints will be assessed. For each endpoint, scoring will 
follow the methods described for the primary endpoint in Section 13.2. 
1. Return of plasma glucose to > 70 mg/dL or neuroglycopenic symptomatic relief within 
30 minutes after receiving glucagon. 


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2. Return of plasma glucose to > 70 mg/dL or an increase in plasma glucose by ≥20 mg/dL 
within 30 minutes after receiving glucagon. 
3. Increase in plasma glucose by ≥ 20.0 mg/dL within 30 minutes after receiving glucagon. 
4. Neuroglycopenic symptomatic relief within 30 minutes after receiving glucagon. 
Secondarily, analysis of these secondary endpoints will be repeated with success/failure 
evaluated at a time point of 30 minutes from a decision to dose (see Section 10.2.1 ). For this 
analysis, the 30-minute value will be determined by linear interpolation between the two adjacent 
time points. 
13.3.2. 
Pharmacodynamic Analyses 
The pharmacodynamic endpoints will be derived from the individual glucose profiles. 
Time for plasma glucose to increase by at least 20 mg/dL, time for plasma glucose to reach 
>70.0 mg/dL, AUC, Cmax and Tmax will be compared between the treatment groups using a mixed 
model with treatment, period and sequence as terms. 
13.3.3. 
Hypoglycemia Symptoms: 
Symptom relief will be analyzed as aggregate scores for the four autonomic, four 
neuroglycopenic symptoms and 8 total 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 global hypoglycemia question will be described and 
compared between the groups. 
13.3.4. 
Glucagon Preparation Time: 
The time between “decision to dose” and time of study drug administration to the abdomen will 
be measured and be called 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 from a 
decision to treat will be compared between the treatment groups, as measured between the time 
of “decision to dose” and time of injection. 
13.4. 
Safety Analysis 
All safety analyses will be performed using the safety population, namely those subjects 
receiving at least one dose of the study treatment. 
The following variables will be compared between the treatments for safety purposes: 
• Adverse events and serious adverse events 
• Laboratory safety variables (Screening to Final Visit) 
• Physical examination (Screening to Final Visit) 
• Vital signs 


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• 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 VAS 
and ordinal pain scales (Appendix 2). 
o Erythema and or edema formation at site of injection assessed using the Draize 
scale (Appendix 3). 
13.4.1. 
Adverse Events 
All verbatim adverse event terms will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) and summarized by system organ class, preferred term, and study drug. 
AE collection will begin from the time of consent. Listings of all AEs (including non-TEAEs), 
serious TEAEs (SAEs), and TEAEs leading to study drug discontinuation will be provided by 
treatment group, site, subject, verbatim term, MedDRA SOC and Preferred Term, 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 Preferred Term; by SOC, Preferred Term, and severity (mild, moderate, 
and severe/life-threatening/death); and by SOC, Preferred Term, 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 Preferred Term) was reported for the same 
subject more than once, then the AE was counted only once for that Preferred Term 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 Preferred Term. 
Subjects will be analyzed for safety according to the study treatment received. 
13.4.2. 
Laboratory Safety Assessments 
Laboratory values (biochemistry and hematology) will be flagged if outside the normal range. A 
listing of clinically significant abnormal values will be presented. The individual values will be 
listed indicating values outside normal range. Laboratory assessments will be summarized at 
Screening and at end of trial. Significant deviations/changes from the Screening Visit to the Final 
Visit will be documented as AEs if the Investigator judges these as being clinically significant. 


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13.4.3. 
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 trial will be recorded as AEs if the 
Investigator judges these as being clinically significant. 
13.4.4. 
Vital signs and body weight 
Vital signs 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 these as being clinically significant.  
13.4.5. 
ECG 
Any clinically significant ECG changes will be recorded and followed as appropriate. The 
Investigator’s evaluations will be summarized in a data listing. 
Significant deviations/changes from the Screening Visit to the Final Visit will be documented as 
AEs if the Investigator judges these as being clinically significant. 
13.4.6. 
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. 
13.5. 
Subgroup Analysis 
Safety and efficacy by gender (male, female), age (18-64 years, 65 years and above), and 
race/ethnicity (i.e. Whites, Hispanics, and African-Americans) will be analyzed descriptively. 
More specific details regarding the analyses will be provided in the Statistical Analysis Plan 
(SAP). 
13.6. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized for all subjects overall and by 
treatment arm.  Summary statistics (e.g., number of subjects, mean, median, standard deviation 
and range) will be generated for continuous variables (.g,, age and weight) and the number and 
percentage of subjects within each category will be presented for categorical variables (e.g,, 
gender, ethnicity, and race). 


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14. 
QUALITY CONTROL AND QUALITY ASSURANCE 
During study conduct, Xeris Pharmaceuticals or its agent will conduct periodic visits to ensure 
that the protocol and Good Clinical Practices are being followed.  The monitor may review 
source documents to confirm that the data recorded on CRFs is accurate.  The Investigator and 
institution will allow Xeris Pharmaceuticals’ monitor or its designee, and appropriate regulatory 
authorities, direct access to source documents to perform this verification. 
The study site may be subjected to review by the Institutional Review Board and/or to quality 
assurance audits performed by Xeris Pharmaceuticals or its designee, and/or to inspection by 
appropriate regulatory authorities.  It is important that the Investigator and study staff are 
available during the monitoring visits and possible audits or inspections and that sufficient time 
is devoted to the process. 


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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 Good Clinical Practice (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 CRF is understood to refer to  an electronic data record, i.e., an 
eCRF.  An eCRF is required and should be completed for each individual subject.  The 
completed original eCRFs are the property of Xeris Pharmaceuticals and should not be made 
available in any form to third parties, except for authorized representatives of Xeris 
Pharmaceuticals or appropriate regulatory authorities, without written permission from Xeris 
Pharmaceuticals.  
Completion of eCRFs will be accomplished using two independent 21 CFR Part 11 compliant 
web-based EDC systems. As described in Section 7.1, one system will be used to enter glucose 
and insulin data during treatment visits via laptop computers provided to the sites by Xeris. Sites 
will use existing computers other than the Xeris-provided laptops to enter all other study-related 
data into a second EDC system.  
The Investigator has the responsibility for the collection and reporting of all clinical, safety and 
laboratory data entered on the CRFs 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 CRFs must be signed by the 
Investigator or by an authorized staff member to attest that the data contained in the CRFs is true.  
Any corrections to entries made in the CRFs 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 CRFs must match the data in those charts.  In some cases, the CRF, 
or part of the CRF, may also serve as source documents.  In these cases, a document should be 
available at the Investigator’s site as well as at Xeris Pharmaceuticals and clearly identify those 
data that will be recorded in the CRF, and for which the CRF 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. 


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15.2. 
Record Retention 
To enable evaluations and/or audits from regulatory authorities or Xeris Pharmaceuticals, the 
Investigator agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records, e.g., CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, and detailed 
records of treatment 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 International Conference on Harmonisation (ICH), local 
regulations, or as specified in the Clinical Study Agreement, whichever is longer.  The 
Investigator must obtain Xeris Pharmaceuticals’ written permission before disposing of any 
records, even if retention requirements have been met. 
15.3. 
Monitoring 
Monitoring and auditing procedures developed by Xeris Pharmaceuticals and/or its designee will 
be implemented to ensure compliance with FDA and ICH GCP and GLP guidelines. 
The Xeris Pharmaceuticals’ 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/Ethics Committee review, with the stipulation that subject 
confidentiality will be maintained in accordance with local and federal regulations, including 
HIPAA requirements.  The monitor will also be responsible for confirming adherence to the 
study protocol, inspecting CRFs and source documents, and ensuring the integrity of the data.  
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 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/Ethics Committee, and/or Xeris 
Pharmaceuticals or their designees have the right to access all CRFs, 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 protocol is written in accordance with the principles established by the 18th World Medical 
Assembly General Assembly (Helsinki, 1964) and amendments and clarifications adopted by the 
29th (Tokyo, 1975), 35th (Venice, 1983), 41st (Hong Kong, 1989), 48th (Somerset West, South 
Africa, 1996), 52nd (Edinburgh, 2000), 53rd (Washington, 2002), 55th (Tokyo, 2004), and 59th 
(Seoul, 2008) General Assemblies.  The Investigator will ensure that the study described in this 
protocol is conducted in full conformance with those principles, the protocol, current FDA 
regulations, ICH Good Clinical Practices (GCP) guidelines, Good Laboratory Practices (GLP) 
guidelines, local ethical and regulatory requirements, including the Federal Food, Drug and 
Cosmetic Act, U.S. applicable Code of Federal Regulations (title 21), any IRB/Ethics Committee 
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 Investigator’s Brochure, prior to the initiation of the study. 
16.2. 
Institutional Review Board and Ethics Committee 
The Ethics Committee/IRB 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 for review and approved before the enrollment of any subject into the 
trial.  Study drug may not be shipped to the Investigator until Xeris Pharmaceuticals has received 
a copy of the letter or certificate of approval from the IRB/Ethics Committee for the protocol and 
any protocol amendments. 
All types of subject recruitment or advertising information must be submitted to Xeris 
Pharmaceuticals or its designee and to the IRB/Ethics Committee 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/Ethics Committee should be notified immediately and the amendment forwarded to the 
IRB/Ethics Committee 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/Ethics Committee.  All correspondence with the 
IRB/Ethics Committee should be retained in the Investigator File.  Copies of IRB/Ethics 
Committee approvals should be forwarded to Xeris Pharmaceuticals. 
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 


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numbering system provided by Xeris Pharmaceuticals to de-identify the study subject.  In the 
case of data transfer, Xeris Pharmaceuticals 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/Ethics Committee and Xeris 
Pharmaceuticals 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 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 subject’s signed consent document.  Receipt of 
written informed consent will be documented in each subject’s or potential subject’s CRF.  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 
Pharmaceuticals or its designee and to the IRB/Ethics Committee for review and approval prior 
to implementation.  Advertisements approved by the IRB/Ethics Committee 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 Pharmaceuticals should be notified immediately.  In addition, 
the Investigator will inform Xeris Pharmaceuticals 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. 
DEFINITION OF END OF TRIAL 
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. 


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18. 
PROCEDURES FOR MODIFYING THE PROTOCOL OR 
TERMINATING THE STUDY 
18.1. 
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 Pharmaceuticals and the 
Investigator.  All protocol modifications must be reviewed and approved by the IRB/Ethics 
Committee before the revised protocol can be implemented.  Emergency revisions that eliminate 
an apparent hazard to subjects do not require preapproval by the IRB/Ethics Committee.  
However, the IRB/Ethics Committee 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 
Pharmaceuticals.  All departures from the protocol must be fully documented in the source 
documents and the CRFs of the subjects involved. Protocol deviations will be tracked in an 
electronic system implemented by the Sponsor or designated representative. 
18.2. 
Study Termination 
The study may be prematurely terminated at any time because of a regulatory authority decision, 
change in opinion of the IRB/Ethics Committee, safety problems resulting in subject deaths, or at 
the discretion of Xeris Pharmaceuticals 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 Pharmaceuticals 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 CRFs completed to the greatest extent possible, and all study 
materials must be returned to Xeris Pharmaceuticals or its designee within an additional 28 days. 


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19. 
PUBLICATION OF STUDY RESULTS 
Publication of study results is discussed in the Clinical Study Agreement. 


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20. 
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™ (glucagon for injection [rDNA origin]) Prescribing Information.  Eli Lilly 
and Company, revised February 2005 
9. Glucagen® (glucagon [rDNA origin] for injection) Prescribing Information.  Novo 
Nordisk, Inc. revised December 2011.  
10. 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.  
11. 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.  
12. FDA CDER #1.  Glucagon (glucagon hydrochloride).  NDA No. 01-2122.  Eli Lilly and 
Company, Indianapolis, IN, November 14, 1960. 
13. 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. 
14. FDA CDER #2.  rDNA Glucagon for Injection, Pharmacology and Toxicology Review.  
NDA No. 20-928.  Eli Lilly and Company, Indianapolis, IN, April 16, 1998. 
15. 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. 


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16. Koch GG. Comments on ‘Current issues in non-inferiority trials.’ Statist.Med. 2008; 27: 
333-342. 


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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 all symptoms have abated 
(i.e., all symptoms have score = 1) or 90 minutes post-dosing, whichever occurs first. 
• Every 30±5 minutes (coinciding with plasma glucose measurements) between 90-180 
minutes post study drug dosing, or until all symptoms have abated (i.e., all symptoms 
have score = 1).  
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 both 10±5 minutes and 30±5 minutes following the 
injection of study drug, and again before the end of the clinic visit (i.e., at 180±5 minutes post-
dosing) if the VAS score at 30±5 minutes is > 0 mm. The subject completes 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 should be completed by the subject at 10±5 
minutes following the injection of study drug. Any subject reporting discomfort other than 
“none,” should complete question 1b. Any subject reporting duration of discomfort of “at least 
10 minutes” should complete follow-up question 1c at the end of the study visit (i.e., at 180±5 
minutes 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 10 ± 5 and 30 ± 5 minutes post-treatment, and again at the end of the 
treatment visit (i.e., at 180 ± 5 minutes post-dosing) if any scores > 0 were noted at 
30-minutes post-dosing. 
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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Statistical Analysis Plan for: 
PROTOCOL XSGP-303 
G-PEN™ (GLUCAGON INJECTION) COMPARED TO LILLY 
GLUCAGON (GLUCAGON FOR INJECTION [RDNA ORIGIN]) 
FOR INDUCED HYPOGLYCEMIA RESCUE IN ADULTS WITH 
T1D: A PHASE 3B MULTI-CENTERED, RANDOMIZED, 
CONTROLLED, SINGLE BLIND, 2-WAY CROSSOVER STUDY 
TO EVALUATE EFFICACY AND SAFETY 
 
NCT03439072 
 
Document Date: May 3, 2018 
 


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STATISTICAL ANALYSIS PLAN 
 
 
G-PEN™ (GLUCAGON INJECTION) 
PROTOCOL XSGP-303 V2.0 
 
G-PEN™ (GLUCAGON INJECTION) COMPARED TO LILLY 
GLUCAGON (GLUCAGON FOR INJECTION [RDNA 
ORIGIN]) FOR INDUCED HYPOGLYCEMIA RESCUE IN 
ADULTS WITH T1D: A PHASE 3B MULTI-CENTERED, 
RANDOMIZED, CONTROLLED, SINGLE BLIND, 2-WAY 
CROSSOVER STUDY TO EVALUATE EFFICACY AND 
SAFETY 
 
Approval:  ___________________ ________________ _______ 
 
Statistician/Name     
Signature 
          Date 
 
 
Approval:  ___________________ _________________ _______ 
 
 Medical Monitor/Name  Signature   
           Date 
 
 
Approval:  ___________________ _________________ _______ 
 
 Sponsor/Name  
Signature   
           Date 
 
This confidential document is the property of IMD and Xeris. No unpublished 
information contained herein may be disclosed without prior written approval from 
IMD and Xeris. Access to this document must be restricted to relevant parties. 
 
 
 


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Table of Contents 
1 
OVERVIEW ............................................................................................................................................. 7 
1.1 
INTRODUCTION ........................................................................................................................................ 7 
1.2 
OBJECTIVES .................................................................................................................................................. 7 
1.2.1 
Primary Objective ........................................................................................................................... 7 
1.2.2 
Secondary Objectives ...................................................................................................................... 7 
1.3 
ANALYSIS SOFTWARE...................................................................................................................................... 8 
1.4 
MODIFICATIONS FROM THE STATISTICAL SECTION IN THE PROTOCOL .................................................... 8 
2 
INVESTIGATIONAL PLAN ........................................................................................................................ 9 
2.1 
STUDY DESIGN AND RANDOMIZATION .................................................................................................... 9 
2.1.1 
Study Design ................................................................................................................................... 9 
2.1.2 
Sample Size ..................................................................................................................................... 9 
2.1.3 
Randomization .............................................................................................................................. 10 
2.1.4 
Unblinding .................................................................................................................................... 10 
3 
STATISTICAL AND ANALYTICAL PROCEDURES....................................................................................... 11 
3.1 
ANALYSIS POPULATIONS ........................................................................................................................ 11 
3.1.1 
Intent-to-Treat (ITT) population.................................................................................................... 11 
3.1.2 
Per-protocol (PP) Population ........................................................................................................ 11 
3.1.3 
Safety Population .......................................................................................................................... 11 
3.2 
ANALYSIS VARIABLES .............................................................................................................................. 11 
3.2.1 
General guideline for define the protocol time ............................................................................. 11 
3.2.2 
For categorical variable, the last value will be used ..................................................................... 12 
3.2.3 
Demographics ............................................................................................................................... 12 
3.2.4 
Efficacy Variables .......................................................................................................................... 13 
3.2.5 
Safety Variables ............................................................................................................................ 17 
3.3 
STATISTICAL METHODS .......................................................................................................................... 20 
3.3.1 
General guideline for descriptive summaries ............................................................................... 20 
3.3.2 
Baseline Characteristics ................................................................................................................ 20 
3.3.3 
Efficacy Analysis ............................................................................................................................ 21 
3.3.4 
Safety Analysis .............................................................................................................................. 24 
3.3.5 
Other statistical Analysis .............................................................................................................. 25 
4 
DATA HANDLING CONVENTIONS ......................................................................................................... 26 
4.1 
MISSING DATA ........................................................................................................................................... 26 
4.2 
REPEATED AND UNSCHEDULED VISIT ............................................................................................................... 26 
4.3 
PROTOCOL VIOLATIONS ................................................................................................................................. 26 
5 
PLANED LISTING, TABLE AND FIGURES ................................................................................................. 27 
6 
SOFTWARE DOCUMENTATION ............................................................................................................. 28 
7 
APPENDIX ............................................................................................................................................ 29 
 
 
 


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Abbreviations and Specialist Terms 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
BP 
Blood Pressure 
CLIA 
Clinical Laboratory Improvement Act 
Cmax 
Maximum Plasma Concentration 
CRF 
Case Report Form 
CRC 
Clinical Research Center 
CRO 
Contract Research Organization 
DBP 
Diastolic Blood Pressure 
DMSO 
Dimethyl sulfoxide 
ECG 
Electrocardiogram 
GCP 
Good Clinical Practice 
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 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
Im 
Intramuscular 


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IRB 
Institutional Review Board 
IUD 
Intra-uterine device 
Iv 
Intravenous 
Kg 
Kilogram 
L 
Liters 
LSLV 
Last Subject Last Visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligram 
min 
Minute 
mmHg 
Millimeters Mercury 
mM 
NOAEL 
PG 
Millimoles per Liter 
No Observed Adverse Effect Level 
Plasma Glucose 
PD 
Pharmacodynamics 
PK 
Pharmacokinetic 
RBC 
Red blood cells 
rDNA 
Recombinant 
RLD 
Reference Listed Drug 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
Sc 
Subcutaneous 
THC 
Tetrahydrocannabinol 
Tmax 
Time to Maximum Plasma Concentration 
T1D 
Type 1 Diabetes Mellitus 
ULN 
Upper Limit of Normal 


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VAS 
Visual Analog Scale 
WHO 
World Health Organization 
YSI 
Yellow Springs Instrument 
 


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1 OVERVIEW 
1.1 INTRODUCTION  
This documentation describes the planed data analyses for clinical trial XSGP-303 
sponsored by Xeris Pharmaceuticals, Inc. 
1.2 OBJECTIVES   
1.2.1 Primary Objective 
The primary objective of this study is to demonstrate the efficacy (return to plasma 
glucose >70.0 mg/dL) of G-Pen 1 mg (test) to be non-inferior to Lilly Glucagon 1 mg 
(reference), in T1D subjects in a state of insulin-induced hypoglycemia. This will be 
assessed by the comparison of failure rates of plasma glucose to have a measured 
value > 70.0 mg/dL within 30 minutes of administration of glucagon. 
1.2.2 Secondary Objectives 
The secondary objectives of this study are: 
• To demonstrate the efficacy (either return to plasma glucose >70.0 mg/dL or 
an increase in plasma glucose ≥ 20 mg/dL within 30 minutes post study drug 
injection) of G-Pen 1 mg (test) to be non-inferior to Lilly Glucagon 1 mg 
(reference), in T1D subjects in a state of insulin-induced hypoglycemia. 
• To demonstrate the efficacy (return to plasma glucose >70.0 mg/dL or 
alleviation of all neuroglycopenic symptoms at 30 minutes post study drug 
injection) of G-Pen 1 mg (test) to be non-inferior to Lilly Glucagon 1 mg 
(reference), in T1D subjects in a state of insulin-induced hypoglycemia. 
• To compare the pharmacodynamics characteristics of G-Pen 1 mg (test) 
versus Lilly Glucagon 1 mg (reference) in T1D subjects who are in a state of 
insulin-induced hypoglycemia. 
• To compare G-Pen (test) and Lilly Glucagon (reference) with regards to 
hypoglycemia symptom relief.  
• To compare G-Pen (test) and Lilly Glucagon (reference) with regards to the 
preparation time required to inject to the abdomen from a decision to treat. 
• To compare the safety and tolerability of G-Pen 1 mg (test) versus Lilly 
Glucagon 1 mg (reference) in T1D subjects who are in a state of insulin-
induced hypoglycemia. 


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1.3 ANALYSIS SOFTWARE 
SAS 9.1.3 or newer (Windows) 
1.4 MODIFICATIONS FROM THE STATISTICAL SECTION IN THE 
PROTOCOL  
None 


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2 INVESTIGATIONAL PLAN 
2.1 STUDY DESIGN AND RANDOMIZATION 
2.1.1 Study Design 
 
This is a non-inferiority, multi-centered, randomized, controlled, single-blind, two-way 
crossover efficacy and safety in-patient study in subjects with Type 1 diabetes 
mellitus (T1D).   
Table 2-1: 
Randomized treatment sequence 
Group 
Dose 1 
Dose 2 
1 
G-Pen™ 1 mg 
Lilly 1 mg 
2 
Lilly 1 mg 
G-Pen™ 1 mg 
The procedure consists of: 
1. Inducing hypoglycemia by IV administration of regular insulin diluted in normal 
saline until the subjects reach a verified stable hypoglycemic state.   
2. Treating subcutaneously with either 1 mg Lilly Glucagon or 1 mg G-Pen™ 
(glucagon injection). 
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.  
The specific hypoglycemia induction procedures and justification, and rules for 
interruption and termination of dosing are listed in the protocol. 
2.1.2 Sample Size  
For the primary objective, a failure is recorded if the subject’s plasma glucose fails to 
rise above 70.0 mg/dL within 30 minutes of administration of the dose of glucagon. 
Using this criterion, a sample size of 85 randomized subjects yields probabilities of 
G-Pen acceptance of 88% if the population failure rate differences of G-Pen and 
control are within 2%, and the rate of missing observations is within 5%.  
Subjects will be recruited at approximately 6 clinical sites with a goal of no single 
center accounting for > 20% of the total sample. 


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2.1.3 Randomization  
Randomization will be carried out via the Vision™ electronic data capture (EDC) 
system, version 9.3. Subjects meeting all eligibility criteria and achieving a baseline 
euglycemic steady state at the first treatment visit as described in the protocol, 
completing the baseline will be randomized 1:1 by site in simple blocks to receive G-
Pen™ glucagon or Lilly glucagon injection at the first treatment visit. 
2.1.4 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 
unbinding needed. 
 


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3 STATISTICAL AND ANALYTICAL PROCEDURES 
3.1 ANALYSIS POPULATIONS 
3.1.1 Intent-to-Treat (ITT) population 
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. 
3.1.2 Per-protocol (PP) Population 
The Per-protocol (PP) population is defined as all randomized patients 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 Lilly Glucagon, or Lilly Glucagon followed 
by G-Pen). 
3.1.3 Safety Population 
The safety population is defined as all subjects randomized. However, the actual 
treatment received will be used for analysis. Safety population will be used for all 
safety analyses (section 3.3.4). 
3.2 ANALYSIS VARIABLES  
3.2.1 Handling of Hypoglycemia Induction Procedure Data 
Specific rules were applied to creation of the analysis dataset for the hypoglycemia 
induction procedure data (Appendix 3). 
3.2.2 General guideline for define the protocol time 
Protocol time is needed to find the 30-minute glucose value as well as to generate 
some 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: 


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o Receiving glucagon:  T0 = actual time stamp of glucagon injection 
o Decision to dose:  T0 = actual time stamp when dose decision is made 
• Subsequent protocol times are calculated by the following minutes plus T0: 
o 5, 10,15,20,25,30,35,40,45,50,55,60,65,70,75,80,85,90 
o 120,150,180 
• 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 
Many analyses will be done using both the protocol time based on receiving 
glucagon and the one based on decision to dose. These analyses will be noted in 
each of the corresponding sections. 
3.2.3 For categorical variables, the last entered value will be used 
3.2.4 Demographics  
3.2.4.1 Age 
Age in years will be calculated as follows: 
Age = (date of screening - Date of birth) / 365.24 
3.2.4.2  Gender, Race and Ethnicity 
These variables will be imported directly from the EDC. The Race and Ethnicity 
category will be combined (i.e. Whites, Hispanics, and African-Americans) for 
subgroup analysis. 
3.2.4.3 Medical History 
Medical History data will be imported directly from the EDC. No coding is planned. 
3.2.4.4 Prior and Concomitant Medications 
Medications will be imported directly from the EDC. It will be coded with the latest 
version of the WHO drug dictionary.  


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• If a medication cannot  be found in WHO dictionary, it will be coded as “Who 
Code Not Defined” 
3.2.5 Efficacy Variables 
The following efficacy variables will be considered in the efficacy analyses.  
3.2.5.1 Primary Endpoint: Sample Mean of Failure Scores 
The primary endpoint of the study is the failure score, where a failure is defined as 
the event when plasma glucose of a subject remains ≤ 70 mg/dL throughout the 0-
30-minute period from the administration of study drug. The 30 minutes referenced 
in this section will be based on the protocol time. If the value to be analyzed was 
not collected at exactly 30 minutes, the value will be determined by linear 
interpolation between the two adjacent time points as mentioned in section 3.2.1. 
The following scoring system will be applied to determine the failure score.   
• If a G-Pen failure is observed then the treatment failure score = 1; similarly 
the control failure score = 1 if a control failure is observed.   
• If the G-Pen treatment outcome is missing then the treatment failure score = 
0.2.  A missing control outcome yields a control failure score = 0.1. Note that 
for PP population, this will not apply since PP subjects always have both 
treatments outcomes. 
• An observed successful plasma glucose rising above 70 mg/dL within 30 
minutes yields a failure score = 0, for either treatment. 
The following variables will be derived from the failure score. 
• For each subject, derived score is the G-Pen minus Lilly failure score (Dht). 
• Then from an analysis population, the sample Mean (Dht) and Standard Error 
SE (Dht) (SE = Standard Deviation of Dht/square root of N) will be obtained. 
Secondarily, this will be repeated with success/failure evaluated at a time point of 
30 minutes from a decision to dose. 


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3.2.5.2 Secondary Endpoints 
3.2.5.2.1 Binary Responses 
The following secondary response endpoints will be assessed. Mean (Dht) and SE 
(Dht)) corresponding to these conditions will be evaluated based on the same 
system defined in section 3.2.5.1. The 30 minutes reference in this section will be 
the protocol time. 
1. Return of plasma glucose to > 70 mg/dL or neuroglycopenic symptomatic 
relief within 30 minutes after receiving glucagon. The Baseline Glucose will be 
the last glucose measurement prior to time 0. 
2. Return of plasma glucose to > 70 mg/dL or an increase in plasma glucose by 
≥20 mg/dL within 30 minutes after receiving glucagon. The Baseline Glucose 
will be the last glucose measurement prior to time 0. 
3. Increase in plasma glucose by ≥ 20.0 mg/dL within 30 minutes after receiving 
glucagon. The Baseline Glucose will be the last glucose measurement prior to 
time 0. 
4. Neuroglycopenic symptomatic relief within 30 minutes after receiving 
glucagon. 
Secondarily, this will be repeated with success/failure evaluated at a time point of 
30 minutes from a decision to dose.  
3.2.5.2.2 Number of subjects having glucose >70 mg/dL within 30 minutes of 
receiving glucagon 
This will be the raw count of subjects at protocol time points: 5, 10,15, 20, 25, and 30 
minutes.  
This analysis will be done both based on time from receiving glucagon and from a 
decision to dose. 
3.2.5.2.3 Pharmacodynamics (PD) Parameters 
The PD endpoints will be derived from the individual glucose profiles. The Baseline 
Glucose will be the last glucose measurement prior to time 0.  
Actual Time will be used to the calculation of the following variables. 
If insulin starts after receiving glucagon, the glucose values post insulin start will be 
censored out and considered as missing. 
• Cmax : Maximum concentration of Glucose 
• TMax : Time (in mins) when Glucose CMax is reached 
• AUC0-30: Area under the curve of Glucose from 0 to 30 minutes  


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o AUC0-30 of Glucose will be calculated as the sum of areas of 
trapezoids, which are composed of adjacent Glucose values. The 
following rules will be considered: 
o If there are missing data points before the last observed value, they will 
be imputed as described in section 3.2.1  
o If there are missing data points after the last observed value, they will 
not be extrapolated and the AUC will be treated as undefined.  
• AUC0-180: Area under the curve of Glucose from 0 to 180 minutes  
o AUC0-180 of Glucose will be calculated as the sum of areas of 
trapezoids, which are composed of adjacent Glucose values. The 
following rules will be considered: 
o If there are missing data points before the last observed value, they will 
be imputed as described in section 3.2.1. 
o If there are missing data points after the last observed value, they will 
not be extrapolated and the AUC will be treated as undefined.  
• Time for plasma glucose to reach >70.0 mg/dL from receiving of glucagon. 
o The time stamp for 70.0 mg/dL will be imputed using linear 
interpolation between the two adjacent time points 
• Time for plasma glucose to increase by at least 20 mg/dL from receiving of 
glucagon. 
o The time stamp for 20 mg/dL increase will be imputed using linear 
interpolation between the two adjacent time points 
These PD parameters will be done based on both receiving glucagon and decision 
to dose. 
3.2.5.2.4 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 
 


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Neuroglycopenic Symptoms 
Severity Score (1-6) 
Tremor 
 
Palpitations 
 
Feeling of nervousness 
 
Overall Assessment of Hypoglycemia 
Yes/No 
Do you currently feel hypoglycemic? 
 
 
The following 3 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, so no means will be calculated. 
This parameter will be analyzed both on time from receiving glucagon and from a 
decision to dose. 
3.2.5.2.5 Symptom relief 
 
Symptom relief of hypoglycemia is defined as a return to a score (ANS, AAS and 
ATS) no more than one unit above baseline symptoms during the euglycemic 
baseline period, where the baseline symptom is the minimal values of score (ANS, 
AAS and ATS) prior to receiving glucagon (T0).  
The time (min) to Symptom relief will be derived for analysis purpose. Actual Time 
will be used in calculation. 


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This parameter will be done based on both receiving glucagon and decision to dose. 
3.2.5.2.6 The time to the minimal score post dose 
 
This will be calculated for sub-scales ANS, AAS and ATS as the difference (in mins) 
between the actual time when the minimal number is observed and the time of 
receiving glucagon. Actual Time will be used to the calculation of the following 
variables. 
• Subjects who never develop symptoms will be assumed to have a value of 0. 
This parameter will be analyzed both on time from receiving glucagon and from a 
decision to dose. 
3.2.5.2.7 The time to first reporting of “no” for the global hypoglycemia question will 
be defined as below: 
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 
receiving glucagon. Actual Time will be used to the calculation of the following 
variables. 
• Subjects who never develop symptoms (never answers No) will be assumed 
to have a value of 0. 
• In very rare cases, if subject answers Yes all the way to the last time point, 
the total time will be recorded. (And it will be analyzed based survival model.) 
This parameter will be analyzed both on time from receiving glucagon and from a 
decision to dose. 
3.2.5.2.8 The Glucagon Preparation Time: 
Glucagon preparation time (min) is defined as the time between “decision to dose”  
and time of study drug administration to the abdomen. Actual Time will be used to 
calculate this variable. 
3.2.6 Safety Variables 
3.2.6.1 Adverse Events (AE) 
All observed or volunteered adverse events regardless of treatment group or 
suspected causal relationship to the study drug will be recorded in the eCRF. This 
information will be imported directly from the EDC.  


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For all safety variables, if there is need of protocol time, it will be done based on time 
of receiving glucagon only. 
3.2.6.2 Laboratory safety assessments 
Laboratory values (biochemistry and hematology) will be imported via a web portal 
from a database maintained by the central laboratory.  
3.2.6.3 Physical examination and ECG 
Physical examination evaluations will be imported directly from EDC. Note that only 
abnormal ECG values will be reported, and these are reported as a sub category on 
the Physical examination CRF. 
3.2.6.4 Vital signs and body weight 
Vital sign variables and body weight will be imported directly from EDC.  
3.2.6.5 Local Tolerability: Visual Analog Scale (VAS), Injection Site Discomfort 
and DRAIZE SCALE 
Local Tolerability includes the VAS, Injection Site Discomfort and Draize scales. 
These data will be imported directly from the EDC. The questionnaires used to 
capture these variables are illustrated briefly below; further details are available in 
the protocol. 
3.2.6.5.1 VAS 
VAS is reported using a 100-mm scale. 
               ├                                                                                    ┤ 
           No Discomfort 
 
 
 
           Worst Possible Discomfort 
 
3.2.6.5.2 Injection Site Discomfort  
The following variable is derived based on the questionnaire: 
• The first question (1a) will derive a category value for discomfort description. 
• Question 1b and 1c will be combined to generate the duration of discomfort: 
o If 1c is answered, then Duration of discomfort = answer in 1c. 
o Otherwise: 
 Duration of discomfort = 0.5 (if less than 1 minute checked) 
 Duration of discomfort = 1.5 (if 1-2 minute checked) 


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 Duration of discomfort = 4 (if 3-5 minute checked) 
 Duration of discomfort = 7.5 (if 6-9 minute checked) 
 
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 
 
3.2.6.5.3 Draize (Erythema and or edema) 
Erythema and edema formation at the site of injection is assessed using the Draize 
scale shown below: 
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 


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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 
3.3 STATISTICAL METHODS 
3.3.1 General guideline for descriptive summaries 
For continuous variables, mean, standard deviation, minimum, and maximum will be 
presented for each treatment group. 
For categorical variables, count and % of subjects/counts in each treatment group 
will be presented.  
3.3.2 Baseline Characteristics  
3.3.2.1 Demographics 
The demographics variables of age, sex, race and ethnicity will be presented 
descriptively. 
3.3.2.2 Subject disposition 
Subject disposition will be summarized for treatment group, population and study 
completions. 
3.3.2.3 Medical History  
Medical History will be summarized by body system. 
3.3.2.1 Prior and Concomitant Medications 
All Medications will be separated as prior and concomitant medication based on 
ending date and randomization date. It will be summarized descriptively.  


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3.3.3 Efficacy Analysis 
3.3.3.1 Primary Endpoint analysis 
The primary endpoint analysis will be based on the sample mean and SE of (Dht, as 
defined in section 3.2.5.1). Descriptive summary will be presented for each treatment 
group.  
H0: G-Pen is inferior to control (population mean failure score difference (G-
Pen - Control) exceeds 0.1 
Ha:  not H0 
Inferential analysis will be based on the following criterion:  
 
Reject H0, if Dht + 2.8 SE ≤ 0.1, (Establish non-inferiority) 
Where SE is the estimated standard error as defined in section 3.2.5.1 
This analysis will be repeated for ITT and PP populations and also time based on both 
“receiving glucagon” and “decision to dose” time. In total, four groups of summary 
tables will be presented. 
3.3.3.2 Secondary Endpoints 
3.3.3.2.1 Binary Responses 
The same test as described in previous section 3.2.5.1 will be applied to each of the 
binary responses defined in section 3.2.5.2.1.  
Note that all of these analyses will be repeated for ITT and PP population as well as 
time based on both “receiving glucagon” and “decision to dose”. 
3.3.3.2.2 Number of subjects having glucose >70 mg/dL within 30 minutes of 
receiving glucagon. 
The number of subjects having glucose >70 mg/dL within 30 minutes of receiving 
glucagon will be presented descriptively.  
This will be done in the ITT population only, and will be done for time based on both 
“receiving glucagon” and “decision to dose”. 
Note that subgroup analysis is needed for this (section 3.3.5.1) 


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3.3.3.2.3 Pharmacodynamics Analyses 
All of the PD parameters (as defined in section 3.2.5.2.2 ) will be presented 
descriptively.  
A mixed model with treatment, period and sequence as fixed factors and subject as a 
repeated 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 90% 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 (section 3.2.1) 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 done based on the ITT population only, and will be done with time based 
on both “receiving glucagon” and “decision to dose”. 
3.3.3.2.4 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 
(section 3.2.1) for each treatment group. 
Additionally, this will also be presented graphically. 
This will be done for ITT population, and will be done with time based on both 
“receiving glucagon” and “decision to dose”. 
3.3.3.2.5 Symptom relief of hypoglycemia 
The time to symptom relief will be presented descriptively.  
A survival analysis will be done to comparing the difference between treatment 
groups. P-value for the difference will be reported. 


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This will be done for ITT population only, and will be done with time based on both 
“receiving glucagon” and “decision to dose”. 
3.3.3.2.6 The time to the minimal score post baseline 
The time to the minimal score will be summarized descriptively for each treatment.   
A survival analysis will be done to comparing the difference between treatment 
groups. P-value for the difference will be reported. 
This will be done for ITT population only, and will be done with time based on both 
“receiving glucagon” and “decision to dose”. 
3.3.3.2.7 The time to first reporting of “no” for the global hypoglycemia question 
The time to first reporting of “no” for the global hypoglycemia question will be 
summarized descriptively for each treatment. In rare cases if a subject does not 
answer “no,” the total time of 180 minutes will be used in the summary, but noted in 
the footnote. 
A survival analysis will be done to compare the difference between treatment 
groups. P-value for the difference will be reported. Again, if a subject does not 
answer “no,” the total time of 180 minutes will be used, but noted as a censored 
value in the analysis model. 
This will be done for ITT population only, and will be done with time based on both 
“receiving glucagon” and “decision to dose”. 
3.3.3.2.8 The Glucagon Preparation Time 
The glucagon preparation time will be summarized descriptively for each treatment.   
A mixed model with treatment, period and sequence as fixed factors and subject as 
a repeated factor will be applied to compare the least square mean differences. Log 
transformation will be applied if skewness is observed. Unstructured structure will be 
used for the covariance matrix unless model failed. In such case, structured 
covariance matrix will be selected based on the one given the smallest AIC (Akaike 
Information). 
This will be done for both the ITT and PP populations. 


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3.3.4 Safety Analysis 
All safety analyses will be performed using the safety population. Note, actual received 
treatment will be used. Analyses will be based on time of receiving glucagon if protocol 
time is involved. 
3.3.4.1 Adverse Events (AE) 
All AEs will be coded using the latest Medical Dictionary for Regulatory Activities and 
summarized descriptively by system organ class and study drug. A summary table 
indicating the number and the percentage of exposed subjects having at least one 
AE will be made. A similar table will provide a breakdown of AEs (all and related) by 
intensity level (mild, moderate, severe).  
Note that subgroup analysis is needed for this (section 3.3.5.1) 
3.3.4.1 Laboratory safety assessments 
Laboratory test results will be presented descriptively for screening visit and follow-
up visit. 
3.3.4.1 Physical examination and ECG 
Physical exam including ECG results will be presented descriptively for screening 
visit and follow-up visit. 
3.3.4.2 Vital signs and body weight 
Height, weight, heart rate and blood pressure will be summarized by descriptive 
statistics.   
3.3.4.3 Local Tolerability 
3.3.4.3.1 Subjective injection site discomfort from VAS 
VAS will be summarized descriptively for each treatment at each protocol defined 
time point. VAS will be treated as a continuous variable, so mean, sd, median, 
minimum, maximum. will be presented. 
Additionally, number and % of subjects with score >0 for each treatment at each 
protocol defined time point will also be presented descriptively. 


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If there are enough data (i.e., data with score >0), a mixed model will also be applied 
to comparing the difference between treatment group. Since we may expect few 
data with score >0, the choice of model will be based on the actual data. 
3.3.4.3.2 Injection site discomfort from ordinal pain scales 
The discomfort description and duration of discomfort (section 3.2.6.5.2) will be 
summarized descriptively. 
3.3.4.3.3 Erythema and edema  
Erythema formation score and edema formation score will be summarized 
descriptively. These scores will be treated as continuous variables. 
3.3.5 Other statistical Analysis 
3.3.5.1 Subgroup Analysis 
The following safety and efficacy variables will be summarized descriptively by 
gender (male, female), age (18.0 – 64.9 years, 65.0 years and above), and race 
(non-Hispanic Whites, Hispanics, and African-Americans): 
• AE (Any) 
• Time (min) to glucose >70 mg/dL within 30 minutes of receiving glucagon 
This will be done in the ITT population only, and will be done with time based on both 
“receiving glucagon” and “decision to dose”. 
3.3.5.2 Interim Analysis 
Interim analysis will not be performed in this study. 


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4 Data Handling Conventions 
4.1 Missing Data 
 
Unless specified in any of the previous sections, no missing data will be imputed. 
4.2 REPEATED AND UNSCHEDULED VISIT 
 
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. 
4.3 PROTOCOL VIOLATIONS 
 
Potential protocol violations are incorporated into the definition of Per Protocol 
Population (see 3.1.2). This definition excludes from PP analysis any subject who has 
one of the following 4 major protocol violations: 
 
1. Fails to meet all eligibility criteria. 
2. Fails to meet the definition of hypoglycemia steady state prior to dosing at either 
treatment visit. A steady state of hypoglycemia is defined as two consecutive 
plasma glucose values between 43.0 and 49.9 mg/dL, and a linearly 
extrapolated 8-minute later glucose value ≥ 42.0 mg/dL. 
3. Fails to complete both treatment visits. 
4. Fails to receive a dose of both test articles during the study (G-Pen and Lilly 
Glucagon). 
 


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5 PLANED LISTING, TABLE AND FIGURES 
 
Please see the Appendix 1. 
 
Note that this is the planned Table of Contents. Based on the actual data, table 
numbers, table names and structures may change. 


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6 SOFTWARE DOCUMENTATION 
 
PC SAS – Windows version 9.1.3 or higher. 
PC R - Windows version 12.0 or higher. 
WinNonlin - Professional Version 5.2 or higher. 
Excel - Microsoft Excel 2007 or higher. 
 
 


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7 APPENDIX 
 
1. Statistical Analysis Plan V2 - Appendix 1 Table of contents V2.xlsx 
2. Protocol XSGP-303 v1.2, 29 Jan 2018 
3. Protocol XSGP-303 Analytical Data Conventions for Hypoglycemia Induction 
Procedure, 02 May 2018 
4. Protocol XSGP-303 Analysis Populations and Protocol Violations, 03 May 2018