Clinical trial NCT03841526
Conditions: Hypoglycemia
Keywords: Exercise Glucagon Insulin
Sponsor: Xeris Pharmaceuticals
Start date: 2019-08-22; Completion date: 2020-04-02
Enrollment: 48 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study is a randomized, placebo-controlled, double-blind, 2-treatment, 2-period, crossover comparison in a clinical research center (CRC) setting, followed by a randomized, placebo-controlled, double-blinded, 2-arm parallel comparison with a third open-label arm in an outpatient setting. The purpose of the study is to evaluate the preliminary efficacy and safety of Glucagon Ready-to-Use \[RTU\] to prevent exercise-induced hypoglycemia (EIH) in adults with Type 1 diabetes mellitus (T1D), who perform regular, moderate-to-high intensity aerobic exercise.

Detailed description:
There were 2 phases of this study: CRC and Outpatient. The initial posting of this study reflected the 3 treatment arms included in the Outpatient Phase of the study, without including the CRC and Outpatient Phases separately.

CRC Phase:

The CRC Phase was comprised of 2 visits that included daytime exercise sessions at the CRC or a comparable setting. Subjects were randomized to receive their first treatment at Visit 3 and crossed over (2 to 28 day washout) to their second treatment at Visit 4. The treatments were a single treatment with 30 microliters of either Glucagon RTU (0.15 mg) or placebo with a 50% insulin pump reduction. Blood glucose was assessed 15 minutes prior to the start of exercise, at the start of exercise, and then 15, 30, 45, 60, and 75 minutes from the start of exercise.

Outpatient Phase:

After completion of the CRC Phase, subjects entered the 12-week Outpatient Phase. Subjects were to maintain a weekly exercise average of 2 to 3 sessions of at least 30 minutes duration. Subjects were assigned randomly in 1:1:1 ratio to administer 30 microliters of one of the following prior to the exercise sessions: Glucagon RTU (0.15 mg) with a 50% insulin pump reduction, placebo with a 50% pump reduction or Glucagon RTU (0.15 mg) without an insulin pump reduction. Blood glucose was assessed 15 minutes prior to the start of exercise, just before exercise, after 30 minutes of exercise, at the end of exercise (if longer than 30 minutes), and 30 minutes post-exercise.

Arms: arm 1: CRC Phase: 2-arm randomized double-blind crossover, Glucagon RTU Injection 30 microliters of 0.15 mg injection with 50% reduction in the insulin pump arm 2: CRC Phase: 2-arm randomized double-blind crossover, Vehicle for Glucagon RTU Injection 30 microliters vehicle with 50% reduction in the insulin pump arm 3: Outpatient Phase: 3-arm randomized comparison (2-arm double-blind, 1-arm open-label), Glucagon RTU Injection 30 microliters of 0.15 mg injection with 50% reduction in the insulin pump (double-blind arm) arm 4: Outpatient Phase: 3-arm randomized comparison (2-arm double-blind, 1-arm open-label), Vehicle for Glucagon RTU Injection 30 microliters vehicle with 50% reduction in the insulin pump (double-blind arm) arm 5: Outpatient Phase: 3-arm randomized comparison (2-arm double-blind, 1-arm open-label), Glucagon RTU Injection 30 microliters of 0.15 mg injection without a reduction in the insulin pump (open-label arm)
Interventions: intervention 1: Glucagon RTU Injection With Insulin Pump Reduction intervention 2: Vehicle for Glucagon RTU Injection With Insulin Pump Reduction intervention 3: Glugaon RTU Injection Without Insulin Pump Reduction
Intervention descriptions: intervention 1: 0.15 mg injection with 50% pump reduction intervention 2: vehicle injection with 50% pump reduction intervention 3: 0.15 mg injection without pump reduction

Protocol documents:
Prot_000.pdf: 
Glucagon RTU (Glucagon Injection) 
Version 4.0  
Protocol XSMP-204 
  
 
Xeris Pharmaceuticals, Inc 
Confidential 
Page 1 of 66 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
A Phase 2 Randomized, Placebo-Controlled, Double-Blind, Parallel Study to Evaluate Glucagon 
RTU (Glucagon Injection) Compared to Standard of Care for the Prevention of Exercise-Induced 
Hypoglycemia During Regular Aerobic Exercise in Adults with Type 1 Diabetes 
 
Protocol Number: 
XSMP-204 
CTA Number: 
222108 
Phase: 
2 
Study Drug: 
GLUCAGON Ready-to-Use (Glucagon Injection) 
Sponsor: 
Xeris Pharmaceuticals, Inc 
180 North LaSalle Street, Suite 1600 
Chicago, IL 60601 
 
 
Medical Monitor: 
Khaled Junaidi, MD 
Date of Protocol: 
Version 4.0, 6/20/2019 
Version 3.0, 25 Feb 2019 
 
 
 
 
GCP Statement: 
This study is to be performed in full compliance with International 
Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use (ICH) and all applicable local Good 
Clinical Practice (GCP) and regulations. All required study documentation 
will be archived as required by regulatory authorities. 
Confidentiality 
Statement: 
This document is confidential. It contains proprietary information of Xeris 
Pharmaceuticals (the sponsor). Any viewing or disclosure of such 
information that is not authorized in writing by the sponsor is strictly 
prohibited. Such information may be used solely for the purpose of 
reviewing or performing the study. 
 
 
 
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1. 
TABLE OF CONTENTS 
1. 
TABLE OF CONTENTS .............................................................................................2 
PROCEDURES IN CASE OF EMERGENCY ...............................................................................6 
PROTOCOL AMENDMENT HISTORY .......................................................................................7 
Summary of Changes From Version 3.0..........................................................................................7 
Summary of Changes from Version 2.0 to 3.0 ................................................................................8 
Summary of Changes from Version 1.0 to 2.0 ................................................................................9 
XERIS PHARMACEUTICALS SIGNATURE PAGE .................................................................10 
STATEMENT OF COMPLIANCE ...............................................................................................11 
2. 
PROTOCOL SUMMARY ..........................................................................................12 
2.1. 
Synopsis ......................................................................................................................12 
2.2. 
Schema ........................................................................................................................15 
2.3. 
Schedule of Activities .................................................................................................16 
3. 
ABBREVIATIONS ....................................................................................................19 
4. 
INTRODUCTION ......................................................................................................21 
4.1. 
Study Rationale ...........................................................................................................21 
4.2. 
Background .................................................................................................................21 
4.3. 
Risk/Benefit Assessment ............................................................................................22 
4.3.1. 
Known Potential Risks ...............................................................................................22 
4.3.2. 
Known Potential Benefits ...........................................................................................23 
5. 
OBJECTIVES AND ENDPOINTS ............................................................................24 
5.1. 
Objectives ...................................................................................................................24 
5.1.1. 
Primary Objective .......................................................................................................24 
5.1.2. 
Secondary Objectives .................................................................................................24 
5.1.3. 
Exploratory Objectives ...............................................................................................24 
5.2. 
Endpoints ....................................................................................................................25 
5.2.1. 
Primary Endpoint ........................................................................................................25 
5.2.2. 
Key Secondary Endpoints ...........................................................................................25 
5.2.3. 
Other Secondary Endpoints ........................................................................................25 
5.2.4. 
Safety Endpoints .........................................................................................................26 
6. 
STUDY DESIGN .......................................................................................................27 
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6.1. 
Overall Design ............................................................................................................27 
6.2. 
Justification for Dose ..................................................................................................27 
6.3. 
End of Study Definition ..............................................................................................28 
7. 
STUDY POPULATION .............................................................................................29 
7.1. 
Inclusion Criteria ........................................................................................................29 
7.2. 
Exclusion Criteria .......................................................................................................29 
7.3. 
Lifestyle Considerations .............................................................................................31 
7.4. 
Screen Failures ............................................................................................................31 
8. 
TREATMENT OF SUBJECTS ..................................................................................32 
8.1. 
Description of Study Drug ..........................................................................................32 
8.2. 
Storage ........................................................................................................................32 
8.3. 
Study Drug Administration.........................................................................................33 
8.4. 
Treatment Compliance ................................................................................................33 
8.5. 
Measures to Minimize Bias: Randomization and Blinding ........................................33 
8.6. 
Unblinding ..................................................................................................................34 
8.7. 
Concomitant Therapy .................................................................................................34 
8.7.1. 
Rescue Medicine .........................................................................................................35 
9. 
ASSESSMENTS.........................................................................................................36 
9.1. 
Efficacy Assessments .................................................................................................36 
9.1.1. 
Wearable Fitness Tracker (Fitbit Ionic) ......................................................................36 
9.1.2. 
Polar Beat H10 Heart Rate Sensor ..............................................................................36 
9.1.3. 
Continuous Glucose Monitoring.................................................................................36 
9.1.4. 
Barriers to Physical Activity Diabetes (Type 1) Questionnaire .................................36 
9.1.5. 
Hypoglycemia Fear Survey II .....................................................................................36 
9.1.6. 
Hypoglycemia Confidence Scale ................................................................................36 
9.1.7. 
Modified Draize Scale ................................................................................................37 
9.1.8. 
Injection Site Discomfort Description and Duration Questionnaire ...........................37 
9.2. 
Pharmacokinetic/Pharmacodynamic Assessments .....................................................37 
9.2.1. 
Immunogenicity Testing .............................................................................................37 
9.3. 
Safety Assessments .....................................................................................................37 
9.3.1. 
Adverse Events and Serious Adverse Events .............................................................37 
9.3.2. 
Events of Special Interest ...........................................................................................40 
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9.3.3. 
Reporting of Pregnancy ..............................................................................................40 
9.4. 
Unanticipated Problems ..............................................................................................41 
9.4.1. 
Definition of Unanticipated Problems (UP) ...............................................................41 
10. 
STUDY PROCEDURES ............................................................................................42 
10.1. 
Visit 1 – Screening (Day -28 to -3) .............................................................................42 
10.2. 
Visit 2 – CGM Placement (Day -2 to -1) ....................................................................42 
10.3. 
CRC Phase ..................................................................................................................43 
10.3.1. 
Visit 3 – Treatment 1 (Day 1) / Visit 4 Treatment 2 (Day 3-29) Clinic Arrival .........43 
10.4. 
Visit 5 Through 10 – Outpatient Stage .......................................................................45 
10.4.1. 
Visits 5 Through 10 – Treatment Day 4-113 ..............................................................45 
10.4.2. 
Visit 11 – Follow-Up Visit (14-21 Days After Last Exercise Session)/Early 
Termination .................................................................................................................46 
11. 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................47 
11.1. 
Discontinuation of Study Intervention ........................................................................47 
11.2. 
Participant Discontinuation/Withdrawal from the Study ............................................47 
12. 
STATISTICAL CONSIDERATIONS .......................................................................48 
12.1. 
General Approach .......................................................................................................48 
12.2. 
Sample Size Determination ........................................................................................48 
12.3. 
Populations for Analyses ............................................................................................48 
12.4. 
Statistical Analyses .....................................................................................................48 
12.4.1. 
Efficacy Hypothesis ....................................................................................................48 
12.4.2. 
Analysis of the Primary Efficacy Endpoint(s) ............................................................49 
12.4.3. 
Analysis of the Key Secondary Endpoint(s) ...............................................................49 
12.4.4. 
Safety Analyses ..........................................................................................................49 
12.4.5. 
Baseline Descriptive Statistics ....................................................................................50 
12.4.6. 
Planned Interim Analyses ...........................................................................................50 
12.4.7. 
Sub-Group Analyses ...................................................................................................51 
12.4.8. 
Tabulation of Individual participant Data ...................................................................51 
12.4.9. 
Exploratory Analyses ..................................................................................................51 
12.4.10. 
Missing Data ...............................................................................................................51 
13. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................52 
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13.1. 
Regulatory, Ethical, and Study Oversight Considerations ..........................................52 
13.1.1. 
Informed Consent Process ..........................................................................................52 
13.1.2. 
Confidentiality and Privacy ........................................................................................53 
13.1.3. 
Safety Oversight .........................................................................................................53 
13.1.4. 
Clinical Monitoring ....................................................................................................53 
13.1.5. 
Quality Assurance and Quality Control ......................................................................53 
13.1.6. 
Data Handling and Record Keeping ...........................................................................53 
13.1.7. 
Protocol Deviations ....................................................................................................54 
14. 
REFERENCES ...........................................................................................................55 
APPENDIX 1. EXERCISE .........................................................................................................57 
CRC EXERCISE ...........................................................................................................................57 
OUTPATIENT EXERCISE...........................................................................................................57 
APPENDIX 2. BAPAD 1 QUESTIONNAIRE...........................................................................59 
APPENDIX 3. HFS-II (ADULTS) QUESTIONNAIRE ............................................................60 
APPENDIX 4. DRAIZE SCALE ................................................................................................63 
APPENDIX 5. HYPOGLYCEMIC CONFIDENCE SCALE .....................................................64 
APPENDIX 6. INJECTION SITE DISCOMFORT DESCRIPTION AND DURATION 
QUESTIONNAIRE ....................................................................................................65 
 
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PROCEDURES IN CASE OF EMERGENCY 
Role in Study 
Name & Title 
Email Address & Telephone Number 
Sponsor’s Study 
Leader & primary 
contact 
Julie Murphy, MSHS 
Clinical Project 
Manager 
jmurphy@xerispharma.com  
(312) 736-1255 (direct) 
(312) 841-9478 (cell) 
Medical Monitor & 
24-hour emergency 
contact 
M. Khaled Junaidi, MD, 
Medical Director, 
Clinical Research 
kjunaidi@xerispharma.com 
(312) 517-1461 (direct) 
(815) 593-2218 (cell) 
Reporting of 
Investigational 
Product concerns, 
including device 
failures 
Xeris Medical Affairs 
Department 
Safety-XSMP204@xerispharma.com 
(630) 915-5885 
(815) 593-2218 
 
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PROTOCOL AMENDMENT HISTORY 
Summary of Changes From Version 3.0 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
Title page 
Updated to add GCP and Confidentiality 
statements 
Consistency with other 
protocol 
Protocol 
Amendment 
History 
Add a list of changes since Version 3.0 
Correctness 
Signature page 
Revised to include all functional areas 
Correctness 
Section 2  
Revised grammar, punctuation, spelling; added 
safety endpoints, revised study schema and 
Schedule of Assessments 
Correctness 
Section 3  
Updated abbreviations 
Correctness 
Section 4  
Updated editorial items (grammar, punctuation, 
spelling) 
Correctness 
Section 5  
Separated Objectives and Endpoints, which had 
been in the same section 
Correctness 
Section 6  
Editorial corrections; updated the definition of 
End of Study 
Correctness 
Section 8  
Moved all information related to treatment of 
subjects to Section 8 from Section 9 
Correctness 
Section 9  
Added a section that describes all assessments 
Completeness 
Section 10  
Corrected missing elements from study 
procedures 
Completeness  
Section 11  
Corrected language in the description of 
withdrawal of a subject 
Correctness 
Section 12  
Editorial corrections 
Completeness 
Section 13.1.3  Added missing information 
Completeness 
Section 14  
Added references 
Completeness 
Appendices 
Updated with references (sources), and corrected 
procedures 
Completeness 
 
 
 
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Summary of Changes from Version 2.0 to 3.0 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
Throughout 
the protocol 
Administrative clarifications located throughout the 
protocol 
To correct pagination and 
version number 
inconsistencies 
Schedule of 
Assessments 
Added Adverse Event Assessment to screening 
visit 
To add consistency 
throughout protocol 
Schedule of 
Assessments 
/ 9.3.1. 
Added the use of Polar Beat H10 heart rate sensor 
to both CRC exercise sessions. 
Site will be using this to 
monitor subject heart rate 
during exercise sessions. 
Table 3 
Removed exploratory endpoint: “Proportion of 
time with 80% max heart rate during exercise 
sessions.” 
 
This endpoint is no longer 
applicable as 80% is a target 
heart rate, but not required, 
during exercise sessions. 
8.1 
Inclusion criteria #4:  Updated inclusion criteria to 
include pmol/L equivalent of ng/mL for random C-
peptide. 
The local lab will report this 
value using pmol/L. 
11.4.4 
Revised wording for start time of collection of 
adverse events from starting “at Visit 2” to “from 
time of consent” 
To add consistency 
throughout protocol. 
N/A 
Clarification to Summary of Changes from Version 
1.0 to 2.0: 
Removed Urinalysis from schedule of assessments 
and body of protocol 
Urinalysis was inadvertently 
added to protocol 1.0 and 
subsequently removed as this 
does not impact safety. 
10.3.1 
Removed verbiage regarding short-term 
excursions 
 
The current stability data 
supports controlled room 
temperature storage only. 
 
 
 
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Summary of Changes from Version 1.0 to 2.0 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
Throughout 
the protocol 
Administrative clarifications located throughout the 
protocol 
To clarify specific points and 
address inconsistencies 
Schedule of 
Assessments 
Removed Urinalysis from schedule of assessments 
and body of protocol 
Data from this procedure will 
not be analyzed 
Appendix 6 
Injection Site Discomfort Description and Duration 
Questionnaire has been added 
Originally left as a stand-
alone document but has now 
been added to the appendix 
for consistency. 
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XERIS PHARMACEUTICALS SIGNATURE PAGE 
A Phase 2 Randomized, Placebo-Controlled, Double-Blind, Parallel Study to Evaluate Glucagon 
RTU (Glucagon Injection) Compared to Standard of Care for the Prevention of Exercise-Induced 
Hypoglycemia During Regular Aerobic Exercise in Adults with Type 1 Diabetes 
Version 4.0 
6/20/2019 
Medical Director:  
See attached electronic signature page 
Khaled Junaidi, MD 
Medical Director, Clinical Research 
Xeris Pharmaceuticals, Inc. 
Clinical Operations: 
See attached electronic signature page 
Martin J. Cummins, BS 
Vice President, Clinical Development 
Xeris Pharmaceuticals, Inc 
Regulatory: 
See attached electronic signature page 
 
Aziz Alam, MS 
Senior Director, Regulatory Affairs 
Xeris Pharmaceuticals, Inc 
Biostatistics and Data 
Management 
See attached electronic signature page 
 
Nicole Close, PhD 
Head of Biostatistics and Clinical Data Management 
Xeris Pharmaceuticals, Inc. 
Director Quality 
Assurance: 
See attached electronic signature page 
Ed Drower, MS 
Director of Good Clinical Practices 
Xeris Pharmaceuticals, Inc 
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STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with the International Conference on Harmonisation 
Good Clinical Practice (ICH GCP) and the applicable United States (US) Code of Federal 
Regulations (CFR). The Principle Investigator will assure that no deviation from or changes to 
the protocol will take place without prior agreement from Xeris Pharmaceuticals, Inc., and 
documented approval from the Research Ethics Board (REB), except where necessary to 
eliminate an immediate hazard(s) to the trial participants. All personnel involved in the conduct 
of this study have completed Human Subjects Protection and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the REB for review and approval. Approval of both the protocol and the 
consent form must be obtained before any participant is enrolled. Any amendment to the 
protocol will require review and approval by the REB before the changes are implemented to 
the study. All changes to the consent form will be REB approved; a determination will be made 
regarding whether a new consent needs to be obtained from participants who provided consent, 
using a previously approved consent form. 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
Signature of Investigator 
 
 
 
Date 
 
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2. 
PROTOCOL SUMMARY 
2.1. 
Synopsis 
Title 
A Phase 2 Randomized, Placebo-Controlled, Double-Blind, Parallel Study To 
Evaluate Glucagon RTU (Glucagon Injection) Compared To Standard Of 
Care For The Prevention Of Exercise-Induced Hypoglycemia During Regular 
Aerobic Exercise In Adults With Type 1 Diabetes. 
Study Description 
This study is a randomized, placebo-controlled, double-blind, two-treatment, 
two- period, crossover comparison in a clinical research center (CRC) setting 
followed by a randomized, placebo-controlled, double-blind, 2-arm parallel 
comparison with a third open-label arm in the Outpatient Phase. The purpose 
of the study is to evaluate the preliminary efficacy of Glucagon Ready-to-Use 
(RTU) to prevent exercise-induced hypoglycemia in adults with Type 1 
diabetes mellitus (T1D) who perform regular, moderate-to-high intensity, 
aerobic exercise of at least 45 minutes duration in an inpatient setting and at 
least 30 minutes duration in the outpatient setting, and who receive daily 
insulin treatment via a subcutaneous infusion pump and to monitor safety in 
this population. 
During the CRC Phase, each subject will undergo two, 45-minute morning 
aerobic exercise sessions. Subjects will be randomized to receive the first 
treatment at Visit 3 and crossed over to the second treatment at Visit 4. All 
CRC exercise sessions will take place in the morning, following an overnight 
fast. At 5 minutes prior to each exercise session, subjects will reduce their 
basal rate of insulin infusion by 50% and maintain this reduction for the 
duration of exercise. Immediately after making the basal rate insulin 
reduction, subjects will self-administer one of the following randomly 
assigned interventions: 
1. Placebo (vehicle) 
2. Glucagon RTU 
During the 12-week Outpatient Phase, subjects will be assigned randomly in a 
1:1:1 ratio to 1 of the following interventions to self-administer prior to 
moderate-to-high intensity aerobic exercise sessions lasting at least 30 
minutes: 
1. A 50% reduction in basal rate insulin 5 minutes before exercise + pre-
exercise injection of placebo (blinded) 
2. A 50% reduction in basal rate insulin 5 minutes before exercise + pre-
exercise injection of Glucagon RTU (blinded) 
3. No reduction in basal rate insulin + pre-exercise injection of 
Glucagon RTU (open-label) 
Objectives 
Primary Objective: 
To evaluate if the subcutaneous (SC) administration of Glucagon RTU 
(Glucagon Injection) just before exercise, with or without a 50% reduction in 
basal rate insulin, compared to a 50% basal rate insulin reduction alone, 
prevents the occurrence of hypoglycemia (ie, blood glucose ≤70 mg/dL; 
3.89 mmol/L) measured by blood glucose meter (BGM) during and after 
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moderate-to-high intensity aerobic exercise by adult subjects with T1D in an 
outpatient setting. 
Secondary Objectives: 
1. To evaluate how Glucagon RTU (Glucagon Injection) contributes 
to prevention of hypoglycemia during exercise and post-exercise 
recovery. 
2. To evaluate the effect of Glucagon RTU (Glucagon Injection) on 
insulin utilization during 12 weeks of out-patient exercise. 
3. To evaluate the effect of Glucagon RTU (Glucagon Injection) on 
patient-reported outcomes (PROs) of: Barriers to Physical 
Activity Diabetes (Type 1) (BAPAD-1), Hypoglycemia Fear 
Survey (HFS) and Hypoglycemia Confidence Scale (HCS) after 
12 weeks of outpatient exercise. 
Endpoints 
Primary Endpoint: 
Incidence of hypoglycemia (ie, blood glucose ≤70 mg/dL; 3.89 mmol/L) 
associated with an exercise session across 12 weeks of outpatient treatment as 
measured by blood glucose measurements (BGM). 
Key Secondary Endpoints: 
1. Glucose levels below target range, measured by unblinded CGM 
(inpatient and outpatient), defined as both time (in minutes) and 
mean decremental area over the curve  
(AUC(0-300 min) in minutes*mg/dL) during exercise: 
 
Below range, as defined by interstitial glucose (IG) ≤ 70 mg/dL 
(3.89 mmol/L) 
 
Below range, as defined by IG between 54 to -
70 mg/dL (3 – 3.89 mmol/L) 
 
Below range, as defined by IG < 54 mg/dL (3 mmol/L) 
 
Proportional time (percentage time within 
hypoglycemia IG ≤ 70 mg/dL (3.89 mmol/L) and 
clinically significant hypoglycemia IG < 54 mg/dL 
(3  mmol/L)) 
2. Change from Baseline at the end of the Outpatient Phase in the 
following PROs: Barriers to Physical Activity in Diabetes (Type 1) 
(BAPAD-1), Hypoglycemia Fear Survey (HFS-II), Hypoglycemic 
Confidence Scale (HCS). 
Other Secondary Endpoints 
 Change from Baseline at Weeks 4, 8, and 12 in insulin utilization 
as reported by the subject in the Outpatient Phase. 
Safety Endpoints 
Safety endpoints include the following: summaries of number of subjects 
(%) with adverse events, including serious adverse events; change from 
Baseline in vital signs and clinical laboratory test values; number of 
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abnormal and clinically significant 12-lead ECG results. All safety 
parameter results will be listed. 
Study Population 
The study will include 48 male and female subjects in North America with 
Type 1 diabetes (T1D) aged 18 to 65 years at Screening, who engage in regular, 
moderate-to-high-intensity aerobic exercise at least 30 minutes in duration, and 
who receive daily insulin therapy via SC infusion pump. Approximately 100 
subjects may be screened to obtain 48 randomized subjects. 
Phase 
2 
Description of 
Sites/Facilities 
Enrolling 
LMC Manna Research 
1929 Bayview Avenue, Suite 107 
Toronto, Ontario M4G 0A1  
Canada  
Principal 
Investigator 
 
Ronnie Aronson, MD, FRCPC, FACE 
Description of 
Study Intervention 
Glucagon RTU is a non-aqueous, injectable liquid formulation of glucagon. 
Glucagon RTU consists of synthetic glucagon peptide dissolved in a DMSO 
diluent, with trehalose and mannitol added as stabilizing excipients. Glucagon 
RTU is presented in a 2-mL glass vial (1 mL fill). The placebo consists of the 
matching Glucagon RTU vehicle without glucagon in the same vial 
presentation. Both products will be administered SC around the umbilicus 
using a staked-needle syringe. The dose is 30 µL per injection, which delivers 
150 µg of glucagon for the active formulation. 
Study Duration 
The estimated duration of the entire study is 8 months. 
Participant 
Duration 
Participant study duration is approximately 20 weeks (5 months). Subjects will 
participate in a 4-week Screening Period, a 2-week CRC Phase, 12-week 
Outpatient Phase, and a 2-week for the End of Study Visit. 
 
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2.2. 
Schema 
Figure 1: 
Schema of Study Design 
 
 
 
 
CRC 
Outpatient 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening 
Randomization 
Treatment A 
washout1 
 
Treatment B 
 
Treatment A 
 
 
 
Follow-up 
 
 
 
 
 
 
 
 
Treatment B 
 
 
 
Randomization 
Treatment B 
washout1 
Treatment A 
 
 
 
 
 
 
 
 
 
 
Treatment C 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day -28 to -3 
 
 
 
Day 13 
 
 
 
Day 3-29 
 
 
 
Day 4-1132 
 
 
 
14 days after last 
outpatient visit 
(after visit 10) 
 
 
1 Single dose cross-over treatment in a CRC setting will be separated by 2 to 28 days.  
2 Outpatient setting where patients are randomized to 1 of 3 parallel treatment arms. 
3 Randomization into1 of 3 Treatment Arms at the beginning of the study: 
Treatment A: Pump reduction of 50% in basal rate 5 minutes before exercise for the duration of exercise, plus pre-exercise placebo injection (30 μLvehicle) 
Treatment B: Pump reduction of 50% in basal rate 5 minutes before exercise for the duration of exercise, plus pre-exercise Glucagon RTU injection 
(30 μL active - 0.15 mg) 
Treatment C: No pump reduction for the duration of exercise, plus pre-exercise Glucagon RTU injection (30 μL active - 0.15 mg)
N=48 
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2.3. 
Schedule of Activities  
Table 1 
Schedule of Assessments and Procedures 
Assessment 
Visit 1 
Visit 2 
Visit 3o 
CRC 1 
Visit 4o 
CRC 2 
Visits 5 to 10 
Outpatient Phase 
Visit 11  
Follow-upf 
/ET 
 
Screening 
Day–28 to 
–3 
CGM 
Placement 
Day –2 to –1 
Treatment 
Period 1 
(Days 1a,b,c) 
Treatment 
Period 2 
Day 3 to 29d 
Treatment 
Period 3 
Day 4 to 113e 
Informed consent 
X 
 
 
 
 
 
Medical History/ 
Demographics 
X 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
Concomitant 
medications (including 
insulin pump data) 
X 
X 
X 
X 
X 
X 
Height, weight and 
physical examination 
X 
 
 
 
 
X 
12-lead ECG 
X 
 
 
 
 
X 
Vital signs 
X 
 
X 
X 
X 
X 
Urine pregnancy test 
X 
 
X 
X 
X 
X 
Urine drug screen 
X 
 
 
 
 
 
Hematology 
X 
 
 
 
 
X 
Clinical chemistry 
X 
 
 
 
 
X 
HbA1c 
X 
 
 
 
 
X 
Plasma Glucose 
X 
 
 
 
 
X 
C-peptide 
X 
 
 
 
 
X 
Immunogenicityg 
 
 
X 
 
X 
X 
CGM 
 
Xd 
Xh 
Xh 
Xh 
Xh 
Exercisei,o 
 
 
X 
X 
 
BGMk 
 
 
X 
Xj 
Xj 
Xj 
Study drug 
administration 
 
 
X 
Xl 
X 
 
Wearable Activity 
Monitors 
(Fitbit Ionic and Polar 
Beat H10) 
 
 
Xm 
Xm 
Xn 
Xn 
HBV, HCV, HIV 
Screen  
X 
 
 
 
 
 
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Assessment 
Visit 1 
Visit 2 
Visit 3o 
CRC 1 
Visit 4o 
CRC 2 
Visits 5 to 10 
Outpatient Phase 
Visit 11  
Follow-upf 
/ET 
 
Screening 
Day–28 to 
–3 
CGM 
Placement 
Day –2 to –1 
Treatment 
Period 1 
(Days 1a,b,c) 
Treatment 
Period 2 
Day 3 to 29d 
Treatment 
Period 3 
Day 4 to 113e 
Outpatient Study 
Training 
 
 
 
X 
 
 
Diaryi 
 
 
X 
X 
X 
X 
Glucose Tabs Log 
 
 
X 
X 
X 
X 
Randomization 
 
 
X 
 
 
 
8-Hour fast 
X 
 
X 
X 
 
X 
Venous blood glucose 
(YSI) 
 
 
X 
X 
 
 
BAPAD-1 
Questionnaire 
 
 
X 
 
 
X 
Draize Scale 
 
 
X 
X 
 
 
HFS 
 
 
X 
 
 
X 
Hypoglycemia 
Confidence Scale 
 
 
X 
 
 
X 
Injection Site 
Discomfort Description 
and Duration 
Questionnaire 
 
 
X 
X 
 
 
Adverse event review 
X 
X 
X 
X 
X 
X 
*Visits will occur every 2 weeks during the out-patient phase. The visit window is +/- 3 days for the outpatient visits. 
BAPAD-1 = Barriers to Physical Activity in Type 1 Diabetes Scale; BGM = blood glucose monitor;  CRC = Clinical 
Research Center; CGM = continuous glucose monitor; ECG = electrocardiogram;  HBV = hepatitis B virus; 
HCV = hepatitis C virus; HFS = Hypoglycemia Fear Survey; HIV = human immunodeficiency virus; YSI = Yellow 
Springs Instrument 
a. As long as the subject has 2 days of rest between each CRC visit. 
b. Subjects will be instructed not to exercise between Visit 2 and Visit 3. 
c. Questionnaires to be completed are Barriers to Physical Activity Diabetes (Type 1) (BAPAD-1), 
Hypoglycemia Fear Survey (HFS) and Hypoglycemia Confidence Scale (HCS). 
d. CGM will be placed approximately 24-48 hours prior to data collection at CRC Visit 2. 
e. Collection timepoints ± 2 minutes are: -15 minutes, 0 minutes (just before initiation of exercise), 
and at 15, 30, 45, 60 and 75 minutes after initiation of exercise. 
f. Follow-Up occurs 14 days after the last exercise period. 
g. An immunogenicity sample will be drawn before the first dose of investigational product, every four weeks (28 
days +/- 2 days) and at the End of Study visit. 
h. CGM data will be downloaded. 
i. During the CRC Phase of the study, subjects will perform moderate-to-high-intensity exercise of at least 45 
minutes duration, with each exercise session separated by at least 2 days  during the inpatient phase of the study.  
During the Outpatient Phase of the study, subjects will be asked to maintain a weekly exercise average of 2 to 3 
sessions weekly of at least 30 minutes. Exercise data will be downloaded from the wearable device. Data include 
heart rate, calories burned, daily steps, floors climbed, distance covered, active minutes.  
j. BGM Measurements will be performed at the following timepoints during CRC visits, ± 2 minutes: 
 
-15 minutes (both YSI and BGM) 
 
Time 0 (immediately before exercise) (both YSI & BGM)) 
 
15 minutes (YSI only) 
 
30 minutes (both YSI & BGM) 
 
45 minutes (both YSI & BGM, end of exercise) 
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 
60 minutes (YSI only) 
 
75 minutes (both YSI & BGM, thirty minutes after completion of exercise) 
k. BGM data will be downloaded at each patient visit. 
l. 
Investigational Product (IP) for first outpatient visit will be dispensed at the end of visit 4. 
m. Subject will wear both Fitbit Ionic and Polar Beat H10 heart rate sensor during this visit. 
n. Subject will wear only the Fitbit Ionic during these visits. 
o. 
Prior to beginning the exercise session, if the subject’s blood glucose is below 100 mg/dL the subject is allowed 
to take dextrose tabs (e.g., 2-4 tabs) to raise the blood glucose, and the blood glucose verified to be within 100-
180 mg/dL (5.56 – 10 mmol/L). The number of dextrose tabs and time administered are recorded. 
Prior to beginning the exercise session, if the blood glucose is >180 mg/dL after repeat test, then the investigator 
may treat with an intravenous (IV) bolus dose of regular insulin, per discretion, to bring the subject into the 
required blood glucose range. Before initiating study treatment, at least 40 minutes should have passed from the 
last dose of administered insulin and the subject’s glucose level should be within the range of 100 to 180 mg/dL. 
At discretion, the investigator may reschedule the visit to occur after a minimum wait of 24 hours. The visit should 
be re-scheduled so it occurs within the originally defined visit window. For example, a rescheduled Visit 3 
(CRC 1) should occur within 28 days of Visit 1 (Screening), while a rescheduled Visit 4 (CRC 2) should occur 
within 28 days of a completed Visit 3 (CRC 1).. 
 
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3. 
ABBREVIATIONS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and Definition of Terms 
Abbreviation/Specialist Term 
Definition 
AE 
adverse event 
ANOVA 
analysis of variance 
AUC 
area under the concentration versus time curve 
AUC∞ 
area under the concentration versus time curve from time 0 
extrapolated to infinity 
AUCt 
area under the concentration versus time curve from time 0 
to the last measurable concentration (time t) 
BGM 
blood glucose measurement 
BMI 
body mass index 
Cmax 
maximum observed concentration 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV% 
coefficient of variation expressed as a percentage 
DBP 
diastolic blood pressure 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
FDA 
United States Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HR 
Heart Rate 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
IM 
intramuscular(ly) 
IMP 
investigational medicinal product 
ITT 
Intent-to-treat 
LDL 
low-density lipoprotein 
LOQ 
limit of quantification 
LPLV 
last patient last visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
maximum tolerated dose 
NOAEL 
no observed adverse effect level 
OECD 
Organization for Economic Cooperation and Development 
OHRP 
Office for Human Research Protections 
QTc 
corrected QT interval 
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Abbreviation/Specialist Term 
Definition 
QTcF 
QT interval corrected for heart rate using Fridericia’s method 
RBC 
red blood cell 
REB 
Research Ethics Board 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
systolic blood pressure 
SC 
subcutaneous(ly) 
SD 
standard deviation 
SOP 
standard operating procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t½ 
elimination half-life 
TEAE 
treatment-emergent adverse event 
tmax 
time to maximum observed plasma concentration 
UP 
Unanticipated Problems 
WBC 
white blood cell 
WHO 
World Health Organization 
YSI 
Yellow Springs Instrument 
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4. 
INTRODUCTION 
4.1. 
Study Rationale 
Exercise is at the cornerstone of Type 1 diabetes (T1D) management [1]. However, blood glucose 
stability during exercise, and for 12-24 hours afterwards, remains a major challenge [2]. Fear of 
hypoglycemia deters many patients from engaging in aerobic exercise [3]. For those who choose to 
exercise on a regular basis, hypoglycemia is a common complaint that often requires breaks in 
exercise sessions, sports and competition, games and training [3]. To reduce the incidence of 
hypoglycemia during and immediately after exercise, patients are recommended to reduce their 
bolus dose at the meal preceding exercise by 25-75% [4], however, this approach frequently results 
in pre-exercise hyperglycemia, particularly if the exercise is performed 2 hours or more after the 
meal [2, 4, 5]. Even exercise in the fasting state in patients on continuous subcutaneous insulin 
infusion (CSII) promotes a drop in glycemia if basal insulin levels are not adjusted [5]. 
Post-exercise hypoglycemia is also very common in T1D, with roughly 50% of young patients 
developing the condition about 7-11 hours after the end of vigorous afternoon exercise [8]. 
Further, if insulin administration is used to correct post-exercise meal-related hyperglycemia (often 
called rebound hyperglycemia), severe post-exercise hypoglycemia may occur which may even 
result in death [9]. Patients can reduce the dose of meal time insulin administered with the dinner 
meal after late day exercise to reduce nocturnal hypoglycemia risk [10] or lower basal insulin 
delivery for 6 hours at bedtime [11] to help mitigate risk, but these strategies often result in 
hyperglycemia [10, 11]. Although extra carbohydrate ingestion not covered by insulin 
administration can help prevent hypoglycemia during and after exercise [12], excessive intake 
defeats the ability of the patient to have a negative caloric balance, thereby limiting the capacity 
for patients to control their body weight. 
Patients on insulin pump therapy have the flexibility to reduce basal insulin delivery in anticipation 
of exercise and in recovery to help guard against hypoglycemia. The International Society for 
Pediatric and Adolescent Diabetes guidelines recommend that basal insulin reductions should be 
done 60-90 minutes before the start of exercise so that circulating insulin levels are lowered by the 
start of the activity [13]. This task is somewhat cumbersome and unpredictable and is usually not 
performed correctly, even by the most educated and motivated patients. Glucose production by the 
liver during moderate intensity exercise is primarily facilitated by a rise in the glucagon to insulin 
ratio [14] and patients with T1D have a reduction in this ratio during exercise because of a relative 
peripheral hyperinsulinemia [14] and impaired glucagon secretion [15], it may be better to attempt 
to change this ratio by the administration of glucagon at the onset of exercise [16]. The recent 
development of a more stable form of soluble glucagon (eg, Glucagon RTU from Xeris 
Pharmaceuticals, Inc. [Xeris]) has given researchers and clinicians the possibility of using this 
product as a preventative strategy to combat exercise-associated hypoglycemia. 
 
4.2. 
Background 
In Protocol No. XSMP-201, a Phase 2a clinical trial, Glucagon RTU was evaluated in a 
dose-seeking study among 12 adults aged 18 to 50 years with T1D. The study was conducted in an 
inpatient clinical research center setting, and tested doses of 75, 150, and 300 µg. Subjects were 
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studied on 3 separate occasions using 2 independent injections of glucagon on each study day. All 
treatments were well tolerated, no SAEs were observed and AEs were generally mild in nature and 
consisted primarily of pain or a burning sensation at the injection site. Observations of edema and 
erythema were generally mild and transient. Nausea occurred at the high dose only, in one- third of 
the patients. 
Glucagon injections were made both after an overnight fast and several hours later, following an 
injection of insulin to mimic the amount they would have taken for a 30-g carbohydrate snack. The 
study results showed a clear dose response with an initial response observed after 15 to 20 minutes, 
and the peak time of response after 30 to 45 minutes, both after an overnight fast and following 
insulin to induce mild hypoglycemia. In all cases, subjects responded to the 150 and 300 µg doses 
with an increase of plasma glucose of 40 to 100 mg/dL following an overnight  fast, and a 
somewhat smaller increase of 40 to 60 mg/dL following insulin. The 75 µg dose resulted in a 
smaller rise in glucose (+30 mg/dL) in most subjects, but in no case did the glucose continue to 
decrease after SC glucagon administration even at that lowest dose. On the basis of these results, a 
dose of 150 micrograms was selected for a follow-up study for prevention of exercise-induced 
hypoglycemia. 
Protocol No. XSMP-203 was a single-blind, randomized 4-way crossover pilot study involving 
15 adult subjects with T1D, ages 18 to 64 years, using continuous subcutaneous insulin infusion 
(CSII) and wearing a continuous glucose monitor. At 5 minutes prior to 45-minute sessions of 
moderate aerobic exercise, subjects received a 150-µg dose of Glucagon RTU or performed one of 
3 alternate approaches for prevention of hypoglycemia: (1) consumed 20-gm glucose tablets, (2) 
implemented a 50% reduction in basal rate insulin, or (3) no intervention prior to exercise (ie, 
untreated control). 
During exercise, plasma glucose increased slightly with Glucagon RTU compared to a decrease 
with control and insulin reduction, and a greater increase with glucose tablets. Insulin levels were 
not different among sessions, while glucagon increased with Glucagon RTU. Hypoglycemia 
(≤70 mg/dL (3.89 mmol/L)) was experienced by 6 subjects in the control arm, 5 subjects in the 
insulin reduction arm, and no subjects using glucose tablets or Glucagon RTU. A total of 
5 subjects experienced hyperglycemia (≥250 mg/dL) with glucose tablets and 1 with Glucagon 
RTU. 
There were no SAEs reported in the study and no subjects discontinued prematurely. No 
participant reported nausea during exercise, but 2 participants reported nausea with symptoms of 
bloating post-exercise after receiving Glucagon RTU. 
4.3. 
Risk/Benefit Assessment 
4.3.1. 
Known Potential Risks 
One of the main complications of glycemic control with insulin is the emergence of hypoglycemia, 
and the absolute or relative excess of therapeutic insulin is the primary determinant of risk. 
Hypoglycemia in diabetes is defined as “all episodes of abnormally low plasma glucose 
concentration that expose the individual to potential harm” [5], and manifests clinically as 
diaphoresis, pallor, nausea, palpitations, tremor, anxiety, cognitive impairment, behavioral changes 
and psychomotor abnormalities, and loss of consciousness, seizure, and coma in severe 
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hypoglycemia. Recent reports have found that from 6 to 10% of deaths of patients with T1D are 
attributable to hypoglycemia [6]. The American Diabetes Association Workgroup recommends 
that patients with drug-treated diabetes (insulin secretagogues or insulin) become concerned about 
developing hypoglycemia at a plasma glucose concentration of ≤ 70 mg/dL (3.89 mmol/L) [17]. 
Therapy with insulin causes hypoglycemia during the course of established T1D 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 T1D treated with 
insulin for <5 years, and an incidence of 320 episodes per 100 patient-years in those with T1D 
treated for >15 years [18]. People living with Type 1 diabetes suffer an average of two 
symptomatic hypoglycemic events per week – and a severe, temporarily disabling event 
approximately once a year [19].  Insulin-using people with Type 2 diabetes typically have several 
hypoglycemic episodes in a given year, 1-2 of these being severe episodes. There are currently 
approximately 1.4 million people with Type 1 diabetes and 3.8 million insulin-using people with 
Type 2 diabetes in the US alone [20]. On average, the total insulin-using patient population 
experiences about 3 million severe hypoglycemic events per year. 
4.3.2. 
Known Potential Benefits 
In response to the unmet medical need for a simple and ready-to-use glucagon for episodes of 
hypoglycemia, Xeris is developing a glucagon product. The Glucagon RTU (Glucagon Injection) 
utilizes Xeris’ biocompatible, non-aqueous peptide/protein reformulation technology. This 
technology has allowed Xeris to create a concentrated, low volume, stable glucagon formulation, 
pre-mixed in a ready-to-use vial for administration by a single use syringe, and ultimately will 
allow development of a multi-dose pen. This creates a product with a number of advantages for the 
treatment of hypoglycemia: 
 Ready-to-use treatment with no reconstitution required, 
 Precise dosing to avoid overtreatment of low blood sugar, 
 Rapid dosing due to room-temperature liquid stability, and 
 Enhanced portability and availability in a multi-use format. 
Current and future studies are aimed at evaluating the safety and efficacy of Glucagon RTU 
(Glucagon Injection) to provide patients with a better option for treatment and prevention of non- 
severe hypoglycemia. 
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5. 
OBJECTIVES AND ENDPOINTS 
5.1. 
Objectives 
5.1.1. 
Primary Objective 
To evaluate whether the SC administration of Glucagon RTU (Glucagon Injection) just before 
exercise, with or without a 50% reduction in basal rate insulin, compared to a 50% basal rate 
insulin reduction alone, prevents the occurrence of hypoglycemia (ie, blood glucose ≤70 mg/dL; 
3.89 mmol/L) measured by blood glucose meter (BGM) during and after moderate-to-high 
intensity aerobic exercise by adult subjects with T1D in an outpatient setting. 
5.1.2. 
Secondary Objectives 
 To evaluate how Glucagon RTU (Glucagon Injection) contributes to prevention of 
hypoglycemia during exercise and post- exercise recovery 
 To evaluate the effect of Glucagon RTU (Glucagon Injection) on insulin utilization 
during exercise. 
 To evaluate the effect of Glucagon RTU (Glucagon Injection) on PROs BAPAD-1, 
HFS-II, and HCS after 12 weeks of outpatient exercise 
5.1.3. 
Exploratory Objectives 
 To evaluate the glycemic time in range associated with exercise sessions and 
post-exercise 
 To evaluate the impact of Glucagon RTU (Glucagon Injection) on the quantity of 
glucose tabs used over time during exercise sessions  
 To evaluate weight loss or weight maintenance over time 
 To examine food intake both before and after exercise 
 To examine the effects of exercise and Glucagon RTU on overnight hypoglycemia 
following episodes of exercise 
 To evaluate the effects of exercise and Glucagon RTU use upon changes in 
hemoglobin A1c 
 To evaluate the intensity and duration of the frequent exercise sessions 
 To evaluate overall frequency of aerobic exercise over the study period 
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 To evaluate effects on exercise duration and intensity as well as daily activity metrics 
5.2. 
Endpoints 
5.2.1. 
Primary Endpoint 
The primary endpoint is the incidence of hypoglycemia (ie,, blood glucose ≤70 mg/dL; 3.89 
mmol/L) associated with an exercise session across 12 weeks of outpatient treatment as 
measured by a blood glucose meter (BGM). 
5.2.2. 
Key Secondary Endpoints 
 Glucose levels below target range, measured by unblinded CGM (inpatient and 
outpatient), defined as both time (in minutes) and mean decremental area over the 
curve (AUC(0-300 min) in minutes*mg/dL) during exercise: 
 • 
Below range, as defined by interstitial glucose (IG) ≤ 70 mg/dL (≤3.89 
mmol/L) 
 • 
Below range, as defined by IG between 54 to 70 mg/dL (3 – 3.89 mmol/L) 
 • 
Below range, as defined by IG < 54 mg/dL (<3 mmol/L) 
 • 
Proportional time (percentage time within hypoglycemia IG ≤ 70 mg/dL 
(3.89 mmol/L) and clinically significant hypoglycemia IG < 54 mg/dL (3 3  
mmol/L)) 
 Insulin utilization as reported by the subject at Baseline, Weeks 4, 8, and 12 in the 
Outpatient Phase. 
 Change from Baseline to the end of the Outpatient Phase in PROs: Barriers to 
Physical Activity in Diabetes (Type 1) (BAPAD-1), Hypoglycemia Fear Survey 
(HFS-II), and Hypoglycemic Confidence Scale (HCS),  
5.2.3. 
Other Secondary Endpoints 
 Change from Baseline in insulin utilization as reported by the subject at Weeks 4, 8, 
and 12 in the Outpatient Phase. 
 Exploratory EndpointsMean time and mean proportional time (%) within range, as 
defined by plasma glucose between 70 and 180 mg/dL (3.89 to 10 mmol/L) (CGM, 0 
to 300 minutes with exercise) 
 The time, proportional time (percentage), and mean incremental area under the curve 
(AUC) during which plasma glucose >180 mg/dL (10 mmol/L), and  (AUC(0- 300 min) 
in minutes*mg/dL) during exercise. 
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 The time, proportional time (percentage), and mean incremental area under the curve 
(AUC) during which plasma glucose >250 mg/dL (AUC(0- 5 hours) in 
minutes*mg/dL) during exercise. 
 Incidence of overnight hypoglycemia as measured by CGM. 
 Compare the glucose tablet utilization during exercise, across the 3 treatment arms. 
 Compare food (carbohydrate) intake pre/post exercise across the 3 treatment arms. 
 Compare the number of exercise sessions performed across the 3 treatment arms. 
 Compare the number of minutes of exercise performed per week. 
 Compare caloric expenditure during exercise, across 3 treatment arms. 
 The change from Baseline in body weight will be measured and analyzed across the 3 
treatment arms. 
 Compare the number of steps taken and the  distance achieved during exercise 
sessions across 3 treatments.. 
 The following assessments during exercise sessions will be captured from the 
wearable activity monitor: heart rate, daily steps, calories burned, distance covered, 
floors climbed, active minutes. 
 Change from baseline in HbA1c 
5.2.4. 
Safety Endpoints 
Safety endpoints include the following: summaries of number of subjects (%) with adverse 
events, including serious adverse events; change from Baseline in  vital signs and clinical 
laboratory test values; number of abnormal and clinically significant 12-lead ECG results. All 
safety parameter results will be listed.  
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6. 
STUDY DESIGN 
6.1. 
Overall Design 
This study is a randomized, placebo-controlled, double-blind, t2-treatment, 2-period, crossover 
comparison in a clinical research center (CRC) setting, followed by a randomized, placebo-
controlled, double-blinded, 2-arm parallel comparison with a 3rd open-label arm in an outpatient 
setting to evaluate the preliminary efficacy and safety of Glucagon RTU to prevent exercise-
induced hypoglycemia (EIH) in adults with Type 1 diabetes mellitus (T1D), who perform 
regular, moderate-to-high intensity aerobic exercise. 
The CRC Stage will involve 2 daytime clinical research center (CRC, or comparable setting) 
exercise sessions 2 to 28 days apart, in a morning exercise session, for the following treatment 
assignments: 
1. Insulin pump reduction (50% reduction in basal rate five minutes before exercise, for 
the duration of the exercise), and pre-exercise placebo injection (30 µL vehicle), or 
2. Insulin pump reduction (50% reduction in basal rate five minutes before exercise, for 
the duration of the exercise), and pre-exercise Glucagon RTU (30 µL active - 0.15 
mg). 
At investigator discretion, the insulin pump rate can be reduced overnight based on the subject’s 
medical history for the duration of the study. 
BGM assessments (Yellow Springs Instrument [YSI] readings) during CRC visits will be at -15, 
0, 30, 45, and 75 minutes from the start of exercise. Subjects will also wear unblinded CGM 
during both the CRC and Outpatient Stages of the study. 
The Outpatient Stage will be 12 weeks in duration, during which subjects will be randomized to 
1 of 3 parallel treatment arms, 2 of which are double-blinded, and 1 is open-label. 
Subjects will receive: 
1. Insulin pump reduction (50% reduction in basal rate five minutes before exercise, for 
the duration of the exercise), and pre-exercise placebo injection (30 µL vehicle), or 
2. Insulin Pump reduction (50% reduction in basal rate five minutes before exercise, for 
the duration of the exercise), and pre-exercise Glucagon RTU (30 µL active - 0.15 
mg), or 
3. Pre-exercise Glucagon RTU (30 µL active - 0.15 mg) without pump changes. 
Subjects will measure blood glucose using BGM at -15 and 0 minutes (ie, just before exercise) 
to establish a baseline, and after 30 minutes of exercise, 30 minutes post-exercise, and at the end 
of exercise (if greater than 30 minutes). Subjects will wear an unblinded CGM during the 
conduct of the study. 
6.2. 
Justification for Dose 
Mild to moderate hypoglycemia is common in individuals with T1D. Many individuals, 
particularly those under tight control, experience glucose levels ≤70 mg/dL (3.89 mmol/L) on a 
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daily or near-daily basis. When hypoglycemia is identified - either by measuring the glucose 
level or by symptoms, standard treatment consists of oral carbohydrate intake. This approach is 
generally successful in preventing more severe hypoglycemia and raising blood glucose 
concentrations. However, hyperglycemia often results and it can be difficult to quickly regain 
good control. In addition, the carbohydrate intake can make weight control challenging. Case 
reports have suggested that it may be more appealing to use small doses of glucagon to 
proactively raise the glucose level, avoiding the caloric value of the carbohydrate intake. 
Although not labeled for use in situations other than severe hypoglycemia, small doses of 
glucagon have been shown to be particularly useful when an individual with T1D is unable to 
eat (e.g., young children who refuse or individuals with gastroenteritis or other illnesses). 
Haymond et al., reported that administration of glucagon by the subcutaneous route at a dose of 
10 micrograms per year of age up to 150 micrograms was sufficient to increase the plasma 
glucose transiently (over 60 to 90 minutes) by 60 to 80 mg/dL and that repeated doses could be 
used for a subsequent mild hypoglycemic event without a worsening of nausea or vomiting [13]. 
This finding was confirmed in a report on the use of mini-dose glucagon in a pediatric practice 
in Australia, at a summer camp for children with diabetes, and in the inpatient setting [14, 15, 
16]. While it is known that some individuals with T1D have successfully used mini-dose 
glucagon, little is known about frequency of use and response to treatment in an outpatient 
setting. 
6.3. 
End of Study Definition 
The end of the study is defined as the last visit date for the last subject in the study. 
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7. 
STUDY POPULATION 
7.1. 
Inclusion Criteria 
1. Clinical diagnosis of presumed autoimmune type 1 diabetes, receiving daily insulin 
via continuous subcutaneous insulin infusion. 
2. Age 18 to < 65 years. 
3. Duration of type 1 diabetes ≥ 2 years. 
4. Random C-peptide < 0.6 ng/mL (< 198 pmol/L). 
5. Using insulin therapy by continuous subcutaneous insulin infusion pump for at least 
6 months. 
6. History of exercise-related hypoglycemia. 
7. Performs aerobic exercise regularly (2-3 times per week), and desires to exercise per 
ADA guidelines (150 minutes per week). Examples of aerobic exercise include 
powerwalking, hiking, running/jogging, cycling, swimming, cross country skiing, 
and aerobic fitness classes. 
8. Will abstain from the use of non-insulin diabetes therapies such as SGLT-2s, GLP-
1s, and metformin for the duration of the study. 
9. Subject must be willing to adhere to the protocol requirements for the duration of the 
study. 
10. Subject has provided informed consent as evidenced by a signed/dated informed 
consent form completed before any trial-related activities occur. 
7.2. 
Exclusion Criteria 
1. Frequently experience hyperglycemia with exercise, in the clinical judgement of the 
investigator. 
2. Pregnant and/ or Nursing: For female 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 
week after the last dose of study drug. Acceptable contraception includes birth 
control pill / patch / vaginal ring, Depo-Provera, Norplant, an IUD, the double 
barrier method (the woman uses a diaphragm and spermicide and the man uses a 
condom), or abstinence. Note, there are no requirements for male subjects. 
3. One or more severe hypoglycemic episodes in the past 12 months (as defined by an 
episode that required third party assistance for treatment). 
4. Uses inhaled insulin. 
5. HbA1c > 9.0% at Screening. 
6. Renal insufficiency (serum creatinine greater than 3 mg/dL (0.17 mmol/L)). 
7. Serum ALT or AST equal to or greater than 3 times the upper limit of normal. 
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8. Hepatic synthetic insufficiency as defined as a serum albumin of less than 3 mg/dL 
(0.17 mmol/L); or serum bilirubin greater than 2 mg/dL (0.11 mmol/L). 
9. Hematocrit of less than or equal to 30%. 
10. Mean of triplicate BP readings at Screening where SBP <90 or >150 mm Hg, or 
DBP <50 or >100 mm Hg. 
11. Clinically significant ECG abnormalities. 
12. Use of > 2.0 U/kg total insulin dose per day. 
13. Inadequate bilateral venous access in both arms. 
14. Congestive heart failure, NYHA class III or IV. 
15. Active malignancy within 5 years from Screening, except basal cell or squamous cell 
skin cancers. 
16. Major surgical operation within 90 days prior to screening, or planned surgical 
operation during the study. 
17. History of seizure disorders. 
18. Current bleeding disorder, treatment with warfarin or any anticoagulants, or  platelet 
count below 50,000. 
19. History of pheochromocytoma or disorder with increased risk of pheochromocytoma 
(MEN 2, neurofibromatosis, or Von Hippel-Lindau disease). 
20. History of insulinoma. 
21. History of allergies to glucagon or glucagon-like products, or any history of 
significant hypersensitivity to glucagon or any related products or to any of the 
excipients (DMSO, mannitol, & trehalose) in the investigational formulation. 
22. History of glycogen storage disease. 
23. Subject tests positive for HIV, HCV or active HBV infection (HBsAg+) at 
Screening. 
24. Any concurrent illness, other than diabetes, that is not controlled by a stable 
therapeutic regimen. 
25. Active substance or alcohol abuse, in the opinion of the investigator. Subjects 
reporting active marijuana use or testing positive for THC via rapid urine test will be 
allowed to participate in the study at the discretion of the investigator. 
26. Participation in other studies involving administration of an investigational 
therapeutic agent (drug or device) within 30 days or 5 half-lives, whichever is 
longer, before Screening for the current study and during participation in the current 
study. 
27. Any reason the investigator deems exclusionary. 
 
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7.3. 
Lifestyle Considerations 
Not applicable. 
 
7.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently randomized. A minimal set of screen failure information is required 
(demographics, inclusion/exclusion criteria, adverse event, protocol deviation, and date of screen 
failure) to ensure transparent reporting of screen failure participants, to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Screen failures may be rescreened after a 30-day waiting period, at 
the discretion of the Investigator. Approximately 100 subjects may be screened to obtain 48 
randomized subjects. 
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8. 
TREATMENT OF SUBJECTS 
8.1. 
Description of Study Drug 
A description of the study drug is presented in Table 2.  
Table 2: 
Investigational Product, Comparator, and Rescue Medication 
 
Investigational 
Product 
Comparator 
Rescue Medication 
Product Name: 
Glucagon RTU 
(Glucagon Injection 
Placebo 
Glucose Tablets 
Glucagon for 
Injection® 
Dosage Form: 
Injectable 
Injectable 
Tablets 
Injectable 
Unit Dose 
150 µg 
150 µg 
16g (4 tabs, 4 g/tab) 
1 mg (1 unit) 
Route of 
Administration 
Injection 
Injection 
Oral 
Injection 
Physical 
Description 
Supplied in 2.0 mL 
Crystal 
Zenith®cyclic olefin 
polymer vials with 
Flurotec® coated 
rubber stoppers 
Placebo to match 
Supplied 
commercially; 50 
4-gm glucose tablets 
per bottle 
The kit contains 1 
IU of glucagon, a 
diluent syringe 
containing 
12 mg/mL of 
glycerin, Water for 
Injection, and 
hydrochloric acid 
Manufacturer 
Pyramid 
Laboratories Inc. 
Costa Mesa, CA, 
USA 
Pyramid 
Laboratories, Inc. 
Costa Mesa, CA, 
USA 
Dex4 Glucose 
Tablets by AMG 
Medical, Montreal, 
QC, Canada 
Eli Lilly, 
Indianapolis, IN, 
USA 
 
8.2. 
Storage 
Glucagon RTU (Glucagon Injection) should be stored at controlled room temperature 20° to 
25°C (68° to 77°F). 
Outpatient storage information will be provided in the Instructions for Use (i.e.,  Investigation 
Product Instruction Manual). 
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8.3. 
Study Drug Administration 
The 30-unit (300 μL) Covidien Monoject syringe (29 G × ½ ” needle) will be used with the 
Glucagon RTU (Glucagon Injection) formulation and matching placebo. The study drug dosage 
is 30µL (150 µg of glucagon or matching volume of vehicle). 
Each dose will be from a new, single-use vial of Glucagon RTU (Glucagon Injection). 
Prior to beginning the exercise session, if the subject’s blood glucose is below 100 mg/dL the 
subject is allowed to take dextrose tabs (e.g., 2-4 tabs) per discretion, to bring the subject into the 
required blood glucose range. Before initiating study treatment, at least 30 minutes should have 
passed from the last dose of administered dextrose tabs and the subject’s glucose level should be 
within the range of 100 to 180 mg/dL 
Prior to beginning the exercise session, if the blood glucose is >180 mg/dL after repeat test, then 
the investigator may treat with an intravenous (IV) bolus dose of regular insulin, per discretion, 
to bring the subject into the required blood glucose range. Before initiating study treatment, at 
least 40 minutes should have passed from the last dose of administered insulin and the subject’s 
glucose level should be within the range of 100 to 180 mg/dL. 
At discretion, the investigator may reschedule the visit to occur after a minimum wait of 
24 hours. The visit should be re-scheduled so it occurs within the originally defined visit 
window. For example, a rescheduled Visit 3 (CRC 1) should occur within 28 days of Visit 1 
(Screening), while a rescheduled Visit 4 (CRC 2) should occur within 28 days of a completed 
Visit 3 (CRC 1). 
8.4. 
Treatment Compliance 
Treatment compliance measures both the exercise performed and the study drug administered. 
During the CRC Phase of the study, subjects will perform moderate-to-high-intensity exercise of 
at least 45 minutes duration, with each exercise session separated by at least 2 days  during the 
inpatient phase of the study. 
During the Outpatient Phase of the study, subjects will be asked to maintain a weekly exercise 
average of 2 to 3 sessions weekly of at least 30 minutes.  
Subjects should self-administer assigned study drug for all qualified exercise sessions. 
Adherence to study drug will be evaluated via the study diary. 
8.5. 
Measures to Minimize Bias: Randomization and Blinding 
The study statistician will create the randomization schedule for the study. The randomization 
assignment for the participant will be conducted once at the time of enrollment with confirmation 
of subject eligibility. The CRC assignments will be by random assignment during the first 
session to either Glucagon RTU or placebo. At the second session , the participant will be 
crossed over to the other treatment assignment. At the completion of the CRC visits, the subject 
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will then have the treatment assignment applied for the parallel group study. The randomization 
schedule methodology for the Outpatient setting is by permuted random block to 1 of 3 treatment 
assignments in a 1:1:1 ratio. 
1. A 50% reduction in basal insulin rate 5 minutes before exercise + pre-exercise injection 
of placebo (blinded) 
2. A 50% reduction in basal insulin rate 5 minutes before exercise + pre-exercise injection 
of Glucagon RTU (blinded) 
3. No reduction in basal insulin rate + pre-exercise injection of Glucagon RTU (open label) 
The cross-over study is blinded to the extent possible since all participants will receive both 
Glucagon RTU and placebo. All staff, participants and study team members will know that the 
participant will receive both study treatments during the CRC sessions. During the outpatient 
study, two of the treatments will be blinded to the study staff, participants and Sponsor. One arm 
of the study will be open-label. It is imperative for the study staff to remain blinded to treatment 
assignment prior to randomization and during the study treatment periods as not to bias the 
outcome. 
Glucagon RTU and placebo will be prepared and administered so that each will be 
indistinguishable from the other. 
8.6. 
Unblinding 
Blinding of study treatment is critical to the integrity of this clinical trial. It is expected that in 
the vast majority of cases, AEs can be properly managed without the need for unblinding. 
However, in the event of a medical emergency in which knowledge of an individual subject’s 
treatment assignment is considered critical to the subject’s management, the treating physician 
may unblind the treatment assignment.  The investigator should contact the responsible Medical 
Director to discuss the subject and circumstances requiring the unblinding. The blind will be 
broken only for the specific subject under discussion. The Sponsor  will remain blinded to the 
treatment assignment. Every effort will be made to restrict knowledge of the treatment 
assignment to the investigator only. 
8.7. 
Concomitant Therapy 
All therapies (prescriptions and over-the-counter medications) other than the study drugs 
administered from informed consent until the last study visit must be recorded in the source 
documents and in the concomitant therapy section of the eCRF (name of the drug, dosage, route 
and dates of administration). 
The Sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered. 
The use of oral, transdermal, implantable, and injectable hormonal contraceptives is to be 
recorded in the source documents and in the concomitant therapy section of the eCRF. 
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8.7.1. 
Rescue Medicine 
8.7.1.1. 
Oral Glucose Tablets 
Standard of care for patients with symptoms of hypoglycemia and confirmed (BGM) blood 
glucose ≤70 mg/dL (3.89 mmol/L) is to take 16g (4 tabs, 4 g/tab) of glucose tabs, or per standard 
of care, and repeat the 16-g carbohydrate serving every 15 minutes until blood glucose is 
>70 mg/dL (3.89 mmol/L). 
8.7.1.2. 
Glucose Emergency Kit 
Subjects should be trained to administer a glucagon emergency kit should the subject experience 
severe hypoglycemia that requires external assistance. 
 
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9. 
ASSESSMENTS 
9.1. 
Efficacy Assessments 
9.1.1. 
Wearable Fitness Tracker (Fitbit Ionic) 
At Visit 2, subjects will be fitted with a wearable fitness tracker. The Fitbit Ionic® is a wearable 
fitness tracker that is worn on the wrist. The Fitbit Ionic provides training workouts and monitors 
heart rate. The fitness tracker will be worn by each subject in this study to monitor the level of 
exercise intensity, and also to measure the 30-minute time periods at which subjects will measure 
their blood glucose. Data can be downloaded via Bluetooth to a central location. 
9.1.2. 
Polar Beat H10 Heart Rate Sensor 
The Polar Beat H10 Heart Rate Sensor will be provided to the subject at Visit 2 and is worn 
during Visit 3 and Visit 4 for accurate measurement of heart rate. It is not provided to the subject 
for use outside of the clinic. 
9.1.3. 
Continuous Glucose Monitoring 
A continuous glucose monitoring device (Dexcom® G5 Continuous Glucose Meter) will be 
placed on the subject and calibrated at Visit 2.  It will be used to collect interstitial glucose 
measurements on a continuous basis. 
9.1.4. 
Barriers to Physical Activity Diabetes (Type 1) Questionnaire 
The Barriers to Physical Activity in Diabetes (Type 1) (BAPAD-1) is a 12-question instrument to 
assess the likelihood that a subject with T1D will exercise within the next 6 months; it is 
completed by the subject for the first time at Visit 3 and is also completed at the Follow-up Visit. 
Subjects are asked the question: “Indicate the likelihood that each of these items would keep you 
from practicing regular physical activity during the next 6 months?” and they are to respond by 
rating the 12 responses with a “1” (unlikely) to “7” (extremely likely). The higher the score, the 
less likely the subject is to engage in exercise. 
9.1.5. 
Hypoglycemia Fear Survey II 
The Hypoglycemia Fear Survey II (HFS-II) is a 33-item questionnaire, with 15 questions 
addressing actions the subject may take to avoid low blood glucose, and the remaining questions 
addressing fears the subject may have about low blood glucose. Responses range from a score of 
0 (never) to 4 (almost always).  The higher the score, the greater the subject’s fear of 
hypoglycemia. The HFS-II is completed at Visit 3 and the Follow-up Visit. 
9.1.6. 
Hypoglycemia Confidence Scale 
The Hypoglycemia Confidence  Scale (HCS) is a 9-item questionnaire that assesses the subject’s 
confidence about safety regarding hypoglycemia. The questionnaire has 4 responses possible for 
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each question, ranging from “not confident at all” to “very confident.  The HCS is completed at 
Visit 3 and the Follow-up Visit. 
9.1.7. 
Modified Draize Scale 
The Modified Draize Scale is used by the study site personnel to assess the degree of erythema 
and edema cause by the study drug injection. Each term (erythema and edema) has 5 choices of 
grades of the reaction, from “slight erythema/edema” to “severe erythema/edema”. The study site 
personnel is to mark the choice that best represents the degree of erythema/edema observed at 
the injection site. The Modified Draize Scale is completed at Visits 3 and 4.  
9.1.8. 
Injection Site Discomfort Description and Duration Questionnaire 
The Injection Site Discomfort Description and Duration Questionnaire is a 3-question instrument 
that assesses a subject’s level of discomfort and its duration post-injection. There are 5 responses 
for each of the the first 2 questions, which address the level of discomfort and the duration of the 
discomfort, respectively, for each injection . For the 3rd question, the total time for the duration 
of discomfort is to be provided. The Injection Site Discomfort and Duration Questionnaire is to 
be completed at Visits 3 and 4. 
9.2. 
Pharmacokinetic/Pharmacodynamic Assessments 
9.2.1. 
Immunogenicity Testing 
An immunogenicity sample will be drawn before the first dose of investigational product, every 
4 weeks (28 days +/- 2 days) and at the End of Study visit (Visit 3, Visit 5, Visit 7, Visit 9, and 
Visit 11 [Follow-up Visit]). 
9.3. 
Safety Assessments 
Safety assessments include the following: collection of adverse events, including serious adverse 
events, measurement of vital signs, clinical laboratory tests, 12-lead ECGs, and physical 
examinations, including measurement of weight. 
9.3.1. 
Adverse Events and Serious Adverse Events 
9.3.1.1. 
Definition of Adverse Events (AE) 
An AE is any untoward medical occurrence in a clinical study subject administered a medicinal 
(investigational or non-investigational) product. An AE does not necessarily have a causal 
relationship with the treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational or non-investigational) product, whether or not related to that 
medicinal (investigational or non-investigational) product. 
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This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal result of diagnostic procedures, including clinical laboratory test 
abnormalities. 
All observed or volunteered AEs regardless of treatment group or suspected causal relationship 
to the study treatment will be reported with the following exception. Hypoglycemia will not be 
considered an AE in this study unless the event is severe hypoglycemia with a BG reading ≤ 54 
mg/dL (3 mmol/L), requires third-party assistance, or if the event meets one of the definitions of 
an SAE. 
 
9.3.1.2. 
Definition of Serious Adverse Events (SAE) 
An SAE is any untoward medical occurrence that at any dose meets any of the following 
conditions: 
 results in death. 
 is life-threatening, i.e., the subject was at risk of death at the time of the event (e.g., 
ventricular fibrillation and anaphylaxis). The term does not refer to an event which 
hypothetically might have caused death if it were more severe. 
 requires inpatient hospitalization or prolongation of existing inpatient 
hospitalization. Hospitalization refers to an overnight admission into hospital for 
the purpose of investigating and/or treating the AE. Hospitalization for an elective 
procedure, or routinely scheduled treatment for a pre-existing condition that has 
not worsened, is not an SAE. 
 results in persistent or significant disability/incapacity, i.e., causing substantial 
disruption of the subject’s ability to conduct normal life. 
 is a congenital anomaly/birth defect. 
 is medically significant, i.e., may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the subject’s health or may require 
intervention to prevent one of the above outcomes. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias, or convulsions that do not result in hospitalization or 
development of drug dependency or drug abuse. 
 
9.3.1.3. 
Classification of an Adverse Event 
9.3.1.3.1. Severity of Event 
The Investigator or delegate 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 3 . 
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Table 3 
AE Severity Assessment 
Mild 
Does not interfere with subject’s usual function 
Moderate 
Interferes to some extent (< 50%) with subject’s usual function 
Severe 
Interferes significantly (≥ 50%) with subject’s usual function 
The terms “serious” and “severe” are not synonymous. The term “severe” is often used to 
describe the intensity (severity) of a specific event. The event itself, however, may be of 
relatively minor medical significance. This is not the same as “serious,” which is based on 
subject/event outcome or action criteria. Accordingly, a severe event is not necessarily a serious 
event. 
9.3.1.3.2. Relationship to Study Intervention 
The Investigator will use the following question when assessing causality between an AE and the 
study drug, where an affirmative answer designates the event as a suspected adverse reaction: “Is 
there a reasonable possibility that the drug caused the event?” A ‘‘reasonable possibility’’ means 
that there is evidence to suggest a causal relationship between the drug and the AE. The 
Investigator’s assessment of causality must be provided for all AEs and recorded in the source 
documentation. The degree of certainty about causality will be graded using the categories 
below: 
 Related – The AE is known to occur with the study intervention, there is a 
reasonable possibility that the study intervention caused the AE, or there is a 
temporal relationship between the study intervention and event. Reasonable 
possibility means that there is evidence to suggest a causal relationship between 
the study intervention and the AE. 
 Not Related – There is not a reasonable possibility that the administration of the 
study intervention caused the event, there is no temporal relationship between the 
study intervention and event onset, or an alternate etiology has been established. 
9.3.1.3.3. Expectedness 
Expected adverse reactions are AEs that are common and known to occur for the study agent 
being studied. Expectedness refers to the awareness of AEs previously observed. The Sponsor 
will be responsible for determining whether an AE is expected or unexpected. An AE will be 
considered unexpected if the nature, severity, or frequency of the event is not consistent with the 
risk information previously described for the study agent. 
9.3.1.4. 
Time Period and Frequency for Event Assessment and Follow-up 
Adverse events will be assessed starting from time of consent through up to 14-21 days after the 
last dose of study drug (Follow-up Visit). The timing of event assessments is detailed in the 
Schedule of Activities (Table 1bookmark7). 
All adverse events will be followed until resolution or the subject is medically stable. 
 
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9.3.1.5. 
Adverse Event Reporting 
The Investigator or delegate 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. All AEs (including SAEs) occurring 
during the clinical investigation must be documented in the source documents and on the AE 
forms of the eCRF. 
Whenever possible, diagnoses should be given when signs and symptoms are due to a common 
etiology (e.g., cough, runny nose, sneezing, sore throat, and head congestion should be reported 
as “upper respiratory infection”). Investigators must record their opinion concerning the 
relationship of the AE to the study drugs in the source documents and on the AE forms of the 
eCRF. All measures required for AE management must be recorded in the source documents and 
reported according to Sponsor’s instructions. 
9.3.1.6. 
Serious Adverse Event Reporting 
All SAEs independent of the circumstances or suspected cause must be reported on a Serious 
Adverse Event Form by the Principal Investigator to the Sponsor within 24 hours of their 
knowledge of the event, preferably by fax (1-312-276-4497) or by e-mail 
(kjunaidi@xerispharma.com or Safety-XSMP204@xerispharma.com). 
The SAE form should include a clearly written narrative describing signs, symptoms, and 
treatment of the event, diagnostic procedures, as well as any relevant laboratory data and any 
sequelae, in order to allow a complete medical assessment of the case and independent 
determination of the possible causality. 
Follow-up and outcomes should be reported for all subjects who experience an SAE. 
It is critical that the information provided on the Serious Adverse Event Form matches the 
information recorded in the source documents and on the (e)CRF for the same event. 
Copies of additional laboratory tests, consultation reports, postmortem reports, hospital case 
reports, autopsy reports, and other documents should be sent when requested and applicable. 
Follow-up reports relative to the subject’s subsequent course must be submitted to the Sponsor 
until the event has subsided or, in case of permanent impairment, until the condition stabilizes. 
 
9.3.2. 
Events of Special Interest 
Not applicable. 
 
9.3.3. 
Reporting of Pregnancy 
All initial reports of pregnancy in subjects must be reported to the Sponsor by the Investigator  or 
delegate within 24 hours of his/her knowledge of the event using a Pregnancy Form. Any subject 
who becomes pregnant during the study must be promptly withdrawn from the study. 
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9.4. 
Unanticipated Problems 
9.4.1. 
Definition of Unanticipated Problems (UP) 
The Office for Human Research Protections (OHRP) considers unanticipated problems (UP) 
involving risks to participants or others to include, in general, any incident, experience, or 
outcome that meets all of the following criteria: 
 Unexpected in terms of nature, severity, or frequency given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB- 
approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; 
 Related or possibly related to participation in the research (“possibly related” 
means there is a reasonable possibility that the incident, experience, or outcome 
may have been caused by the procedures involved in the research); and 
 Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
This study will use the OHRP definition of UP. 
 
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10. 
STUDY PROCEDURES 
A schedule of activities for this study is provided below in Section Section 10.1-Section 10.3 
bookmark27(screening and CRC Stage) and Section 10.4 (Outpatient Stage). 
10.1. 
Visit 1 – Screening (Day -28 to -3) 
Prior to completing any screening activities, the investigator or study team member will obtain 
informed consent from each subject. 
A Screening visit must be completed at least 3 days (to allow for receipt of blood test results), and 
no more than 28 days prior to the anticipated date of the first treatment visit (Day 1). The following 
evaluations will be completed during the screening visit: 
1. Assessment of inclusion/exclusion criteria by a study investigator, including a 
review of the subject’s medical history, and demographics. 
2. Review of concomitant medications. 
3. Physical exam, including measurement of height and weight (no shoes, lightly 
clothed), but excluding genital/pelvic exams. 
4. 12-lead ECG after subject has completed a minimum 5-minute supine rest. 
5. Vital signs measurements, including measurements of temperature, respiration rate, 
heart rate, and BP, after a 5-minute seated rest. 
6. Urine pregnancy test for women of childbearing potential and discussion about study 
requirements regarding contraception. 
7. Sample collection for urinary drug screen. 
8. Collection of venous blood for complete blood count (without differential), serum 
chemistry, and screening for HIV, HBV, and HCV. 
9. A fasting blood sample (minimum 8 hours) will be taken for measurement of plasma 
glucose, HbA1c, and C-peptide. 
10. Assessment of baseline AEs. 
Once laboratory results are obtained and a final determination of eligibility is made, subjects 
will be contacted to schedule the CGM Placement Visit. 
10.2. 
Visit 2 – CGM Placement (Day -2 to -1) 
1. Concomitant Medication Review. 
2. CGM Placement. 
a. The CGM will be placed 24 to 48 hours prior to data collection on CRC 
visit 3 and Visit 4 and the subject will be trained on calibration 
procedures. 
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3. A wearable activity monitor, Fitbit Ionic, will be provided to the subject for 
use during the study. The wearable activity monitor will be set up and training 
will be provided to the subject. 
4. Adverse Event Review. 
10.3. 
CRC Phase 
10.3.1. 
Visit 3 – Treatment 1 (Day 1) / Visit 4 Treatment 2 (Day 3-29) Clinic Arrival 
1. Subjects will arrive to clinic in the morning, after an overnight fast of at least 8 
hours. 
 Subjects may proceed with exercise if BG is 100-180 mg/dL (5.56 – 10 
mmol/L), as measured by the blood glucose meter.  
• 
If the subject’s blood glucose is below 100 mg/dL the subject is 
allowed to take dextrose tabs (e.g., 2-4 tabs) per discretion, to bring 
the subject into the required blood glucose range. Before initiating 
study treatment, at least 30 minutes should have passed from the last 
dose of administered dextrose tabs and the subject's glucose level 
should be within the range of 100 to 180 mg/dL 
• 
 Prior to beginning the exercise session, if the blood glucose is 
>180 mg/dL after repeat test, then the investigator may treat with an 
intravenous (IV) bolus dose of regular insulin, per discretion, to bring 
the subject into the required blood glucose range. Before initiating 
study treatment, at least 40 minutes should have passed from the last 
dose of administered insulin and the subject’s glucose level should be 
within the range of 100 to 180 mg/dL 
• 
If the subject’s blood glucose cannot be optimized to 80 to 150 mg/dL 
within 2 hours, then the visit should be rescheduled after a minimum 
24 hour wait, per investigator’s discretion. 
• 
At discretion, the investigator may reschedule the visit to occur after a 
minimum wait of 24 hours. The visit should be re-scheduled so it 
occurs within the originally defined visit window. For example, a 
rescheduled Visit 3 (CRC 1) should occur within 28 days of Visit 1 
(Screening), while a rescheduled Visit 4 (CRC 2) should occur within 
28 days of a completed Visit 3 (CRC 1). 
2. It will be confirmed that the CGM placed at Visit 2 is active and that the subject has 
followed calibration instructions. 
3. Concomitant medications will be assessed. 
4. Vital signs measurements, including measurements of temperature, respiration rate, 
heart rate, and BP, after a 5-minute seated rest. 
5. Urine pregnancy test for women of childbearing potential. 
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6. Blood sample for immunogenicity testing (Only performed at Visit 3). 
7. The wearable activity monitor will be worn by the subject during each exercise 
session. 
 Subject will wear both the Fitbit® Ionic and Polar Beat H10 heart rate sensor 
provided by the site during these visits. 
8. Questionnaires/Forms will be filled out: Barriers to Physical Activity Diabetes (Type 
1) (BAPAD-1), Hypoglycemia Fear Survey (HFS) and Hypoglycemia Confidence 
Scale (HCS). These questionnaires are only administered at Visit 3/ Treatment 1. 
9. The subject will be randomized for this study. (This only occurs at Visit 3/ 
Treatment 1). 
10. Starting at 5 minutes prior to exercise: 
a. The subject will reduce the basal infusion rate of insulin by 50%. 
b. Study Medication will be administered based upon randomization assignment. 
11. Subject will then complete an exercise session (See Appendix 1bookmark99). 
a. Heart rate will be monitored via the Fitbit Ionic device and Polar Beat H10 heart 
rate sensor during these exercise sessions. 
b. During the exercise session, the subject is to drink carbohydrate free liquids only 
(e.g., Powerade Zero or comparable product) and will be provided with 
glucose/dextrose tabs to use as needed. 
c. Per ADA guidelines, if a subject’s glucose falls to ≤ 70 mg/dL (3.89 mmol/L) 
during any exercise session, then the exercise session should be stopped, the 
subject should rest, and glucose tabs should be taken every 15 minutes until the 
hypoglycemia is corrected and euglycemia (confirmed by BGM) is maintained. 
Subjects will be provided with a supply of glucose tabs and instructed to use 
these rather than other sources of carbohydrate to treat hypoglycemia. 
12. Following completion of exercise: 
a. Basal rate insulin will be returned to the pre-exercise infusion rate. 
b. PI or delegate will administer Draize Scales for erythema and edema and the 
Injection Site Discomfort Description and Duration Questionnaire. 
13. Before, during and after exercise, venous blood samples (YSI) for glucose 
measurements will take place at the following time points. Subjects will perform a 
blood glucose measurement using a BGM as indicated below with a window of ± 2 
minutes: 
a. -15 minutes (both YSI and BGM) 
b. Time 0 (immediately before exercise) (both) 
c. 15 minutes (YSI only) 
d. 30 minutes (both) 
e. 45 minutes (both, end of exercise) 
f. 60 minutes (YSI only) 
g. 75 minutes (both, thirty minutes after completion of exercise) 
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14. AE assessment. 
10.4. 
Visit 5 Through 10 – Outpatient Stage 
10.4.1. 
Visits 5 Through 10 – Treatment Day 4-113 
During the outpatient stage, subjects will return for clinic visits every two weeks. Activities to be 
performed at these visits are outlined in the Schedule of Activities (Table 1bookmark7). 
In the outpatient setting, subjects will perform moderate to high intensity aerobic exercise with a 
target of at least 2-3 qualifying sessions per week. To be eligible for study drug dosing, the 
planned aerobic exercise will be 30-75 minutes in duration. Additionally, the subject’s BGM 
must range between 100-180 mg/dL (5.56 – 10 mmol/L) before the exercise session. Subjects 
must record their carbohydrate intake (eg, both dextrose tabs and carbohydrates from food) 
15 minutes before exercise, during the exercise session, and up to 5 hours post-exercise session. 
During the exercise session, the subject is to only drink carbohydrate free liquids (e.g., Powerade 
Zero or comparable product) and will be provided with glucose tabs to use as needed. The 
subject will take 5 BGM measurements with exercise: at -15 minutes and just before exercise to 
establish baseline value, at 30 minutes into the exercise session, at the end of the exercise 
session, and at 30 minutes after the exercise session. There is a ±2 minute window on all of these 
time points. 
Per ADA guidelines, if a subject’s glucose falls to ≤70 mg/dL (3.89 mmol/L) during any exercise 
session, then the exercise session should be stopped, and no more exercise should be completed 
that same day; the subject should rest, and glucose tabs should be taken every 15 minutes until 
the hypoglycemia is corrected and euglycemia (confirmed by BGM) is maintained. Subjects will 
be provided with a supply of glucose tabs and instructed to use these rather than other sources of 
carbohydrate to treat hypoglycemia. 
During the outpatient phase the subject will be provided with the following items for recording 
study data and will be provided with instructions for use and uploading data to the cloud if 
applicable. 
1. Blood Glucose Meter: Bayer® Contour Next One 
a. Used to collect blood glucose values during exercise sessions and to confirm blood 
glucose if a value ≤ 70 mg/dL (3.89 mmol/L) is indicated by CGM. 
2. Dexcom® G5 Continuous Glucose Meter 
a. Used to collect interstitial glucose measurements on a continuous basis. 
3. Fitbit® Ionic 
a. Use to collect exercise session metrics (heart rate) and daily activity metrics 
b. Subjects will maintain a food log in the Fitbit application 
4. Paper Diary 
a. Description of exercise type, start/stop time of exercise 
b. Glucose tab usage and emergency kit usage 
c. Time and volume of administration of Study Medication 
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10.4.2. 
Visit 11 – Follow-Up Visit (14-21 Days After Last Exercise Session)/Early 
Termination 
Subjects will be asked to return the clinic 14 - 21 days from the last exercise session for the 
following evaluations. The subject will be asked to return to the clinic for this same list of 
evaluations upon early termination from the study. 
1. Concomitant medication changes. 
2. Focused PE, including measurement of height and weight (no shoes, lightly clothed), but 
excluding genital/pelvic exams. 
3. 12-lead ECG after subject has completed a minimum of 5-minute supine rest. 
4. Vital signs measurements, including measurements of temperature, respiration rate, 
heart rate, and BP, after a 5-minute seated rest. 
5. Urine pregnancy test for women of childbearing potential. 
6. Collection of venous blood for complete blood count (without differential) and serum 
chemistry. 
A fasting blood sample (minimum 8 hours) will be taken for measurement of HbA1c. 
7. AE assessment. 
8. Questionnaires/Forms will be filled out: Barriers to Physical Activity Diabetes (Type 1) 
(BAPAD-1), Hypoglycemia Fear Survey (HFS) and Hypoglycemia Confidence Scale 
(HCS). 
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11. 
STUDY INTERVENTION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
11.1. 
Discontinuation of Study Intervention 
The Sponsor has the right to terminate the study at any time. In case of an early termination of 
the study for safety reasons, or temporary halt by the Sponsor, the REB should be notified by the 
Investigator within 15 calendar days and should be provided with a detailed written explanation 
for the termination/halt. 
An end-of-study declaration will be submitted to the regulatory authorities and REB after study 
termination (once all subjects have completed their last follow-up visit). To allow close-out 
procedures, this notification should be submitted within 90 days after the end of the study. 
 
11.2. 
Participant Discontinuation/Withdrawal from the Study 
Subjects have the right to withdraw from the study at any time for any reason, including personal 
reasons. A subject can withdraw without giving a reason. The Principal Investigator should 
however try to find out why a subject withdraws from the study and document the reason for 
withdrawal in the source documents and on the electronic Case Report Form (eCRF). 
Subjects may be withdrawn from the study in the event of: 
 A severe AE or serious AE (SAE); 
 Failure of the subject to comply with the protocol requirements or to 
cooperate with the Principal Investigator. 
Subjects must be withdrawn from the study in the event of: 
 Withdrawal of consent; 
 Difficulties in obtaining blood or other samples; 
 For safety reasons, in the Investigator’s opinion, it is in the best 
interest of the subject that he/she be withdrawn; 
 A positive pregnancy test (or if the subject is non-compliant with the 
contraception requirements; 
 Development of a medical condition that requires concomitant 
treatment with a prohibited therapy. 
The monitor and Sponsor should be informed: in case of subject withdrawal due to an SAE (for 
details on AE reporting), and the Sponsor should be notified within 24 hours. In case of 
withdrawal for other reasons; the Sponsor should be notified within 2 days from the event. 
Subjects who are withdrawn from the study prior to completion of the scheduled study 
procedures for any reason (AE, withdrawal of consent, etc.) should be invited to complete the 
assessments as indicated in the Schedule of Activities, Early Termination Visit (Table 1). In case 
of an AE, the appropriate follow-up will be conducted. 
 
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12. 
STATISTICAL CONSIDERATIONS 
12.1. 
General Approach 
Descriptive statistical methods will be used to summarize the data from this study, with 
hypothesis testing performed for the primary and other selected key efficacy endpoints. Unless 
stated otherwise, the term “descriptive statistics” refers to number of subjects (n), mean, median, 
SD, minimum, and maximum for continuous data and frequencies and percentages for 
categorical data. Subject disposition will be presented for all subjects for each stage (CRC and 
Outpatient). The number of subjects who completed the study and discontinued from the study 
will be provided. The reasons for early discontinuation also will be presented. 
Analyses will be performed for data collected during the CRC visits separately from the data 
collected during the parallel designed outpatient part of the study. A stand-alone Statistical 
Analysis Plan (SAP) will be developed to include complete details for all planned analyses. 
 
12.2. 
Sample Size Determination 
The primary endpoint of the study is the incidence of hypoglycemia (glucose ≤ 70 mg/dL (3.89 
mmol/L)) associated with an exercise session, which occurred within the 12 weeks outpatient 
follow-up, as measured by BGM. The null hypothesis is that there is no difference between the 
treatment groups in the mean incidence of exercise associated hypoglycemia, and the alternative 
is there is a difference between the treatment groups in terms of the mean incidence of exercise 
associated hypoglycemia. With an effect size estimate of 0.262 (variance of means 59, common 
standard deviation 15), 80% power and an alpha of 0.05,using a one way analysis of variance, 14 
subjects per treatment group in the Outpatient Stage is required. 
Accounting for 15% attrition, a total of 48 subjects will be randomized. 
 
12.3. 
Populations for Analyses 
The following analysis populations have been defined for the parallel group study analysis: 
 Intention to Treat (ITT): All randomized participants regardless of whether they 
received Study Drug. 
 Per Protocol (PP): ITT participants who completed a qualified exercise session, 
and who was dosed in the study window and did not meet any of the key 
exclusion criteria at screening. The definition of qualified exercise and key 
exclusion criteria will be specified in the Statistical Analysis Plan (SAP). 
 Safety: All randomized participants who received any amount of Study Drug. 
12.4. 
Statistical Analyses 
12.4.1. 
Efficacy Hypothesis 
The primary efficacy hypothesis test for the study is as follows: 
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Null Hypothesis: There is no difference between the treatment groups in the mean incidence of 
hypoglycemia (glucose ≤ 70 mg/dL (3.89 mmol/L)) associated with an exercise session 
occurring within the 12 weeks of out-patient treatment as measured by BGM. 
Alternative Hypothesis: There is a difference between treatment groups in the mean incidence of 
hypoglycemia (glucose ≤ 70 mg/dL (3.89 mmol/L)) associated with an exercise session 
occurring within the 12 weeks of out-patient treatment as measured by BGM. 
Incidence rate per subject is calculated by summing the number of exercise sessions completed 
within 12 weeks and dividing this denominator by the number of hypoglycemic events that 
occurred during those exercise sessions. 
 
12.4.2. 
Analysis of the Primary Efficacy Endpoint(s) 
The primary efficacy analysis will be analyzed by ANOVA comparing the mean incidence rate 
among the 3 treatment groups. All statistical significance testing will be 2-sided with a p-value 
<0.05. Efficacy endpoints will be analyzed using the ITT and PP analysis populations. After 
performing the F-test and if an overall p<0.05 is achieved, post-hoc analysis of group means will 
be conducted to statistically determine which group means differ. 
12.4.3. 
Analysis of the Key Secondary Endpoint(s) 
Glucose levels will be measured and analyzed as the mean decremental area over the curve 
(AUC(0-5hrs) in minutes*mg/dL) during exercise. Analysis will be conducted for glucose levels 
below range (interstitial glucose ≤70 mg/dL (3.89 mmol/L), interstitial glucose between 54-70 
mg/dL (3 – 3.89 mmol/L), <54 mg/dL (3 mmol/L)) and proportional time (percentage within 
serious hypoglycemia <54 mg/dL (3 mmol/L)). Differences between treatment groups in daily 
glucose requirements with exercise and adherence to IP with exercise will be made using t- tests 
(not corrected for multiple comparisons). Change from baseline to end of study in BAPAD- 1, 
HFS-II and HCS will be conducted. Changes from baseline in PROs may be correlated with 
clinical measurements during the study. 
Secondary endpoints will be analyzed using the ITT and PP populations. Glucose levels will be 
measured and analyzed as the mean decremental area over the curve (AUC(0-5hrs) in 
minutes*mg/dL) during exercise. Analysis will be conducted for glucose levels below range 
(interstitial glucose ≤70 mg/dL (3.89 mmol/L), interstitial glucose between 54-70 mg/dL (3 - 
3.89 mmol/L), <54 mg/dL (3 mmol/L)) and proportional time (percentage within serious 
hypoglycemia <54 mg/dL (3 mmol/L)). Differences between treatment groups in daily glucose 
requirements with exercise and adherence to IP with exercise to determine if subjects use fewer 
glucose tabs will be made using t-tests (not corrected for multiple comparisons). Change from 
baseline to end of study in BAPAD-1, HFS-II and HCS will be conducted. Changes from 
baseline in PROs may be correlated with clinical measurements during the study. 
12.4.4. 
Safety Analyses 
All analyses will be conducted in the safety population. Adverse events will be recorded from the 
time of consent until completion of study. The number and percentage of participants with AEs 
will be displayed by body system and preferred term using Medical Dictionary for Regulatory 
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Activities (MedDRA) version 20.0 or higher, by study treatment. Summaries in terms of severity 
and relationship to Study Drug will also be provided. All SAEs will be summarized in a similar 
manner. Participant listings of all AEs causing discontinuation of study medication and SAEs 
will be produced. 
All AEs will be listed for individual participants showing both verbatim and preferred terms. 
Separate summaries of treatment-emergent SAEs and TEAEs related to Study Drug will be 
generated. 
AEs will be summarized separately during the CRC treatment visits. Any AE that occurs after 
administration of study drug at Visit 3 and prior to administration of the alternate study drug at 
Visit 4 will be treatment emergent with respect to the study drug received at Visit 3. Any AE that 
occurs after administration of study drug at Visit 4 and prior to the first administration of study 
drug in the out-patient phase will be treatment emergent for the study drug received at Visit 4. 
Any event reported on the eCRF that occurs at the time of or after the initiation of Study Drug in 
the out-patient phase is defined as treatment-emergent for that study drug. Additionally, an AE 
that was reported to have started on Day 1 without an associated onset time is assumed to have 
occurred after the initiation of Study Drug. Hence, AEs occurring on Day 1 with no associated 
onset time are assumed to be treatment-emergent. 
SAEs associated with a protocol specified procedure and occurring after the time of consent but 
before administration of first dose of Study Drug are defined as Non-Treatment Emergent AEs 
(NTEAE). 
12.4.5. 
Baseline Descriptive Statistics 
 
All subjects will be summarized at baseline using descriptive statistics overall and by treatment 
group, including demographics and laboratory measurements. Analyses will be presented by 
CRC setting and by Outpatient setting separately. Summary statistics (e.g., number of 
participants, mean, median, standard and range) will be generated for continuous variables 
(e.g., age and weight) and the number and percentage of participants within each category will be 
presented for categorical variables (e.g., gender, ethnicity, and race). 
A detailed description of participant disposition will be provided. It will include: 
 A summary of overall participant enrollment status (screened, screen failures, 
randomized) 
 A summary of participants who discontinued the study (CRC, Outpatient) 
 An account of identified protocol deviations 
All participants who are consented for the study will be accounted for in the summation. The 
number of participants who do not qualify for certain analysis populations will be summarized. 
 
12.4.6. 
Planned Interim Analyses 
There are no planned interim analyses for this study. 
 
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12.4.7. 
Sub-Group Analyses 
There are no planned and powered study sub-group analyses for the study. However, subgroups 
of interest may be defined in the Statistical Analysis Plan for exploratory purposes. 
12.4.8. 
Tabulation of Individual participant Data 
Disposition, demographic, efficacy, and safety data will be listed as specified in the SAP. All 
eCRFs will have a corresponding listing of raw data reported. 
12.4.9. 
Exploratory Analyses 
Exploratory analyses will be described in the SAP. 
 
12.4.10. 
Missing Data 
Every effort will be made to limit the number of missing data elements for the study. All study 
endpoints for the primary and secondary analyses will be reviewed for missing data and 
appropriate methodology applied if applicable, as described in the SAP. Sensitivity analyses may 
be performed. 
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13. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
13.1. 
Regulatory, Ethical, and Study Oversight Considerations 
13.1.1. 
Informed Consent Process 
 
13.1.1.1. Consent/Assent and Other Informational Documents Provided to Participants 
Each subject must give written consent according to local requirements after the nature of the 
study has been fully explained. The consent form must be signed before performance of any 
study-related activity. The consent form that is used must be approved by both the Sponsor and 
the reviewing IRB. The informed consent is in accordance with the principles that originated in 
the Belmont Principles, current ICH and GCP guidelines, applicable regulatory requirements, 
and Sponsor policy. 
13.1.1.2. Consent Procedures and Documentation 
Before enrollment in the study, the Investigator or an authorized member of the clinical staff 
must explain to potential subjects the aims, methods, reasonably anticipated benefits, and 
potential hazards of the study, and any discomfort participation in the study may entail. Subjects 
will be informed that their participation is voluntary and that they may refuse to participate or 
withdraw consent to participate at any time, without penalty or loss of benefits to which the 
subject was entitled. Finally, they will be told that the Investigator will maintain a subject 
identification register for the purposes of long-term follow-up if needed and that their records 
may be accessed by health authorities and authorized Sponsor staff without violating the 
confidentiality of the subject, to the extent permitted by the applicable law(s) or regulations. By 
signing the ICF the subject is authorizing such access, and agrees to allow his or her Principal 
Investigator to recontact the subject for the purpose of obtaining consent for additional safety 
evaluations, if needed. 
The language about the study used in the oral and written information, including the ICF, will be 
non-technical and practical and should be understandable to the subject (or the subject’s legally 
acceptable representative). The subject will be given sufficient time to read the ICF and the 
opportunity to ask questions. After this explanation and before entry into the study, consent 
should be appropriately recorded by means of the subject's personally dated signature. After 
having obtained consent, a copy of the ICF must be given to the subject. 
If a subject (or legally acceptable representative) is unable to read or write, an impartial witness 
should be present during the entire informed consent discussion. After the written ICF and any 
other written information to be provided to the subjects, is read and explained to the subject (or 
legally acceptable representative), and after the subject (or legally acceptable representative) has 
orally consented to the subject’s participation in the study and, if capable of doing so, has 
personally dated and signed the ICF, the witness should personally date and sign the consent 
form. By signing the ICF, the witness attests that the information in the ICF and any other 
written information was accurately explained to, and apparently understood by, the subject (or 
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legally acceptable representative), and that informed consent was freely given by the subject (or 
legally acceptable representative). 
 
13.1.2. 
Confidentiality and Privacy 
Refer to Informed Consent Form. 
 
13.1.3. 
Safety Oversight 
Provided by Xeris Pharmaceuticals Medical Monitor. 
 
13.1.4. 
Clinical Monitoring 
Monitoring and auditing procedures developed by Xeris and/or its designee will be implemented 
to ensure compliance with FDA and ICH GCP guidelines. 
The Xeris designated representative (the monitor or auditor) will contact the Investigator and 
conduct regular visits to the clinical site. The monitor will be expected and allowed to verify the 
Investigator’s qualifications, to inspect clinical site facilities, and to inspect study records, 
including proof of IRB/IEC review, with the stipulation that subject confidentiality will be 
maintained in accordance with regional, local, and federal regulations (including Health 
Insurance Portability and Accountability Act of 1996 [HIPAA] requirements). The monitor will 
also be responsible for confirming adherence to the study protocol, inspecting eCRFs and source 
documents, and ensuring the integrity of the data. Electronic CRFs will be checked for accuracy, 
completeness, and clarity and will be cross-checked for consistency with source documents, 
including laboratory test reports and other subject records. Instances of missing or 
uninterpretable data will be resolved in coordination with the Investigator. 
The monitor/auditor will also investigate any questions concerning adherence to regulatory 
requirements. Any administrative concerns will be clarified and followed. The monitor will 
maintain contact with the site through frequent direct communications with the study site by e-
mail, telephone, facsimile, and postal mail. The Investigator and all other site personnel agree to 
cooperate fully with the monitor and will work in good faith with the monitor to resolve all 
questions raised, and difficulties detected by the monitor. 
13.1.5. 
Quality Assurance and Quality Control 
13.1.6. 
Data Handling and Record Keeping 
13.1.6.1. Data Collection and Management Responsibilities 
Data collection is the responsibility of the clinical study staff under the supervision of the 
Investigator. During the study, the Investigator will maintain complete and accurate 
documentation for the study. 
As defined in the ICH Guidelines for GCP (E6(R2)), Section 1.52, source documents may 
include: original documents, data, and records (e.g., hospital records, clinical and office charts, 
laboratory notes, memoranda, participant’s diaries or evaluation checklists, pharmacy dispensing 
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records, recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate and complete, microfiches, photographic negatives, microfilm or 
magnetic media, x-rays, participant files, and records kept at the pharmacy, at the laboratories, 
and at medico-technical departments involved in the clinical study). 
As used in this protocol, the term eCRF is understood to refer to an electronic data record. An 
eCRF is required and should be completed for each individual subject. The completed original 
eCRFs are the property of Xeris and should not be made available in any form to third parties, 
except for authorized representatives of Xeris or appropriate regulatory authorities, without 
written permission from Xeris. 
Completion of eCRFs will be accomplished using a 21 CFR Part 11 compliant web-based EDC 
system. Sites will use existing computers to enter all other study-related data into the EDC 
system. 
The Investigator has the responsibility for the collection and reporting of all clinical, safety and 
laboratory data entered on the eCRFs and any other data collection forms (source documents) 
and ensuring that these are accurate, authentic, attributable, complete, consistent, legible, 
contemporaneous, enduring and available when required. The eCRFs must be signed by the 
Investigator or by an authorized study staff member to attest that the data contained in the eCRFs 
is true. Any corrections to entries made in the source documents must be dated, initialed and 
explained (if necessary), and should not obscure the original entry. 
In most cases, the source documents are the hospital’s or physician’s subject chart. In these 
cases, data collected on the eCRFs must match the data in those charts. In some cases, the eCRF, 
or part of the eCRF, may also serve as source documents. In these cases, a document should be 
available at the Investigator’s site as well as at Xeris and clearly identify those data that will be 
recorded in the eCRF, and for which the eCRF will stand as the source document. Queries 
generated by Data Management will be sent to the study site for resolution. The Investigator is 
responsible for the review and approval of all responses to eCRF queries. 
 
13.1.7. 
Protocol Deviations 
The principal Investigator must sign this protocol and its amendments (if any) before initiating 
the study at a particular site. The Investigator will make all reasonable efforts to comply with the 
written protocol. Protocol modifications to ongoing studies that affect the safety of subjects or 
that alter the scope of the investigation, the scientific quality of the study, the experimental 
design, dosing, study assessments, the number of subjects exposed to test drug, or subject 
selection criteria must be made only after consultation between Xeris and the Investigator. All 
protocol modifications must be reviewed and approved by the IRB/IEC before the revised 
protocol can be implemented. Emergency revisions that eliminate an apparent hazard to subjects 
do not require preapproval by the IRB/IEC. However, the IRB/IEC must be notified in writing as 
soon as possible after the modification has been made. A copy of this communication must be 
forwarded to Xeris. All departures from the protocol must be fully documented in the source 
documents and the eCRFs of the subjects involved. Protocol deviations will be tracked in an 
electronic system implemented by the Sponsor or designated representative. 
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14. 
REFERENCES 
1. Chu L, Hamilton J, Riddell MC (2011) Clinical management of the physically active patient 
with type 1 diabetes. Physiol Sports Med 39: 64–77. 
2. West DJ, Morton RD, Bain SC, Stephens JW, Bracken RM (2010) Blood glucose responses 
to reductions in pre-exercise rapid-acting insulin for 24 h after running in individuals with 
type 1 diabetes. J Sports Sci 28: 781–788. 
3. Brazeau AS, Rabasa-Lhoret R, Strychar I, Mircescu H. Barriers to physical activity among 
patients with type 1 diabetes. Diabetes Care. 2008 Nov;31(11):2108-9. 
4. Rabasa-Lhoret R, Bourque J, Ducros F, Chiasson JL (2001) Guidelines for premeal insulin 
dose reduction for postprandial exercise of different intensities and durations in type 1 
diabetic subjects treated intensively with a basal-bolus insulin regimen (ultralente-lispro). 
Diabetes Care 24: 625–630. 
5. Campbell MD, Walker M, Trenell MI, Jakovljevic DG, Stevenson EJ, et al. (2013) Large 
Pre-and Postexercise Rapid-Acting Insulin Reductions Preserves Glycemia and Prevents 
Early-but Not Late-Onset Hypoglycemia in Patients With Type 1 Diabetes. Diabetes Care 
36: 2217–2224. 
6. Severe Hypoglycemia Predicts Mortality in Diabetes Philip E. Cryer Diabetes Care Sep 
2012, 35 (9) 1814-1816; DOI: 10.2337/dc12-0749 
7. Stenerson M, Cameron F, Payne SR, Payne SL, Ly TT, Wilson DM, Buckingham BA. The 
Impact of Accelerometer Use in Exercise-Associated Hypoglycemia Prevention in Type 1 
Diabetes. J Diabetes Sci Technol. 2014 Sep 17. pii: 1932296814551045.[Epub ahead of print] 
PubMed PMID: 25231116. 
8. Tsalikian E, Mauras N, Beck RW, Tamborlane WV, Janz KF, Chase HP, Wysocki T, 
Weinzimer SA, Buckingham BA, Kollman C, Xing D, Ruedy KJ; Diabetes Research In 
Children Network Direcnet Study Group. Impact of exercise on overnight glycemic control 
in children with type 1 diabetes mellitus. J Pediatr. 2005 Oct;147(4):528-34. 
9. Tanenberg RJ, Newton CA, Drake AJ. Confirmation of hypoglycemia in the "dead-in- bed" 
syndrome, as captured by a retrospective continuous glucose monitoring system. Endocr Pract. 
2010 Mar-Apr;16(2):244-8. 
10. Campbell MD, Walker M, Trenell MI, Luzio S, Dunseath G, Tuner D, Bracken RM, Bain 
SC, Russell M, Stevenson EJ, West DJ. Metabolic implications when employing heavy pre- 
and post-exercise rapid-acting insulin reductions to prevent hypoglycaemia in type 1 diabetes 
patients: a randomised clinical trial. PLoS One. 2014 May 23;9(5):e97143. 
11. Taplin CE, Cobry E, Messer L, McFann K, Chase HP, Fiallo-Scharer R. Preventing post-
exercise nocturnal hypoglycemia in children with type 1 diabetes. J Pediatr.2010 
Nov;157(5):784-8 .e1. doi: 10.1016/j.jpeds.2010.06.004. 
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12. 
Riddell MC, Bar-Or O, Ayub BV, Calvert RE, Heigenhauser GJ. Glucose ingestion matched 
with total carbohydrate utilization attenuates hypoglycemia during exercise in adolescents 
with IDDM. Int J Sport Nutr. 1999 Mar;9(1):24-34. 
13. Robertson K, Riddell MC, Guinhouya BC, Adolfsson P, Hanas R. Exercise in children and 
adolescents with diabetes. Pediatr Diabetes. 2014 Sep;15 Suppl 20:203-23. doi: 
10.1111/pedi.12176. 
14. Camacho RC, Galassetti P, Davis SN, Wasserman DH. Glucoregulation during and after 
exercise in health and insulin-dependent diabetes. Exerc Sport Sci Rev. 2005 Jan;33(1):17-
23. 
15. Oskarsson PR, Lins PE, Wallberg Henriksson H, Adamson UC. Metabolic and hormonal 
responses to exercise in type 1 diabetic patients during continuous subcutaneous, as 
compared to continuous intraperitoneal, insulin infusion. Diabetes Metab. 1999 
Dec;25(6):491-7. 
16. Busselo JTM, Domingo AJ, Marra EM. Mini-dose of glucagon: Great efficacy avoiding 
admission of insulin-dependent-diabetic children with decreasing normoglycemia or 
hypoglycemie due to vomiting or gastroenteritis. Pediatr Res. 2010; 68:363-4. 
17. Glycemic Targets: Standards of Medical Care in Diabetes—2018 American Diabetes 
Association Diabetes Care Jan 2018, 41 (Supplement 1) S55-S64; DOI: 10.2337/dc18- S006. 
18. 2007 Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and 
their duration. UK Hypoglycaemia Study Group. Diabetologia 50:1140–1147 
19. Ratzki-Leewing A, Harris SB, Mequanint S, et al. Real-world crude incidence of 
hypoglycemia in adults with diabetes: Results of the InHypo-DM Study, Canada.BMJ Open 
Diab Res Care 2018;6:e000503. doi:10.1136/bmjdrc-2017-000503. 
20. CDC, National Diabetes Statistics Report, 2017 
21. Dubé MC, Balois P, Prudhomme D, Weisnagel SJ, Lavoie C. Physical activity barriers in 
diabetes: Development and validation of a new scale. Diabetes Res and Clin Prac. 2006; 72 
(1):20-7. 
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APPENDIX 1. 
EXERCISE 
CRC EXERCISE 
Subjects may proceed with exercise if BG is 100-180 mg/dL (5.56 – 10 mmol/L). 
Exercise will consist of 45-minute session of moderate intensity aerobic activity (eg, 
treadmill jogging/brisk walking/cycling, elliptical). Breaks in exercise may be taken 
to perform study procedures. Each break will be 5 minutes or less with an aggregate 
break time of no more than 10 minutes. 
The same type of aerobic activity will be performed for each exercise session and for 
the entire duration of each exercise session. The target is for exercise sessions to be 
initiated at approximately the same clock time during each CRC visit, with a window 
of ±1 hour. 
The goal is to achieve a target of 80% of maximum calculated heart rate during the 
session as shown in the following equation: 
Recommended exercise goal: 
Heart Rate = 0.80 x (220 – Age in Years) 
Stopping rule:  As long as glucose remains >70 mg/dL, exercise may continue. If the 
subject’s glucose falls to ≤ 70 mg/dL (3.89 mmol/L), the exercise session will be 
stopped, the subject should rest, and 16g (4 tabs, 4g/tab) of glucose tabs, or per 
standard of care, should be taken every 15 minutes until hypoglycemia is corrected 
and euglycemia is maintained. 
OUTPATIENT EXERCISE 
During the out-patient phase, subjects will be instructed to self-administer Study 
Medication when the following three conditions are met: 
1. The subject plans to perform an aerobic to exercise session lasting at least 
30 minutes and not more than 75 minutes in duration, 
2. The subject plans to exercise continuously at moderate-to-high intensity to 
achieve a target heart rate of 80% of maximum calculated heart rate, 
during the session. 
3. The subject has a confirmed blood glucose (BGM) of 100-180 
mg/dL (5.56–10 mmol/L). 
Subjects may perform exercise at any point in the day, but dose themselves for a 
maximum of one exercise session per day. The requested exercise frequency is an 
average of 2-3 sessions weekly. An instruction manual for self-administration of study 
drug will be provided to subjects. 
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Examples of aerobic exercise qualifying for dosing include powerwalking, 
hiking, running/jogging, cycling, swimming, cross country skiing, and 
aerobic fitness classes. 
High intensity interval training (HIIT) such as sprinting, volleyball, basketball, 
hockey, CrossFit, weight lifting, etc. is not eligible for investigational product dosing. 
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APPENDIX 2. 
BAPAD 1 QUESTIONNAIRE 
 
Indicate the likelihood that each of these 
items would keep you from practicing 
regular physical activity during the next 6 
months? 
Score 
(1=extremely unlikely, to 7=extremely 
likely). 
1. The loss of control over your diabetes 
1 
2 
3 
4 
5 
6 
7 
2. The risk of hypoglycemia 
1 
2 
3 
4 
5 
6 
7 
3. The fear of being tired 
1 
2 
3 
4 
5 
6 
7 
4. The fear of hurting yourself 
1 
2 
3 
4 
5 
6 
7 
5. The fear of suffering a heart attack 
1 
2 
3 
4 
5 
6 
7 
6. A low fitness level 
1 
2 
3 
4 
5 
6 
7 
7. The fact that you have diabetes 
1 
2 
3 
4 
5 
6 
7 
8. The risk of hyperglycemia 
1 
2 
3 
4 
5 
6 
7 
9. Your actual physical health status 
excluding your diabetes 
1 
2 
3 
4 
5 
6 
7 
10. Weather conditions 
1 
2 
3 
4 
5 
6 
7 
11. The location of a gym 
1 
2 
3 
4 
5 
6 
7 
12. Your work schedule 
1 
2 
3 
4 
5 
6 
7 
 
Source: Dubé MC, Balois P, Prudhomme D, Weisnagel SJ, Lavoie C. Physical activity barriers in diabetes: 
Development and validation of a new scale. Diabetes Res and Clin Prac. 2006; 72 (1):20-7. 
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APPENDIX 3. 
HFS-II (ADULTS) QUESTIONNAIRE 
© University of Virginia 1998 
I. 
Behavior: Below is a list of things people with diabetes sometimes do in 
order to avoid low blood sugar and its consequences. Circle one of the 
numbers to the right that best describes what you have done during the 
last 6 months in your daily routine to AVOID low blood sugar and its 
consequences. (Please do not skip any!). 
 
Never Rarely 
Sometimes 
Often 
Almost 
Always 
To avoid low blood sugar and how it affects 
me, I … 
1. Ate large snacks. 
0 
1 
2 
3 
4 
2. Tried to keep my blood sugar above 150. 
0 
1 
2 
3 
4 
3. Reduced my insulin when my blood sugar 
was low. 
0 
1 
2 
3 
4 
4. Measured my blood sugar six or more 
times a day. 
0 
1 
2 
3 
4 
5. Made sure I had someone with me when I 
go out. 
0 
1 
2 
3 
4 
6. Limited my out of town travel. 
0 
1 
2 
3 
4 
7. Limited my driving (car, truck or bicycle). 
0 
1 
2 
3 
4 
8. Avoided visiting friends. 
0 
1 
2 
3 
4 
9. Stayed at home more than I liked. 
0 
1 
2 
3 
4 
10. Limited my exercise/physical activity. 
0 
1 
2 
3 
4 
11. Made sure there were other people 
around. 
0 
1 
2 
3 
4 
12. Avoided sex. 
0 
1 
2 
3 
4 
13. Kept my blood sugar higher than usual in 
social situations. 
0 
1 
2 
3 
4 
14. Kept my blood sugar higher than usual 
when doing important tasks. 
0 
1 
2 
3 
4 
15. Had people check on me several times 
during the day or night. 
0 
1 
2 
3 
4 
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II. 
Worry: Below is a list of concerns people with diabetes sometimes have 
about low blood sugar. Please read each item carefully (do not skip 
any). Circle one of the numbers to the right that best describes how 
often in the last 6 months you WORRIED about each item because of 
low blood sugar. 
 
Never Rarely Sometimes Often 
Almost 
Always 
Because my blood sugar could 
go low, I worried about … 
16. Not recognizing / 
realizing I was having 
low blood sugar. 
0 
1 
2 
3 
4 
17. Not having food, fruit, or 
juice available. 
0 
1 
2 
3 
4 
18. Passing out in public. 
0 
1 
2 
3 
4 
19. Embarrassing myself 
or my friends in a 
social situation. 
0 
1 
2 
3 
4 
20. Having a 
hypoglycemic 
episode while alone. 
0 
1 
2 
3 
4 
21. Appearing stupid or drunk. 
0 
1 
2 
3 
4 
22. Losing control. 
0 
1 
2 
3 
4 
23. No one being around to 
help me during a 
hypoglycemic episode. 
0 
1 
2 
3 
4 
24. Having a 
hypoglycemic 
episode while 
driving. 
0 
1 
2 
3 
4 
25. Making a mistake or 
having an accident. 
0 
1 
2 
3 
4 
26. Getting a bad 
evaluation or 
being criticized. 
0 
1 
2 
3 
4 
27. Difficulty thinking 
clearly when 
responsible for others. 
0 
1 
2 
3 
4 
28. Feeling lightheaded or 
dizzy. 
0 
1 
2 
3 
4 
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29. Accidently injuring myself 
or others. 
0 
1 
2 
3 
4 
30. Permanent injury or 
damage to my health or 
body. 
0 
1 
2 
3 
4 
31. Low blood 
sugar 
interfering with 
important 
things I was 
doing. 
0 
1 
2 
3 
4 
32. Becoming hypoglycemic 
during sleep. 
0 
1 
2 
3 
4 
33. Getting emotionally 
upset and difficult to 
deal with. 
0 
1 
2 
3 
4 
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APPENDIX 4. 
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 60 ± 5 minutes after the 
completion of the exercise session 
 
 
 
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 
Slight edema (edges of 
area well defined by 
definite raising) 
2 
Moderate erythema 
3 
Moderate edema 
Raised approx. 1 mm 
3 
Severe erythema Beet 
redness to slight eschar 
formation 
4 
Severe edema Raised 
more than 1 mm and 
beyond exposure area 
4 
Source: Guidance for Industry, Skin Irritation and Sensitization Testing of Generic Transdermal Drug 
Products. US Department of Health and Human Services Food and Drug Administration Center for Drug 
Evaluation and Research (CDER). December 1999. Appendix A. 
Draize JH, Woodard G, Calvery HO. Methods for the study of irritation and toxicity of substances 
applied topically to the skin and mucous membranes. Journal of Pharmacology and Experimental 
Therapeutics.  November 1944;82(3):377-390. 
 
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APPENDIX 5. 
HYPOGLYCEMIC CONFIDENCE SCALE 
How confident are you that you can 
stay safe from serious problems with 
hypoglycemia: 
Not 
Confident 
At All 
A Little 
Confident 
Moderately 
Confident 
Very 
Confident 
1. When you are exercising? 
2. When you are asleep? 
3. When you are driving? 
4. When you are in social situations? 
5. When you are alone? 
 
In general, how confident are you that 
you can: 
Not 
Confident 
At All 
A Little 
Confident 
Moderately 
Confident 
Very 
Confident 
6. Avoid serious problems due 
to hypoglycemia? 
7. Catch and respond to 
hypoglycemia before your 
blood sugars get too low? 
8. Continue to do things you really 
want to do in your life, despite 
the risks of hypoglycemia? 
 
 
9. If you have a spouse or partner: 
What is your best guess about 
how confident your spouse or 
partner feels about your ability to 
avoid serious problems due to 
hypoglycemia? 
 
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APPENDIX 6. 
INJECTION SITE DISCOMFORT DESCRIPTION AND 
DURATION QUESTIONNAIRE 
Study Personnel Instructions: Question 1a should be completed by the 
subject after injection of study drug and when the exercise is completed. Any 
subject reporting discomfort other than “none,” should complete Question 1b 
at the same time. All subjects should also answer Question 1c at the end of 
the visit (90 ±5 mins post-injection). The goal is for the subject to report the 
qualitative nature and duration of discomfort, if any, associated with injection 
of study drug, ignoring any transient pain associated with needle insertion. 
Note: If a subject is unable to physically complete the questionnaire, the 
subject will provide verbal responses, which will be recorded on the 
questionnaire by study staff. Documentation will be provided on each 
completed questionnaire as to who completed the form (subject or staff). 
 
Subject Instructions: Please answer question 1a and, if applicable to you, questions 1b and 
1c. In answering these questions, you should ignore any pain from insertion of the needle. 
Please complete question 1c before leaving the clinic. 
 
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 
 
 
1c. In total, how long did the discomfort last after the injection? (Please enter a number 
below): 
  
 Minute 
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Source: Downie WW, Leatham PA, Rhind VM, Wright V, Branco JA, Anderson JA. Studies with pain 
rating scales. Ann Rheum Dis. 1978;37:378–381. 
Hawker GA, Mian S, Kendzerska T, French M.  Measures of adult pain: Visual Analog Scale for Pain 
(VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain Questionnaire (MPQ), Short-Form 
McGill Pain Questionnaire (SF-MPQ), Chronic Pain Grade Scale (CPGS), Short Form-36 Bodily Pain 
Scale (SF-36 BPS), and Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP). Arthritis Care 
& Research. November 2011;63(S11):S240-S252. 
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Document Approvals
Approved Date: 6/20/2019
Approval Task
Verdict:  Approve
Khaled Junaidi,
(kjunaidi@xerispharma.com)
Medical Affairs Approval
17-Jun-2019 16:43:49 GMT+0000
Approval Task
Verdict:  Approve
Marty Cummins,
(mcummins@xerispharma.com)
SME Approval
17-Jun-2019 21:07:43 GMT+0000
Approval Task
Verdict:  Approve
Nicole Close,
(nclose@xerispharma.com)
SME Approval
18-Jun-2019 13:40:07 GMT+0000
Approval Task
Verdict:  Approve
Aziz Alam,
(aalam@xerispharma.com)
Regulatory Approval
20-Jun-2019 04:46:42 GMT+0000
QA Approval Task
Verdict:  Approve
Ed Drower,
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Quality Assurance Approval
20-Jun-2019 15:18:16 GMT+0000
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TABLE OF CONTENTS 
PAGE 
 
REVISION HISTORY............................................................................................................. 4 
LIST OF ABBREVIATIONS .................................................................................................. 5 
INTRODUCTION ................................................................................................................... 7 
1. STUDY DETAILS............................................................................................................... 7 
1.1 STUDY OBJECTIVES ...................................................................................................... 7 
1.2 STUDY DESIGN: ............................................................................................................. 8 
1.3 DETERMINATION OF SAMPLE SIZE ........................................................................ 13 
2. STATISTICAL AND DATA ANALYSIS CONSIDERATION ...................................... 14 
2.1 Protocol Deviation: .......................................................................................................... 15 
2.2 Handling of Missing Data: ............................................................................................... 16 
2.3 Treatment Group Labelling in TFLs: ............................................................................... 17 
2.4 Definition ......................................................................................................................... 17 
3. STUDY ENDPOINTS ....................................................................................................... 20 
4. STATISTICAL METHODOLOGY .................................................................................. 23 
4.1 Definition of Analysis Population ................................................................................... 23 
4.2 Coding Dictionaries Used ................................................................................................ 23 
4.3 Wearable Monitoring Devices ......................................................................................... 23 
4.3 Statistical Methods and Data Analysis ............................................................................ 25 
4.3.1 Disposition .................................................................................................................... 25 
4.3.2 Demographics and Baseline Characteristics ................................................................. 26 
4.3.3 Study Drug Administration and Accountability ........................................................... 26 
4.3.4 Medical History ............................................................................................................ 26 
4.3.5 Prior and Concomitant Medications ............................................................................. 26 
4.3.6 Primary Endpoint Analysis: .......................................................................................... 27 
4.3.7 Secondary Endpoint Analysis: ...................................................................................... 28 
4.3.8 Exploratory Analysis: ................................................................................................... 29 
4.3.9 Safety Analysis: ............................................................................................................ 30 
4.4 CHANGES FROM PROTOCOL .................................................................................... 32 
4.5 REFERENCES ................................................................................................................ 32 
4.6 APPENDICES ................................................................................................................. 32 
4.6.1 APPENDIX 1. Example of SAS syntax code for primary endpoint analysis. .............. 32 
4.6.2 APPENDIX 2. Example of SAS syntax code for secondary endpoint analysis. .......... 33 
4.6.3 APPENDIX 3. Example of SAS syntax code for exploratory analysis. ....................... 35 
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5. LIST OF TABLES, LISTINGS AND FIGURES .............................................................. 35 
5.1 Summary Tables .............................................................................................................. 35 
5.2 Listings ............................................................................................................................. 40 
5.3 Figures.............................................................................................................................. 42 
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REVISION HISTORY 
Version 
Date 
Author 
Reasons 
      1.0 
   05 Dec 2019 
Roman Ganzha 
Initial version 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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LIST OF ABBREVIATIONS 
Abbreviation or 
special term 
Explanation 
AE 
Adverse event 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
AOC 
Area Over the Curve 
AUC0-xh 
Area under the plasma concentration vs time curve from time 0 to X hours 
post-dose (where x=1 hour, 2 hours, 4 hours post-dose). AUC0-xh is 
estimated using the trapezoidal method. 
BGM 
Blood Glucose Monitoring 
BGMT 
Blood Glucose Measurement 
BMI 
Body Mass Index 
CBP 
Childbearing potential 
CGM 
Continuous Glucose Monitoring 
CI 
Confidence Interval 
 
CRF 
Case Report Form 
CRO 
Contract Research Organization  
CTCAE  
Common Terminology Criteria for Adverse Events 
CV% 
Coefficient of Variation expressed as a percentage 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ER 
Extended Analysis 
FDA 
United States Food and Drug Administration  
GCP 
Good Clinical Practice 
HR 
Heart Rate 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization  
IG 
Interstitial Glucose 
IMP 
Investigational Medicinal Product 
ITT 
Intent-to-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
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Statistical Analysis Plan 
Version Final 1.0 
                                                                           Protocol Number: XSMP-204
                                                         Page 6 of 42
 
Abbreviation or 
special term 
Explanation 
PP 
Per Protocol 
PROs 
Patient Reported Outcomes 
PT 
Preferred Term 
QTc 
Corrected QT interval 
QTcF 
QT interval corrected for heart rate using Fridericia’s method 
RBC 
Red Blood Cell 
RTY 
Ready To Use 
SAE 
Serious Adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
WBC 
White Blood Cell 
WHO 
World Health Organization  
YSI 
Yellow Springs Instrument 
 
 
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Statistical Analysis Plan 
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                                                                           Protocol Number: XSMP-204
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INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide the details of the planned 
statistical analyses that were outlined within the protocol for the study “A Phase 2 Randomized, 
Placebo-Controlled, Double-Blind, Parallel Study to Evaluate Glucagon Ready-to-Use (RTU) 
(Glucagon Injection) Compared to Standard of Care for the Prevention of Exercise-Induced 
Hypoglycemia During Regular Aerobic Exercise in Adults with Type 1 Diabetes”, XSMP-204, 
version 4.0 dated 20 June 2019. The SAP will further define and expand those analyses.  The 
SAP will take precedence over the protocol. 
1. STUDY DETAILS 
1.1 STUDY OBJECTIVES 
Primary Objectives 
 
The primary objective of this study is: 
1. To evaluate if the subcutaneous administration of Glucagon RTU (Glucagon Injection) 
just before exercise, with or without a 50% reduction in basal rate insulin, compared to a 
50% basal rate insulin reduction alone, prevents the occurrence of hypoglycemia (i.e., 
blood glucose ≤ 70 mg/dL; 3.89 mmol/L) measured by blood glucose meter (BGM) 
during and after moderate-to-high intensity aerobic exercise by adult subjects with T1D 
in an outpatient setting. 
Secondary Objectives 
1. To evaluate how Glucagon RTU (Glucagon Injection) contributes to prevention of 
hypoglycemia during exercise and post exercise recovery. 
2. To evaluate the effect of Glucagon RTU (Glucagon Injection) on insulin utilization 
during exercise. 
3. To evaluate the effect of Glucagon RTU (Glucagon Injection) on PROs: Barriers to 
Physical Activity in Diabetes (Type 1) (BAPAD-1), Hypoglycemia Fear Survey (HFS-
II), and Hypoglycemic Confidence Scale (HCS) after 12 weeks of outpatient exercise. 
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Statistical Analysis Plan 
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                                                                           Protocol Number: XSMP-204
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Exploratory Objectives 
1. To evaluate the glycemic time in range associated with exercise sessions and post 
exercise. 
2. To evaluate the impact of Glucagon RTU (Glucagon Injection) on the quantity of glucose 
tabs used over time during exercise sessions. 
3. To evaluate weight loss or weight maintenance over time. 
4. To examine food intake both before and after exercise. 
5. To examine the effect of exercise and Glucagon RTU on overnight hypoglycemia 
following episodes of exercise. 
6. To evaluate the effects of exercise and Glucagon RTU use upon changes in hemoglobin 
A1c. 
7. To evaluate the intensity and duration of the frequent exercise sessions. 
8. To evaluate overall frequency of aerobic exercise over study period. 
9. To evaluate effects on exercise duration and intensity as well as daily activity metrics. 
1.2 STUDY DESIGN: 
This study is a randomized, placebo-controlled, double-blind, two-treatment, two-period, 
crossover comparison in a clinical research center (CRC) setting, followed by a randomized, 
placebo-controlled, partially double-blinded, 3-arm parallel comparison in an outpatient setting 
to evaluate the preliminary efficacy and safety of Glucagon RTU to prevent exercise-induced 
hypoglycemia (EIH) in adults with Type 1 diabetes mellitus (T1D), who perform regular, 
moderate-to-high intensity aerobic exercise. 
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                                                                            Private and Confidential 
Statistical Analysis Plan 
Version Final 1.0 
                                                                           Protocol Number: XSMP-204
                                                         Page 9 of 42
 
 
Figure 1. Schema of Study Design 
 
The CRC Stage will involve two daytime clinical research centers (CRC, or comparable setting) 
exercise sessions 2-28 days apart, in a morning exercise session, for the following treatment 
assignments: 
• Insulin pump reduction (50% reduction in basal rate five minutes before exercise, for the 
duration of the exercise), and pre-exercise placebo injection (30 μL vehicle), or  
• Insulin pump reduction (50% reduction in basal rate five minutes before exercise, for the 
duration of the exercise), and pre-exercise Glucagon RTU (30 μL active - 0.15 mg). 
At Investigator discretion, the insulin pump rate can be reduced overnight based on subject’s 
medical history for the duration of the study. 
BGM assessments during CRC visits will be at -15, 0, 30, 45 and 75 minutes from the start of 
exercise. Venous Blood Glucose assessments (Yellow Springs Instrument [YSI] readings) during 
CRC visits will be at -15, 0, 15, 30, 45, 60 and 75 minutes from the start of exercise. Subjects 
will also wear unblinded continuous glucose monitoring (CGM) both the CRC and Outpatient 
Stages of the study.  
The Outpatient Stage will be 12 weeks in duration during which subjects are randomized to one 
of three parallel treatment arms, two of which are double-blinded, and one is open-label. 
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                                                                            Private and Confidential 
Statistical Analysis Plan 
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                                                                           Protocol Number: XSMP-204
                                                         Page 10 of 42
 
During the Outpatient Stage, subjects will receive one of the following randomly assigned 
treatments: 
• Insulin Pump reduction (50% reduction in basal rate five minutes before exercise, for the 
duration of the exercise), and pre-exercise placebo injection (30 μL vehicle), or 
• Insulin Pump reduction (50% reduction in basal rate five minutes before exercise, for the 
duration of the exercise), and pre-exercise Glucagon RTU (30 μL active - 0.15 mg), or 
• Pre-exercise Glucagon RTU (30 μL active - 0.15 mg) without pump changes. 
Subjects will measure blood glucose using BGM at -15 and 0 minutes (just before exercise) to 
establish baseline, at 30 minutes of exercise, at the end of exercise, and 30 minutes post-exercise. 
Subjects will also wear unblinded CGM during the conduct of the study. 
Table 1. Schedule of Activities 
Assessment 
Visit 1 
Visit 2 
Visit 3o 
CRC 1 
Visit 4o 
CRC 2 
Visits 5 to 10 
Outpatient Phase 
Visit 11  
Follow-upf 
/ET 
 
Screening 
Day–28 to 
–3 
CGM 
Placement 
Day –2 to –1 
Treatment 
Period 1 
(Days 1a,b,c) 
Treatment 
Period 2 
Day 3 to 29d 
Treatment 
Period 3 
Day 4 to 113e 
Informed consent 
X 
 
 
 
 
 
Medical History/ 
Demographics 
X 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
Concomitant 
medications (including 
insulin pump data) 
X 
X 
X 
X 
X 
X 
Height, weight and 
physical 
examination 
X 
 
 
 
 
X 
12-lead ECG 
X 
 
 
 
 
X 
Vital signs 
X 
 
X 
X 
X 
X 
Urine pregnancy test 
X 
 
X 
X 
X 
X 
Urine drug screen 
X 
 
 
 
 
 
Hematology 
X 
 
 
 
 
X 
Clinical chemistry 
X 
 
 
 
 
X 
HbA1c 
X 
 
 
 
 
X 
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                                                                            Private and Confidential 
Statistical Analysis Plan 
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                                                                           Protocol Number: XSMP-204
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Assessment 
Visit 1 
Visit 2 
Visit 3o 
CRC 1 
Visit 4o 
CRC 2 
Visits 5 to 10 
Outpatient Phase 
Visit 11  
Follow-upf 
/ET 
 
Screening 
Day–28 to 
–3 
CGM 
Placement 
Day –2 to –1 
Treatment 
Period 1 
(Days 1a,b,c) 
Treatment 
Period 2 
Day 3 to 29d 
Treatment 
Period 3 
Day 4 to 113e 
Plasma Glucose 
X 
 
 
 
 
X 
C-peptide 
X 
 
 
 
 
X 
Immunogenicityg 
 
 
X 
 
X 
X 
CGM 
 
Xd 
Xh 
Xh 
Xh 
Xh 
Exercisei,o 
 
 
X 
X 
 
BGMk 
 
 
X 
Xj 
Xj 
Xj 
Study drug 
administration 
 
 
X 
Xl 
X 
 
Wearable Activity 
Monitors 
(Fitbit Ionic and Polar 
Beat H10) 
 
 
Xm 
Xm 
Xn 
Xn 
HBV, HCV, HIV 
Screen  
X 
 
 
 
 
 
Outpatient Study 
Training 
 
 
 
X 
 
 
Diaryi 
 
 
X 
X 
X 
X 
Glucose Tabs Log 
 
 
X 
X 
X 
X 
Randomization 
 
 
X 
 
 
 
8-Hour fast 
X 
 
X 
X 
 
X 
Venous blood glucose 
(YSI) 
 
 
X 
X 
 
 
BAPAD-1 
Questionnaire 
 
 
X 
 
 
X 
Draize Scale 
 
 
X 
X 
 
 
HFS 
 
 
X 
 
 
X 
Hypoglycemia 
Confidence Scale 
 
 
X 
 
 
X 
Injection Site 
Discomfort 
Description and 
Duration 
Questionnaire 
 
 
X 
X 
 
 
Adverse event review 
X 
X 
X 
X 
X 
X 
*Visits will occur every 2 weeks during the out-patient phase. The visit window is +/- 3 days for the outpatient 
visits. 
BAPAD-1 = Barriers to Physical Activity in Type 1 Diabetes Scale; BGM = blood glucose monitor;  CRC = 
Clinical Research Center; CGM = continuous glucose monitor; ECG = electrocardiogram;  HBV = hepatitis B 
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                                                                            Private and Confidential 
Statistical Analysis Plan 
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                                                                           Protocol Number: XSMP-204
                                                         Page 12 of 42
 
virus; HCV = hepatitis C virus; HFS = Hypoglycemia Fear Survey; HIV = human immunodeficiency virus; YSI = 
Yellow Springs Instrument 
a. As long as the subject has 2 days of rest between each CRC visit. 
b. Subjects will be instructed not to exercise between Visit 2 and Visit 3. 
c. Questionnaires to be completed are Barriers to Physical Activity Diabetes (Type 1) (BAPAD-1), 
Hypoglycemia Fear Survey (HFS) and Hypoglycemia Confidence Scale (HCS). 
d. CGM will be placed approximately 24-48 hours prior to data collection at CRC Visit 2. 
e. Collection timepoints ± 2 minutes are: -15 minutes, 0 minutes (just before initiation of exercise), 
and at 15, 30, 45, 60 and 75 minutes after initiation of exercise. 
f. Follow-Up occurs 14 days after the last exercise period. 
g. An immunogenicity sample will be drawn before the first dose of investigational product, every four weeks (28 
days +/- 2 days) and at the End of Study visit. 
h. CGM data will be downloaded. 
i. During the CRC Phase of the study, subjects will perform moderate-to-high-intensity exercise of at least 45 
minutes duration, with each exercise session separated by at least 2 days  during the inpatient phase of the study.  
During the Outpatient Phase of the study, subjects will be asked to maintain a weekly exercise average of 2 to 3 
sessions weekly of at least 30 minutes. Exercise data will be downloaded from the wearable device. Data 
include heart rate, calories burned, daily steps, floors climbed, distance covered, active minutes.  
j. BGM Measurements will be performed at the following timepoints during CRC visits, ± 2 minutes: 
• 
-15 minutes (both YSI and BGM) 
• 
Time 0 (immediately before exercise) (both YSI & BGM)) 
• 
15 minutes (YSI only) 
• 
30 minutes (both YSI & BGM) 
• 
45 minutes (both YSI & BGM, end of exercise) 
• 
60 minutes (YSI only) 
• 
75 minutes (both YSI & BGM, thirty minutes after completion of exercise) 
k. BGM data will be downloaded at each patient visit. 
l. 
Investigational Product (IP) for first outpatient visit will be dispensed at the end of visit 4. 
m. Subject will wear both Fitbit Ionic and Polar Beat H10 heart rate sensor during this visit. 
n. 
Subject will wear only the Fitbit Ionic during these visits. 
o. 
Prior to beginning the exercise session, if the subject’s blood glucose is below 100 mg/dL the subject is 
allowed to take dextrose tabs (e.g., 2-4 tabs) to raise the blood glucose, and the blood glucose verified to be 
within 100-180 mg/dL (5.56 – 10 mmol/L). The number of dextrose tabs and time administered are recorded. 
Prior to beginning the exercise session, if the blood glucose is >180 mg/dL after repeat test, then the 
investigator may treat with an intravenous (IV) bolus dose of regular insulin, per discretion, to bring the 
subject into the required blood glucose range. Before initiating study treatment, at least 40 minutes should have 
passed from the last dose of administered insulin and the subject’s glucose level should be within the range of 
100 to 180 mg/dL. 
At discretion, the investigator may reschedule the visit to occur after a minimum wait of 24 hours. The visit 
should be re-scheduled so it occurs within the originally defined visit window. For example, a rescheduled Visit 
3 (CRC 1) should occur within 28 days of Visit 1 (Screening), while a rescheduled Visit 4 (CRC 2) should occur 
within 28 days of a completed Visit 3 (CRC 1). 
 
 
 
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                                                                           Protocol Number: XSMP-204
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1.3 DETERMINATION OF SAMPLE SIZE 
The primary endpoint of the study is the incidence of hypoglycemia (glucose ≤ 70 mg/dL (3.89 
mmol/L)) associated with an exercise session, which occurred within the 12-week outpatient 
follow-up, as measured by BGM. The null hypothesis is that there is no difference between the 
treatment groups in the incidence of exercise-associated hypoglycemia, and the alternative is 
there is a difference between the treatment groups in terms of the incidence of exercise-
associated hypoglycemia. With an effect size estimate of 0.262 (variance of means 59, common 
standard deviation 15), 80% power and an alpha of 0.05, using a one-way analysis of variance, 
14 subjects per treatment group in the Outpatient Stage is required. Accounting for 15% attrition, 
a total of 48 subjects will be randomized. 
1.3.1 Randomization and Blinding 
The study statistician will create the randomization schedule for the study. The randomization 
assignment for the subject will be conducted once at the time of enrollment and confirmation of 
eligibility. The CRC assignments will be by random assignment during the first session to either 
Glucagon RTU or Placebo. At the second session, the subject will be crossed over to the other 
treatment assignment. At the completion of the CRC visits, the subject will then have his/her 
treatment assignment applied for the parallel group study.  
The cross-over study is blinded to the extent possible since all subjects will receive both 
Glucagon RTU and placebo. All staff, subjects and study team members will know that the 
subject will receive both study treatments during the CRC sessions. During the outpatient study, 
two of the treatments will be blinded to the study staff, subjects and Sponsor. One arm of the 
study will be open label. It is imperative for the study staff to remain blinded to treatment 
assignment prior to randomization and during the study treatment periods as not to bias the 
outcome. 
Glucagon RTU and Placebo will be prepared and administered so that the two will be 
indistinguishable. 
Blinding of study treatment is critical to the integrity of this clinical trial. It is expected that in 
the majority of cases, AEs can be properly managed without the need for unblinding. However, 
in the event of a medical emergency in which knowledge of an individual subject’s treatment 
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Statistical Analysis Plan 
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                                                                           Protocol Number: XSMP-204
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assignment is considered critical to the subject’s management, the treating physician may 
unblind the treatment assignment. The investigator should contact the responsible Medical 
Director to discuss the subject and circumstances requiring the unblinding. The blind will be 
broken only for the specific subject under discussion. The Sponsor will remain blinded to the 
treatment assignment. Every effort will be made to restrict knowledge of the treatment 
assignment to the investigator only. 
2. STATISTICAL AND DATA ANALYSIS CONSIDERATION 
The statistical analyses will be performed by EmpiriStat, Inc., using SAS Version 9.3 (or higher). 
All tables, listings and figures (TLFs) will be produced in landscape format. In general, all data 
will be listed by the subject and visit/time point where appropriate.  
Data will be summarized by treatment/treatment sequence and by period where appropriate. The 
total number of subjects in the study group (N) under the stated population will be displayed in 
the treatment sequence/treatment header of summary tables. 
Data will be summarized using descriptive statistics for continuous variables. Unless otherwise 
stated, descriptive statistics will include number of subjects, mean, standard deviation, minimum, 
median and maximum. In case of n<2, where n indicates the number of evaluable subjects at the 
particular time point, only n, mean, minimum and maximum will be displayed. The statistic 
“Missing” will also be evaluated by enumerating the number of missing entries/subjects, if any at 
that visit, and presented as a summary statistic only for the resulting time points.  
Decimal Precision Convention: The minimum and maximum statistics will be presented to the 
same number of decimal places as the original data. The mean and median will be presented to 
one more decimal place than the original data, whereas the standard deviation will be presented 
to two more decimal places than the original data.  
In summary tables of categorical variables, counts and percentages will be used. The count [n] 
indicates the actual number of subjects with a particular value of a variable or event, which 
should always be less than or equal to the total number of subjects in the respective treatment 
sequence [N]. Percentage will be obtained by: % = (n/N)*100. Unless otherwise stated, all 
percentages will be expressed to one decimal place. 
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                                                                           Protocol Number: XSMP-204
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The closest non-missing measurement (whether from scheduled or unscheduled visit) taken prior 
to the first dose administration will be considered as the baseline value. The Post-baseline values 
are defined as measurements taken after the first administration of study drug. For summarizing 
vital signs follow-up visits, screening value will be considered as baseline, and change from 
baseline to follow-up visit is the change in measurement from baseline (screening) to follow-up 
visit. For other visits, baseline is the measurement taken at pre-dose in each period and change in 
measurement from baseline (pre-dose) to each post-dose in each period.  
The following conventions will be applied to analyses/data presentation: 
All dates will be displayed in DDMMMYYYY format. 
All unscheduled visit data will be presented in Listings, and last repeated unscheduled visit data 
(if applicable) which will be flagged as analysis value will also be used in summarizing data for 
Tables and Figures. 
For Listings, data will be presented by subject, sequence, treatment, period, parameter, 
assessment date in chronological order, but not limited to the above variables. The number of 
variables presented in each listing can vary. Please refer to the Mock tables, listings and figures. 
2.1 Protocol Deviation: 
The Principal Investigator must sign the protocol and its amendments (if any) before initiating 
the study at a particular site. The Investigator will make all reasonable efforts to comply with the 
written protocol. Protocol modifications to ongoing studies that affect the safety of subjects or 
that alter the scope of the investigation, the scientific quality of the study, the experimental 
design, dosing, study assessments, the number of subjects exposed to test drug, or subject 
selection criteria must be made only after consultation between Xeris and the Investigator. All 
protocol modifications must be reviewed and approved by the IRB/IEC before the revised 
protocol can be implemented. Emergency revisions that eliminate an apparent hazard to subjects 
do not require preapproval by the IRB/IEC. However, the IRB/IEC must be notified in writing as 
soon as possible after the modification has been made. A copy of this communication must be 
forwarded to Xeris. All departures from the protocol must be fully documented in the source 
documents and the eCRFs of the subjects involved. Protocol deviations will be tracked in an 
electronic system implemented by the Sponsor or designated representative. Protocol Deviations 
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                                                                           Protocol Number: XSMP-204
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will be summarized as per the impact (Major/Minor) and category across the treatments 
throughout the different phases of the study. This classification is designated by the Sponsor and 
documented prior to locking and unblinding the study. 
A summary of protocol deviations will be created for the CRC phase and Outpatient phase of the 
study using the ITT and Safety population for each phase. 
A listing of subjects with Protocol Deviations (PD) will be provided for both CRC phase and 
Outpatient phase. 
2.2 Handling of Missing Data: 
Imputation of missing data will not be performed. 
To handle missing or partial AE and concomitant medication dates, the following rules will be 
applied. 
For partial start dates: 
1. If the year is unknown, then do not impute the date but assign a missing value. 
2. If the month is unknown, then assign “January.” 
3. If the day is unknown, then assign “01.”  
 For partial end dates: 
4. If the year is unknown, then do not impute the date but assign a missing value. 
5. If the month is unknown, then assign “December.” 
6. If the day is unknown, then assign the last day of the month. 
After implementing the rules above, to determine whether AEs (or medications) with missing 
start or stop dates are pretreatment or on/after treatment, the following strategy will be used: 
1. If the start date and stop date are both missing, then the most conservative approach is 
taken and the AE (or medication) is considered to be treatment emergent (or concomitant 
medication). 
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                                                                           Protocol Number: XSMP-204
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2. If the start date is missing but the stop date is not missing and is on or after the day of 
study dose administration, then the most conservative approach is taken and the AE (or 
medication) is considered to be treatment emergent (or concomitant medication). 
3. If the start date is missing but the stop date is not missing and is before the day of 
study dose and after the date of signed informed consent, then the AE (or medication) is 
considered to be before treatment (or prior medication). 
4. If the start date is not missing but the stop date is missing, then the most conservative 
approach is taken, and medication is considered to be concomitant while the AE is 
defined by start date. 
If the Adverse Event Relationship flag is missing, the relationship for adverse event will be 
defined as related. If the Adverse Event Severity flag is missing, the severity for adverse event 
will be defined as severe. 
2.3 Treatment Group Labelling in TFLs:  
The Treatments in the CRC phase will be labelled as “Treatment A” and “Treatment B” 
The Treatments in the Outpatient phase will be labelled as “Treatment A,” “Treatment B,” 
“Treatment C” in the footnote for the respective TFLs.  A Footnote will be added for the 
treatment columns as below: 
“Treatment A” = “Glucagon RTU (30 μL active - 0.15 mg) with 50% insulin pump reduction” 
“Treatment B” = “Placebo injection (30 μL vehicle) with 50% insulin pump reduction” 
“Treatment C” =” Glucagon RTU (30 μL active - 0.15 mg) without 50% insulin pump reduction” 
2.4 Definition 
Baseline for CRC Phase:  
The Baseline for the CRC Phase is defined as the latest assessment prior to the first 
administration of the study drug in the CRC Phase for period 1, and the first assessment prior to 
the first administration of the study drug in period 2 for the analysis pertaining to CRC Phase, 
unless otherwise stated.  
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Statistical Analysis Plan 
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                                                                           Protocol Number: XSMP-204
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Baseline will be calculated as the average of the blood glucose measurements at: -15 minutes 
(both YSI and BGM) and Time 0 (immediately before exercise) (both).  
Baseline for Outpatient Phase:  
The Baseline for Outpatient Phase is defined as the latest assessment prior to the first 
administration of the study drug in the Outpatient Phase for the analysis pertaining to Outpatient 
Phase, unless otherwise stated. 
If the assessment occurs on the same day as the first study drug administration for either of the 
phases, then the time of assessment should be compared to the time of first dose administration 
for both CRC and Outpatient Phase. 
Baseline will be calculated as the average of the blood glucose measurements (BGMT) at: -15 
minutes and just before the exercise session (Time 0). 
Change from Baseline: The change from baseline values will be calculated as post baseline 
value minus the baseline value. 
If BGM readings are missing from the CRC phase, the YSI readings can be used. 
Shift from Baseline: The shift from baseline is defined as a change in categorical variable from 
baseline to subsequent visits for each subject. 
Percentage Change from Baseline: The percentage change from baseline is defined as the ratio 
of change (Analysis value – Baseline value) and baseline value expressed in terms of percentage. 
% Change from Baseline = ((value – baseline) /baseline) *100;  
Treatment Emergent Adverse Event (TEAE): TEAE is any AE does not present prior to the 
initiation of IMP (Investigation Medicinal Product) administration at CRC phase or any event 
already present that worsens in either intensity or frequency following exposure to the IMP at 
CRC phase. 
An SAE is any AE that results in death, is life-threatening (this refers to an event in which the 
subject was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death had it been more severe), requires inpatient 
hospitalization or prolongation of existing hospitalization, results in persistent or significant 
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Statistical Analysis Plan 
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                                                                           Protocol Number: XSMP-204
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disability/incapacity, is a congenital anomaly/birth defect, is medically important (this refers to 
an event that may not be immediately life-threatening or result in death or hospitalization, but 
may jeopardize the subject or may require intervention to prevent any of the SAEs defined 
above). 
Qualified Exercise Session: For inclusion in the statistical analysis for the per protocol 
population (defined in section 4.1) a qualified exercise session will be defined.  Exercise sessions 
will be performed in both the CRC and Outpatient phases. In the CRC phase, a qualified exercise 
session will be defined as the subject having (1) a blood glucose value of 100-180 mg/dL (5.56 – 
10 mmol/L) prior to starting exercise, (2) completed  45 minutes of exercise (not including 
breaks), (3) achieved a target heart rate of 80% of maximum calculated heart rate at least once 
during the workout session, and (4) fasted at least 8 hours prior to that exercise session. 
Primary analysis in the CRC Phase will be based on the above definition of qualified exercise 
session. Additional subgroup analysis will be applied to analyze exercise sessions in which 
subjects achieved a target heart rate of 80% of maximum calculated heart rate for 30% and 505 
of the exercise time. 
 
In Outpatient phase, a qualified exercise session will be defined as the subject having (1) a 
confirmed blood glucose value of 100-180 mg/dL (5.56 – 10 mmol/L) prior to starting exercise, 
(2) self-administered the study drug no more than 10 minutes prior to exercise (five minutes is 
the target), (3) conducted a protocol allowed exercise for moderate to high intensity for at least 
30 minutes and no longer than 75 minutes, and (4) achieved a target heart rate of 80% of 
maximum calculated heart rate at least once during the session.  If a subject has more than one 
exercise session in a day that is deemed a qualified exercise session, only the first qualified 
exercise session that day will be used in the analysis.  
Primary analysis in the Outpatient Phase will be based on the above definition of qualified 
exercise session. Additional subgroup analysis will be applied to analyze exercise sessions in 
which subjects achieved a target heart rate of 80% of maximum calculated heart rate for 30% and 
50% of the exercise time. 
 
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Target Heart Rate: Per protocol, the goal is to achieve a target of 80% of maximum calculated 
heart rate during the session as shown by the following equation: 
- 
Target Heart Rate = 0.80 x (220 – Age in Years) 
 
Overnight Hypoglycemia: Throughout the study, overnight hypoglycemia will be defined as 
any instance of a subject’s CGM reading changing from being above 70 mg/dL (> 3.89 mmol/L) 
to at or below 70 mg/dL ( ≤ 3.89 mmol/L) between Midnight and 6am (T00:00 – T06:00). Please 
note this definition will enable analysis of multiple instances in a given night. 
 
3. STUDY ENDPOINTS 
As applicable, the 2 (CRC phase) or 3 (Outpatient phase) treatment groups will be compared 
based on the following primary, secondary and exploratory endpoints. 
Primary Endpoint: 
The primary endpoint is the incidence of hypoglycemia (i.e, blood glucose ≤70 mg/dL; 3.89 
mmol/L) associated with an exercise session across 12 weeks of outpatient treatment as 
measured by blood glucose meter (BGM). 
For primary endpoint  analysis the exercise session must meet the criteria defined in Section 2.4 
as being a ‘qualified exercise session’ by requiring (1) a confirmed blood glucose value of 100-
180 mg/dL (5.56 – 10 mmol/L) prior to starting exercise, (2) self-administered the study drug no 
more than 10 minutes prior to exercise (five minutes is the target), (3) conducted a protocol 
allowed exercise for moderate to high intensity for at least 30 minutes and no longer than 75 
minutes, and (4) achieved a target heart rate of 80% of maximum calculated heart rate at least 
once during the session. 
Secondary Endpoints: 
1. Interstitial glucose (IG) levels below target range, measured by unblinded CGM (inpatient 
and outpatient), defined as both time (in minutes) and mean decremental area over the curve 
(AOC (0-300 min) in minutes*mg/dL) during exercise: 
• Below range, as defined by IG ≤ 70 mg/dL (≤ 3.89 mmol/L) 
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• Below range, as defined by IG between 54 to 70 mg/dL (3–3.89 mmol/L) 
• Below range, as defined by IG < 54 mg/dL (<3 mmol/L) 
• Proportional time (percentage time within hypoglycemia IG ≤ 70 mg/dL (3.89 mmol/L) 
and clinically significant hypoglycemia IG < 54 mg/dL (3mmol/L)). 
2. Insulin utilization as reported by subject at baseline, and weeks 4, 8 and 12 in the outpatient 
setting. 
3. Change from Baseline to the end of the Outpatient Phase in PROs: Barriers to Physical 
Activity in Diabetes (Type 1) (BAPAD-1), Hypoglycemia Fear Survey (HFS-II), and 
Hypoglycemic Confidence Scale (HCS). 
Other Secondary Endpoints:  
Change from Baseline in insulin utilization as reported by the subject at Weeks 4, 8, and 12 in 
the Outpatient Phase. 
Exploratory Endpoints: 
1. Mean time and mean proportional time (%) within range, as defined by IG between 70 and 
180 mg/dL (3.89 to 10 mmol/L) (CGM, 0 to 300 minutes with exercise), across the 2 CRC 
treatment arms. 
2. Time, proportional time (percentage), and mean incremental Area Under Curve, plasma 
glucose > 180 mg/dL (10 mmol/L), and (AUC (0-300 min) in minutes*mg/dL) during 
exercise, across the 2 CRC treatment arms and the 3 outpatient treatment arms. 
3. The time, proportional time (percentage), and mean incremental area under the curve (AUC) 
during which plasma glucose >250 mg/dL (AUC (0-300 min) in minutes*mg/dL) during 
exercise, across the 2 CRC treatment arms and the 3 outpatient treatment arms. 
4. Incidence of overnight hypoglycemia as measured by CGM, across the 2 CRC treatment 
arms and the 3 outpatient treatment arms. 
5. Compare the glucose tablet utilization during exercise, across the 2 CRC treatment arms and 
the 3 outpatient treatment arms. 
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6. Compare food (carbohydrate) intake pre/post exercise, across the 3 outpatient treatment 
arms. 
7. Compare number of exercise sessions performed across the 3 outpatient treatment arms. 
a. Conduct subgroup analysis for: 
i. comparison of the number of qualified exercise sessions out of total 
number of exercise sessions conducted 
ii. comparison of the number of qualified sessions meeting less than 30% 
proportional time at target HR 
iii. comparison of the number of qualified sessions meeting greater than or 
equal to 30% proportional time at target HR 
8. Compare number of minutes of exercise performed per week, across the 3 outpatient 
treatment arms. 
9. Compare caloric expenditure during exercise, across 3 treatment arms. 
10. The change from Baseline to end of study in body weight will be measured and analyzed 
across the 3 treatment arms. 
11.  Compare number of steps taken, and the distance achieved during exercise sessions across 
the 3 outpatient treatments arms. 
12. The following assessments during exercise sessions will be captured from the wearable 
activity monitor: heart rate, daily steps, calories burned, distance covered, floors climbed, 
active minutes. 
13. Change from baseline in HbA1c. 
 
Safety Variables: 
• AEs, SAEs (incidence, frequency, severity), and AEs leading to discontinuation. 
• Vital signs (heart rate, blood pressure, respiration rate, temperature). 
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• 12-Lead ECG. 
• Clinical laboratory tests (clinical chemistry, hematology, urinalysis). 
• Physical examination findings. 
• Draize Scales, Injection Site Discomfort and Duration Questionnaires. 
 
4. STATISTICAL METHODOLOGY 
4.1 Definition of Analysis Population  
All Screened Subjects: All Screened subjects will include any subject who signed the informed 
consent form. 
Intention to Treat (ITT) Population: All randomized subjects regardless of whether they 
received Study Drug. 
Per Protocol (PP) Population: ITT participants who completed a qualified exercise session, and 
who was dosed within the study window and did not meet any of the key exclusion criteria at 
screening. The definition of qualified exercise is defined in Section 2.4. 
Safety Population: All randomized subjects who received any amount of Study Drug. 
4.2 Coding Dictionaries Used 
Adverse events and Medical history will be coded using Medical Dictionary for Regulatory 
Activities (MedDRA) version 22.1. 
Prior & concomitant medication will be coded using World Health Organization-Drug Reference 
List (WHO-DRL) (Version WHODD-B3-MAR 2019). 
4.3 Wearable Monitoring Devices 
There are three wearable devices used for collection and analysis of metrics related to the study 
endpoints. Each subject has data collected from a wearable fitness tracker (Fitbit Ionic), 
continuous glucose meter (CGM), and a blood glucose meter (BGM). Endpoint Analysis will 
require confluence of data from these sources and therefore understanding of each is imperative. 
 
4.3.1 Fitbit® Ionic 
 
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The Fitbit is used to collect exercise session metrics, daily activity metrics, and a daily food log. 
Data collected from this source is based on the reporting capabilities of the online portal fitabase. 
The Sponsor Study Specific Procedure-002 defines the process for collecting reports from the 
fitabase source. The metrics collected for analysis are as follows: 
- The Activity Log report is collected to capture Date, Start Time, Duration (in 
milliseconds), Steps, Distance (in kilometres), Elevation Gain (in meters), Calories (in 
kilocalories), Average Heart Rate (beats per minute), and Active Minutes (in minutes) for 
each tracked exercise session. Active Minutes are separated into three categories titled 
Lightly Active, Fairly Active, and Very Active. Specific details for collection and data 
entry related to the Activity Log report are summarized in the 4-Sep-2019 Xeris 
Memorandum titled ‘Fitbit Data Entry Clarification’.  
- The Food Log report is collected to capture Date and the Nutritional Value of the food item 
in Grams of Carbohydrates. Specific Time of food consumption is not tracked. For 
analysis, cumulative carbohydrate intake will be summarized each day of a qualified 
session and compared across the treatment arms.  
- The Heart Rate report is collected to capture Date, Time, and Heart Rate Value. Instances 
of heart rate are collected every minute and will be used to determine qualified exercise 
sessions. 
4.3.2 Dexcom® G5 Continuous Glucose Meter 
 
The CGM is used to collect interstitial glucose measurements on a continuous basis. The source 
data is stored in the cloud-based portal Dexcom CLARITY and outputted as .csv. The Sponsor 
Study Specific Procedure-001 and Study Specific Procedure-003 define the process for 
collecting this data and cleaning it to assure integrity. The metrics collected for analysis are as 
follows: 
- 
Date and Time of Reading, Event Type (EGV or Calibration reading), and Glucose Value 
(in mmol/L). 
Glucose Values for this device are only recorded in the range of 2.2-22.2 mmol/L. Values less 
than 2.2 will be recorded as “Low” and values greater than 22.2 will be recorded as “High.” 
 
4.3.3 Blood Glucose Meter: Bayer® Contour Next One 
 
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The BGM is used to collect blood glucose values during exercise sessions and to confirm blood 
glucose levels indicated by CGM.  These data are being transferred by the Sponsor to the CRO.  
Variables included in this transfer are: 
Date and Time of Reading to 1-minute precision, Blood Sugar (in mmol/L), and Control (binary 
indicator of whether the reading was a controlled calibration). Control readings will be excluded 
from analysis. 
4.3.4 Duplicate Timestamps: 
Some of the reports collected from the wearable devices are related to a specific timestamp. 
Upon routine data management review, it has been identified that some reports contain duplicate 
timestamps and therefore have multiple results tied to one unit of time. Whenever duplicate 
timestamps are encountered in analysis, the mean of all duplicate instances will be calculated and 
used as the result at that given timestamp. The mean result will be rounded to as many decimals 
as the original data. 
 
4.3 Statistical Methods and Data Analysis 
4.3.1 Disposition 
The number and percentage of screened subjects, screen failures, subjects who entered the CRC 
phase, completed the CRC phase, and subjects included in each of the study populations will be 
summarized using the ITT population for CRC phase.  
The number and percentage of subjects who entered the Outpatient phase, completed the 
Outpatient phase and subjects included in the various study populations will be summarized 
using the ITT population for Outpatient phase.  
The number and percentage of subjects who prematurely discontinued from the CRC Phase 
along with reasons for study discontinuation will be summarized by last treatment received using 
the ITT population for CRC phase. 
The number and percentage of subjects who prematurely discontinued from the Outpatient phase 
along with reasons for study discontinuation will be summarized by last treatment received using 
the ITT population for Outpatient phase. 
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For all subjects, analysis population inclusions, disposition and reason for discontinuation will be 
listed for both CRC and Outpatient phase. 
A listing of the subject eligibility (inclusion/exclusion met/not met, reasons for screen failure) at 
CRC phase will be provided. 
4.3.2 Demographics and Baseline Characteristics 
Demographic and baseline characteristics (age [years], sex, ethnicity, race, body weight [kg], 
height[cm], and body mass index [BMI; kg/m2], will be summarized by treatment for the CRC 
phase and Outpatient phase separately using descriptive statistics for subjects in the safety 
population.  Qualitative variables (gender, ethnicity, race, CBP, contraceptive methods) will be 
summarized using frequencies, while quantitative variables (age, weight, height, BMI) will be 
summarized using mean, SD, median, minimum, and maximum. 
The screening tests such as Urine Pregnancy Test (women of childbearing age), HIV, HbA1c, C-
peptide, HCV, HBV and urine drug screen will be listed using all screened subjects for the 
applicable phase (Screening and/or Treatment) of the study. 
4.3.3 Study Drug Administration and Accountability 
A listing will be provided for both CRC and Outpatient phases for study drug administration 
information, including date and time of dosing, dose administered and comment in case dose was 
not administered. 
4.3.4 Medical History 
Listings of Medical History will be provided for all screened subjects. Summary table of Medical 
History will be provided using Safety population. Medical history will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA) version 22.1. 
4.3.5.1 Prior and Concomitant Medications 
All prior and concomitant medications will be presented in separate listings for CRC phase and 
Outpatient phases of the study using Safety population. 
Each medication will be classified as prior, concomitant or both and will be assigned to CRC 
Stage, Outpatient Stage or both. 
Any medication taken within 4 weeks before first study drug administration will be considered as 
prior.  
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Any medication taken on or after the first study drug administration or with a start date prior to 
and ongoing at the time of the first dose will be considered as concomitant. 
In case when start/stop date is incomplete, or medication is ongoing, the following assumption 
will be made for Prior/Concomitant classification: 
- 
If there is reasonable possibility that medication was taken within 4 weeks (28 days) 
before study drug administration, the medication will be considered as prior; 
- 
If there is no evidence that medication was taken before the drug administration, 
medication will not be classified as prior; 
Use of prohibited concomitant medications will be listed using ITT population. Also, prior 
medications will be presented as a separate listing. 
The medication name, dose, units, route, frequency, indication or reason taken, start and end 
dates will be presented. 
Prior and concomitant therapy will be coded using World Health Organization-Drug Reference 
List (WHO-DRL) (Version WHO-DDE Mar-2019). 
4.3.5.1 Rescue Medications 
Standard of care for patients with symptoms of hypoglycemia and confirmed (BGM) blood 
glucose ≤70 mg/dL (3.89 mmol/L) is to take 16g (4 tabs, 4 g/tab) of glucose tabs, and repeat the 
16-g carbohydrate serving every 15 minutes until blood glucose is >70 mg/dL (3.89 mmol/L). 
Use of rescue medications will be presented in separate listings using Safety population.  
 
4.3.6 Primary Endpoint Analysis: 
The primary efficacy hypothesis test for the study is as follows:  
Null Hypothesis: There is no difference between the treatment groups in the mean incidence of 
hypoglycemia (glucose ≤ 70 mg/dL (3.89 mmol/L)) associated with an exercise session 
occurring within the 12 weeks of out-patient treatment as measured by BGM.  
Alternative Hypothesis: There is a difference between treatment groups in the mean incidence of 
hypoglycemia (glucose ≤ 70 mg/dL (3.89 mmol/L)) associated with an exercise session 
occurring within the 12 weeks of out-patient treatment as measured by BGM.  
Incidence rate per subject is calculated by summing the number of exercise sessions completed 
within 12 weeks and dividing this denominator by the number of hypoglycemic events that 
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occurred during those exercise sessions (Incidence Rate = number of exercise sessions / 
inter/post-exercise hypoglycemic events). Events associated with an exercise session are defined 
as hypoglycemic events that occur during or within 30 minutes of exercise completion. 
The primary efficacy analysis will be analyzed by ANOVA comparing the mean incidence rate 
between the three treatment groups. All statistical significance testing will be two-sided with a p-
value <0.05. Efficacy endpoints will be analyzed using the ITT and PP analysis populations for 
Outpatient phase, if performed F-test yields an overall p-value less than 0.05 (p<0.05), post-hoc 
analysis of groups means will be conducted to statistically determine which group means differ. 
 
Parameters that do not meet normality criterion will be analyzed non-parametrically. Overall 
treatment effect will be assessed using Friedman’s test. If the overall treatment effect is 
significant in the Friedman’s test, pairwise treatment comparisons will be assessed using the 
following tests. 
• 
If the difference between two treatments is normally distributed (i.e., the p-value is ≥0.05 
for Shapiro-Wilk test, the Tukey Test will be used. 
 
• 
If the difference between two treatments is not normally distributed and the distribution is 
highly skewed, then the sign test/Kruskal Wallis test will be used.  
 
Example of SAS syntax code that can be used for primary endpoint analysis is provided in 
APPENDIX 1.     
 
4.3.7 Secondary Endpoint Analysis: 
Glucose levels below target range will be measured and analyzed as the mean decremental area 
over the curve (AOC(0-5hrs) in minutes*mg/dL) during exercise. AOC will be estimated using 
Trapezoidal Rule.  
 
Analysis will be conducted for glucose levels below range (interstitial glucose ≤70 mg/dL (3.89 
mmol/L), interstitial glucose between 54-70 mg/dL (3 – 3.89 mmol/L), <54 mg/dL (3 mmol/L)) 
using a contingency table and treatment difference will be calculated using Chi square/Fisher’s 
exact test. 
 
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Proportional time (percentage within serious hypoglycemia <54 mg/dL (3 mmol/L)) will be 
calculated and treatment difference will be calculated using ANOVA/Kruskal–Wallis test, based 
on whether the data is normally distributed or not respectively. 
 
Insulin utilization as reported by subjects in Outpatient phase and change from baseline will be 
analyzed using ANOVA. 
 
The Questionnaires will be analyzed using T Test/ANOVA for CRC/outpatient phase. For 
ANOVA, significant value will lead to a post hoc analysis for identifying the treatment pairs 
which are significantly different. 
 
Changes from baseline in questionnaire values (numeric) will be analyzed by the ANCOVA 
model using treatment arm at Outpatient phase, treatment sequence in CRC phase, sex as factors 
with age, weight and baseline value as covariates. 
Example of SAS syntax code that can be used for secondary endpoint analysis is provided in 
APPENDICES 2.     
 
4.3.8 Exploratory Analysis: 
Glucose levels within range, >180 mg/dl, >250 mg/dl will be measured and analyzed as the mean 
incremental area under the curve (AUC(0-5hrs) in minutes*mg/dL) during exercise.  
Time and Proportional time (percentage within range, >180 mg/dl, >250 mg/dl) will be 
calculated and treatment difference will be calculated using ANOVA/Kruskal–Wallis test, based 
on whether the data is normally distributed or not respectively. 
 
Generally, unless otherwise stated, the mean incidence rates will be compared using the T tests/ 
ANOVA or ANCOVA models using treatment arm at Outpatient phase, treatment sequence, 
obtained by combining the received treatments at CRC and Outpatient phase, sex as factors with, 
if applicable, age and weight as covariates. 
Glucose tablet utilization during exercise, food (carbohydrate) intake pre/post exercise, number 
of exercise sessions completed across the 3 outpatient treatment arms , number of minutes 
exercised per week, number of calories burned per exercise sessions, number of steps, distance 
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covered, heart rate, floors climbed and change from Baseline in body weight will be compared 
for the treatment arms using T tests/ ANOVA at CRC/ Outpatient phase.  
Incidence of overnight hypoglycemia will be compared for the treatment arms using Chi-
Square/Fisher’s exact tests at CRC/ Outpatient phase. 
HbA1c data will be summarized using descriptive statistics (n, mean, SD, median, min, and max) 
for each scheduled study assessment, as well as change from baseline, will be summarized using 
ITT and PP Population.  
Example of SAS syntax code that can be used for exploratory analysis is provided in 
APPENDIX 3.     
 
4.3.9 Safety Analysis 
Adverse Events:  
All analyses will be conducted in the safety population. Adverse events will be recorded from the 
time of consent until completion of study. The number and percentage of subjects with AEs will 
be displayed by body system and preferred term (MedDRA), by study treatment. Summaries in 
terms of severity and relationship to Study Drug will also be provided. All SAEs will be 
summarized in a similar manner. Participant listings of all AEs causing discontinuation of study 
medication and SAEs will be produced. 
All AEs will be listed for individual subjects showing both verbatim and preferred terms. 
Separate summaries of treatment emergent SAEs and TEAEs related to Study Drug will be 
generated. 
AEs will be summarized separately during the CRC treatment visits. Any AE that occurs after 
administration of study drug at Visit 3 and prior to administration of the alternate study drug at 
Visit 4 will be treatment emergent with respect to the study drug received at Visit 3. Any AE that 
occurs after administration of study drug at Visit 4 and prior to the first administration of study 
drug in the out-patient phase will be treatment emergent for the study drug received at Visit 4. 
Any event reported on the eCRF that occurs at the time of or after the initiation of Study Drug in 
the out-patient phase is defined as treatment-emergent for that study drug. Additionally, an AE 
that was reported to have started on Day 1 without an associated onset time is assumed to have 
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occurred after the initiation of Study Drug. Hence, AEs occurring on Day 1 with no associated 
onset time are assumed to be treatment emergent. 
SAEs associated with a protocol specified procedure and occurring after the time of consent but 
before administration of first dose of Study Drug are defined as Non-Treatment Emergent AEs 
(NTEAE).  
Physical Examination: 
All physical examination findings will be provided in the listings. 
12-Lead ECG:  
ECG results will be summarized using frequency counts for Overall Evaluation (normal, 
abnormal NCS, and abnormal CS) by treatment for Screening and EOS using Safety Population.  
All ECG data will be listed for each subject with abnormal values flagged in the listing. 
Vital Signs: 
Vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, temperature) will be 
summarized using the descriptive statistics for each vital sign measurement and change from 
baseline by treatment and timepoint for CRC phase and Outpatient phase using the Safety 
Population.  
Vital Sign data will be listed by timepoint for each parameter and subject by treatment. 
Laboratory: 
Laboratory evaluation results for observed values and change from baseline will be summarized 
descriptively by treatment and visit using Safety Population. Unless otherwise specified, all 
continuous laboratory data will be summarized using descriptive statistics (n, mean, SD, median, 
min, and max) for each scheduled study assessment as well as change from baseline by 
parameter class (Hematology and Biochemistry). Abnormal laboratory values will be 
summarized using frequency and percentage using the safety population. 
Hematology and Chemistry data will be summarized by displaying shifts from baseline value 
(low/normal/high or Normal/Abnormal as applicable) to subsequent assessment. 
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Safety laboratory data (Hematology and Chemistry) will be listed by timepoint for each 
parameter and subject. All abnormal values will be flagged on the listing. Serology, HbA1c and 
C-peptide data will also be listed. 
Draize Scales, Injection Site Discomfort and Duration Questionnaire: 
Erythema formation, Edema formation and Injection Site Discomfort data will be summarized at 
CRC phase using Safety population.  
The Injection Site Discomfort Description and Duration Questionnaire is a 3-question instrument 
that assesses a subject’s level of discomfort and its duration post-injection. There are 5 responses 
for each of the first 2 questions, which address the level of discomfort and the duration of the 
discomfort, respectively, for each injection. For the 3rd question, the total time for the duration 
of discomfort is to be provided.  
All categorical data will be summarized by using and frequency and percentage and continuous 
data will be summarized using descriptive statistics.  
 
4.3.10 Immunogenicity 
Details and results for immunogenicity sample analysis will be provided in a separate analysis 
document. 
 
 
4.3.11 Interim Analysis 
There are no planned interim analyses for this study.  
 
4.4 CHANGES FROM PROTOCOL 
 NA 
 
4.5 REFERENCES 
NA 
 
4.6 APPENDICES 
 
4.6.1 APPENDIX 1. Example of SAS syntax code for primary endpoint analysis.  
The following SAS syntax code can be referred to during programming of primary endpoint 
analysis: 
 
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PROC ANOVA DATA = clover; 
CLASS trt_o; 
MODEL param = trt_o; 
RUN;  
 
Alternative: 
 
PROC GLM DATA = xx; 
 
CLASS trt_o; 
 
MODEL param = trt_o/ ss3; 
 
LSMEANS trt_o / PDIFF CL ALPHA=0.05; 
RUN; 
 
Alternative: 
 
PROC MIXED DATA=school METHOD=type3; 
CLASS trt_o; 
MODEL param= trt_o; 
RUN; 
 
The following SAS syntax example code can be referred to during testing the normality of the 
residuals using the Shapiro-Wilk W-test. 
 
PROC UNIVARIATE DATA=xxxxx NORMAL PLOT;  
VAR yyyyy;  
QQPLOT yyyyy /NORMAL (MU=EST SIGMA=EST COLOR=RED L=1);  
RUN; 
 
 
4.6.2 APPENDIX 2. Example of SAS syntax code for secondary endpoint analysis. 
 
The following macro can be used for the calculation of area over the curve (AOC):  
 
%macro auc (dsn);  
data auctree;  
set &dsn;  
if concentration = 0 and time > tlast then delete;  
x = time;  
y = concentration;  
xpre = lag(x);  
ypre = lag(y);  
xdif = x - xpre;  
if x <= tmax or y = ypre or y =0 or ypre = 0 then do;  
auc = xdif * (( y + ypre ) / 2 );*linear rule;  
end;  
else do;  
auc = xdif * ((y - ypre) / log (y / ypre));  
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end;  
run;  
 
proc summary data = auctree noprint;  
var auc;  
output out = aucest sum = aucL;  
run;  
 
proc sort data = auctree out = part1 nodupkey ;  
by subject ; 
run;  
data AUCs&i (keep = subject period aucL);  
merge part1 aucest;  
run;  
%mend auc;  
 
The following macro can be used to perform estimation according to Trapezoidal Rule:  
 
%macro trap(a,b,n, function); 
data f1; 
do i = 0 to &n ; 
if i = 0 then do; 
x = &a ; 
y = ((&b - &a)/&n )*( &function / 2 ); 
output; 
end; 
else if i = &n then do; 
x = &b ; 
y = ((&b - &a)/&n )*( &function / 2 ); 
output; 
end; 
else do; 
x = ( &a + i * (( &b - &a) / &n ) ); 
y = ((&b - &a) / &n) * &function; 
output; 
end; 
end; 
run; 
proc summary data=f1; 
var y; 
output out=p1 sum=areau;run; 
proc print data=p1; 
run; 
%mend; 
 
The Chi-Square/Fisher’s exact test can be done using the following SAS code example: 
 
PROC FREQ DATA = data; 
 
TABLES param*trt / CHISQ FISHER EXPECTED; 
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WEIGHT count; 
RUN; 
 
Kruskal Wallis test can be performed in SAS using the following reference code: 
 
PROC NPAR1WAY DATA=soil WILCOXON; 
 
CLASS location; 
 
EXACT WILCOXON / MC; 
 
VAR claypct; 
RUN; 
 
T test within the cross over design in CRC phase can be done with the help of the following 
reference code: 
 
PROC TTEST DATA=data PLOTS=interval; 
 
VAR aval1 aval2 / CROSSOVER = (TrtA TrtB); 
RUN; 
 
4.6.3 APPENDIX 3. Example of SAS syntax code for exploratory analysis.  
The ANCOVA model can be analyzed using the following SAS code example: 
 
 PROC MIXED DATA= XXXX; 
CLASS SUBJECT TREATMENT trtSEQ sex; 
MODEL &par= TREATMENT trtSEQ sex age weight/DDFM=SATTERTH; 
RANDOM SUBJECT (SEQ); 
REPEATED / GROUP=TREATMENT SUB=SUBJECT R; 
LSMEANS TREATMENT / CL; 
LSMESTIMATE TREATMENT ‘Treatment A vs. Treatment B’ 1 1 0 /  
CL ALPHA=0.025 E LOWER; 
RUN; 
 
5. LIST OF TABLES, LISTINGS AND FIGURES 
The following is the list of anticipated Tables, Listings and Figures for the study.  Modifications 
may be made to this list to follow the SAP and for revisions with the Sponsor.  If any new 
endpoints or new analyses are requested, they will be evaluated for whether an Amendment to 
the SAP is required.   
 
5.1 Summary Tables  
Number 
Title 
Table 14.1.1.1 
Summary of Subject Disposition for CRC Phase All Screened Subjects   
Table 14.1.1.2 
Summary of Subject Disposition for Outpatient Phase All Screened 
Subjects              
Table 14.1.2.1.1 
Summary of Demographic and Baseline Characteristics for CRC Phase 
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Number 
Title 
Safety Population             
Table 14.1.2.1.2 
Summary of Demographic and Baseline Characteristics for Outpatient 
Phase Safety Population             
Table 14.1.3.1 
Summary of Medical History Safety Population                  
Table 14.1.6.1 
Summary of Protocol Deviations at CRC Phase ITT Population               
Table 14.1.6.2 
Summary of Protocol Deviations at CRC Phase Safety Population           
Table 14.1.6.3 
Summary of Protocol Deviations at Outpatient Phase ITT Population      
Table 14.1.6.4 
Summary of Protocol Deviations at Outpatient Phase Safety Population  
Table 14.2.1.1.1 
Mean Incidence Rate of Hypoglycemia at CRC Phase ITT Population     
Table 14.2.1.1.2 
Mean Incidence Rate of Hypoglycemia at CRC Phase PP Population       
Table 14.2.1.1.3 
Summary of Percent Change from baseline in the 80% target heart rate 
reached at least once during the qualified exercise session CRC Phase 
ITT Population              
Table 14.2.1.1.4 
Summary of Percent Change from baseline in the 80% target heart rate 
reached at least once during the qualified exercise session CRC Phase 
PP Population              
Table 14.2.1.2.1 
Mean Incidence Rate of Hypoglycemia at Outpatient Phase ITT 
Population              
Table 14.2.1.2.2 
Mean Incidence Rate of Hypoglycemia at Outpatient Phase PP 
Population              
Table 14.2.1.2.3 
Summary of Percent Change from baseline in the 80% target heart rate 
reached at least once during the qualified exercise session Outpatient 
Phase ITT Population              
Table 14.2.1.2.4 
Summary of Percent Change from baseline in the 80% target heart rate 
reached at least once during the qualified exercise session Outpatient 
Phase PP Population              
Table 14.2.2.1.1 
Summary of Insulin Utilization at Outpatient Phase ITT Population         
Table 14.2.2.1.2 
Summary of Insulin Utilization at Outpatient Phase PP Population           
Table 14.2.2.2.1 
Summary of BAPAD-1 score for Outpatient Phase ITT Population          
Table 14.2.2.2.2 
Summary of BAPAD-1 score for Outpatient Phase PP Population            
Table 14.2.2.3.1 
Summary of HFS-II score for Outpatient Phase ITT Population                
Table 14.2.2.3.2 
Summary of HFS-II score for Outpatient Phase PP Population                 
Table 14.2.2.4.1 
Summary of HCS score for Outpatient Phase ITT Population                  
Table 14.2.2.4.2 
Summary of HCS score for Outpatient Phase PP Population                  
Table 14.2.3.1.1.1 
Summary of Overnight Hypoglycemia at CRC Phase ITT Population      
Table 14.2.3.1.1.2 
Summary of Overnight Hypoglycemia at CRC Phase PP Population        
Table 14.2.3.1.2.1 
Summary of Incidence of Overnight Hypoglycemia at CRC Phase 
ITT Population 
Table 14.2.3.1.2.2 
Summary of Incidence of Overnight Hypoglycemia at CRC Phase 
PP Population 
Table 14.2.3.2.1.1 
Summary of Overnight Hypoglycemia at Outpatient Phase ITT 
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Number 
Title 
Population 
Table 14.2.3.2.1.2 
Summary of Overnight Hypoglycemia at Outpatient Phase PP 
Population 
Table 14.2.3.2.2.1 
Summary of Incidence of Overnight Hypoglycemia at Outpatient 
Phase ITT Population 
Table 14.2.3.2.2.2 
Summary of Incidence of Overnight Hypoglycemia at Outpatient 
Phase PP Population 
Table 14.2.3.3.1.1 
Summary of Glucose Tablet Usage at CRC Phase ITT Population            
Table 14.2.3.3.1.2 
Summary of Glucose Tablet Usage at CRC Phase PP Population              
Table 14.2.3.3.2.1 
Summary of Glucose Tablet Usage at Outpatient Phase ITT Population   
Table 14.2.3.3.2.2 
Summary of Glucose Tablet Usage at Outpatient Phase PP Population     
Table 14.2.3.4.2.1 
Summary of Changes in Weight at Outpatient Phase ITT Population        
Table 14.2.3.4.2.2 
Summary of Changes in Weight at Outpatient Phase PP Population         
Table 14.2.3.5.2.1.1 
Summary of Exercise Sessions completed at Outpatient Phase ITT 
Population              
Table 14.2.3.5.2.1.2 
Summary of Exercise Sessions by subgroup at Outpatient Phase ITT 
Population              
Table 14.2.3.5.2.2.1 
Summary of Exercise Sessions completed at Outpatient Phase PP 
Population              
Table 14.2.3.5.2.2.1 
Summary of Exercise Sessions by subgroup at Outpatient Phase PP 
Population              
Table 14.2.3.6.2.1 
Summary of Number of Minutes Exercised per week at Outpatient 
Phase ITT Population           
Table 14.2.3.6.2.2 
Summary of Number of Minutes Exercised per week at Outpatient 
Phase PP Population           
Table 14.2.3.7.2.1 
Summary of Number of Calories Burned per Exercise sessions at 
Outpatient Phase ITT Population          
Table 14.2.3.7.2.2 
Summary of Number of Calories Burned per Exercise Sessions at 
Outpatient Phase PP Population          
Table 14.2.3.8.2.1 
Summary of Number of Steps, Distance achieved During Exercise 
Sessions at Outpatient Phase ITT Population         
Table 14.2.3.8.2.2 
Summary of Number of Steps, Distance achieved During Exercise 
Sessions at Outpatient Phase PP Population         
Table 14.2.3.9.1.1 
Summary of Mean Carbohydrate Intake at Outpatient Phase ITT 
Population 
Table 14.2.3.9.1.2 
Summary of Mean Carbohydrate Intake at Outpatient Phase PP 
Population 
Table 14.2.3.9.2.1 
Summary of Carbohydrate Intake by Hypoglycaemic Events at 
Outpatient Phase ITT Population 
Table 14.2.3.9.2.2 
Summary of Carbohydrate Intake by Hypoglycaemic Events at 
Outpatient Phase PP Population 
Table 14.2.3.10.1.1 
Summary of Heart Rate at CRC Phase ITT Population              
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Number 
Title 
Table 14.2.3.10.1.2 
Summary of Heart Rate at CRC Phase PP Population              
Table 14.2.3.10.2.1 
Summary of Heart Rate at Outpatient Phase ITT Population              
Table 14.2.3.10.2.2 
Summary of Heart Rate at Outpatient Phase PP Population              
Table 14.2.3.11.1.1 
Summary of Daily Assessments at CRC Phase ITT Population              
Table 14.2.3.11.1.2 
Summary of Daily Assessments at CRC Phase PP Population              
Table 14.2.3.11.2.1 
Summary of Daily Assessments at Outpatient Phase ITT Population        
Table 14.2.3.11.2.2 
Summary of Daily Assessments at Outpatient Phase PP Population          
Table 14.2.3.12.1.1 
Summary of HbA1c ITT Population 
Table 14.2.3.12.1.2 
Summary of HbA1c PP Population 
Table 14.2.4.1.1 
Analysis of Incidence of Hypoglycemia at CRC Phase ITT Population    
Table 14.2.4.1.2 
Analysis of Incidence of Hypoglycemia CRC Phase PP Population          
Table 14.2.4.1.3 
Analysis of Incidence of Hypoglycemia at Outpatient Phase ITT 
Population              
Table 14.2.4.1.4 
Analysis of Incidence of Hypoglycemia Outpatient Phase PP 
Population                
Table 14.2.4.2.1 
Analysis of Change from baseline in BAPAD-1 score at Outpatient 
Phase ITT Population                
Table 14.2.4.2.2 
Analysis of Change from baseline in BAPAD-1 score at Outpatient 
Phase PP Population                
Table 14.2.4.3.1 
Analysis of Change from baseline in HFS-II score at Outpatient Phase 
ITT Population                
Table 14.2.4.3.2 
Analysis of Change from baseline in HFS-II score at Outpatient Phase 
PP Population                
Table 14.2.4.4.1 
Analysis of Change from baseline in HCS score at Outpatient Phase 
ITT Population                
Table 14.2.4.4.2 
Analysis of Change from baseline in HCS score at Outpatient Phase PP 
Population                
Table 14.2.4.5.1.1 
Analysis of Interstitial Glucose (IG) below Target Range at CRC Phase 
ITT Population 
Table 14.2.4.5.1.2 
Analysis of Interstitial Glucose (IG) below Target Range at CRC Phase 
PP Population 
Table 14.2.4.5.2.1 
Analysis of Interstitial Glucose (IG) below Target Range at Outpatient 
Phase ITT Population 
Table 14.2.4.5.2.2 
Analysis of Interstitial Glucose (IG) below Target Range at Outpatient 
Phase PP Population 
Table 14.2.4.5.3.1 
Analysis of Time within Hypoglycemia at CRC Phase ITT Population 
Table 14.2.4.5.3.2 
Analysis of Time within Hypoglycemia at CRC Phase PP Population 
Table 14.2.4.5.4.1 
Analysis of Time within Hypoglycemia at Outpatient Phase ITT 
Population 
Table 14.2.4.5.4.2 
Analysis of Time within Hypoglycemia at Outpatient Phase PP 
Population 
Table 14.2.4.5.5.1 
Analysis of Interstitial Glucose (IG) within Target Range at CRC 
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Number 
Title 
Phase ITT Population 
Table 14.2.4.5.5.2 
Analysis of Interstitial Glucose (IG) within Target Range at CRC 
Phase PP Population 
Table 14.2.4.5.6.1 
Analysis of Interstitial Glucose (IG) above Target Range at CRC Phase 
ITT Population 
Table 14.2.4.5.6.2 
Analysis of Interstitial Glucose (IG) above Target Range at CRC Phase 
PP Population 
Table 14.2.4.5.7.1 
Analysis of Interstitial Glucose (IG) above Target Range at Outpatient 
Phase ITT Population 
Table 14.2.4.5.7.2 
Analysis of Interstitial Glucose (IG) above Target Range at Outpatient 
Phase PP Population 
Table 14.3.1.1.1 
Overall Summary of Adverse Events at CRC Phase Safety Population     
Table 14.3.1.1.2 
Overall Summary of Adverse Events at Outpatient Phase Safety 
Population              
Table 14.3.1.2.1 
Summary of Treatment Emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term at CRC Phase Safety 
Population     
Table 14.3.1.2.2 
Summary of Treatment Emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term at Outpatient Phase Safety 
Population     
Table 14.3.1.3.1 
Summary of Serious Adverse Events by MedDRA System Organ Class 
and Preferred Term at CRC Phase Safety Population      
Table 14.3.1.3.2 
Summary of Serious Adverse Events by MedDRA System Organ Class 
and Preferred Term at Outpatient phase Safety Population      
Table 14.3.1.4.1 
Summary of Treatment-Emergent Serious Adverse Events by 
MedDRA System Organ Class and Preferred Term at CRC Phase 
Safety Population     
Table 14.3.1.4.2 
Summary of Treatment-Emergent Serious Adverse Events by 
MedDRA System Organ Class and Preferred Term at Outpatient Phase 
Safety Population       
Table 14.3.1.5.1 
Summary of Treatment-Emergent Adverse Events by Highest Severity, 
MedDRA System Organ Class and Preferred Term for CRC Phase 
Safety Population    
Table 14.3.1.5.2 
Summary of Treatment-Emergent Adverse Events by Highest Severity, 
MedDRA System Organ Class and Preferred Term for Outpatient 
Phase Safety Population    
Table 14.3.1.6.1 
Summary of Treatment-Emergent Adverse Events by System Organ 
Class, Preferred Term, Relationship to Study Drug and by Treatment at 
CRC Phase Safety Population    
Table 14.3.1.6.2 
Summary of Treatment-Emergent Adverse Events by System Organ 
Class, Preferred Term, Relationship to Study Drug and by Treatment at 
Outpatient Phase Safety Population    
Table 14.3.1.7.1 
Summary of Deaths due to Treatment-Emergent Adverse Events at 
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Number 
Title 
CRC Phase Safety Population                
Table 14.3.1.7.2 
Summary of Deaths due to Treatment-Emergent Adverse Events at 
Outpatient Phase Safety Population                
Table 14.3.1.8.1 
Summary of Treatment-Emergent Adverse Events Leading to Study 
Discontinuation by MedDRA System Organ Class and Preferred Term 
at CRC Phase Safety Population     
Table 14.3.1.8.2 
Summary of Treatment-Emergent Adverse Events Leading to Study 
Discontinuation by MedDRA System Organ Class and Preferred Term 
at Outpatient Phase Safety Population     
Table 14.3.2.1 
Listing of Deaths at CRC Phase Safety Population     
Table 14.3.2.2 
Listing of Deaths at Outpatient Phase Safety Population     
Table 14.3.2.3 
Listing of Serious Adverse Events at CRC Phase Safety Population     
Table 14.3.2.4 
Listing of Serious Adverse Events at Outpatient Phase Safety 
Population     
Table 14.3.2.5 
Listing of Treatment-Emergent Adverse Events leading to Premature 
Discontinuation of Study Drug at CRC Phase Safety Population     
Table 14.3.2.6 
Listing of Treatment-Emergent Adverse Events leading to Premature 
Discontinuation of Study Drug at Outpatient Phase Safety Population      
Table 14.3.4.1.1 
Summary of Vital Signs at CRC Phase Safety Population      
Table 14.3.4.1.2 
Summary of Vital Signs at Outpatient Phase Safety Population      
Table 14.3.4.2.1 
Summary of Laboratory Data – Hematology Safety Population      
Table 14.3.4.2.2 
Summary of Laboratory Data – Clinical Chemistry Safety Population      
Table 14.3.4.2.3 
Summary of Abnormal Laboratory Findings Safety Population      
Table 14.3.4.3.1 
Summary of 12 Lead ECG Findings Safety Population      
Table 14.3.4.3.2 
Summary of Draize Scales at CRC Phase Safety Population      
Table 14.3.4.3.3 
Summary of Injection Site Discomfort and Duration at CRC Phase 
Safety Population      
Table 14.3.4.4.1 
Summary of Observed Laboratory Data: Shift from Baseline – 
Hematology Safety Population      
Table 14.3.4.4.2 
Summary of Observed Laboratory Data: Shift from Baseline– Clinical 
Chemistry Safety Population      
 
5.2 Listings 
Number 
Title 
Listing 16.2.1.1.1 
Listing of Subject Disposition at CRC Phase All Screened Subjects         
Listing 16.2.1.1.2 
Listing of Subject Disposition at Outpatient Phase All Screened 
Subjects               
Listing 16.2.1.3 
Listing of Qualification Criteria Status at CRC Phase All Screened 
Subjects             
Listing 16.2.1.4 
Listing of Analysis Population at CRC Phase All Screened Subjects 
Listing 16.2.1.5 
Listing of Analysis Population at Outpatient Phase All Screened 
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Number 
Title 
Subjects 
Listing 16.2.1.6 
Listing of Subject Eligibility at CRC Phase All Screened Subjects 
Listing 16.2.2.1 
Listing of Protocol Deviations at CRC Phase All Screened Subjects 
Listing 16.2.2.2 
Listing of Protocol Deviations at Outpatient Phase All Screened 
Subjects  
Listing 16.2.4.1.1 
Listing of Subject Demographic and Baseline Characteristics Safety 
Population               
Listing 16.2.4.1.2  
Listing of Urine Pregnancy at CRC Phase All Screened Subjects              
Listing 16.2.4.1.3 
Listing of Urine Pregnancy at Outpatient Phase All Screened Subjects     
Listing 16.2.4.2.1 
Listing of Medical History All Screened Subjects                 
Listing 16.2.5.1 
Listing of Study Drug Administration for CRC Phase ITT Population      
Listing 16.2.5.2 
Listing of Study Drug Administration for Outpatient Phase ITT 
Population              
Listing 16.2.5.3 
Listing of Prior Medication at CRC Phase Safety Population              
Listing 16.2.5.4 
Listing of Prior Medication at Outpatient Phase Safety Population           
Listing 16.2.5.5 
Listing of Concomitant Medication at CRC Phase Safety Population       
Listing 16.2.5.6 
Listing of Concomitant Medication at Outpatient Phase Safety 
Population              
Listing 16.2.5.7 
Listing of Rescue Medication at CRC Phase Safety Population              
Listing 16.2.5.8 
Listing of Rescue Medication at Outpatient Phase Safety Population        
Listing 16.2.6.1.1 
Listing of BGM Assessments at CRC Phase ITT Population 
Listing 16.2.6.1.2 
Listing of BGM Assessments at Outpatient Phase ITT Population 
Listing 16.2.6.1.3 
Listing of Exercise Sessions at CRC Phase ITT Population 
Listing 16.2.6.1.4 
Listing of Exercise Sessions at Outpatient Phase ITT Population 
Listing 16.2.6.1.5 
Listing of CGM Assessments at CRC Phase ITT Population 
Listing 16.2.6.1.6 
Listing of CGM Assessments at Outpatient Phase ITT Population 
Listing 16.2.6.1.7 
Listing of Draize Scale Scores at CRC Phase ITT Population  
Listing 16.2.6.1.8 
Listing of Injection Site Discomfort and Duration Results at CRC 
Phase ITT Population  
Listing 16.2.6.1.9 
Listing of Venous Blood Glucose (YSI Readings) at CRC Phase 
Listing 16.2.6.1.10 
Listing of Interstitial Glucose (IG) at CRC Phase ITT Population 
Listing 16.2.6.1.11 
Listing of Interstitial Glucose (IG) at Outpatient Phase ITT Population 
Listing 16.2.6.1.12 
Listing of Insulin Utilization at Outpatient Phase ITT Population 
Listing 16.2.6.1.13 
Listing of HbA1c ITT Population 
Listing 16.2.7.1.1 
Listing of Adverse Events at CRC Phase Safety Population               
Listing 16.2.7.1.2 
Listing of Adverse Events at Outpatient Phase Safety Population             
Listing 16.2.8.1.1 
Listing of Laboratory Results: Clinical Chemistry Safety Population        
Listing 16.2.8.1.2 
Listing of Laboratory Results: Hematology Safety Population                 
Listing 16.2.8.1.3 
Listing of Laboratory Results: C-Peptide Safety Population                 
Listing 16.2.8.1.4 
Listing of Laboratory Results: HIV Antibodies Safety Population            
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Number 
Title 
Listing 16.2.8.1.5 
Listing of Urine Drug Screen Results Safety Population                
Listing 16.2.9.1.1 
Listing of Vital Signs at CRC Phase Safety Population                  
Listing 16.2.9.1.2 
Listing of Vital Signs at Outpatient Phase Safety Population                  
Listing 16.2.9.2.1 
Listing of Electrocardiogram (ECG Results Safety Population                 
Listing 16.2.9.3.1 
Listing of Physical Examination Findings Safety Population                  
Listing 16.2.9.3.2 
Listing of Barriers to Physical Activity Diabetes (Type 1) (BAPAD-1) 
Results ITT Population                 
Listing 16.2.9.3.3 
Listing of Hypoglycemia Fear Survey (HFS) Results ITT Population       
Listing 16.2.9.3.4 
Listing of Hypoglycemic Confidence Scale (HCS) Results ITT 
Population                 
Listing 16.2.10.1.1 
Listing of General Comment Log All Screened Subjects                
 
5.3 Figures 
Number 
Title 
Figure 14.2.1.1.1 
Bar Diagram for Mean Incidence Rate by Treatment in CRC Phase ITT 
Population  
Figure 14.2.1.1.2 
Bar Diagram for Mean Incidence Rate by Treatment in CRC Phase PP 
Population 
Figure 14.2.1.2.1 
Bar Diagram for Mean Incidence Rate by Treatment in Outpatient Phase 
ITT Population 
Figure 14.2.1.2.2 
Bar Diagram for Mean Incidence Rate by Treatment in Outpatient Phase 
PP Population 
 
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