Clinical trial NCT03091673
Conditions: Diabetes Mellitus, Type 1
Sponsor: Xeris Pharmaceuticals
Start date: 2017-03-27; Completion date: 2017-09-27
Enrollment: 31 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a sequential efficacy and safety study in pediatric patients with type 1 diabetes. Subjects will be administered insulin to induce a low normal glycemic state and will then receive an age-appropriate dose of G-Pen (glucagon injection) in a clinical research center (CRC) or comparable setting.

Detailed description:
This is an open-label, Phase 3 sequential efficacy and safety study in pediatric patients ages 2-17 with type 1 diabetes. Patients will complete the screening procedures up to 30 days before dosing to determine eligibility before enrollment to the treatment phase.

The procedure to evaluate the efficacy of G-Pen (glucagon injection) consists of inducing a low normal glycemic state by administration of insulin. Subjects ages 2-11 will then be given a 0.5 mg dose of G-Pen, while subjects ages 12-17 will receive a 1 mg dose of G-Pen. Subjects ages 12-17 will return for a second visit 1-4 weeks later and will receive a 0.5 mg dose of G-Pen when in a low normal glycemic stare. Plasma glucose and glucagon levels will be monitored for 90 and 180 minutes post-dosing, respectively, at all visits.

A follow-up phone call as a safety check will be conducted 3 - 14 days following administration of the final dose.

Arms: arm 1: A single 0.5 mg subcutaneous (SC) injection of G-Pen (glucagon injection) arm 2: A single 1.0 mg subcutaneous (SC) injection of G-Pen (glucagon injection)
Interventions: intervention 1: Glucagon
Intervention descriptions: intervention 1: 0.5 or 1.0 mg of pre-mixed liquid Xeris glucagon delivered via auto-injector

Protocol documents:
Prot_000.pdf: 
1. 
TITLE PAGE 
 
G-PEN™ (GLUCAGON INJECTION) 
PROTOCOL XSGP-302 
 
A PHASE 3 STUDY TO EVALUATE THE GLUCOSE RESPONSE 
OF G-PEN™ (GLUCAGON INJECTION) IN PEDIATRIC 
PATIENTS WITH TYPE 1 DIABETES 
 
 
 
 
 
 
 
 
 
 
 
Version 1.3 
December 6, 2016 


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INVESTIGATOR’S AGREEMENT 
 
I have received and read the current Investigator’s Brochure for G-Pen™ (glucagon injection).  I 
have read the XSGP-302 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 
Address and Telephone Number 
Clinical Study Leader 
Dr. Nilay Shah 
Medical Officer 
Emmes Corporation 
401 North Washington Street 
Suite 700 
Rockville, MD 20850 
nshah@emmes.com 
Phone: 301-251-1161 
Medical Monitor & 24-Hour 
emergency contact  
Dr. Poul Strange 
Medical Director 
Xeris Pharmaceuticals, Inc.  
Pstrange@imdcro.com 
Phone: 606-897-0505 x213 
Fax: 609-897-0555 
 


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2. 
SYNOPSIS 
Protocol Number XSGP-302 
A PHASE 3 STUDY TO EVALUATE THE GLUCOSE RESPONSE OF G-PEN™ (GLUCAGON 
INJECTION) IN PEDIATRIC PATIENTS WITH TYPE 1 DIABETES 
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 3  
Compound(s):   
G-Pen™ (glucagon injection) 
Objectives: 
The primary objective of this study is to assess the increase in plasma glucose 
from baseline to 30 minutes in subjects in a low normal glycemic state after 
injection of an age-appropriate dose of G-Pen™ (glucagon injection), in each 
of three age groups (2.0-<6.0 years, 6.0-<12.0 years and 12.0-<18.0 years) of 
pediatric patients with type 1 diabetes mellitus (T1D). 
Secondary objectives of this study include: 
1. In the 12-<18 year-old age group, to additionally assess the plasma 
glucose change from baseline to 30 minutes after administration of G-
Pen™ (glucagon injection) at a dose of 0.5 mg. 
2. Determine G-Pen™ (glucagon injection) pharmacokinetics for each age 
group, and 
3. Determine the safety and tolerability of G-Pen™ (glucagon injection) for 
each age group. 
Study design:   
This is a sequential efficacy and safety study in pediatric patients with T1D.  
Subjects using insulin injections will be administered IV insulin and subjects 
using an insulin pump will have the basal rate increased to induce a low 
normal glycemic state and will then receive an age-appropriate dose of G-
Pen™ (glucagon injection) in a clinical research center (CRC) or comparable 
setting. 
Subjects ages 2-<12 will complete a single treatment visit and will receive a 
0.5 mg dose of G-Pen™. Subjects ages 12-<18 will receive a 1 mg dose of G-
Pen™ at an initial treatment visit, and will be given the 0.5 mg dose at a 
second visit occurring 7-28 days later. 
Study location: 
Approximately 8 US-based pediatric clinics. 
Study duration: 
Estimated duration of study participation for individual subjects is 
approximately 2-6 weeks. Estimated duration of the study is 5 months. 


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Sample size: 
Approximately 48 subjects are anticipated to be screened for this study, and 
approximately 24 (up to 8 per cohort) will receive study drug to achieve the 
goal of 18 evaluable subjects equally distributed (n=6 per cohort) across the 
three age groups: 2.0-<6.0, 6.0-<12.0 and 12.0-<18.0 years.  
Subjects: 
Male or female patients with T1D ages 2.0-<18.0 years, inclusive. 
Inclusion Criteria: 
1. Males or females diagnosed with T1D for at least 6 months at Screening. 
2. Current usage of daily insulin treatment. 
3. Age 2.0 <18.0 years, provided that subject will be <18.0 years for the 
duration of the study. 
4. Willingness of subject and adult guardian to follow all study procedures, 
including attending all clinic visits. 
5. Parent or guardian has provided written informed consent and assent has 
been obtained from subjects if appropriate for age according to IRB 
requirements. 
Exclusion Criteria: 
1. Pregnant and/or Nursing: For subjects of childbearing potential, there is a 
requirement for a negative urine pregnancy test and for agreement to use 
contraception and to refrain from breast feeding during the study and for at 
least 1 month after participating in the study. Acceptable contraception 
includes birth control pill / patch / vaginal ring, Depo-Provera, Norplant, 
an IUD, the double barrier method (the female uses a diaphragm and 
spermicide and the male uses a condom), or abstinence. 
2. Renal insufficiency (serum creatinine of ≥1.5 mg/dL [males], ≥1.4 mg/dL 
[females]). 
3. Serum ALT or AST equal to or greater than 3 times the upper limit of 
normal 
4. Hepatic synthetic insufficiency as defined as a serum albumin of less than 
3.0 g/dL; or serum bilirubin of over 2.0 mg/dL. 
5. Hematocrit of less than or equal to 30%. 
6. Mean of triplicate BP readings at Screening where SBP or DBP >95% of 
normal for age and height percentile. 
7. Use of > 2.0 U/kg total insulin dose per day. 
8. Inadequate venous access. 
9. Current seizure disorder. 
10. History of pheochromocytoma or disorder with increased risk of 
pheochromocytoma (MEN 2, neurofibromatosis, or Von Hippel-Lindau 
disease). 
11. History of insulinoma. 
12. 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.  
13. History of glycogen storage disease. 
14. Any concurrent illness, other than diabetes, that is not controlled by a 
stable therapeutic regimen. 


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15. Active use of alcohol or drugs of abuse. 
16. Administration of glucagon within 14 days of the first treatment visit. 
17. 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. 
18. Any reason the principal investigator deems exclusionary. 
Brief outline of 
treatments: 
 
Subjects will complete the screening procedures up to 30 days before dosing to 
determine eligibility before enrollment in the treatment phase.  
For treatment visits, subjects will arrive at the clinical center in the morning, 
having fasted for at least 8 hours prior to dosing.   
The following procedures will be performed: 
• 
The glucose level will be checked: 
o If >300 mg/dL, ketones will be checked. 
o If ketones are found to be moderate or greater, the visit will be 
postponed. 
• 
Assessment of any severe hypoglycemic events (requiring the assistance 
of another person) since the screening visit: 
o If a severe hypoglycemic event has occurred in the 2 weeks prior to 
the admission, the visit will be postponed until it has been at least 2 
weeks since the last severe hypoglycemic event. 
• 
For females of child-bearing potential, a urine pregnancy test will be 
performed: 
o If positive, the subject will be discontinued from the study. 
• 
Insertion of intravenous catheter for blood sampling: 
o Those subjects using injection therapy will have a second intravenous 
catheter inserted in the other arm for insulin infusion. 
Procedures for Insulin Infusion 
 
Insulin Pump Users:  At the start of the test, the basal insulin rate will be 
increased by approximately 25-50% to provide a gradual decline in blood 
glucose.  A small priming bolus dose of insulin equal to approximately one 
hour of the subject’s usual basal dose may also be given at the discretion of the 
investigator in addition to the 25-50% increase in the basal insulin. 
 
• 
The basal insulin rate may be increased an additional amount and 
additional bolus insulin doses may be given at the discretion of the 
investigator in order to get a gradual decline in glucose concentration.  
  
Insulin Injection Users:  If the starting glucose level is >200 mg/dL, a 
priming dose of 2-4 units of IV insulin may be given.  An intravenous infusion 
of regular insulin diluted in normal saline at a rate of 1 mU/kg/min will be 
administered. The infusion rate will be adjusted as necessary to reach the 
target glucose level of <80 mg/dL.   
 


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For Both Pump and Injection Users: For all subjects, plasma glucose levels 
will be measured using a bedside rapid glucose analyzer (Analox, YSI or 
equivalent). During the insulin infusion, glucose levels will be measured no 
more than 10 minutes apart while the plasma glucose level is ≥100 mg/dL and 
no more than 5 minutes apart when the plasma glucose level is <100 mg/dL. 
 
Once a plasma glucose level of <80 mg/dL is reached, the basal rate will be 
returned to normal for subjects using an insulin pump and the insulin infusion 
will be stopped for subjects using insulin injections.   
 
If the starting plasma glucose is <80 mg/dL, no additional insulin will be given 
and the procedures below will be followed. 
Dosing with glucagon will be at 5 minutes following a measurement of plasma 
glucose < 80 mg/dL. Subjects will receive a subcutaneous injection of G-
Pen™ glucagon at an age appropriate dose (0.5 mg for 2-<12 years, 0.5 or 1.0 
mg for 12-<18 years). 
Plasma glucose will be measured at bedside at -5 and 0 minutes, and every 5 
minutes for 90 minutes after dosing. In addition, blood samples will be 
collected at -5, 0, 10, 20, 30, 45, 60, 90, 120, and 180 minutes and stored at -
80 ±20 C for determination of plasma glucagon concentration.  Body weight 
may limit the number of blood draws (see below). 
After this, the subject will be given a meal and will receive insulin according 
to her or his normal dosing regimen. The subject can then leave the clinic. 
Tolerability will be assessed by comparing adverse event reports between the 
groups. Subjects will also complete age-appropriate questionnaires concerning 
injection site discomfort. In addition, modified Draize scales will be used by 
an investigator to evaluate the injection site at 10, 30 and 180 minutes 
following administration, as appropriate. 
Volume of Blood Draws 
The maximum blood volume to be collected will not exceed 5% of the 
subject’s blood volume.  The number of blood draws will be reduced for 
subjects who do not weigh enough to allow for the full schedule to be 
completed. Early collections (-5 to 30 minutes) will be preferred over later 
blood draws, and Pharmacodynamics samples will be prioritized over 
Pharmacokinetic samples. 
Data management 
and statistical 
analysis: 
Data will be entered from the source (e.g Case Report Forms) into Advantage 
eClinical an Electronic Database Capture (EDC) system by site personnel. 
Data will be monitored remotely and at on-site visits by the Clinical Research 
Associate (CRA). 
Both primary and secondary endpoints will be summarized descriptively 
within each of the 3 age groups. Mean, standard deviation, median, minimum 
and maximum will be presented for continuous variables. Count and 
percentage variables will be presented for discrete variables. The primary 
endpoint will also be compared to 0 change using a simple t-test. 
Pharmacokinetic data will be analyzed descriptively by dose/age cohort. 
Sample Size 
Determination: 
Based on results of a prior study, G-PenTM (glucagon injection) is expected to 
increase glucose by minimally 25 mg/dL from baseline within 30 minutes of 
administration in every subject. Assuming a standard deviation of 18 mg/dL, a 


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sample size of 6 subjects per cohort has been chosen to provide 90% power to 
detect an increase of plasma glucose from baseline to 30 minutes after 
treatment. 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................4 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES .................9 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................13 
5. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................16 
5.1. 
Primary Objective .......................................................................................................16 
5.2. 
Secondary Objectives .................................................................................................16 
5.3. 
Endpoints ....................................................................................................................16 
5.3.1. 
Primary Endpoint ........................................................................................................16 
5.3.2. 
Secondary Endpoint ....................................................................................................16 
6. 
BACKGROUND AND RATIONALE .......................................................................17 
6.1. 
Indication ....................................................................................................................17 
6.1.1. 
Background .................................................................................................................17 
6.1.2. 
Rationale .....................................................................................................................18 
6.2. 
Non-Clinical Pharmacology and Toxicology Experience with Glucagon .................18 
6.2.1. 
Nonclinical Pharmacology and Toxicology of Xeris G-Pen™ (glucagon 
injection) Investigational Non-Aqueous, Synthetic Glucagon ...................................19 
6.3. 
Description and Composition of Drug Product ..........................................................19 
6.4. 
Clinical Experience with Glucagon ............................................................................19 
7. 
STUDY DESIGN .......................................................................................................20 
7.1. 
Study Overview ..........................................................................................................20 
7.2. 
Procedures for Insulin Infusion ..................................................................................21 
7.3. 
Interruption and Termination of Dosing .....................................................................21 
8. 
ELIGIBILITY CRITERIA AND STUDY ENROLLMENT .....................................23 
8.1. 
Inclusion Criteria ........................................................................................................23 
8.2. 
Exclusion Criteria .......................................................................................................23 
8.3. 
Enrollment ..................................................................................................................24 
9. 
STUDY TREATMENTS............................................................................................25 
9.1. 
Allocation to Treatment ..............................................................................................25 
9.2. 
Blinding ......................................................................................................................25 


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9.3. 
Drug Supplies .............................................................................................................25 
9.3.1. 
Drug Product Formulation and Packaging .................................................................25 
9.3.2. 
Preparation, Dispensing and Administration ..............................................................25 
9.3.3. 
Drug Storage and Drug Accountability ......................................................................26 
9.4. 
Concomitant Medications ...........................................................................................26 
10. 
STUDY PROCEDURES ............................................................................................27 
10.1. 
Screening Visit (Day -30 to -3) ..................................................................................27 
10.2. 
Treatment Phase ..........................................................................................................27 
10.2.1. 
Treatment Visit 1 (Day 0) ...........................................................................................27 
10.2.2. 
Treatment Visit 2 (7-28 days after the first treatment) ...............................................29 
10.2.3. 
Follow-Up Phone Call (3-14 days after the final treatment) ......................................29 
10.3. 
Subject Withdrawal ....................................................................................................30 
11. 
ASSESSMENTS.........................................................................................................32 
11.1. 
Blood Volume .............................................................................................................32 
11.2. 
Clinical Laboratory Tests ...........................................................................................33 
11.3. 
Vital Signs ..................................................................................................................33 
12. 
SAFETY AND ADVERSE EVENT (AE) REPORTING..........................................34 
12.1. 
Definition of an Adverse Event ..................................................................................34 
12.2. 
Reporting Adverse Events ..........................................................................................34 
12.3. 
Reporting Period .........................................................................................................35 
12.4. 
Serious Adverse Events ..............................................................................................35 
12.5. 
Severity Assessment ...................................................................................................35 
12.6. 
Causality Assessment .................................................................................................36 
12.7. 
Withdrawal Due to Adverse Events ...........................................................................36 
12.8. 
Eliciting Adverse Event Information and Reporting ..................................................36 
12.9. 
Serious Adverse Event Reporting Requirements .......................................................36 
12.10. 
Non-Serious Adverse Event Reporting Requirements ...............................................36 
12.11. 
AE Reporting Requirements to Regulatory Authorities .............................................37 
12.12. 
Pregnancy ...................................................................................................................37 
12.13. 
Subject Monitoring .....................................................................................................37 
13. 
DATA ANALYSIS AND STATISTICAL METHODS ............................................38 
13.1. 
Sample Size Determination ........................................................................................38 
13.2. 
Pharmacokinetic and Pharmacodynamic Analyses ....................................................38 


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13.2.1. 
Primary endpoint ........................................................................................................38 
13.2.2. 
Pharmacokinetic Secondary Endpoints: .....................................................................38 
13.2.3. 
Pharmacodynamic Secondary Endpoints: ..................................................................38 
13.3. 
Safety Analysis ...........................................................................................................38 
13.3.1. 
Adverse events: ...........................................................................................................39 
13.3.2. 
Physical examination: .................................................................................................39 
13.3.3. 
Vital signs: ..................................................................................................................39 
13.3.4. 
Local Tolerability: ......................................................................................................39 
13.4. 
Subgroup Analysis ......................................................................................................39 
13.5. 
Interim Analysis ..........................................................................................................39 
14. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................40 
15. 
DATA HANDLING, RECORD KEEPING, MONITORING AND AUDITS ..........41 
15.1. 
Case Report Forms/Electronic Data Record ...............................................................41 
15.2. 
Record Retention ........................................................................................................41 
15.3. 
Monitoring ..................................................................................................................42 
15.4. 
Audits and Inspections ................................................................................................42 
16. 
ETHICAL CONSIDERATIONS................................................................................43 
16.1. 
Conduct .......................................................................................................................43 
16.2. 
Institutional Review Board (IRB) ...............................................................................43 
16.3. 
Subject Information and Consent ...............................................................................43 
16.4. 
Subject Recruitment ....................................................................................................44 
16.5. 
Reporting of Safety Issues and Serious Breaches of the Protocol ..............................44 
17. 
DEFINITION OF END OF TRIAL ...........................................................................45 
18. 
PROCEDURES FOR MODIFYING THE PROTOCOL OR 
TERMINATING THE STUDY .................................................................................46 
18.1. 
Protocol Modifications and Deviations ......................................................................46 
18.2. 
Study Termination ......................................................................................................46 
19. 
PUBLICATION OF STUDY RESULTS ...................................................................47 
20. 
REFERENCES ...........................................................................................................48 
APPENDIX 1. INJECTION SITE DISCOMFORT ASSESSMENT .........................................50 
APPENDIX 2. DRAIZE SCALE ................................................................................................52 
APPENDIX 3. INSTRUCTIONS FOR USE ..............................................................................53 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................13 
Table 3: 
Treatment sequence ....................................................................................................20 
Table 4: 
Schedule of Assessments ............................................................................................31 
Table 5: 
Frequency and Volume of Blood Collections ............................................................32 
Table 6: 
Clinical and Safety related Laboratory Tests Performed at Site .................................33 
Table 7: 
AE Severity Assessment .............................................................................................35 
 


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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 
CGM 
CRF 
Continuous Glucose Monitor 
Case Report Form 
CRC 
Clinical Research Center 
CRO 
Contract Research Organization 
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 
NOAEL 
No Observed Adverse Effect Level 
PD 
Pharmacodynamics 
PK 
Pharmacokinetic 
RBC 
Red blood cells 
rDNA 
Recombinant 
RLD 
Reference Listed Drug 
SAE 
Serious Adverse Event 
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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5. 
STUDY OBJECTIVES AND ENDPOINTS 
5.1. 
Primary Objective 
The primary objective of this study is to assess the increase in plasma glucose of subjects from 
baseline to 30 minutes in subjects in a low normal glycemic state after injection of an age-
appropriate dose of G-Pen™ (glucagon injection), in each of three age groups (2.0-<6.0 years, 
6.0-<12.0 years and 12.0-<18.0 years) of pediatric patients with type 1 diabetes mellitus (T1D). 
5.2. 
Secondary Objectives 
The secondary objectives of this study are: 
• In the 12-<18 year-old age group, to additionally assess the plasma glucose change from 
baseline to 30 minutes after administration of G-Pen™ (glucagon injection) at a dose of 
0.5 mg. 
• Determine G-Pen™ (glucagon injection) pharmacokinetics for each age group. 
• Determine the safety and tolerability of G-Pen™ (glucagon injection) for each age group. 
5.3. 
Endpoints 
5.3.1. 
Primary Endpoint 
The primary endpoint for this study is an evaluation of change in plasma glucose following 
treatment with G-PenTM, with an emphasis on the increase from baseline to 30 minutes post-
dosing. 
5.3.2. 
Secondary Endpoint 
The secondary endpoints for this study are as follows:  
• Pharmacokinetic parameters, including: descriptive analysis of AUC0-120m, Cmax and 
Tmax of the different age cohorts. 
• Pharmacodynamic characteristics, including: plasma glucose AUC0-120m, Cmax, Tmax 
and time to achieve an increase in plasma glucose of at least 25 mg/dL. 
• Safety-related parameters including:  
o Vital signs 
o Incidence of adverse events (AEs) and serious adverse events (SAEs) 
o Subjective injection site discomfort using the Faces Pain Scale [FPS-R] 
o Subjects with sufficient comprehension will further describe the nature and 
duration of any injection site discomfort using a second questionnaire 
(Appendix 1). 
o Erythema and/or edema formation at site of injection assessed by an investigator 
using the modified Draize scale (see Appendix 2) 


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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 
One of the main complications of glycemic control with insulin is the occurrence 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 manifests clinically as 
diaphoresis, pallor, nausea, palpitations, tremor, anxiety, cognitive impairment, behavioral 
changes and psychomotor abnormalities, loss of consciousness, seizure, and coma in severe 
hypoglycemia [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, UK Hypoglycaemia Study Group].   The American Diabetes Association (ADA) 
Workgroup recommends that patients with drug-treated diabetes (insulin secretagogue or insulin) 
become concerned about developing hypoglycemia at a plasma glucose concentration of ≤70 
mg/dL (3.9 mmol/L) [ADA]. 
Therapy with insulin causes hypoglycemia during the course of established type 1 diabetes, and 
progressively more frequently over time in type 2 diabetes.  The U.K. Hypoglycemia Study 
Group reported an incidence of 110 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 [UK 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. 
In children, the T1D Exchange clinic registry has shown that severe hypoglycemia is relatively 
common.  The registry indicates that the most severe form of hypoglycemia resulting in seizure 
or loss of consciousness was more common in participants 2-<6 years old than in the older 
children (9.6% in 2-<6 years, 5.2% in 6-<13 years, and 6.3% in 13 -<18 years).  After adjusting 
for age, severe hypoglycemia was more common in participants who were non-Hispanic black 
(p<0.001), were from families with lower annual household income (p<0.001), were without 
private health insurance (p<0.001), had longer duration of diabetes (p<0.001), had higher HbA1c 
(p=0.001), and used multiple daily injections (MDI) for insulin delivery (compared with pump 
users, p<0.001).  In a multivariate analysis, associations were similar, except there was not a 
significant association of severe hypoglycemia with either the average HbA1c in the prior 12 
months or method of insulin delivery [Cengiz]. 
The American Diabetes Association 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.  Because glucagon is unstable in solution, 
administration of glucagon with current products (i.e. Lilly Glucagon for Injection, and Novo 
GlucaGen®) is a nine-step process including assembly of the kit, aqueous reconstitution of the 
powdered glucagon, and manual administration of the dose [Glucagon, Glucagen].   For adults 
and for children weighing more than 44 lbs (Lilly Glucagon) or 55 lbs (Novo GlucaGen 
HypoKit), the recommended dose of glucagon is 1 mg by subcutaneous (SC), IM or IV injection. 
For children weighing less than 44 lbs (Lilly Glucagon) or 55 lbs (Novo GlucaGen HypoKit), the 
recommended dose of glucagon is 0.5 mg. 
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].    
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 hypoglycemic events. 
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™.  The G-Pen™ will utilize 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 subject of 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 


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peptide synthesis (SPPS), which also conserves the glucagon peptide sequence, the rDNA 
glucagon information is pertinent to the development of G-Pen™ (glucagon injection) 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 
(glucacon injection) is referenced to Xeris’ current Investigator’s Brochure.  
6.3. 
Description and Composition of Drug Product 
Synthetic glucagon is the drug substance in G-Pen™ (glucagon injection).  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™ (glucagon 
injection) is a sterile subcutaneous injectable non-aqueous formulation for treatment of severe 
hypoglycemia.  The G-Pen™ (glucagon injection) delivers 0.5 or 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™ (glucagon injection) is supplied in a 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 packaged in a sealed pouch. 
The 0.5 and 1 mg versions of G-PenTM are distinguished by two strikingly different labeling 
colors utilized on the carton, pouch, and injector device. 
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 Drug (RLDs) 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 Agency first approved glucagon 
for use in humans in 1960. 
As of September 25, 2013, IND 115091 went into effect and Study No. XSGP-201 was 
completed in January 2014. This study examined safety, PK, and efficacy of rescue doses (0.5 
and 1.0 mg) of G-Pen™ (glucagon injection) as compared to Lilly Glucagon (1.0 mg) in healthy 
volunteers. The results of this study 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 sequential efficacy and safety study in pediatric patients with T1D.  Subjects will be 
administered insulin to induce a low normal glycemic state and will then receive an age-
appropriate dose of G-Pen™ (glucagon injection) in a clinical research center (CRC) or 
comparable setting. 
Subjects ages 2-<12 will complete a single treatment visit and will receive a 0.5 mg dose of G-
Pen™. Subjects ages 12-<18 will receive a 1 mg dose of G-Pen™ at an initial treatment visit, 
and will be given the 0.5 mg dose at a second visit occurring 1-4 weeks later (Table 3). Patients 
will complete the screening procedures up to 30 days before dosing to determine eligibility 
before enrollment to the treatment phase.  
Table 3: 
Treatment sequence 
Subject Age 
Dose 1 
Dose 2 
2.0-<12.0 
G-Pen™ 0.5 mg 
Not applicable 
12.0-<18.0 
G-Pen™ 1 mg 
G-Pen™ 0.5 mg 
The procedure to evaluate the efficacy of G-Pen™ (glucagon injection) consists essentially of 
inducing a low normal glycemic state by administration of insulin. For subjects using an insulin 
pump, the basal rate will be increased to induce a gradual decrease in blood glucose. For subjects 
using long-acting insulin, an IV infusion of regular insulin diluted in normal saline will be started 
to effect a decrease in blood glucose. The exact procedures to be followed are outlined below in 
Section 7.2. 
For subjects using injection insulin therapy, a combination of one or more bolus doses of insulin 
along an infusion of insulin will be used to decrease a subject’s plasma glucose to a target <80 
mg/dL.  The insulin infusion will be stopped once the plasma glucose is <80 mg/dL.  For 
subjects using an insulin pump, the basal rate will be increased until the target of <80 mg/dL is 
reached. A priming bolus equal to approximately 1 hour of basal insulin may also be given at 
investigator discretion. 
After a confirmatory plasma glucose of <80 mg/dL is obtained at least 5 minutes after stopping 
the insulin infusion, the subject will be treated subcutaneously in the upper arm, leg or abdomen 
with the age-appropriate dose of G-Pen™ (glucagon injection) administered sc (see Section 
9.3.2). Blood glucose levels will be monitored for 90 minutes post-dosing.   
After a wash-out period of 7 to 28 days, subjects ages 12.0-<18.0 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 treatment days, subjects will be discharged after 
receiving a standardized meal and their usual dose of insulin.  A follow-up phone call as a safety 
check will be conducted 3 ± 14 days following administration of the final dose. 
Tolerability will be assessed by examining adverse event reports. In addition, subjects will 
complete age-appropriate questionnaires concerning injection site discomfort and an investigator 


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will use modified Draize scales to evaluate the injection site at 10±5, 30±5 and 180±5 minutes 
following administration.   
7.2. 
Procedures for Insulin Infusion 
Insulin injection users will receive intravenous insulin to reduce the glucose level while insulin 
pump users will have the basal insulin rate increased to achieve a blood glucose reduction.  The 
value in handling pump users this way is that the delivery of subcutaneous insulin and the 
restoration of the usual basal rate when the glucose target level is achieved are more similar to 
real-world conditions than giving IV insulin.  In addition, use of the insulin pump only requires 
one IV line, an important consideration in a pediatric study. 
Insulin Pump Users:  At the start of the test, the basal insulin rate will be increased by 
approximately 25-50% to provide a gradual decline in blood glucose.  A small priming bolus 
dose of insulin equal to approximately one hour of the subject’s usual basal dose may also be 
given at the discretion of the investigator in addition to the 25-50% increase in the basal insulin. 
The basal insulin rate may be increased an additional amount and additional bolus insulin doses 
may be given at the discretion of the investigator in order to get a gradual decline in glucose 
concentration.  
Insulin Injection Users:  If the starting glucose level is >200 mg/dL, a priming dose of 2-4 units 
of IV insulin may be given.  An intravenous infusion of regular insulin diluted in normal saline at 
a rate of 1 mU/kg/min will be administered. The infusion rate will be adjusted as necessary to 
reach the target glucose level of <80 mg/dL.   
For Both Pump and Injection Users: For all subjects, plasma glucose levels will be measured 
using a bedside rapid glucose analyzer (Analox, YSI or equivalent). During the insulin infusion, 
glucose levels will be measured no more than 10 minutes apart while the plasma glucose level is 
≥100 mg/dL and no more than 5 minutes apart when the plasma glucose level is <100 mg/dL. To 
reduce the volume of blood draws, a continuous glucose monitor (CGM) may be used to assess 
glucose levels during the induction phase only. However before treatment is given, BG <80 
mg/dL will be confirmed by bedside glucose analyzer. 
Once a plasma glucose level of <80 mg/dL is confirmed, the basal rate will be returned to normal 
for subjects using an insulin pump and the insulin infusion will be stopped for subjects using 
insulin injections.   
If the starting plasma glucose is <80 mg/dL, no additional insulin will be given. If a plasma 
glucose level of <80 mg/dL is not achieved within 3 hours of starting the insulin infusion, 
treatment with study drug should not be given, and the visit should be rescheduled after a 
minimum 7-day wash-out. 
7.3. 
Interruption and Termination of Dosing 
Dosing will be paused for any SAE which occurs in a subject receiving treatment until causality 
is fully assessed by the Investigator.  Dosing will cease if the SAE is determined to be either 
drug-related or unknown, and may resume if the SAE is determined to be not drug-related by the 
investigator and the Sponsor is in agreement. 


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Visits in which glucagon is not given will not be included in the primary analyses.  A visit will 
be considered completed for purposes of the sample size when glucagon is given and there is at 
least one blood glucose measurement 30 or more minutes after the glucagon injection. 


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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 or females diagnosed with T1D for at least 6 months at Screening. 
2. Current usage of daily insulin treatment. 
3. Age 2.0 <18.0 years, provided that subject will be <18.0 years for the duration of the study. 
4. Willingness of subject and adult guardian to follow all study procedures, including attending 
all clinic visits. 
5. Parent or guardian has provided written informed consent and assent has been obtained from 
subjects if appropriate for age according to IRB requirements. 
8.2. 
Exclusion Criteria 
1. Pregnancy or Nursing: For subjects of childbearing potential, there is a requirement for a 
negative urine pregnancy test and for agreement to use contraception and to refrain from 
breast feeding during the study and for at least 7 days after the last dose of study medication 
in the study. Acceptable contraception includes birth control pill / patch / vaginal ring, Depo-
Provera, Norplant, an IUD, the double barrier method (the female uses a diaphragm and 
spermicide and the male uses a condom), or abstinence. 
2. Renal insufficiency (serum creatinine of ≥1.5 mg/dL [males], ≥1.4 mg/dL [females]). 
3. Serum ALT or AST equal to or greater than 3 times the upper limit of normal 
4. Hepatic synthetic insufficiency as defined as a serum albumin of less than 3.0 g/dL; or serum 
bilirubin of over 2.0 mg/dL. 
5. Hematocrit of less than or equal to 30%. 
6. Mean of triplicate BP readings at Screening where SBP or DBP >95% of normal for age and 
height percentile. 
7. Use of > 2.0 U/kg total insulin dose per day. 
8. Inadequate venous access. 
9. Current seizure disorder. 
10. History of pheochromocytoma or disorder with increased risk of pheochromocytoma (MEN 
2, neurofibromatosis, or Von Hippel-Lindau disease). 
11. History of insulinoma. 
12. 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.  


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13. History of glycogen storage disease. 
14. Any concurrent illness, other than diabetes, that is not controlled by a stable therapeutic 
regimen. 
15. Active use of alcohol or drugs of abuse. 
16. Administration of glucagon within 14 days of the first treatment visit. 
17. 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. 
18. Any reason the principal investigator deems exclusionary. 
8.3. 
Enrollment  
A subject will be considered enrolled after the informed consent form is signed by the 
parent/guardian, assent is provided if needed per IRB requirements, and eligibility is confirmed. 


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9. 
STUDY TREATMENTS 
9.1. 
Allocation to Treatment 
Subjects will be allocated to treatment based on age at the Screening Visit to receive the 
appropriate dose(s) of study medication (see Table 3).  Prior to treatment,   age should be 
confirmed to ensure the age-appropriate dose of study drug is administered. Subjects who are 
expected to reach their 18th birthday before completion of study treatment should not be enrolled.  
Approximately 24 patients will be enrolled to treatment with a goal of completing 18 subjects, or 
roughly 6 evaluable subjects per age cohort.   
9.2. 
Blinding 
For this study, subject and investigator will be unblinded.   
9.3. 
Drug Supplies 
9.3.1. 
Drug Product Formulation and Packaging 
G-Pen™ (glucagon injection) from Xeris Pharmaceuticals, Inc. is a non-aqueous, injectable 
liquid formulation of glucagon.  The G-Pen™ drug product consists of 0.5 or 1 mg synthetic 
glucagon peptide dissolved in a primary DMSO solvent, with trehalose added as a stabilizing 
excipients.  The appropriate amount of 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 a SHL Molly™ single-
use, disposable auto-injector, and packaged in a sealed pouch.  The 0.5 mg and 1 mg dose 
devices are distinguished by two strikingly different labeling colors utilized on the carton, pouch, 
and injector device. 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 and labeled under cGMP by SHL Group (DeerField Beach, FL), both 
Xeris Pharmaceuticals’ contract manufacturers. 
9.3.2. 
Preparation, Dispensing and Administration 
G-Pen™ (glucagon injection) will be supplied as 0.1 mL or 0.2 mL of non-aqueous solution in a 
plastic Crystal Zenith (CZ) 1 mL long syringe loaded into a Molly™ disposable auto-injector.  
Subcutaneous administration will be performed by a qualified site staff member who has read the 
Instructions for Use (Appendix 3).  
The injection site should be rotated between subjects such that the first subject at a particular site 
will receive injection(s) in the arm, the next subject will receive injection(s) in the leg, and the 
next subject, in the abdomen. This cycle will be repeated for every 3 subjects. 
For subjects ages 12-<18 who will receive two treatments, the injection site for a particular 
subject will remain fixed between the two treatment visits (i.e., arm, leg or abdomen) but will be 
varied between the left and right upper arm, leg or abdominal quadrant for the first and second 
dose of study medication. 


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Note: Numbing cream should not be used at injection sites, though it may be used at the 
discretion of the investigator for other study procedures (e.g., placement of IV catheters or blood 
draws).  
9.3.3. 
Drug Storage and Drug Accountability 
Unless notified otherwise by the Sponsor, all supplied G-Pen™ (glucagon injection) auto-
injectors 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 
appropriate course of action taken regarding the future use of the study medications upon 
consultation with Xeris Pharmaceuticals. 
The investigator must maintain adequate records documenting the receipt, use, loss or other 
disposition of the investigational drug products and supplies, and will return the products to 
Xeris or destroy them according to local regulation and applicable Xeris Pharmaceuticals SOPs, 
following directions from Xeris Pharmaceuticals. 
9.4. 
Concomitant Medications 
All subjects and their adult guardians must be questioned about concomitant medications at each 
visit.  Medications taken within 4 weeks before Day 0 will be documented in Advantage 
eClinical. Subjects will be encouraged to avoid making changes to their concomitant medication 
regimen during their participation in the study. Any changes to a subject’s concomitant 
medication regimen after the first Treatment on Day 0 will also be documented in Advantage 
eClinical. 
With the exception of other agents that are currently considered investigational, which are 
absolutely proscribed, there are no medications that are specifically prohibited during 
participation in the study. Subjects should be on a stable dose of all concomitant medications for 
at least 30 days prior to screening, and they will be encouraged to avoid making changes to their 
concomitant medication regimen during participation in the study. In addition, investigators are 
encouraged to avoid adding to or changing a subject’s medications during study participation 
unless deemed absolutely medically necessary. 


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10. 
STUDY PROCEDURES 
A schedule of assessments for this study is provided below in Table 4.  
10.1. 
Screening Visit (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 and their adult guardian 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 site visit at least 3 (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 qualified member of the study staff, including 
a review of the subject’s medical history and medications.  
2. Measurement of height and weight. 
3. Physical examination, excluding breast, pelvic and genitourinary exams. 
4. Assessment of vital signs, including triplicate measurements of BP, after a 5-minute seated 
rest. 
5. Urine pregnancy test for females of childbearing potential. 
6. Collection of venous blood for the following tests as outlined in the Schedule of Activities: 
hemoglobin A1C, complete blood count (without differential), metabolic set (including 
creatinine, liver set, and electrolytes) (Table 6).  
Once laboratory results are obtained and a final determination of eligibility is made, subjects will 
be contacted to schedule the first treatment visit. Subjects will be instructed to fast, taking 
nothing but water by mouth from midnight prior to the next visit. Subjects will be instructed to 
take their long acting insulin in the morning, if that is their usual practice, and that they should 
also take any corrective insulin as they would normally do.  
10.2. 
Treatment Phase 
The subject will arrive to the clinic in the morning, having fasted for at least 8 hours prior to 
dosing, at which time the following procedures will be completed: 
10.2.1. 
Treatment Visit 1 (Day 0) 
The following procedures will be carried out at this visit. 
1. The subject will be asked about any severe hypoglycemic events (requiring the assistance of 
another person) since the screening visit. 


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a. If a severe hypoglycemic event has occurred in the 2 weeks prior to the admission, the 
visit will be postponed until it has been at least 2 weeks since the last severe 
hypoglycemic event. 
2. If it has been more than 30 days since the Screening Visit, venous blood will be collected for 
a repeat of baseline hematology and serum chemistry assessments. However, the treatment 
visit may continue based upon qualification at the Screening Visit. 
3. The subject will be questioned and any changes in concomitant medications will be 
documented in the CRF. 
4. For females of child-bearing potential, a urine pregnancy test will be performed  
a. If positive, the subject will be discontinued from the study. 
b. Full vital signs, including triplicate BP, will be assessed after a 5-minute seated rest. 
Heart rate and single BP will be repeated immediately prior to dosing and at 30, 60, 120 
and 180 minutes post, with ± 10 minutes per collection time point. 
5. Insertion of intravenous catheter for blood sampling. 
a. Starting plasma glucose level will be assessed: 
i. If >300 mg/dL, ketones will be checked 
ii. If ketones are found to be moderate or greater, the visit will be postponed. 
6. Optional placement of a CGM for assessment of glucose levels during the induction phase. 
a. If used, the CGM will be calibrated against glucose measurements obtained from the 
point-of-care, rapid glucose analyzer. 
7. Insulin infusion will be started as described in Section 7.2.  
a. Those subjects using injection therapy will have a second intravenous catheter inserted in 
the other arm for insulin infusion. 
b. Plasma glucose levels will be measured no more than 10 minutes apart while the plasma 
glucose level is ≥100 mg/dL and no more than 5 minutes apart when the plasma glucose 
level is <100 mg/dL. 
8. Once an initial plasma glucose measurement < 80 mg/dL is achieved, 
a. The basal rate will be returned to normal for subjects using an insulin pump and the 
insulin infusion will be stopped for subjects using insulin injections. 
b. A first baseline PK blood sample should be collected at the point that plasma glucose first 
reaches a concentration < 80 mg/dL.  
9. After 5 minutes, a confirmatory plasma glucose measurement will be performed. 
a. If plasma glucose remains < 80 mg/dL, collect a second baseline PK blood sample, and 
begin administration of the study drug (see Section 9.3.2). 
b. If plasma glucose has risen to ≥ 80 mg/dL, return to step 7b and repeat the process. 
10. Following study dosing, plasma glucose will be measured every 5±2 minutes until 90 
minutes post-dosing. 


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11. Additional blood samples will be collected at 10, 20, 30, 45, 60, 90, 120, and 180 minutes 
post-dosing, with ± 5 minutes per collection, and processed and stored at -80 ± 20 C for 
determination of plasma glucagon levels. 
12. After completing all collections and procedures at 180 minutes post-dosing, the subject will 
be given a meal as per the standard practice at each site, and their usual dose of insulin. The 
subject can then leave the clinic after plasma glucose is confirmed to be between 70 and 180 
mg/dL. 
13. Local tolerability will be assessed as follows: 
a. Subjects will complete age-appropriate questionnaires regarding injection site discomfort 
(Appendix 1) at 10±5 and 30±5 minutes post-dosing, and again at 180±5 minutes post-
dosing if the FPS score reported at 30 minutes is > 0. 
b. An investigator will use the modified Draize scales (Appendix 2) 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. 
14. Adverse events reported by the subject or observed by an investigator will be recorded in 
Advantage eClincial and managed as medically appropriate. 
If a subject exhibits signs of distress at any time post-dosing or if plasma glucose drops below < 
70 mg/dL, glucose tablets may be given at the discretion of the investigator. Signs and symptoms 
should be monitored and if the subject’s condition fails to improve within 15 minutes, additional 
glucose tablets or other intervention (e.g., IV dextrose) may be given at the discretion of the 
investigator. Every attempt should be made to complete all remaining safety and efficacy 
evaluations, to the extent this can be done while safeguarding the subject. 
10.2.2. 
Treatment Visit 2 (7-28 days after the first treatment) 
Subjects ages 12-<18 will return for a second visit at least 7 days and no more than 28 days 
following the first treatment visit. The procedures to be followed at this visit are as listed in 
Section 10.2.1, but the 0.5 mg dose of G-Pen™ (glucagon injection) will be given.  If scheduled 
more than 28 days after the first treatment, body weight will be assessed at the second treatment 
visit. 
10.2.3. 
Follow-Up Phone Call (3-14 days after the final treatment) 
The parent or guardian will be contacted by telephone within 3-14 days of completing each 
dosing visit or premature discontinuation. This phone call will include the following 
assessments: 
1. Review of changes in concomitant medications.  
2. Adverse event questioning by asking the subjects to respond to a non-leading question 
such as “how do you feel?” 
If the subject cannot be reached by 14-days post-treatment, a registered letter will be sent to the 
parent/guardian to facilitate scheduling of the follow-up phone call. 


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10.3. 
Subject Withdrawal 
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or Sponsor for safety, behavioral or 
administrative reasons.  If a subject does not return for a scheduled visit, every effort should be 
made to contact the subject to determine the reason(s) why the subject failed to return for the 
scheduled visit, and to reschedule the missed visit. In any circumstance, every effort should be 
made to document subject outcome.  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 exposed to at least one 
dose of study drug, a follow-up phone call should be completed as per Section 10.2.3.  
If a subject is to be withdrawn from the study during a treatment visit, every attempt should be 
made to complete all remaining safety and efficacy evaluations, to the extent this can be done 
while safeguarding the subject. 
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 4: 
Schedule of Assessments 
Assessment 
Screening 
Treatment 1 
Treatment 2* 
Follow-up 
CRC Visit 
Day -30 to -3 
CRC Visit 
Day 0 
CRC Visit 
7-28 days 
after first 
treatment 
Phone call  
3-14 days 
after each 
treatment 
Informed consent 
x 
— 
— 
— 
Inclusion/exclusion review 
x 
— 
— 
— 
Height and weight 
x 
— 
(x) 
— 
Physical exam a 
x 
— 
— 
— 
Demographic data 
x 
— 
— 
— 
Medical History 
x 
— 
— 
— 
Concomitant medications 
x 
xb 
xb 
xb 
Urine pregnancy test, if applicable 
x 
x 
x 
— 
Hematology/Clinical chemistry 
x 
— 
— 
— 
HbA1c 
x 
— 
— 
— 
Vital signs 
x 
x 
x 
— 
Overnight fast from midnight  
— 
x 
x 
— 
Administration of study 
medication  
— 
x 
x 
— 
Subject questionnaires for 
injection site discomfort 
— 
x 
x 
— 
Draize scales for erythema/edema 
— 
x 
x 
— 
Glucagon levels (PK)c  
— 
x 
x 
— 
Venous blood glucose (PD)d 
— 
x 
x 
— 
Adverse events (AE) 
x 
x 
x 
xb 
*Subjects ages 12-<18 only. 
(x) Applies to weight only; repeat if >28 days have passed since the Treatment 1 visit. 
 
a  Excluding breast and pelvic/genital exams. 
b Changes from prior visit. 
c Venous blood at -5, 0, 10, 20, 30, 45, 60, 90, 120, and 180 minutes post dose, with ±2 minutes per 
collection for the samples from -5 and 0 minutes, and ±5 minutes for later samples. 
d Via rapid glucose analyzer at -5, 0, and every 5 minutes post dose to 90 minutes, with ±2 minutes per 
collection.  


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11. 
ASSESSMENTS 
Every effort should be made to ensure that the protocol 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 samples collected, all efforts must be made to obtain these samples at the 
same clock time as well as 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 30 PD samples of about 2cc each and 10 PK samples of 2 cc each 
drawn for a total of about 80 cc per treatment visit. This may be reduced by use of a CGM during 
the induction phase. Subjects ages 2-<12 will complete a single treatment visit, while subjects 
12-<18 will complete two such visits 7 to 28 days apart. There will be a 13.5 cc sample at 
Screening for a clinical chemistry panel, hematology and HbA1c determination. A total of about 
94 cc of blood will be drawn over the total study for subjects 2-<12 years of age and about 174 
cc for subjects ages 12-<18 (Table 5). 
Table 5: 
Frequency and Volume of Blood Collections 
Sample Type 
Sample 
Volume 
(mL) 
Blood Volume (mL) by Sample Type/Visit 
Total 
Volume 
(mL) 
Screening 
Treatment 
Visit #1 
Treatment 
Visit #2 
Clinical Chemistry 
7.5 
7.5 
- 
- 
7.5 
Hematology 
3 
3 
- 
- 
3 
HbA1c 
3 
3 
- 
- 
3 
Pharmacodynamicsa 
2 
- 
40-60* 
40-60* 
60/120 
Pharmacokinetics 
2 
- 
20 
20 
20/40 
Total 
2-7.5 
13.5 
60-80 
60-80 
93.5/173.5 
a Single plasma glucose measurements at bedside via rapid glucose analyzer. 
 
Volume of Blood Draws 
The maximum blood volume to be collected will not exceed 5% of the subject’s blood volume.  
The number of blood draws will be reduced for subjects who do not weigh enough to allow for 
the full schedule to be completed. Early collections (-5 to 30 minutes) will be preferred over later 
blood draws, and PD samples will be prioritized over PK samples. 


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11.2. 
Clinical Laboratory Tests 
The tests outlined in Table 6 will be performed at the specified time points described in the 
Schedule of Activities.   
Table 6: 
Clinical and Safety related Laboratory Tests Performed at Site 
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 
 
HbA1c 
Glucagon levels 
 
a Female subjects of childbearing potential require a negative urine 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. 
Each site’s local laboratory will be utilized for analysis of all variables with the exception of 
urine pregnancy tests, glucagon and rapid plasma glucose measurements made during treatment 
visits. Local laboratory procedures will be followed. Each laboratory will provide their Clinical 
Laboratory Improvement Act (CLIA) certification and normal ranges to the Sponsor or its 
designee.  
Each site will locally source point-of-care urine pregnancy tests.  
A central analytical lab will analyze the PK samples collected in this study. The procedures for 
preparing, storing and shipping PK samples to the analytical lab will be outlined in a manual that 
will be provided by the lab to all investigators prior to initiation of the study. 
During post-treatment evaluations, plasma glucose levels will be measured using a bedside rapid 
glucose analyzer (Analox, YSI or equivalent). The glucose analyzer will be calibrated before 
each subject visit and sites will maintain a log of calibration results. To reduce the total volume 
of blood needed for smaller subjects, a continuous blood glucose monitor may be substituted 
during the induction phase only (see Section 7.2).   
11.3. 
Vital Signs 
The BP and heart rate will be measured at the times specified in the Schedule of Activities.  
Additional collection times, or changes to collection times of BP and heart rate using automated 
device is permitted, as necessary, to ensure appropriate subject’s safety. 
BP and heart rate will be measured in the supine position with the subject’s arm supported at the 
level of the heart, and recorded to the nearest mmHg. The dominant arm will be used throughout 
the study.  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, or 
• 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 the exception that 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 entry of applicable information into Advantage 
eClinical.  For AEs with a causal relationship to the investigational product, follow-up by the 
investigator is required until the event resolves or stabilizes at a level acceptable to the 
investigator to consider it closed, and the Medical Monitor should concur with that assessment. 


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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 a 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 begins from the time the subject provides informed consent, 
through the Follow-up Visit.  All adverse events will be followed until resolution or the subject 
is medically stable or the subject exits the study. 
12.4. 
Serious Adverse Events 
An SAE is any untoward medical occurrence at any dose which: 
• Results in death 
• Is life-threatening 
• Requires inpatient hospitalization or extends existing hospitalization 
• Results in persistent or significant disability 
• Is another important medical event 
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in hospitalization or death.  However, if it is determined that the event may jeopardize the 
subject or may require intervention to prevent an AE outcome, the important medical event 
should be reported as 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 
If required 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 7 below. 
Table 7: 
AE Severity Assessment 
Mild 
Does not interfere with subject’s usual function 
Moderate 
Interferes to some extent (<50%) with subject’s usual function 
Severe 
Interferes significantly (≥50%) with subject’s usual function 
The terms “serious” and “severe” are not synonymous.  The term “severe” is often used to 
describe the intensity (severity) of a specific event.  The event itself, however, may be of 
relatively minor medical significance.  This is not the same as “serious,” which is based on 


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subject/event outcome or action criteria.  Accordingly, a severe event is not necessarily a serious 
event. 
12.6. 
Causality Assessment 
The investigator’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.  The investigator 
will use the following question when assessing causality of an adverse event to 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. 
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, relevant information must be entered into Advantage eClinical within 24 hours 
of awareness of the event by the investigator.  In particular, if the SAE is fatal or life-threatening, 
updates to Advantage eClinical  must be made within 24 hours, irrespective of the extent of 
available AE information.  This time frame also applies to follow-up on previously forwarded 
SAE reports. 
In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (e.g., a study subject initially seeks treatment elsewhere), the investigator is to 
report the event within 24 hours after learning of the event and document the time of first 
awareness of the AE.   
A death occurring during the study or the per-protocol follow-up period, must be reported to the 
CRA immediately, whether or not it is considered treatment-related.  Initial SAE reports must be 
followed by detailed descriptions.  These should include copies of redacted hospital case records 
and other documents when requested, all of which must be uploaded directly into Advantage 
eClinical.  Telephone and e-mail reports must be confirmed promptly either by facsimile or by 
overnight courier or mail. 
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. 


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12.11. 
AE Reporting Requirements to Regulatory Authorities 
AE reporting, including suspected unexpected serious adverse reactions, will be carried out by 
the Sponsor in accordance with applicable regulations. 
To the extent required by local regulations, the investigator must notify the IRB of the 
occurrence of SAEs, in writing, as soon as is practicable.  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 by the Sponsor for submission to the FDA and any other applicable authorities. 
12.12. 
Pregnancy 
The active pharmaceutical product in Xeris Pharmaceuticals’ G-Pen™ (glucagon injection) is 
Glucagon, which is in Pregnancy Category B.  Any subject found to be pregnant at any time 
during the study will be withdrawn from the study immediately.   If a pregnancy is reported or 
initiated within 7 days following administration of the study medication, the pregnancy will be 
followed until resolution (i.e., birth or voluntary or spontaneous termination of the pregnancy) 
and reported using the pregnancy case report form.  Any pregnancy outcome that meets the 
criteria for an SAE will be reported both as a SAE and on the pregnancy Case Report Form. 
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 4 
hours after administration of study drug to the last subject of the day.  The principal investigator 
or designated sub-investigator will also be on call for the remainder of the study.  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 their 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. 
Sample Size Determination 
In Phase 2 study XSGP-201, healthy normal adults were dosed with G-Pen™ after an overnight 
fast with baseline plasma glucose values that were similar to the target (< 80 mg/dL) planned for 
this study. The mean increase in glucose at 30 minutes post-dosing was approximately 35 mg/dL 
(SD = 18). Based on these findings, a sample size of 6 subjects per cohort has been chosen to 
provide 90% power to detect an increase of plasma glucose from baseline to 30 minutes after 
treatment, assuming a type 1 error rate of 5%. 
13.2. 
Pharmacokinetic and Pharmacodynamic Analyses 
The pharmacokinetic endpoints will be derived from the individual serum glucagon profiles. The 
pharmacodynamic endpoints will be derived from the individual glucose profiles. All endpoints 
will be analyzed descriptively within each of the 3 age groups. Mean, standard deviation, 
median, minimum and maximum will be presented for continues variables. Count and percentage 
will be presented for discrete variable.  
13.2.1. 
Primary endpoint 
The primary endpoint is the change in plasma glucose at 30 minutes post-dosing from baseline, 
which is defined as the average of the two plasma glucose measurements (i.e., -5 and 0 minutes) 
completed immediately prior to dosing. Last observation carried forward (LOCF) will be applied 
for subjects who drop out before 30 minutes post-dosing or who otherwise have missing primary 
endpoint data (e.g. missed blood draws). In additional to the descriptive summary, a simple t-test 
will be used to compare the glucose change from baseline to zero change within each of the 3 
age groups. 
13.2.2. 
Pharmacokinetic Secondary Endpoints: 
The data for each age cohort and the overall population will be analyzed descriptively, including 
AUC0-120m, Cmax and Tmax. 
13.2.3. 
Pharmacodynamic Secondary Endpoints: 
Time for plasma glucose to increase by ≥25 mg/dL from baseline, AUC0-120m, Cmax and Tmax 
will be analyzed descriptively for each age cohort and by dose for subjects ages 12-<18.  
13.3. 
Safety Analysis 
The following variables will be evaluated for safety purposes: 
• Adverse events and serious adverse events. 
• Vital signs 
• Local tolerability, including: 
o Subjective injection site discomfort as reported by subjects using age-appropriate 
discomfort scales (Appendix 1). 


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o Erythema and or edema formation at site of injection assessed using the Draize 
scale (Appendix 2). 
13.3.1. 
Adverse events: 
All AEs will be coded by the Sponsor or its designee using the Medical Dictionary for 
Regulatory Activities (MedDRA) and summarized 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. 
13.3.2. 
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. 
13.3.3. 
Vital signs: 
Vital signs will be summarized by descriptive statistics. 
13.3.4. 
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.). 
13.4. 
Subgroup Analysis 
No subgroup analyses are planned for this study. 
13.5. 
Interim Analysis 
No interim analysis is planned for this study. 


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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, 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, 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 
As used in this protocol, the term “case report form” (CRF) should be understood to refer to 
either a paper form or an electronic data record, or both.  A complete set of CRFs is required and 
should be completed for each individual subject.  The completed original CRFs 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. 
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 are 
true.   
In some cases, data may be entered directly into electronic CRFs as part of a web-based 
electronic data collection (EDC) system. When data are entered directly, eCRFs will be 
considered as source documents.  Other electronic data will be uploaded into the EDC system 
directly from downloads of devices or from datasets provided by laboratories that are processing 
blood samples. These electronic data will be considered as source documents. 
Other data will be collected first on paper worksheets or CRFs and then transcribed into the EDC 
system. In such cases, the paper forms will be considered source documents for the electronic 
entries. In some cases, source documents are hospital records or the subject’s chart.  In these 
cases, data collected in the CRFs must match the data in those charts. A document should be 
available that clearly identifies which data are being entered directly into the electronic CRF, and 
which data have a paper source. 
Any corrections to entries made in the CRFs must be dated, initialed and explained (if necessary) 
and should not obscure the original entry. An equivalent electronic process will utilized for 
changes to eCRFs or other changes to data entered into the EDC system. 
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), 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. 


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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 clinical research associate (CRA) or 
auditor) will contact the investigator and conduct regular visits to the clinical site.  The CRA 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 review, with the stipulation that 
subject confidentiality will be maintained in accordance with local and federal regulations, 
including HIPAA requirements.  The CRA 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 CRA/auditor will also investigate any questions concerning adherence to regulatory 
requirements.  Any administrative concerns will be clarified and followed.  The CRA 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 any and 
all questions raised and difficulties detected by the monitor. 
15.4. 
Audits and Inspections 
The investigator understands that regulatory authorities, the IRB, 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 IEC requirements 
relative to clinical studies.  
Should a conflict arise, the investigator will follow whichever law or guideline affords the 
greater protection to the individual subject. The investigator will also ensure thorough familiarity 
with the appropriate administration and potential risks of administration of the study drug, as 
described in this protocol and the Investigator’s Brochure, prior to the initiation of the study. 
16.2. 
Institutional Review Board (IRB) 
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 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 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 should be notified 
immediately and the amendment forwarded to the IRB 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.  All correspondence with the IRB should be retained 
in the Investigator File.  Copies of IRB approvals should be forwarded to Xeris Pharmaceuticals 
or its designee. 
16.3. 
Subject Information and Consent 
Potential eligibility will be assessed as part of a routine-care examination. Prior to completing 
any procedures or collecting any data that are not part of usual care, written informed consent 
will be obtained from the parent/guardian and assent will be obtained from the subject if required 
per local IRB requirements.  For potential study subjects who are considered potentially eligible 


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for the study based on a routine-care exam, the study protocol will be discussed with the 
potential study subject and parent/guardian by a study investigator and clinic coordinator.  The 
parent/guardian will be given the Informed Consent Form to read.  The parent/guardian will be 
encouraged to discuss the study with family members and their personal physician(s) before 
deciding whether to participate in the study.  Subjects of appropriate age (per IRB requirements) 
will either be given the Child Assent Form to read or it will be read to the child.  If the 
parent/guardian agrees to have the child participate, the Informed Consent Form and Child 
Assent Form (if applicable) will be signed.  A copy of the consent form and the assent form (if 
applicable) will be provided to the parent/guardian and another copy will be added to the 
subject’s chart or retained by the center research staff. The signed informed consent and assent 
(if applicable) documents must be available for verification by the study monitors at all times. 
All parties will ensure protection of subject personal data and will not include subject names on 
any sponsor forms, reports, publications, or in any other disclosures.  Subject names, address, 
date of birth and other identifiable data will be replaced by a numerical code consisting of a 
numbering system provided by Xeris Pharmaceuticals or its designee 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 and Xeris Pharmaceuticals before 
use.   
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 for review and approval prior to implementation.  
Advertisements approved by the IRB 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 
LSLV is defined as the date the investigator reviews the last subject’s final safety data and 
determined that no further evaluation is required for the subject to complete the trial. 


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18. 
PROCEDURES FOR MODIFYING THE PROTOCOL OR 
TERMINATING THE STUDY 
18.1. 
Protocol Modifications and Deviations 
The principal investigator and the sponsor’s representative 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 before the revised protocol can be implemented.  Emergency revisions that 
eliminate an apparent hazard to subjects do not require preapproval by the IRB.  However, the 
IRB 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. 
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, safety problems, 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 investigator documenting the reason for study termination, and specific procedures for 
termination will be arranged by the sponsor in coordination with the investigator.  After 
notification, the investigator 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. Bieri D, Reeve R, Champion GD, Addicoat L, Ziegler J. The Faces Pain Scale – Revised: 
Toward a common metric in pediatric pain measurement. Pain 93:173-183, 2001. 
2. American Diabetes Association (ADA) Workgroup on Hypoglycemia: Defining and 
reporting hypoglycemia in diabetes. Diabetes Care 28:1245–1249, 2005  
3. 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.  
4. 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.  
5. 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. 
6. McLeod KM, Hepburn DA, Frier BM. Frequency and morbidity of severe 
hypoglycaemia in insulin-treated diabetic patients. Diabet. Med. 1993. 10: 238-245. 
7. 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 
8. Close Concerns, Inc.  Market Survey (2,808 respondents).  2010.  
9. Glucagon™ (glucagon for injection [rDNA origin]) Prescribing Information.  Eli Lilly 
and Company, revised February 2005 
10. Glucagen® (glucagon [rDNA origin] for injection) Prescribing Information.  Novo 
Nordisk, Inc. revised December 2011.  
11. Jelinek LJ, Lok S, Rosenberg GB, Smith RA, Grant FJ, Biggs S, Bensch PA, Kuijper JL, 
Sheppard PO, Sprecher CA, et al.  Expression cloning and signaling properties of the rat 
glucagon receptor. Science. 1993 Mar 12; 259(5101): 1614-6.  
12. Wakelam MJ, Murphy GJ, Hruby VJ, Houslay MD.  Activation of two signal-
transduction systems in hepatocytes by glucagon.  Nature. 1986 Sep 4-10; 323(6083): 68-
71.  
13. FDA CDER #1.  Glucagon (glucagon hydrochloride).  NDA No. 01-2122.  Eli Lilly and 
Company, Indianapolis, IN, November 14, 1960. 
14. Eistrup, C., Hjortkjæ, R. K., Pickersgill, N., Virgo, D. M. and Woolley, A. P. A. H. 
(1993), Glucagon Produced by Recombinant DNA Technology: Repeated Dose Toxicity 
Studies, Intravenous Administration to CD Rats and Beagle Dogs for Four Weeks. 
Pharmacology & Toxicology, 73: 103–108. 
15. FDA CDER #2.  rDNA Glucagon for Injection, Pharmacology and Toxicology Review.  
NDA No. 20-928.  Eli Lilly and Company, Indianapolis, IN, April 16, 1998. 


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16. Nermoen I, Jorde R, Sager G, Sundsfjord J and Birkeland K. Effects of Exercise on 
Hypoglycaemic Responses in Insulin-Dependent Diabetes Mellitus. Diabetes & 
Metabolism. 1998. 24: 131-6. 
17. Cengiz E, Xing D, Wong JC, Wolfsdorf JI, Haymond MW, Rewers A, et al. Severe 
Hypoglycemia and Diabetic Ketoacidosis among Youth with Type 1 Diabetes in the T1D 
Exchange Clinic Registry. Pediatric Diabetes. 2013; 14:447-54. 


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APPENDIX 1. INJECTION SITE DISCOMFORT ASSESSMENT 
Faces Pain Scale – Revised (FPS-R) 
Investigative Site Instructions: The subject should complete the  FPS-R regarding 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 if the FPS score at 30±5 minutes is > 0. The subject 
completes the FPS by choosing the face that corresponds to their current level of pain. 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. 
Show the faces to the subject and provide the following instructions, using the words “hurt” or 
“pain,” whichever seems right for a particular subject: 
“These faces show how much something can hurt. This face [point to the face on far left] 
shows no pain. The faces show more and more pain [point to each from left to right] up to 
this one [point to face on far right] – It shows very much pain. Point to the face that shows 
how much you hurt right now.”  
Score the chosen face 0, 2, 4, 6, 8 or 10, counting left to right, so 0 = no pain and 10 = very much 
pain. 
 
 


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Injection Site Discomfort Description and Duration Questionnaire 
Study Personnel Instructions:  Question 1a 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. 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. 
Subject Instructions: Please answer question 1a and, if they apply 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 2. 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 
approximately 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 3. INSTRUCTIONS FOR USE 
 

SAP_001.pdf: 
 
 
STATISTICAL ANALYSIS PLAN 
FOR 
G-PEN™ (GLUCAGON INJECTION) 
PROTOCOL XSGP-302 
 
A PHASE 3 STUDY TO EVALUATE THE GLUCOSE 
RESPONSE OF G-PEN™ (GLUCAGON INJECTION) IN 
PEDIATRIC PATIENTS WITH TYPE 1 DIABETES 
 
 
Version 1.0 
 
DATE: 16 August 2017 
 
Prepared and distributed by: 
The Emmes Corporation 
Rockville, Maryland USA 
THIS COMMUNICATION IS PRIVILEGED AND CONFIDENTIAL 
 


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SYNOPSIS 
Protocol Number Code: 
Protocol XSGP-302 
Development Phase: 
Phase 3 
Products: 
G-Pen™ (glucagon injection) 
Form/Route: 
 
Subcutaneous injection of G-Pen™ glucagon at an age 
appropriate dose (0.5 mg for 2-<12 years, 0.5 or 1.0 mg 
for 12-<18 years). 
Indication Studied: 
Severe hypoglycemia 
Sponsor: 
Xeris Pharmaceuticals, Inc. 
Clinical Study Lead (CRO): 
Nilay Shah, MD 
The Emmes Corporation 
401 North Washington Street, Suite 700 
Rockville, MD 20850 
Scientific Lead: 
 
Marty Cummins 
The Xeris Pharmaceuticals, Inc. 
Medical Monitor: 
 
Poul Strange, MD, PhD 
The Xeris Pharmaceuticals, Inc. 
Biostatistician: 
 
 
 
Lily Chen, PhD 
The Emmes Corporation 
401 North Washington Street, Suite 700 
Rockville, MD 20850 
Clinical Trial Initiation Date: 
27 March 2017 
Clinical Trial Completion Date: 
30 June 2017 
Date of the Analysis Plan: 
09 August 2017 
Version Number: 
1.0 
This study was performed in compliance with Good Clinical Practice. 
 
 


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SIGNATURE PAGE 
SPONSOR:   
 
Xeris Pharmaceuticals 
STUDY TITLE: 
A Phase 3 study to evaluate the glucose response of G-Pen™ 
(glucagon injection) in pediatric patients with type 1 diabetes 
PROTOCOL NUMBER: 
XSGP-302 
 
Clinical Study Lead: Nilay Shah, MD 
Signed: 
 
Date: 
 
 
 
Title: Project Leader 
 
 
Scientific Lead: Marty Cummins 
Signed:  
 
Date:  
 
 
Title: Vice President, Drug Development 
 
 
 
 
 
The Emmes Corporation: Lily Chen, PhD 
Signed: 
 
Date: 
 
 
Title: Statistician 
 
 
 
 
 
 


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TABLE OF CONTENTS 
1 
STUDY OVERVIEW ........................................................................................................... 3 
1.1 
Study Objectives .......................................................................................................... 3 
1.1.1 
Primary Objectives ............................................................................................... 3 
1.1.2 
Secondary Objectives .......................................................................................... 4 
1.2 
Endpoints ..................................................................................................................... 4 
1.2.1 
Primary Endpoints ............................................................................................... 4 
1.2.2 
Secondary Endpoints ........................................................................................... 4 
1.3 
Sample Size ................................................................................................................. 5 
2 
ANALYSIS PLAN ............................................................................................................... 5 
2.1 
Analysis Population and Protocol Compliance .............................................................. 5 
2.2 
Demographic and Baseline Clinical Characteristics ...................................................... 5 
2.3 
Efficacy Analysis .......................................................................................................... 5 
2.3.1 
Efficacy Primary Endpoint .................................................................................... 5 
2.4 
Pharmacokinetic and Pharmacodynamic Analyses ...................................................... 6 
2.4.1 
Pharmacokinetic Endpoints ................................................................................. 6 
2.4.2 
Pharmacodynamic Endpoints .............................................................................. 6 
2.5 
Safety Analysis ............................................................................................................. 6 
2.5.1 
Adverse events .................................................................................................... 7 
2.5.2 
Physical examination ........................................................................................... 7 
2.5.3 
Vital signs ............................................................................................................ 7 
2.5.4 
Local Tolerability .................................................................................................. 7 
2.5.5 
Pregnancies ......................................................................................................... 7 
3 
STATISTICAL CONSIDERATIONS.................................................................................... 8 
3.1 
Timing of Analyses ....................................................................................................... 8 
3.2 
Analysis Cohort ............................................................................................................ 8 
3.3 
Missing Data ................................................................................................................ 8 
3.4 
Interim Analyses and Data Monitoring .......................................................................... 8 
3.5 
Multicenter Studies ....................................................................................................... 8 
3.6 
Multiple Comparisons/Multiplicity .................................................................................. 9 
3.7 
Covariates and Subgroups ........................................................................................... 9 
4 
REPORTING CONVENTIONS ........................................................................................... 9 
5 
TECHNICAL DETAILS ....................................................................................................... 9 
 


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Appendix I: TABLE/FIGURE/LISTING MOCK-UPS ................................................................. 11 
Demographic Data ............................................................................................................... 11 
Efficacy Data ........................................................................................................................ 24 
Safety Data .......................................................................................................................... 31 
Appendix II: PHARMACOKINETIC ANALYSIS CONDECUTED BY IMD ................................. 47 
1 
PK Analysis Population .................................................................................................... 47 
2 
PK Endpoints ................................................................................................................... 47 
3 
Analysis variables ............................................................................................................ 47 
3.1 
Handling of the missing values ................................................................................... 47 
3.2 
Calculation of the PK variables ................................................................................... 47 
3.2.1 
CMax ................................................................................................................... 47 
3.2.2 
TMax .................................................................................................................... 48 
3.2.3 
AUC0-120min ......................................................................................................... 48 
4 
Statistical Analysis ........................................................................................................... 48 
5 
Planned Output Table of Content ..................................................................................... 48 
6 
Mock-ups Tables/Listings/Figures .................................................................................... 49 
 
 


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1 
STUDY OVERVIEW 
1.1 
Study Objectives 
This is a sequential efficacy and safety study of G-Pen™ (glucagon injection) in pediatric 
patients with Type 1 diabetes (T1D). In addition, the pharmacokinetics of G-Pen™ will be 
evaluated. 
Subjects 2.0 to <18.0 years old with T1D receiving daily insulin for at least 6 months from the 
time of diagnosis will be enrolled to the multi-center study across three age groups (2.0-<6.0, 
6.0-<12.0, and 12.0-<18.0 years). Subjects using insulin injections will be administered 
intravenous (IV) insulin and subjects using an insulin pump will have the basal rate increased 
to induce a low normal glycemic state (plasma glucose of <80 mg/dl). All subjects will then 
receive an age-appropriate dose of G-Pen™. Subjects aged 2.0-<12.0 will complete a single 
treatment visit and receive a 0.5 mg dose of G-Pen™. Subjects aged 12.0-<18.0 will receive 
a 1.0 mg dose of G-Pen™ at an initial treatment visit, and will also be given a 0.5 mg dose at 
a second treatment visit occurring 7-28 days later. The second visit comprises a secondary 
analysis. The study protocol consists of: 
• 
Screening visit; 
• 
Treatment 1visit:  One daytime clinical research center visit for subjects aged 2.0-
<12.0 to receive a 0.5 mg dose of G-Pen™ and for subjects aged 12.0-<18.0 to 
receive a 1.0 mg dose; 
• 
Treatment 2 visit (7-28 days after the first treatment):  Only subjects aged 12.0-<18.0 
will return for a second visit to receive a 0.5 mg dose of G-Pen™; and 
• 
Follow-up phone call: The parent or guardian will be contacted by telephone within 3-
14 days of completing each dosing visit or premature discontinuation. 
Figure 1 further details the flow for study assessments. This document describes the 
analyses that will be performed to assess efficacy and safety of G-Pen™ for each age group. 
1.1.1   
Primary Objectives 
The primary objective of this study is to assess the increase in plasma glucose of subjects 
from baseline to 30 minutes after G-Pen™ glucagon injection, without additional 
interventions. The assessment will be conducted in each of three age groups (2.0-<6.0, 6.0-
<12.0, and 12.0-<18.0 years). The mean of the initial plasma glucose measurement <80 
mg/dL and a second confirmatory measurement at least 5 minutes later after stopping the 
insulin infusion comprises the baseline measurement. 


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1.1.2   
Secondary Objectives 
The secondary objectives of this study are: 
• Evaluate the pharmacodynamics (PD) of G-Pen™. Additionally, in the 12.0-<18.0 year-
old age group, to independently assess the plasma glucose change from baseline to 30 
minutes after administration of G-Pen™ at a dose of 0.5 mg. 
• Determine the safety and tolerability of G-Pen™ for each age group. 
• Evaluate the pharmacokinetics (PK) of G-Pen™. The PK analysis will be performed by 
another organization, IMD (See Appendix II). 
1.2 
Endpoints 
1.2.1   
Primary Endpoints  
The primary endpoint for this study is an evaluation of the change in plasma glucose 
following treatment with G-Pen™ (glucagon injection), particularly to quantify the increase 
from baseline to 30 minutes post-dosing, in each of three age groups. 
1.2.2   
Secondary Endpoints 
The secondary endpoints for this study are as follows: 
• PK parameters, including: descriptive analysis of serum glucagon AUC0-180m, Cmax and 
Tmax of the different age group and overall population. These analyses will be 
conducted by IMD (See Appendix II). 
• PD characteristics, including: descriptive analysis of plasma glucose AUC0-90m, Cmax, 
Tmax and time to achieve an increase in plasma glucose of at least 25 mg/dL for each 
age group. In addition, in the 12.0-<18.0 year-old age group, plasma glucose change 
from baseline to 30 minutes after administration of G-Pen™ at a dose of 0.5 mg will be 
evaluated. 
• Safety-related endpoints including: 
- Vital signs, including blood pressure (BP) and heart rate. 
- Incidence of adverse events (AEs) and serious adverse events (SAEs). 
- Subjective injection site discomfort assessed using the Faces Pain Scale (FPS-R). 
- Subjects with sufficient comprehension will further describe the nature and duration 
of any injection site discomfort using a second questionnaire. 
- Erythema and/or edema formation at site of injection assessed by an investigator 
using the modified Draize Scale. 


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1.3 
Sample Size 
In the Phase 2 study XSGP-201, healthy normal adults were treated using the G-Pen™ after 
subject completed an overnight fast and presented with baseline plasma glucose values 
similar to the target levels (< 80 mg/dL) planned for this study. The mean increase in glucose 
at 30 minutes post-dosing was approximately 25 mg/dL (standard deviation = 18). Based on 
these assumptions, a sample size of 6 subjects per age group is required to provide 90% 
power to detect at least this change in the primary endpoint, i.e., an increase of plasma 
glucose from baseline to 30 minutes after treatment, assuming a type 1 error rate of 5%. 
Therefore, approximately forty-eight subjects are anticipated to be screened for this study, 
and 36 (up to 12 per age group) will be enrolled and receive study treatment to achieve the 
goal of 18 evaluable subjects equally distributed (n=6 per age group) across the three age 
groups: 2.0-<6.0, 6.0-<12.0, and 12.0-<18.0 years old. Each age group is an independent 
clinical experiment with its own α-level of 0.05. 
2 
ANALYSIS PLAN 
All endpoints will be analyzed descriptively within each of the three age groups. N (non-
missing sample size), mean, standard deviation, median, minimum, and maximum will be 
presented for continuous variables. Count and percentage (based on the non-missing 
sample size) will be presented for discrete variables. 
2.1 
Analysis Population and Protocol Compliance 
The study flow chart displays the enrollment process from screened subjects to the analysis 
population (Figure 1). Reasons for screening failures will be summarized (Table 1). Subject 
disposition will be summarized by age group (Table 2). Reasons for discontinued treatment 
and early termination (Table 3), as well as completion rate for the post-dosing phone call 
follow-up (Table 4), will be additionally summarized by age group. Protocol deviations will be 
summarized by age group (Table 5), and a full listing of all deviations will be summarized by 
site (Listing 1). 
2.2 
Demographic and Baseline Clinical Characteristics 
Summaries of age, gender, ethnicity, race, clinical sites, and baseline clinical characteristics 
will be presented by age group (Table 6). Ethnicity is categorized as Hispanic or Latino, or 
not Hispanic or Latino. 
2.3 
Efficacy Analysis 
2.3.1   
Efficacy Primary Endpoint 
The primary endpoint is the change in plasma glucose at 30 minutes post-dosing from 
baseline, which is defined as the average of the two plasma glucose measurements (i.e., -5 
and 0 minutes) completed immediately prior to dosing. In additional to the descriptive 
summary, a simple t-test will be used to test whether there is a significant change in glucose 
from baseline to 30 minutes within each of the three age groups (Table 7). All three tests are 
2-sided with α-level of 0.05. 


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2.4 
Pharmacokinetic and Pharmacodynamic Analyses 
The PK endpoints will be derived from the individual serum glucagon profiles. The PD 
endpoints will be derived from the individual glucose profiles. 
2.4.1   
Pharmacokinetic Endpoints 
The data for each age group and the overall population will be analyzed descriptively, 
including serum glucagon AUC0-180m, Cmax and Tmax. The analysis will be conducted by IMD 
(See Appendix II). 
2.4.2   
Pharmacodynamic Endpoints 
In the 12.0-<18.0 year-old age group, the plasma glucose change from baseline to 30 
minutes after administration of G-Pen™ at a dose of 0.5 mg will be evaluated using the same 
approach described in Section 2.3.1 (Table 8). 
Time for plasma glucose to increase by ≥25 mg/dL from baseline, maximum glucose 
concentration (Cmax) between 0 and 90 min, the time to maximum concentration (Tmax) will be 
directly obtained from the observed glucose concentration-time profile. If two identical values 
are recorded for Cmax, the first one will be used for Tmax. The area under the curve from 0 to 
90 min (AUC0-90m) 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: 
1. If there are missing data points before the last observed value, they will not be imputed. 
2. If there are missing data points after the last observed value, they will be extrapolated 
using the last two data points.  
Baseline-adjusted AUC0-90m with negative values set at 0 will also be calculated. All PD 
endpoints will be analyzed descriptively for each age group (Table 9) and by treatment dose 
for subjects aged 12.0-<18.0 (Table 10). Actual time instead of protocol time will be used for 
calculating the time for plasma glucose to increase by ≥25 mg/dL from baseline, Tmax, AUC0-
90m, and baseline-adjusted AUC0-90m. In addition, plasma glucose concentration-time profile by 
age group (Figure 2 and Table 11) and by treatment dose for subjects aged 12.0-<18.0 
(Figure 3 and Table 11) will be presented. 
2.5 
Safety Analysis 
The following variables will be evaluated for safety purposes: 
• AEs and SAEs. 
• Vital signs, including BP and heart rate. 
• Local tolerability, including: 
- Subjective injection site discomfort as reported by subjects using age-appropriate 
discomfort scales. 
- Erythema and/or edema formation at site of injection assessed using the Draize 
scale. 


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2.5.1   
Adverse events 
All AEs will be coded by the Data Coordinating Center (The Emmes Corporation) using the 
Medical Dictionary for Regulatory Activities (MedDRA) and summarized by system organ 
class and preferred term, as well as by treatment dose. Number and percentage of subjects 
experiencing at least one AE after the G-Pen™ was administrated will be presented (Table 
12). In addition, the severity of AEs post-dosing and their relatedness to study drug, device, 
and procedure will be assessed (Tables 13). Treatment emergent adverse event (TEAE), 
defined by AE occurring after administration of G-Pen™, and non-TEAE, defined by any AE 
that occurred after signing informed consent, will be presented in Tables 12 and 13. 
2.5.2   
Physical examination 
Subjects with any abnormal physical examination findings at screening will be listed (Listing 
2). Changes in physical examination findings from screening to end of trial will be recorded 
as AEs if they are untoward or the investigator judges them to be clinically significant 
changes. 
2.5.3   
Vital signs 
BP and heart rate immediately before and after administration of G-Pen™ in each age group 
and by treatment dose for subjects aged 12.0-<18.0 will be summarized by descriptive 
statistics (Table 14 and Figure 4). 
2.5.4   
Local Tolerability 
The incidence of any injection site discomfort (i.e., FPS-R score >0 on the ordinal rating 
scale) by age group and by treatment dose for subjects aged 12.0-<18.0 will be analyzed 
descriptively (Table 15 and Figure 5). The incidences of erythema (Table 16 and Figure 5) 
and edema (Table 17, and Figure 5) will be analyzed in a similar manner. Descriptive 
statistics will be provided for time of onset, duration (of discomfort), and discomfort 
description (i.e., pain, irritation, itching, etc.) by age group and by treatment dose for subjects 
aged 12.0-<18.0 (Table 18). 
2.5.5   
Pregnancies 
The active pharmaceutical product in Xeris Pharmaceuticals’ G-Pen™ is Glucagon, which is 
in Pregnancy Category B. Any subject found to be pregnant at any time during the study will 
be withdrawn from the study immediately. If a pregnancy is reported or initiated within 7 days 
following administration of the study medication, the pregnancy will be followed until 
resolution (i.e., birth or voluntary or spontaneous termination of the pregnancy) and reported 
using the pregnancy Case Report Form. Any pregnancy outcome that meets the criteria for 
an SAE will be reported both as a SAE and on the pregnancy Case Report Form. 
A listing of pregnancies and outcomes will be presented (Listing 3). 


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3 
STATISTICAL CONSIDERATIONS 
3.1 
Timing of Analyses 
No interim analysis is planned for this study.  The final analysis will be performed after the 
final database lock. There will be a single database lock after all data capture and cleaning is 
completed. 
3.2 
Analysis Cohort 
The efficacy and PD analyses will include all participants who completed the dosing visit with 
the following exceptions: 
• Dosing visits during which a glucose-elevating intervention is given after administration 
of G-Pen™ will be included in the analysis, but the glucose values after the additional 
intervention post-dosing will be censored. 
• For the efficacy analysis, if the additional intervention is given before 30 minutes post-
dosing, then the 30-minute post-dosing measurement will be replaced with the last 
glucose measurement prior to the intervention. 
• For the PD analysis., if the additional intervention is given shortly after administration of 
G-Pen™ (i.e., more than half of the glucose values is censored), the subject will be 
excluded from the analysis. 
3.3 
Missing Data 
For the efficacy analyses, last observation carried forward (LOCF) will be applied for subjects 
who drop out before 30 minutes post-dosing or who otherwise have missing primary endpoint 
data (e.g. missed blood draws). Baseline glucose is calculated as the mean of the initial 
glucose measurement <80 mg/dL and a second confirmatory measurement prior to dosing. If 
either one measurement is missing, then the available one will be used as the baseline 
glucose value. If both measurements are missing, the patient will not be included in the 
efficacy analyses, given there is no confirmation measurements the subject reached a blood 
glucose value of <80 mg/dL prior to receiving the glucagon injection. The proportion of non-
analyzable subjects is expected to be low and will be monitored by the Clinical Research 
Associate (CRA) (or designee) throughout the trial. 
3.4 
Interim Analyses and Data Monitoring 
As detailed in Section 15.3 of the protocol, the CRA (or designee) will review and evaluate 
each related AE in addition to accumulated trial data for participant safety, trial conduct and 
trial progress after trial initiation. Since this is a single-arm trial, safety results will be listed in 
an unblinded fashion and reviewed by the Sponsor regularly. There will be no interim 
analysis of the efficacy endpoint planned for this study. 
3.5 
Multicenter Studies 
Data will be pooled within each age group across all clinical sites. Center effects are not 
anticipated because the sites are using standardized procedures for treatment with G-Pen™ 
and assessment of solicited and unsolicited adverse events. 


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3.6 
Multiple Comparisons/Multiplicity  
There is only one primary endpoint. Each age group is individually powered. No adjustments 
for multiple testing are planned. 
3.7 
Covariates and Subgroups 
Neither covariate adjustments nor additional subgroup analyses are planned for this study. 
4 
REPORTING CONVENTIONS  
P-values ≥0.001 and ≤0.999 will be reported to 3 decimal places; P-values less than 0.001 
will be reported as “<0.001”; P-values greater than 0.999 will be reported as “>0.999”. The 
mean, standard deviation (SD), and any other statistics other than quantiles, will be reported 
to one decimal place greater than the original data. Quantiles, such as median, or minimum 
and maximum will use the same number of decimal places as the original data. 
5 
TECHNICAL DETAILS 
SAS version 9.4 will be used to generate all tables, figures and listings and perform statistical 
analyses, and Phoenix WinNonLin version 6.4 will be used to perform the PD analysis. 
 
 


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APPENDICES 
 
Appendix I: TABLE/FIGURE/LISTING MOCK-UPS  
 
Appendix II: PHARMACOKINETIC ANALYSIS (CONDUCTED BY INTEGRATED 
MEDICAL DEVELOPMENT, NEW JERSEY USA) 
 
 


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Appendix I: TABLE/FIGURE/LISTING MOCK-UPS 
Demographic Data 
Figure 1: Study flow chart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 1 
Visit 
Enrollment 
Treatment 2 
Visit 
Screening Failure (N=X) 
• Inclusion criteria (n=X) 
• Exclusion criteria (n=X) 
Enrolled (N=X) 
Subjects Screened (N=X) 
Early Discontinuation 
(N=X) 
Secondary Analysis (N=X) 
• Excluded from analysis (n=X) 
• Received 0.5 mg glucagon (n=X) 
• Did not receive glucagon (n=X) 
Primary Analysis (N=X) 
• Excluded from analysis (n=X) 
Primary Analysis (N=X) 
• Excluded from analysis (n=X) 
Primary Analysis (N=X) 
• Excluded from analysis (n=X) 
Allocation 
12.0 - <18.0 Years (N=X) 
• Received 1.0 mg glucagon (n=X) 
• Did not receive glucagon (n=X) 
6.0 - <12.0 Years (N=X) 
• Received 0.5 mg glucagon (n=X) 
• Did not receive glucagon (n=X) 
2.0 - <6.0 Years (N=X) 
• Received 0.5 mg glucagon (n=X) 
• Did not receive glucagon (n=X) 


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Table 1: Ineligibility summary of screen failures 
Inclusion/Exclusion  
Category 
Inclusion/Exclusion Criterion 
Number of Subjects 
who did not meet the 
criteriaa 
Inclusion and Exclusion  
Number of subjects failing any eligibility criterion  
x 
Inclusion  
Any inclusion criterion  
x 
 
1.Subject is a male or female diagnosed with T1D for at least 6 months at Screening 
x 
 
2.Subject is currently using daily insulin treatment 
x 
 
3.Subject is at least 2.0 and less than 18.0 years of age, and will be <18.0 for the 
duration of the study 
x 
 
4.Subject and adult guardian are willing to follow all study procedures, including 
attending all clinic visits 
x 
 
5.Parent or guardian has provided written informed consent, and assent has been 
obtained from subjects if appropriate for age according to IRB requirements 
x 
Exclusion  
Any exclusion criterion  
x 
 
1.Subject is pregnant and/or nursing 
x 
 
2.Subject has renal insufficiency (serum creatinine >1.5 mg/dL in males or >1.4 
mg/dL in females) 
x 
 
3.Subject has serum ALT > 3 times the upper limit of normal 
x 
 
4.Subject has serum AST > 3 times the upper limit of normal 
x 
 
5.Subject has hepatic synthetic insufficiency as defined as a serum albumin of <3.0 
g/dL 
x 
 
6.Subject has serum bilirubin >2.0 mg/dL 
x 
 
7.Subject has hematocrit of <30% 
x 
 
8.Subject has mean of triplicate blood pressure readings at Screening where systolic 
blood pressure or diastolic blood pressure was >95% of normal for age and height 
percentile 
x 
 
9.Subject uses >2.0 U/kg total insulin dose per day 
x 


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Table 1: Ineligibility summary of screen failures 
Inclusion/Exclusion  
Category 
Inclusion/Exclusion Criterion 
Number of Subjects 
who did not meet the 
criteriaa 
 
10.Subject has inadequate venous access 
x 
 
11.Subject has a current seizure disorder 
x 
 
12.Subject has a history of pheochromocytoma or a disorder with increased risk of 
pheochromocytoma (e.g. MEN 2, neurofibromatosis, or Von Hippel-Lindau 
disease) 
x 
 
13.Subject has a history of insulinoma 
x 
 
14.Subject has a history of allergies to glucagon or glucagon-like products, or any 
history of significant hypersensitivity to glucagon or any related products or to any 
of the excipients (DMSO and trehalose) in the investigational formulation 
x 
 
15.Subject has a history of glycogen storage disease 
x 
 
16.Subject has any concurrent illness, other than diabetes, that is not controlled by a 
stable therapeutic regimen 
x 
 
17.Subject is an active user of alcohol or drugs of abuse 
x 
 
18.Subject has had an administration of glucagon within 14 days of the first treatment 
visit 
x 
 
19.Subject has participated 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 
x 
 
20.The principal investigator deems this subject exclusionary 
x 
a A subject may fail to meet more than one eligibility criteria. 
 
 
 


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Table 2: Subject disposition by age group 
Subject  
Disposition 
Age Group 
2.0-<6.0 years 
(N=X) 
6.0-<12.0 years 
(N=X) 
12.0-<18.0 years 
(N=X) 
n 
% 
n 
% 
n 
% 
Screened  
x 
x.x 
x 
x.x 
x 
x.x 
Enrolled 
x 
x.x 
x 
x.x 
x 
x.x 
Received All Scheduled Treatmentsa 
x 
x.x 
x 
x.x 
x 
x.x 
Completed All Study Follow-upsb 
x 
x.x 
x 
x.x 
x 
x.x 
a Refer to Table 3 for reasons subjects discontinued treatment or terminated early.  
b Refer to Table 4 for reasons subjects who did not complete the follow-up phone call. 
 
 
 


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Table 3: Reasons for discontinued treatment or early termination by age group 
Category 
Reason 
Age Group 
2.0-<6.0 years 
(N=X) 
6.0-<12.0 years 
(N=X) 
12.0-<18.0 years 
(N=X) 
n 
% 
n 
% 
n 
% 
Early Termination Prior to 
Treatment 1 Visit 
Subject did not fast for at least 8 hours 
x 
x.x 
x 
x.x 
x 
x.x 
Subject has severe hypoglycemic event within last 2 weeks 
x 
x.x 
x 
x.x 
x 
x.x 
Ketone results were moderate or greater 
x 
x.x 
x 
x.x 
x 
x.x 
Subject decision 
x 
x.x 
x 
x.x 
x 
x.x 
Investigator/Physician decision 
x 
x.x 
x 
x.x 
x 
x.x 
Sponsor decision 
x 
x.x 
x 
x.x 
x 
x.x 
Other reason 
x 
x.x 
x 
x.x 
x 
x.x 
Discontinued After 
Treatment 1 Visit 
Withdrawal early due to adverse event 
x 
x.x 
x 
x.x 
x 
x.x 
Missed visits, lost to follow-up, or lack of cooperation 
x 
x.x 
x 
x.x 
x 
x.x 
Voluntary withdrawal 
x 
x.x 
x 
x.x 
x 
x.x 
Terminated early due to protocol deviation 
x 
x.x 
x 
x.x 
x 
x.x 
Death 
x 
x.x 
x 
x.x 
x 
x.x 
Early Termination Prior to 
Subject did not fast for at least 8 hours 
NA 
 
NA 
 
x 
x.x 


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Table 3: Reasons for discontinued treatment or early termination by age group 
Category 
Reason 
Age Group 
2.0-<6.0 years 
(N=X) 
6.0-<12.0 years 
(N=X) 
12.0-<18.0 years 
(N=X) 
n 
% 
n 
% 
n 
% 
Treatment 2 Visit (12.0 - 
<18.0 year-old only)  
Subject has severe hypoglycemic event within last 2 weeks 
NA 
 
NA 
 
x 
x.x 
Ketone results were moderate or greater 
NA 
 
NA 
 
x 
x.x 
Subject decision 
NA 
 
NA 
 
x 
x.x 
Investigator/Physician decision 
NA 
 
NA 
 
x 
x.x 
Sponsor decision 
NA 
 
NA 
 
x 
x.x 
Other reason 
NA 
 
NA 
 
x 
x.x 
NA=not applicable. 
 
 


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Table 4: Completion rate of follow-up phone call after each treatment visit by age group 
Follow-up Phone Call Assessment 
Age Group 
2.0-<6.0 years 
(N=X) 
6.0-<12.0 years 
(N=X) 
12.0-<18.0 years 
(N=X) 
n 
% 
n 
% 
n 
% 
Completed After Treatment Visit 1 
 
 
 
 
 
 
Yes 
x 
x.x 
x 
x.x 
x 
x.x 
No 
x 
x.x 
x 
x.x 
x 
x.x 
Reason 1 
x 
x.x 
x 
x.x 
x 
x.x 
Reason 2 
x 
x.x 
x 
x.x 
x 
x.x 
Completed After Treatment Visit 2 
 
 
 
 
 
 
Yes 
NA 
 
NA 
 
x 
x.x 
No 
NA 
 
NA 
 
x 
x.x 
Reason 1 
NA 
 
NA 
 
x 
x.x 
Reason 2 
NA 
 
NA 
 
x 
x.x 
NA=not applicable. 
 
 


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Table 5: Distribution of protocol deviations  
A. Subject-specific protocol deviations by age group 
Category 
Age Group 
2.0-<6.0 years 
(N=X) 
6.0-<12.0 years 
(N=X) 
12.0-<18.0 years 
(N=X) 
No. of 
Subjects 
No. of 
Deviations 
No. of 
Subjects 
No. of 
Deviations 
No. of 
Subjects 
No. of 
Deviations 
Any Category 
xx 
xx 
xx 
xx 
xx 
xx 
Informed consent procedures 
xx 
xx 
xx 
xx 
xx 
xx 
Eligibility/exclusion criteria  
xx 
xx 
xx 
xx 
xx 
xx 
Missed scheduled study 
xx 
xx 
xx 
xx 
xx 
xx 
Scheduled visit/procedure conducted outside of 
window 
xx 
xx 
xx 
xx 
xx 
xx 
Laboratory assessment not performed  
xx 
xx 
xx 
xx 
xx 
xx 
Study procedure/ assessment not performed 
xx 
xx 
xx 
xx 
xx 
xx 
Procedure/assessment not performed per protocol 
xx 
xx 
xx 
xx 
xx 
xx 
Temperature excursion 
xx 
xx 
xx 
xx 
xx 
xx 
Specimen excursion 
xx 
xx 
xx 
xx 
xx 
xx 
Specimen collected outside of window 
xx 
xx 
xx 
xx 
xx 
xx 
Other 
xx 
xx 
xx 
xx 
xx 
xx 
 
 


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Table 5: Distribution of protocol deviations (continued) 
B. Study-specific protocol deviation by site 
Category 
No. of Deviations at Each Site 
Barbara 
Davis 
Center for 
Childhood 
Diabetes 
Women & 
Children's 
Hospital of 
Buffalo 
University 
of Florida 
Diabetes 
Institute 
Riley 
Hospital 
for 
Children at 
IU Health 
University 
of Iowa 
Hospitals 
and 
Clinics 
Nemours 
Children's 
Clinic 
Lucile 
Packard 
Children's 
Hospital at 
Stanford 
Yale 
University 
School of 
Medicine 
Any Category 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
Informed consent procedures 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
Eligibility/exclusion criteria  
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
Missed scheduled study 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
Scheduled visit/procedure conducted 
outside of window 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
Laboratory assessment not performed  
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
Study procedure/ assessment not 
performed 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
Procedure/assessment not performed per 
protocol 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
Temperature excursion 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
Specimen excursion 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
Specimen collected outside of window 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
Other 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 


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Listing 1: Listing of protocol deviations by site 
Site 
Date 
Deviation 
identified 
Subject-
specific  
Deviation? 
Subject  
ID 
Treatment 
Group 
Deviation  
Category 
Deviation  
Description 
Resulted in  
Subject  
Termination? 
Deviation  
Severity 
Deviation  
Resolution 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 6: Demographic and baseline clinical characteristics by age group  
 
Age Group 
2.0-<6.0 years (N=X) 
6.0-<12.0 years (N=X) 
12.0-<18.0 years (N=X) 
Age, years 
 
 
 
N 
x 
x 
x 
Mean (SD) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
Median 
xx.x 
xx.x 
xx.x 
[Min-Max] 
[xx.x-xx.x] 
[xx.x-xx.x] 
[xx.x-xx.x] 
Gender – n (%)  
 
 
 
Male  
x (x.x) 
x (x.x) 
x (x.x) 
Female 
x (x.x) 
x (x.x) 
x (x.x) 
Ethnicity – n (%)  
 
 
 
Hispanic or Latino  
x (x.x) 
x (x.x) 
x (x.x) 
Not Hispanic or Latino  
x (x.x) 
x (x.x) 
x (x.x) 
Race – n (%) 
 
 
 
White  
x (x.x) 
x (x.x) 
x (x.x) 
Black/African American  
x (x.x) 
x (x.x) 
x (x.x) 
Native Hawaiian/Other Pacific Islander 
x (x.x) 
x (x.x) 
x (x.x) 
Asian  
x (x.x) 
x (x.x) 
x (x.x) 
American Indian/Alaskan Native 
x (x.x) 
x (x.x) 
x (x.x) 
Multi-Racial  
x (x.x) 
x (x.x) 
x (x.x) 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 6: Demographic and baseline clinical characteristics by age group  
 
Age Group 
2.0-<6.0 years (N=X) 
6.0-<12.0 years (N=X) 
12.0-<18.0 years (N=X) 
Body Mass Indexa, kg/m2 
 
 
 
N 
x 
x 
x 
Mean (SD) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
Median 
xx.x 
xx.x 
xx.x 
[Min-Max] 
[xx.x-xx.x] 
[xx.x-xx.x] 
[xx.x-xx.x] 
Duration of Type 1 Diabetes, years 
 
 
 
N 
x 
x 
x 
Mean (SD) 
xx.xxx (xx.xxx) 
xx.xxx (xx.xxx) 
xx.xx (xx.xxx) 
Median 
xx.xx 
xx.xx 
xx.xx 
[Min-Max] 
[xx.xx-xx.xx] 
[xx.xx-xx.xx] 
[xx.xx-xx.xx] 
Hemoglobin A1c, % 
 
 
 
N 
x 
x 
x 
Mean (SD) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
Median 
xx.x 
xx.x 
xx.x 
[Min-Max] 
[xx.x-xx.x] 
[xx.x-xx.x] 
[xx.x-xx.x] 
Primary Insulin Modality – n (%) 
 
 
 
Insulin pump 
x (x.x) 
x (x.x) 
x (x.x) 
Insulin injections 
x (x.x) 
x (x.x) 
x (x.x) 
Both pump and injections 
x (x.x) 
x (x.x) 
x (x.x) 
 
 
 
 
 
 
 
 


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Table 6: Demographic and baseline clinical characteristics by age group  
 
Age Group 
2.0-<6.0 years (N=X) 
6.0-<12.0 years (N=X) 
12.0-<18.0 years (N=X) 
Average Daily Insulin Dose for Pumpers, total units 
 
 
 
N 
x 
x 
x 
Mean (SD) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
Median 
xxx 
xxx 
xxx 
[Min-Max] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
Number of Injections Per Day for Injectors 
 
 
 
N 
x 
x 
x 
Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
Median 
xx 
xx 
xx 
[Min-Max] 
[xx-xx] 
[xx-xx] 
[xx-xx] 
Clinical Site – n (%)  
 
 
 
Barbara Davis Center for Childhood Diabetes 
x (x.x) 
x (x.x) 
x (x.x) 
Women & Children's Hospital of Buffalo 
x (x.x) 
x (x.x) 
x (x.x) 
University of Florida Diabetes Institute 
x (x.x) 
x (x.x) 
x (x.x) 
Riley Hospital for Children at IU Health 
x (x.x) 
x (x.x) 
x (x.x) 
University of Iowa Hospitals and Clinics 
x (x.x) 
x (x.x) 
x (x.x) 
Nemours Children's Clinic 
x (x.x) 
x (x.x) 
x (x.x) 
Lucile Packard Children's Hospital at Stanford 
x (x.x) 
x (x.x) 
x (x.x) 
Yale University School of Medicine 
x (x.x) 
x (x.x) 
x (x.x) 
a Calculated as weight in kilograms divided by height in meters squared. 
SD=standard deviation. 


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Efficacy Data 
Table 7: Plasma glucose before and 30 minutes after administration of G-Pen™ by age group 
 
 
Age Group 
Plasma Glucose (mg/dL) 
Mean (SD), median, [min – max] 
 
 
P-valuea 
Baseline 
30 minutes  
Change 
2.0-<6.0 years (N=X) 
xx.x (xx.x), xx, [xx-xx] 
xxx.x (xxx.x), xxx, [xxx-xxx] 
xxx.x (xxx.x), xxx, [xxx-xxx] 
x.xxx 
6.0-<12.0 years (N=X) 
xx.x (xx.x), xx, [xx-xx] 
xxx.x (xxx.x), xxx, [xxx-xxx] 
xxx.x (xxx.x), xxx, [xxx-xxx] 
x.xxx 
12.0-<18.0 years (N=X) 
xx.x (xx.x), xx, [xx-xx] 
xxx.x (xxx.x), xxx, [xxx-xxx] 
xxx.x (xxx.x), xxx, [xxx-xxx] 
x.xxx 
a P-value computed using t-test for testing whether the change in glucose from baseline to 30 minutes is zero. 
SD= standard deviation. 
 
 


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Table 8: Plasma glucose before and 30 minutes after administration of G-Pen™ in the 12.0-<18.0 year-old age group at a dose of 0.5 mg 
 
 
Age Group 
Plasma Glucose (mg/dL) 
Mean (SD), median, [min – max] 
 
 
P-valuea 
Baseline 
30 minutes  
Change 
12.0-<18.0 years (N=X) 
xx.x (xx.x), xx, [xx-xx] 
xxx.x (xxx.x), xxx, [xxx-xxx] 
xxx.x (xxx.x), xxx, [xxx-xxx] 
x.xxx 
a P-value computed using t-test for testing whether the change in glucose from baseline to 30 minutes is zero. 
SD= standard deviation. 
 
 


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AUC= area under the curve; Cmax= maximum plasma concentration; Tmax= time to maximum plasma concentration; SD= standard deviation. 
 
 
Table 9: Plasma glucose AUC0-90m, Cmax, Tmax, and time to increase by ≥25 mg/dL from baseline by age group 
Age Group 
G-Pen™ 
Dose 
Summary 
Statistics 
Cmax 
(mg/dL) 
Tmax 
(min) 
AUC0-90m 
(min*mg/dL) 
Baseline-adjusted 
AUC0-90m 
(min*mg/dL) 
Time to increase 
by ≥25 mg/dL 
from baseline 
2.0-<6.0 years 
0.5 mg 
N 
x 
x 
x 
x 
x 
Mean (SD) 
xxx.x (xxx.x) 
xx.x (xx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xx.x (xx.x) 
Median 
xxx 
xx 
xxx 
xxx 
xx 
[Min-Max] 
[xxx-xxx] 
[xx-xx] 
[xxx-xxx] 
[xxx-xxx] 
[xx-xx] 
6.0-<12.0 years 
0.5 mg 
N 
x 
x 
x 
x 
x 
Mean (SD) 
xxx.x (xxx.x) 
xx.x (xx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xx.x (xx.x) 
Median 
xxx 
xx 
xxx 
xxx 
xx 
[Min-Max] 
[xxx-xxx] 
[xx-xx] 
[xxx-xxx] 
[xxx-xxx] 
[xx-xx] 
12.0-<18.0 years 
1.0 mg 
N 
x 
x 
x 
x 
x 
Mean (SD) 
xxx.x (xxx.x) 
xx.x (xx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xx.x (xx.x) 
Median 
xxx 
xx 
xxx 
xxx 
xx 
[Min-Max] 
[xxx-xxx] 
[xx-xx] 
[xxx-xxx] 
[xxx-xxx] 
[xx-xx] 


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AUC= area under the curve; Cmax= maximum plasma concentration; Tmax= time to maximum plasma concentration; SD= standard 
deviation. 
 
 
Table 10: Plasma glucose AUC0-90m, Cmax, Tmax, and time to increase by ≥25 mg/dL from baseline by treatment dose for 
subjects aged 12.0-<18.0 
G-Pen™ 
Dose 
Summary 
Statistics 
Cmax 
(mg/dL) 
Tmax 
(min) 
AUC0-90m 
(min*mg/dL) 
Baseline-adjusted 
AUC0-90m 
(min*mg/dL) 
Time to increase 
by ≥25 mg/dL 
from baseline 
1.0 mg 
N 
x 
x 
x 
x 
x 
Mean (SD) 
xxx.x (xxx.x) 
xx.x (xx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xx.x (xx.x) 
Median 
xxx 
xx 
xxx 
xxx 
xx 
[Min-Max] 
[xxx-xxx] 
[xx-xx] 
[xxx-xxx] 
[xxx-xxx] 
[xx-xx] 
0.5 mg 
N 
x 
x 
x 
x 
x 
Mean (SD) 
xxx.x (xxx.x) 
xx.x (xx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xx.x (xx.x) 
Median 
xxx 
xx 
xxx 
xxx 
xx 
[Min-Max] 
[xxx-xxx] 
[xx-xx] 
[xxx-xxx] 
[xxx-xxx] 
[xx-xx] 


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Figure 2: Plasma glucose over time by age group 
 
 
 
 


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Figure 3: Plasma glucose over time by treatment dose for subjects aged 12.0-<18.0 
 
 
 
 


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Table 11: Plasma glucose over time by age group and by treatment dose for subjects aged 12.0-<18.0 
Plasma Glucose, 
mg/dL 
Mean (SD) 
Time (min) 
Age 
Group 
G-Pen™ 
Dose 
-5 
0 
5 
10 
15 
20 
25 
30 
35 
40 
45 
50 
55 
60 
65 
70 
75 
80 
85 
90 
2.0-<6.0 
years  
(N=X) 
0.5 mg 
xx.x 
(xx.x) 
xx.x 
(xx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
6.0-<12.0 
years  
(N=X) 
0.5 mg 
xx.x 
(xx.x) 
xx.x 
(xx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
12.0-<18.0 
years  
(N=X) 
1.0 mg 
xx.x 
(xx.x) 
xx.x 
(xx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
12.0-<18.0 
years  
(N=X) 
0.5 mg 
xx.x 
(xx.x) 
xx.x 
(xx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
xxx.x 
(xxx.x) 
SD= standard deviation. 
 
 


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Safety Data 
Table 12: Number and percentage of subjects experiencing adverse events by MedDRA® system 
organ class and preferred term, and treatment dose 
Non-treatment emergent adverse events (non-TEAE) 
MedDRA®  
System Organ Class (SOC) 
MedDRA®  
Preferred Term (PT) 
G-Pen™ Dose 
0.5 mg 
(N=X) 
1.0 mg 
(N=X) 
n 
% 
n 
% 
Any SOC 
Any PT 
xx 
x.x 
x 
x.x 
[SOC 1]  
Any PT 
xx 
x.x 
x 
x.x 
 
[PT 1]  
xx 
x.x 
x 
x.x 
 
[PT 2]  
xx 
x.x 
x 
x.x 
[SOC 2]  
Any PT 
xx 
x.x 
x 
x.x 
 
[PT 1]  
xx 
x.x 
x 
x.x 
 
[PT 2]  
xx 
x.x 
x 
x.x 
1Note: This table presents number and percentage of subjects. A subject is only counted once per PT. A 
subject may have multiple PTs. 
2Any SAE occurred will be summarized in the footnote. 
 
 


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Table 12: Number and percentage of subjects experiencing adverse events by MedDRA® system 
organ class and preferred term, and treatment dose (continued) 
Treatment emergent adverse events (TEAE) 
MedDRA®  
System Organ Class (SOC) 
MedDRA®  
Preferred Term (PT) 
G-Pen™ Dose 
0.5 mg 
(N=X) 
1.0 mg 
(N=X) 
n 
% 
n 
% 
Any SOC 
Any PT 
xx 
x.x 
x 
x.x 
[SOC 1]  
Any PT 
xx 
x.x 
x 
x.x 
 
[PT 1]  
xx 
x.x 
x 
x.x 
 
[PT 2]  
xx 
x.x 
x 
x.x 
[SOC 2]  
Any PT 
xx 
x.x 
x 
x.x 
 
[PT 1]  
xx 
x.x 
x 
x.x 
 
[PT 2]  
xx 
x.x 
x 
x.x 
1Note: This table presents number and percentage of subjects. A subject is only counted once per PT. A 
subject may have multiple PTs. 
2Any SAE occurred will be summarized in the footnote. 
 
 


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Table 13: Severity of adverse events and their relatedness to study by MedDRA® system organ class and preferred term, and treatment dose 
Non-treatment emergent adverse events (non-TEAE) 
MedDRA® 
System 
Organ Class 
(SOC) 
MedDRA® 
Preferred 
Term (PT) 
G-Pen™ Dose 
0.5 mg (N=X) 
1.0 mg (N=X) 
Severity 
Relatedness 
Severity 
Relatedness 
Mild 
Moderate 
Severe 
Study 
Drug 
Study 
Device 
Study 
Procedure 
Mild 
Moderate 
Severe 
Study 
Drug 
Study 
Device 
Study 
Procedure 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Any SOC 
Any PT 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
[SOC 1]  
Any PT 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
 
[PT 1]  
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
 
[PT 2]  
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
[SOC 2]  
Any PT 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
 
[PT 1]  
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
 
[PT 2]  
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
1Note: This table presents number and percentage of subjects. A subject is only counted once per PT and is summarized according to their highest severity and closest 
relationship. A subject may have multiple PTs. 
2Any SAE occurred will be summarized in the footnote. 
 
 


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Table 14: Severity of adverse events and their relatedness to study by MedDRA® system organ class and preferred term, and treatment dose (continued) 
Treatment emergent adverse events (TEAE) 
MedDRA® 
System 
Organ Class 
(SOC) 
MedDRA® 
Preferred 
Term (PT) 
G-Pen™ Dose 
0.5 mg (N=X) 
1.0 mg (N=X) 
Severity 
Relatedness 
Severity 
Relatedness 
Mild 
Moderate 
Severe 
Study 
Drug 
Study 
Device 
Study 
Procedure 
Mild 
Moderate 
Severe 
Study 
Drug 
Study 
Device 
Study 
Procedure 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Any SOC 
Any PT 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
[SOC 1]  
Any PT 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
 
[PT 1]  
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
 
[PT 2]  
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
[SOC 2]  
Any PT 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
 
[PT 1]  
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
 
[PT 2]  
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
1Note: This table presents number and percentage of subjects. A subject is only counted once per PT and is summarized according to their highest severity and closest 
relationship. A subject may have multiple PTs. 
2Any SAE occurred will be summarized in the footnote. 
 
 


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Listing 2: Abnormality in the physical examination evaluation at screening 
Subject ID  
Age Group 
Physical Exam 
Abnormal Finding 
 
 
 
 
 
 


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Table 15: Vital signs before and after administration of G-Pen™ by age group and by treatment dose for subjects aged 12.0-<18.0 
Age Group: 2.0-<6.0 years (N=X) 
 
Time 
Change from Baselinea 
Baseline 
30 minutes 
60 minutes 
120 minutes 
180 minutes 
Max Increase 
Max Decrease 
Heart Rate, beats/min 
 
 
 
 
 
 
 
N 
x 
x 
x 
x 
x 
x 
x 
Mean (SD) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
Median 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
[Min-Max] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
Systolic BP, mmHg 
 
 
 
 
 
 
 
N 
x 
x 
x 
x 
x 
x 
x 
Mean (SD) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
Median 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
[Min-Max] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
Diastolic BP, mmHg 
 
 
 
 
 
 
 
N 
x 
x 
x 
x 
x 
x 
x 
Mean (SD) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
Median 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
[Min-Max] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
SD= standard deviation; BP= blood pressure. 
a Positive value indicates an increase from baseline and negative value indicates a decrease. 
 
 


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Table 14: Vital signs before and after administration of G-Pen™ by age group and by treatment dose for subjects aged 12.0-<18.0 
Age Group: 6.0-<12.0 years (N=X) 
 
Time 
Change from Baselinea 
Baseline 
30 minutes 
60 minutes 
120 minutes 
180 minutes 
Max Increase 
Max Decrease 
Heart Rate, beats/min 
 
 
 
 
 
 
 
N 
x 
x 
x 
x 
x 
x 
x 
Mean (SD) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
Median 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
[Min-Max] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
Systolic BP, mmHg 
 
 
 
 
 
 
 
N 
x 
x 
x 
x 
x 
x 
x 
Mean (SD) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
Median 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
[Min-Max] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
Diastolic BP, mmHg 
 
 
 
 
 
 
 
N 
x 
x 
x 
x 
x 
x 
x 
Mean (SD) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
Median 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
[Min-Max] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
SD= standard deviation; BP= blood pressure. 
a Positive value indicates an increase from baseline and negative value indicates a decrease. 
 
 


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Table 14: Vital signs before and after administration of G-Pen™ by age group and by treatment dose for subjects aged 12.0-<18.0 
(continued) 
Age Group: 12.0-<18.0 years with a dose of 1.0 mg (N=X) 
 
Time 
Change from Baselinea 
Baseline 
30 minutes 
60 minutes 
120 minutes 
180 minutes 
Max Increase 
Max Decrease 
Heart Rate, beats/min 
 
 
 
 
 
 
 
N 
x 
x 
x 
x 
x 
x 
x 
Mean (SD) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
Median 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
[Min-Max] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
Systolic BP, mmHg 
 
 
 
 
 
 
 
N 
x 
x 
x 
x 
x 
x 
x 
Mean (SD) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
Median 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
[Min-Max] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
Diastolic BP, mmHg 
 
 
 
 
 
 
 
N 
x 
x 
x 
x 
x 
x 
x 
Mean (SD) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
Median 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
[Min-Max] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
SD= standard deviation; BP= blood pressure. 
a Positive value indicates an increase from baseline and negative value indicates a decrease. 
 
 


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Table 14: Vital signs before and after administration of G-Pen™ by age group and by treatment dose for subjects aged 12.0-<18.0 
(continued) 
Age Group: 12.0-<18.0 years with a dose of 0.5 mg (N=X) 
 
Time 
Change from Baselinea 
Baseline 
30 minutes 
60 minutes 
120 minutes 
180 minutes 
Max Increase 
Max Decrease 
Heart Rate, beats/min 
 
 
 
 
 
 
 
N 
x 
x 
x 
x 
x 
x 
x 
Mean (SD) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
Median 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
[Min-Max] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
Systolic BP, mmHg 
 
 
 
 
 
 
 
N 
x 
x 
x 
x 
x 
x 
x 
Mean (SD) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
Median 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
[Min-Max] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
Diastolic BP, mmHg 
 
 
 
 
 
 
 
N 
x 
x 
x 
x 
x 
x 
x 
Mean (SD) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
Median 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
[Min-Max] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
[xxx-xxx] 
SD= standard deviation; BP= blood pressure. 
a Positive value indicates an increase from baseline and negative value indicates a decrease. 
 


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Figure 4: Vital signs before and after administration of G-Pen™ by age group and by treatment 
dose for subjects aged 12.0-<18.0 
 
 
 
BP= blood pressure. 
 
 


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Table 16: Incidence of any injection site discomfort by age group and by treatment dose for subjects 
aged 12.0-<18.0 
Age Group 
G-Pen™ 
Dose 
Incidence of Any Injection Site Discomforta 
10 minutes 
30 minutes 
180 minutes 
n 
% 
n 
% 
n 
% 
2.0-<6.0 years (N=X) 
0.5 mg 
x 
x.x 
x 
x.x 
x 
x.x 
6.0-<12.0 years (N=X) 
0.5 mg 
x 
x.x 
x 
x.x 
x 
x.x 
12.0-<18.0 years (N=X) 
1.0 mg 
x 
x.x 
x 
x.x 
x 
x.x 
12.0-<18.0 years (N=X) 
0.5 mg 
x 
x.x 
x 
x.x 
x 
x.x 
a Any injection site discomfort is defined as Faces Pain Scale – Revised (FPS-R) score >0.  
 
 
 


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Table 17: Incidence of erythema after administration of G-Pen™ by age group and by treatment dose 
for subjects aged 12.0-<18.0 
Age Group 
G-Pen™ 
Dose 
Incidence of Erythemaa 
10 minutes 
30 minutes 
180 minutes 
n 
% 
n 
% 
n 
% 
2.0-<6.0 years (N=X) 
0.5 mg 
x 
x.x 
x 
x.x 
x 
x.x 
6.0-<12.0 years (N=X) 
0.5 mg 
x 
x.x 
x 
x.x 
x 
x.x 
12.0-<18.0 years (N=X) 
1.0 mg 
x 
x.x 
x 
x.x 
x 
x.x 
12.0-<18.0 years (N=X) 
0.5 mg 
x 
x.x 
x 
x.x 
x 
x.x 
a Erythema formation is defined as Modified Draize Scale score for erythema >0. 
 
 


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Table 18: Incidence of edema after administration of G-Pen™ by age group and by treatment dose for 
subjects aged 12.0-<18.0 
Age Group 
G-Pen™ 
Dose 
Incidence of Edemaa 
10 minutes 
30 minutes 
180 minutes 
n 
% 
n 
% 
n 
% 
2.0-<6.0 years (N=X) 
0.5 mg 
x 
x.x 
x 
x.x 
x 
x.x 
6.0-<12.0 years (N=X) 
0.5 mg 
x 
x.x 
x 
x.x 
x 
x.x 
12.0-<18.0 years (N=X) 
1.0 mg 
x 
x.x 
x 
x.x 
x 
x.x 
12.0-<18.0 years (N=X) 
0.5 mg 
x 
x.x 
x 
x.x 
x 
x.x 
a Edema formation is defined as Modified Draize Scale score for edema >0. 
 
 


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Figure 5: Local tolerability by age group and by treatment dose for subjects aged 12.0-<18.0 
 
 
 
 
 
 


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Table 19: Time of onset and duration of discomfort and discomfort description by age group and by treatment dose for 
subjects aged 12.0-<18.0 
 
2.0-<6.0 years 
(N=Xa,b) 
6.0-<12.0 years 
(N=Xa) 
12.0-<18.0 years 
with 1.0 mg 
(N=Xa) 
12.0-<18.0 years 
with 0.5 mg 
(N=Xa) 
Time of Onset, minute 
 
 
 
 
N 
x 
x 
x 
x 
Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
Median 
xx 
xx 
xx 
xx 
[Min-Max] 
[xx-xx] 
[xx-xx] 
[xx-xx] 
[xx-xx] 
Duration – n (%) 
 
 
 
 
< 1 minute 
x (x.x) 
x (x.x) 
x (x.x) 
x (x.x) 
1-2 minutes 
x (x.x) 
x (x.x) 
x (x.x) 
x (x.x) 
3-5 minutes 
x (x.x) 
x (x.x) 
x (x.x) 
x (x.x) 
6-9 minutes 
x (x.x) 
x (x.x) 
x (x.x) 
x (x.x) 
10-15 minutes 
x (x.x) 
x (x.x) 
x (x.x) 
x (x.x) 
16-30 minutes 
x (x.x) 
x (x.x) 
x (x.x) 
x (x.x) 
30-120 minutes 
x (x.x) 
x (x.x) 
x (x.x) 
x (x.x) 
121-180 minutes 
x (x.x) 
x (x.x) 
x (x.x) 
x (x.x) 
Discomfort Description c  
 
 
 
 
Pain (e.g. throbbing, soreness, muscle ache) – n (%) 
x (x.x) 
x (x.x) 
x (x.x) 
x (x.x) 
Itching – n (%) 
x (x.x) 
x (x.x) 
x (x.x) 
x (x.x) 
Tingling, twitching, or numbness – n (%) 
x (x.x) 
x (x.x) 
x (x.x) 
x (x.x) 
Irritation (e.g. burning, stinging) – n (%) 
x (x.x) 
x (x.x) 
x (x.x) 
x (x.x) 
a Only those who reported having at least one discomfort post-injection are included in the table. 
b X subjects are not applicable because they are too young for comprehension. 
c A subject may report more than one discomfort. 
 


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Listing 3: Pregnancies and outcomes 
Subject 
ID 
Age 
group 
G-Pen™ 
dose 
Number of 
Embryos, 
Fetuses, and/or 
Infants 
Outcome 
Congenital 
Anomaly? 
Gestational Age 
(weeks and days) 
Gender 
Weight 
(lbs) 
Length 
(in) 
Head 
Circumference 
(cm) 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix II: PHARMACOKINETIC ANALYSIS CONDECUTED BY Integrated 
Medical Development, New jersey USA 
1 
PK Analysis Population 
There is only one population for PK analysis. It is defined as all subjects randomized. 
2 
PK Endpoints 
The following PK endpoints will be analyzed: 
• 
CMax, maximum concentration of G-Pen Glucagon 
• 
TMax, the time when maximum concentration of G-Pen Glucagon reached 
• 
AUC0-120min, area under the curve of G-Pen Glucagon from 0 to 120 minutes 
3 
Analysis variables 
3.1 
Handling of the missing values 
The PK samples are drawn blood at -5, 0, 10, 20, 30, 45, 60, 90, 120, and 180 minutes post 
dose, with ±2 minutes per collection for the samples from -5 and 0 minutes, and ±5 minutes 
for later samples. The following procedures will be applied to handle any missing values of 
the PK:  
• 
If PK at time 0 minute (T0) is missing, then PK at -5 minute will be substituted. If both -
5 minute and 0 minute PK are missing, then the PK at later minutes will be used to 
impute the PK at 0 minute. In such case, linear imputation will be used. 
• 
If PK at 120 minute is missing, then cubic imputation will be used to impute the PK at 
120 minute. Exception: if PK at 120 minute is missing and the last available PK is the 
Cmax, i.e, PK never comes down, and then no imputation will be done. 
• 
All other missing PK values will not be imputed 
3.2 
Calculation of the PK variables 
The following PK analysis variables will be calculated as the data handle procedures 
described above (section 3.1). If 2 draws of the PK at time 0 were done, the average of two 
will be used for time 0. 
3.2.1 CMax 
CMax is defined as the maximum concentration of G-Pen Glucagon after time 0 minute. 


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3.2.2 TMax 
TMax is defined as time (min) when maximum concentration of G-Pen Glucagon reached after 
T0. If there are multiple CMax following the injection, TMax will be the first time when CMax is 
reached. Actual time instead of protocol time will be used. 
3.2.3 AUC0-120min 
AUC0-120min is calculated using Trapezoidal rule from T0 to T120. Actual time instead of protocol 
time will be used. 
4 
Statistical Analysis 
The three PK variables defined in section 3.2 will be analyzed descriptive for the age groups 
and doses (2.0-<6.0yr 0.5mg, 6.0-<12.0yr 0.5mg, 12.0-<18.0yr 1mg, and 12.0-<18.0yr 
0.5mg). Mean, standard deviation, median, minimum and maximum will be presented.  
Individual figures of each subject each dose will be presented. Mean G-Pen Glucagon vs 
protocol time point will be presented for each age group and doses. Protocol time point will 
be used to allow aggregation. 
5 
Planned Output Table of Content 
Tables 
14.2.1.1 
Glucagon : Cmax by age and dose 
  
14.2.1.2 
Glucagon : Tmax by age and dose 
  
14.2.1.3 
Glucagon : AUC0-120 by age and dose 
  
  
  
Listing 
16.2.5.1 
PK profile for each subject 
  
16.2.5.2 
PK Cmax, Tmax, AUC for each subject 
  
  
  
Figure 
14.4.1.1.subjid 
Individual Glucagon profile of each subject 
  
14.4.1.2 
average Glucagon vs time for each age group and dose 
 
 
 


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6 
Mock-ups Tables/Listings/Figures 
Table 14.2.1.1 Glucagon: Cmax by age and dose 
 Glucagon: Cmax 
CATEGORY 
2-6yr 0.5mg 
6-12yr 0.5mg 
12-18yr 1mg 12-18yr 0.5mg 
N 
6 
6 
6 
6 
Mean(SD) 
x.x(x.xx) 
x.x(x.xx) 
x.x(x.xx) 
x.x(x.xx) 
Min, Median, Max 
x.x(x.xx) 
x.x(x.xx) 
x.x(x.xx) 
x.x(x.xx) 
 
Table 14.2.1.2 Glucagon: Tmax by age and dose 
 Glucagon: Tmax 
CATEGORY 
2-6yr 0.5mg 
6-12yr 0.5mg 
12-18yr 1mg 12-18yr 0.5mg 
N 
6 
6 
6 
6 
Mean(SD) 
x.x(x.xx) 
x.x(x.xx) 
x.x(x.xx) 
x.x(x.xx) 
Min, Median, Max 
x.x(x.xx) 
x.x(x.xx) 
x.x(x.xx) 
x.x(x.xx) 
 
Table 14.2.1.3 Glucagon: AUC0-120 by age and dose 
 Glucagon: Auc0-120 
CATEGORY 
2-6yr 0.5mg 
6-12yr 0.5mg 
12-18yr 1mg 12-18yr 0.5mg 
N 
6 
6 
6 
6 
Mean(SD) 
x.x(x.xx) 
x.x(x.xx) 
x.x(x.xx) 
x.x(x.xx) 
Min, Median, Max 
x.x(x.xx) 
x.x(x.xx) 
x.x(x.xx) 
x.x(x.xx) 
 
Listing 16.2.5.1 Glucagon of each subject 
PATIENT ID 
Actual Date/Time 
Protocol Time 
Glucagon 
xxxx 
Xx/xx/xxxx xx:xx 
-5 
xx 
xxxx 
Xx/xx/xxxx xx:xx 
0 
xx 
xxxx 
Xx/xx/xxxx xx:xx 
10 
xx 
xxxx 
Xx/xx/xxxx xx:xx 
20 
xx 
 
Listing 16.2.5.2 Glucagon Cmax, TMax, AUC of each subject 


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PATIENT ID 
CMax  
TMax 
AUC01-20 
xxxx 
xx 
xx 
xx 
xxxx 
xx 
xx 
xx 
xxxx 
xx 
xx 
xx 
xxxx 
xx 
xx 
xx 
 
 
 
 


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Figure 14.4.1.1.xxxx Glucagon at each time points 
 
 
 
 
0
100
200
300
400
500
600
-5
15
35
55
75
95
115
135
155
175
195
Glucagon (pg/ml)
Protocol Time Point (min from first dose)
Glucagon of Subject
xxxx 0.5mg
Age1


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Figure 14.4.1.2 Mean Glucagon at each time points for age/dose group 
 
 
0
100
200
300
400
500
600
700
-5
45
95
145
195
Glucagon (pg/ml)
Protocol Time Point (min from first dose)
Mean Glucagon at each time point
.
Age1
Age2
Age3dose1
Age3dose2