Clinical trial NCT02937558
Conditions: Congenital Hyperinsulinism
Keywords: hypoglycemia
Sponsor: Xeris Pharmaceuticals
Start date: 2016-10-01; Completion date: 2018-10-01
Enrollment: 5 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 2, multi-center, randomized, placebo-controlled, double-blind trial with open-label follow-up designed to assess the efficacy of Xeris Glucagon delivered as a continuous subcutaneous infusion to prevent hypoglycemia with lower intravenous glucose infusion rates in children \< 1 year of age with congenital hyperinsulinism.

Detailed description:
This is a Phase 2, multi-center, randomized, placebo-controlled, double-blind (DB) parallel group study with open-label follow-up designed to evaluate the efficacy of CSI-Glucagon™ for the prevention of hypoglycemia with lower IV glucose infusion rates when delivered subcutaneously to patients up to 1 year of age with congenital hyperinsulinism. CSI-Glucagon™ is expected to provide a better inpatient treatment option compared to the current standard of care.

The study will consist of three phases:

1. Baseline Phase: First is a baseline stabilization phase during which concomitant therapy with octreotide and diazoxide will be safely weaned and continuous enteric feed will be held constant to the degree possible, with the only factors varying being meal size and IV glucose infusion rate (GIR) adjusted by a set plasma glucose measurement driven algorithm.
2. Blinded, Randomized Treatment Phase: Following the stabilization phase, subjects will be randomly assigned to blinded treatment with either glucagon or placebo, which will be delivered for up to 48 hours with an OmniPod® infusion pump with the controller set to a starting basal rate for glucagon of 5 μg/kg/hr and GIR adjustments used to maintain euglycemia. After 48 hours of blinded treatment, all subjects will transition to open-label active treatment. However, if GIR reduction from baseline is \< 20% at 24 hours, subjects will be transitioned early to the open-label phase.
3. Open-label Treatment Phase: The third study period will involve use of CSI-Glucagon™ to manage blood glucose with minimal GIR for up to 28 days of cumulative exposure.

Arms: arm 1: Glucagon solution delivered as a continuous subcutaneous infusion via a patch pump at a starting dosage of 5 mcg/kg/hr. arm 2: Vehicle solution delivered as a 24-hour continuous subcutaneous infusion via a patch pump. arm 3: Glucagon solution delivered as a continuous subcutaneous infusion via a patch pump at a starting dosage of 5 mcg/kg/hr.
Interventions: intervention 1: Glucagon intervention 2: Placebo
Intervention descriptions: intervention 1: Room-temperature-stable, non-aqueous injectable liquid formulation of synthetic glucagon peptide intervention 2: Isotonic saline

Protocol documents:
Prot_SAP_000.pdf: 
Protocol XSGO-CH01 v1.7 
 
09 Feb 2018 
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1. 
TITLE PAGE 
PROTOCOL XSGO-CHO1 
 
A PHASE 2 PROOF-OF-CONCEPT STUDY OF CSI-
GLUCAGON™ (CONTINUOUS SUBCUTANEOUS 
GLUCAGON INFUSION) TO PREVENT 
HYPOGLYCEMIA WITH LOWER INTRAVENOUS 
GLUCOSE INFUSION RATES IN CHILDREN UP TO 
ONE YEAR OF AGE WITH CONGENITAL 
HYPERINSULINISM 
 
 
 
 
 
 
 
 
 
 
Version 1.7 
February 9, 2018 
 


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INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for CSI-Glucagon™ (continuous 
subcutaneous glucagon infusion).  I have read protocol XSGO-CH01 Version 1.7 dated February 
9, 2018 and agree to conduct the study as outlined.  I agree to maintain the confidentiality of all 
information received or developed in connection with this protocol.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 


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PROCEDURES IN CASE OF EMERGENCY 
Table 1: 
Emergency Sponsor Contact Information 
Role in Study 
Name & Title 
Email Address & Telephone Number 
Sponsor’s Study Leader & 
primary contact 
Martin J. Cummins, 
VP, Drug Development 
mcummins@xerispharma.com 
512-498-2675 or 806-282-2120 
Medical Monitor & 
24-hour emergency contact 
Dr. Poul Strange, 
Medical Consultant 
Pstrange@imdcro.com  
609-897-0505 x 213, fax 609-897-0555 
 


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2. 
SYNOPSIS 
Protocol Number XSGO-CH01 
A Phase 2 Proof-of-Concept Study of CSI-Glucagon™ (continuous subcutaneous glucagon 
infusion) to Prevent Hypoglycemia with Lower Intravenous Glucose Infusion Rates in Children 
up to One Year of Age with Congenital Hyperinsulinism 
Principal 
Investigators:   
Each participating clinical site will nominate a physician who, based on 
training and experience, will serve as principal investigator for that site. 
IND: 
123039 
Project phase: 
Phase 2 
Compound(s):   
CSI-Glucagon™ (continuous subcutaneous glucagon infusion)  
Objectives: 
The primary objective is to assess the efficacy of CSI-Glucagon™ delivered 
with an OmniPod® pump as a continuous subcutaneous (sc) glucagon 
infusion to prevent hypoglycemia with lower intravenous glucose infusion 
rates (GIRs) in patients < 1 year of age with congenital hyperinsulinism, as 
compared to placebo. This primary objective will be assessed by comparing 
the treatments for the ability to reduce baseline GIR by at least 20% within 
24 hours, and at least 33% within 48 hours of the initiation of treatment.    
The secondary objectives include the following: 
• Compare average proportional GIR reduction from baseline between 
CSI-Glucagon™ and placebo. 
• Confirm the dosing algorithms for CSI-Glucagon™ delivered with 
an infusion pump in infants and neonates when used to lower the 
GIR required to maintain euglycemia (blood glucose ≥ 70 µg/dL) or 
extend the fasting period in patients who are on a stable drug 
regimen over a period of 2 days.  
• Compare the groups for the percentage of subjects that achieve GIR 
≤ 8 mg/(kg*min) during treatment.  
• Compare the groups for the percentage of subjects that achieve daily 
total caloric intake from carbohydrate, combining oral, tube and IV 
sources ≤ 8 mg/(kg*min) glucose. 
• Assess safety of pump switch out procedures as assessed by 
occurrence of glucose < 50 mg/dL. 
• Assess safety and tolerability of glucagon delivered with the 
OmniPod® for up to 28 days of cumulative use. 


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• Assess performance of the OmniPod®, including accuracy of dose 
delivery and the rate of failures/malfunctions. 
Study design:   
This will be a Phase 2, multi-center, randomized, placebo-controlled, 
double-blind trial with open-label follow-up designed to assess the efficacy 
of CSI-Glucagon™ delivered with an OmniPod® pump as a continuous 
subcutaneous glucagon infusion to prevent hypoglycemia with lower 
intravenous GIRs in patients < 1 year of age with congenital hypoglycemia. 
The study will consist of three periods: 
1. A baseline stabilization phase during which concomitant therapy 
with glucagon, octreotide and diazoxide will be discontinued and 
continuous “basal” enteric feed will be held constant to the degree 
possible, with the only factors varying being meal size and IV GIR. 
Basal enteric feed will be held constant to the degree possible during 
the study, except for extending the fast after meal feeding when GIR 
= 0. 
2. The first 2-day period during which randomized, blinded treatment is 
given and GIR adjustments are used to maintain euglycemia. 
3. An open-label treatment period during which CSI-Glucagon™ may 
be delivered to manage glucose levels and minimize glucose 
infusions for a maximum of 28 days of cumulative treatment until a 
long-term management plan is in place. 
Study locations: 
Approximately 6 pediatric medical centers in the US. . 
Study duration: 
The total length of the study will be up to 5 weeks per patient, and total time 
on drug will be up to 28 days.  The total time for enrollment and treatment to 
reach the planned interim analysis will be approximately 12 months per site. 
Sample size: 
This is a parallel group adaptive design with one interim analysis after 6 
subjects fulfilling final protocol GIR selection criteria in each study arm 
have completed their post-treatment success-failure determination.    
Depending on the comparison of the treatment and placebo failure rates the 
study will either be stopped with an early claim for treatment efficacy, or 
continued with either 3 or 6 additional subjects per study arm so that the 
final comparison of failure rates will be based on 9 or 12 subjects per study 
arm.  This final sample size will be based on the outcome of the interim 
analysis.   
The criteria for stopping early at 6 subjects per group or continuing to a final 
sample size of 9 or 12 subjects per group was designed so that the type 1 
error is no larger than 0.025 for treatment = control failure rates at any 
failure rate value.  The overall power for concluding that the treatment 
failure rate is less than control is over 98% if the placebo failure rate is at 
least 0.9 and the treatment rate is no more than 0.1, with early efficacy 


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having a power of 66%.   If the placebo failure rate is at least 0.95 and the 
treatment rate is no more than 0.05 then the chance for an early efficacy 
determination is 88%.     
Subjects: 
Hospitalized infant male or female patients with congenital hyperinsulinism 
less than 1 year of age at screening. 
Inclusion 
Criteria: 
1) Patients diagnosed with hyperinsulinism  
a. Biochemical; detectable insulin (i.e., ≥1 mU/L) at time of 
hypoglycemia (i.e. blood glucose <50 mg/dL), and/or suppressed 
FFA, and/or suppressed BOHB and/or glycemic response to 
glucagon at time of hypoglycemia 
     and  
2) Absolute necessity of intravenous glucose to prevent hypoglycemia as 
defined as attempts at weaning being unsuccessful. 
a. Having failed diazoxide therapy. 
b. Subject may be on diazoxide and/or octreotide, but these will be 
weaned off prior to randomization. 
c. Subject may be on dextrose feeds.  
3) Patient may be a participant in other study protocols such as observational 
studies, as long as no investigational intervention has taken place within 24 
hours of screening. 
4) Less than 12 months of age at screening. 
Exclusion 
Criteria: 
1) Patients with history of allergy to glucagon or the excipients in Xeris’ 
glucagon formulation. 
2) Patients currently receiving, or less than 12 hours removed from IV 
glucagon treatment that resulted in a best achievable GIR > 8 mg/(kg*min), 
prior to the start of study drug. 
3) Patients who are diazoxide naïve. 
4) Patients within five days of starting diazoxide. 
5) Patients on steroids at doses larger than 20 mg/m2/day (hydrocortisone 
equivalent). 
6) Patients with sepsis.  
7) Patients on Alpha or beta agonists for blood pressure support. 
8) Patient received an investigational drug or a study drug within 5 half-lives 
of drug. 
9) Weight less than or equal to 2.3 kg/5.0 lbs 
10) Subjects with a history of pancreatectomy and a GIR < 8 mg/(kg*min) 


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after weaning of all concomitant therapies.  
Brief outline of 
treatments: 
 
Methods: 
Period 1. Baseline 
Day -1: 
Octreotide and diazoxide will be safely withdrawn. Continuous “basal” 
enteric feed will be held constant unless when GIR=0. Subjects will 
consume meals as needed and GIR will be adjusted to achieve pre-meal 
glucose minimally above 70 mg/dL. 
Determine minimal stable GIR required to keep glucose >70mg/dL by 
weaning the IV glucose Q3H pre-feeds (or Q3H if on continuous feeds). 
During all study periods, point-of-care (POC) blood glucose will be 
monitored by use of the Nova StatStrip® Hospital Glucose Measuring 
System, ACCU-CHEK Inform II, or an equivalent system. As per standard 
care practices, blood glucose will be checked every 3 hours at a minimum, 
or more frequently at the discretion of the PI as the clinical situation dictates. 
Wean IV fluids as follows: 
• if POC glucose is >70 mg/dL (3.3 mmol/L) and < 90 mg/dL (5 
mmol/L), reduce the GIR 1 mg/kg/min and check blood glucose in 3 
hours.   
• if POC glucose is >90 mg/dL (5 mmol/L) and <120 mg/dL (6.7 
mmol/L), reduce the GIR by 2 mg/kg/min and check blood glucose 
in 1 hour.  
• if POC glucose is >120 mg/dL (6.7 mmol/L), reduce GIR by 3 
mg/kg/min and check the blood glucose in 1 hour. 
• If GIR is unable to be reduced because glucose level is <70mg/dL 
(3.9 mmol/L), increase GIR by 2 mg/kg/min and check blood 
glucose in 1 hour. 
• If glucose is <50 mg/dL (2.8 mmol/L), give 200 mg/kg dextrose by 
IV push, increase GIR by 2 mg/kg/min, and check blood glucose in 
30 minutes. 
More frequent, or smaller, GIR changes may be done at the investigator’s 
discretion should the clinical condition so require.  
The average of the GIR levels after the initial 2 hours will be considered as 
the baseline GIR. Should time of day scheduling make transition to the 
randomized period 2difficult, the investigator has discretion to keep the 
subject at a “safe” GIR, which is higher than the minimal rate determined 
during weaning, until transition to period 2 can be achieved without risk of 
protocol deviations.  The identified baseline GIR must be achieved twice 
within ±20% before proceeding to period 2. 


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Period 2. Randomized Treatment 
Day 0: 
• Insert CGMS (Dexcom® G4 Platinum) and calibrate per 
manufacturer. The CGM will be used for rapid alerts, which will 
trigger POC assessments of blood glucose that will be used to guide 
clinical decisions. At the investigator’s discretion, this may be 
inserted during Period 1. 
• Obtain randomization and OmniPod® containing randomized 
treatment. 
• When CGM has stabilized (minimally 2 hours) and is reporting 
glucose values, draw blood for plasma insulin and glucagon levels 
and immunogenicity testing prior to application of the OmniPod® 
pump. 
• Photograph the site of approximate cannula insertion prior to 
application of the patch pump. 
• Using the appropriate syringe (see Section 9.3.3), the treatment 
dispenser should load a fresh OmniPod® pump with 1 mL CSI-
Glucagon™ solution (5 mg/mL concentration) or placebo as per the 
randomization scheme, and provide the loaded pump to study staff. 
• Study staff will weigh the loaded pump to the nearest whole mg (see 
Appendix 2), and then apply the OmniPod® pump containing CSI-
Glucagon™ solution or  placebo to the abdomen of the subject (see 
Section 9.1).  
• Use the PDM to instruct the pump to insert the cannula and ensure 
deployment as follows:   
o Listen for an audible “click.” 
o Confirm pink slide insert has moved into the window on the 
surface of the pump, indicating deployment. 
o Use the clear window on one end of the pump to view the 
inserted cannula. 
• Once cannula deployment is confirmed, set basal rate at 5 μg/kg/hr 
(t=0). 
• Monitor POC glucose every hour for the first three hours after study 
drug start and every 3 hours thereafter; or more frequently if the 
CGM shows glucose trending towards <70 mg/dL (3.9mmol/L) or 
>200 mg/dL (11.1mmol/L).  
• Adjust IV fluids as per period 1 with the following additions: 
o if POC glucose is >70 mg/dL (3.3 mmol/L) and GIR=0, 
introduce and/or extend the fast after meal feeding as long as 


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possible, while maintaining POC glucose > 70 mg/dL. 
o If GIR cannot be reduced because glucose level is <70mg/dL 
(3.9 mmol/L), restore continuous enteric feeding if that has 
been suspended, or both increase GIR by 2 mg/kg/min and 
increase study drug infusion rate by 5 µg/kg/hr (up to a 
maximum of 20 µg/kg/hr) and check blood glucose in 1 hour. 
o If glucose is <50 mg/dL (2.8 mmol/L), give 200 mg/kg 
dextrose by IV push, increase GIR by 2 mg/kg/min, increase 
study drug infusion rate by 5 µg/kg/hr (up to a maximum of 
20 µg/kg/hr) and check blood glucose in 30 minutes. 
• At 12 hours after initial start of study drug, if GIR has not been 
reduced by < 20% from the baseline value determined in Period 1: 
o Remove and weigh the pump and replace it with a new one 
and a fresh supply of the same, blinded study drug at the 
same flow rate setting as the previous pump. 
o Monitor POC glucose over the next 12 hours, adjust GIR 
using the same rules as above for making IV fluid 
adjustments in the interim. 
Day 1:  
At 24 hours after the start of study drug, if average GIR has been reduced by 
< 20% from the baseline value determined in Period 1, complete the 
following procedures: 
• Draw blood for plasma insulin and glucagon levels as well as CBC 
and CMP. 
• Remove and weigh the OmniPod® pump (Appendix 2) and: 
o Photograph the application site, paying particular attention to 
the cannula insertion site. 
o Assess site for edema and erythema using the Draize scale. 
Any Draize scores >0 should be followed to resolution, 
including a follow-up photograph. 
• Proceed to Period 3 (see 10.2.3).  
 
If GIR has been reduced by ≥ 20% from the baseline value determined in 
Period 1, complete the following procedures: 
• Continue to adjust the GIR during day 1 as per day 0.  
• If IV glucose is weaned off, introduce and/or extend the fast after 
meal feeding as long as possible while maintaining POC glucose > 
70 mg/dL. 
• Should the plasma glucose continue to rise, the study drug infusion 


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rate may be reduced by 2.5 μg/kg/hr every 6 hours, as long as the 
pre-feed blood glucose can be maintained >70 mg/dL (3.3 mmol/L) 
At 48 hours after the initial start of blinded study drug, complete the 
following procedures: 
• Draw blood for plasma insulin and glucagon levels as well as CBC 
and CMP. 
• Remove the OmniPod® pump and weigh it to the nearest whole mg. 
• Photograph the application site and assess for edema and erythema 
using the Draize scale, with particular attention to the cannula 
insertion site. 
Period 3. Open-label Treatment 
Note: For subjects not meeting the criteria for response at 24 hours, the 
open-label period will begin after 24 hours of blinded study drug. For 
subjects meeting the criteria for response at 24 hours, the open-label period 
will begin after 48 hours of blinded study drug. 
At the start of day open-label treatment: 
• Using the same procedures for loading and weighing the pump, and 
confirming cannula deployment as detailed for Day 0, place a new 
OmniPod® pump containing CSI-Glucagon™ solution (5 mg/mL 
concentration) and run for 4 hours.  
• Basal rate should initially be set at 5 μg/kg/hr with hourly POC 
glucose measurements and fluid adjustments as per Period 2. 
• At 4 hours, remove and the OmniPod® pump and: 
o Photograph the application site, paying particular attention to 
the cannula insertion site. 
o Assess site for edema and erythema using the Draize scale. 
Any Draize scores >0 should be followed to resolution, 
including a follow-up photograph. 
• Determine whether, in the investigator’s assessment, continued 
treatment is helpful for clinical care. 
o If yes, and open-label treatment will be continuing, perform 
“real-world” pump change-out procedure (see Section 9.3.3). 
o If no, and open label treatment is ending, remove CGM and 
draw blood for immunogenicity testing, plasma insulin and 
glucagon levels as well as CBC and CMP. Do not perform 
the “real-world” pump change-out procedure in this case. 
• If yes, therapy may continue, including intermittently should 
procedures, e.g., PET scan, require temporary discontinuation, for up 
to a cumulative 28 days of glucagon exposure. 


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o A new OmniPod® pump containing CSI-Glucagon™ 
solution should be placed at least every 72 hours. The 
procedures for loading and weighing the pump and 
confirming successful cannula deployment should be 
followed each time a new pump is placed. 
o Each time a pump it replaced, determine safety of pump 
switch out procedures as assessed by occurrence of blood 
glucose < 50 mg/dL. 
o Each time a pump is removed, including at final termination 
of therapy, it should be weighed to the nearest whole mg, and 
the placement site should be photographed and assessed with 
Draize scales. 
o At least 2 hours prior to each planned pump change, confirm 
the CGM sensor is working and place another as needed. 
o Every 7 days during treatment, dosing will be adjusted as 
applicable based on current subject body weight. 
o Every 2 weeks during treatment, draw a 1 mL blood sample 
for immunogenicity testing. 
• Each time study treatment is paused, and when treatment ends, draw 
blood for immunogenicity testing, plasma glucagon and insulin 
levels as well as CBC and CMP, resume IV fluids at pre-study rate 
and then manage glucose as per standard procedures. 
Period 4, Post-treatment Immunogenicity Testing 
• At 28 ±14 days after the last dose of study drug, the subject should 
have blood drawn for immunogenicity testing. This blood draw can 
be done at a local hospital, laboratory or clinic, or by home health 
care professional if subject is not able to return to the clinical site due 
to travel considerations. 
Bio-statistical 
Considerations: 
For each subject, the average GIR will be computed for periods 1 (baseline) 
and 2 (treatment) by determining the area under the curve of GIR excluding 
the first 2 hours versus time and then dividing by the time duration for each 
of the periods excluding the first 2 hours, using the last 24 hours for each 
period, or if less than 24 hours is available, the available data, excluding the 
first 2 hours.  The primary comparison of treatment and placebo will be 
based on a success-failure determination (see Section 5.1).  The primary 
comparison will be based on the observed treatment and placebo failure 
rates, using subjects having enough information from periods 1 and 2 to 
determine success or failure. 
This is a parallel group adaptive design with one interim analysis after 6 
subjects in each study arm have completed their success-failure 
determination.  If, at the interim analysis, the observed treatment failure rate 


Protocol XSGO-CH01 v1.7 
 
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is lower than placebo so that the one-tailed p value is less than or equal to 
0.0124 (Fisher's exact test, hypergeometric distribution based on the total 
number of observed failures) then the study will be stopped due to early 
demonstration of treatment efficacy. 
If this interim hypergeometric one-tailed p value is greater than 0.0124 but 
less than or equal to 0.05, then the study will continue and an additional 3 
more subjects per study arm will be randomized.  If this interim one-tailed p 
value exceeds 0.05 then the study will continue, and an additional 6 subjects 
will be randomized.   The final analysis will be based on the observed 
treatment and placebo failure rates using all subjects with a success-failure 
determination.   If, at the final analysis, the observed treatment failure rate is 
lower than placebo so that the one-tailed hypergeometric p value is less than 
or equal to 0.04 then treatment efficacy will be established  
The actual type 1 errors are smaller than the efficacy criteria would suggest 
because of the small sample sizes and the use of Fisher's exact test.  From 
Monte-Carlo simulations the overall type 1 error for this design is bounded 
above by 0.016 for null hypothesis treatment = placebo failure rates at any 
failure rate using the above criteria. 
Secondary analyses will include baseline adjusted analyses of the natural 
logarithm of GIR to obtain confidence bounds on ratio of treatment to 
placebo mean GIR.   Other secondary endpoints will consider the average 
GIR over the last 24 hours during period 2.  The chance that this final rate is 
less than 8 mg/kg/min will be estimated and compared.  Also, the 
cumulative glucose infusion will be combined with the total enteric feeding 
for the last 24 hours.  The chance that this combined value is less than or 
equal to 8 mg/kg/min will be estimated and compared. 
Pharmacokinetic (PK) data of steady state glucagon concentrations 
following continuous subcutaneous infusion will be analyzed descriptively. 
Safety analysis: all subjects who have received at least one dose of study 
medication will be included.  Safety data will be presented in tabular and/or 
graphical format and summarized descriptively.  For continuous data, 
change from baseline will be analyzed using analysis of covariance.  The 
proportion of study participants experiencing a particular AE will be 
compared by group (dose) using Fisher’s Exact Test. 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................4 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............13 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................18 
5. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................20 
5.1. 
Primary Objective .......................................................................................................20 
5.2. 
Secondary Objectives .................................................................................................20 
6. 
BACKGROUND AND RATIONALE .......................................................................22 
6.1. 
Indication ....................................................................................................................22 
6.1.1. 
Background .................................................................................................................22 
6.1.2. 
Rationale .....................................................................................................................22 
6.2. 
Nonclinical Pharmacology and Toxicology Experience with Glucagon ....................23 
6.3. 
Nonclinical Pharmacology and Toxicology Experience with CSI-
Glucagon™ .................................................................................................................24 
6.3.1. 
Nonclinical Pharmacology ..........................................................................................24 
6.3.2. 
Description and Composition of Drug Product ..........................................................24 
6.4. 
Clinical Experience with Glucagon ............................................................................24 
6.4.1. 
Clinical Experience with Approved Glucagon Products ............................................24 
6.4.2. 
Clinical Experience with Approved Glucagon Products used Off-label to 
Treat Congenital Hyperinsulinism ..............................................................................24 
6.4.3. 
Clinical Experience with XeriSol™ Glucagon ...........................................................26 
6.4.4. 
Clinical Pharmacology ................................................................................................26 
7. 
STUDY DESIGN .......................................................................................................27 
7.1. 
Study Overview ..........................................................................................................27 
7.2. 
Interruption and Termination of Dosing .....................................................................27 
8. 
ELIGIBILITY CRITERIA AND STUDY ENROLLMENT .....................................29 
8.1. 
Inclusion Criteria ........................................................................................................29 
8.2. 
Exclusion Criteria .......................................................................................................29 
8.3. 
Randomization Criteria ...............................................................................................30 


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9. 
STUDY TREATMENTS............................................................................................31 
9.1. 
Allocation to Treatment ..............................................................................................31 
9.2. 
Blinding ......................................................................................................................31 
9.3. 
Drug Supplies .............................................................................................................31 
9.3.1. 
Drug Product Formulation and Packaging .................................................................31 
9.3.2. 
Drug Delivery Devices ...............................................................................................31 
9.3.3. 
Preparation, Dispensing and Administration ..............................................................32 
9.3.4. 
Device Reliability .......................................................................................................33 
9.3.5. 
Drug Storage and Drug Accountability ......................................................................33 
9.4. 
Concomitant Medications ...........................................................................................33 
10. 
STUDY PROCEDURES ............................................................................................34 
10.1. 
Screening Visit ............................................................................................................34 
10.2. 
Treatment and Evaluation Phase ................................................................................34 
10.2.1. 
Period 1: Baseline GIR (Day -1) ................................................................................34 
10.2.2. 
Period 2: Blinded, Randomized Treatment (Days 0-1) ..............................................35 
10.2.3. 
Period 3: Open-label Treatment ..................................................................................37 
10.2.4. 
Period 4, Post-treatment Immunogenicity Testing .....................................................39 
10.3. 
Subject Withdrawal ....................................................................................................39 
11. 
ASSESSMENTS.........................................................................................................41 
11.1. 
Blood Volume .............................................................................................................41 
11.2. 
Clinical Laboratory Tests ...........................................................................................42 
11.3. 
Vital Signs ..................................................................................................................43 
11.4. 
Photographs ................................................................................................................43 
12. 
SAFETY AND ADVERSE EVENT (AE) REPORTING..........................................45 
12.1. 
Adverse Events ...........................................................................................................45 
12.2. 
Reporting Period .........................................................................................................45 
12.3. 
Definition of an Adverse Event ..................................................................................45 
12.4. 
Serious Adverse Events ..............................................................................................46 
12.5. 
Severity Assessment ...................................................................................................46 
12.6. 
Causality Assessment .................................................................................................47 
12.7. 
Withdrawal Due to Adverse Events ...........................................................................47 
12.8. 
Eliciting Adverse Event Information and Reporting ..................................................47 
12.9. 
Serious Adverse Event Reporting Requirements .......................................................47 


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12.10. 
Non-Serious Adverse Event Reporting Requirements ...............................................48 
12.11. 
Sponsor Reporting Requirements to Regulatory Authorities .....................................48 
12.12. 
Pregnancy ...................................................................................................................48 
12.13. 
Subject Monitoring .....................................................................................................48 
12.14. 
Medical Device Reports .............................................................................................48 
13. 
DATA ANALYSIS AND STATISTICAL METHODS ............................................50 
13.1. 
Sample Size Determination ........................................................................................50 
13.2. 
Statistical Analyses .....................................................................................................50 
13.2.1. 
Primary Endpoint (Pharmacodynamic) ......................................................................50 
13.2.2. 
Secondary Endpoints (Pharmacodynamic) .................................................................51 
13.2.3. 
Pharmacokinetics ........................................................................................................51 
13.2.4. 
Device Performance ....................................................................................................51 
13.2.5. 
Safety/Tolerability ......................................................................................................52 
13.2.5.1. 
Adverse events: ...........................................................................................................52 
13.2.5.2. 
Laboratory safety assessments:...................................................................................52 
13.2.5.3. 
Physical examination: .................................................................................................52 
13.2.5.4. 
Vital signs: ..................................................................................................................52 
13.2.5.5. 
Local Tolerability .......................................................................................................52 
13.3. 
Subgroup Analysis ......................................................................................................52 
13.4. 
Interim Analysis ..........................................................................................................52 
14. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................54 
15. 
DATA HANDLING, RECORD KEEPING, MONITORING AND AUDITS ..........55 
15.1. 
Case Report Forms/Electronic Data Record ...............................................................55 
15.2. 
Records Retention .......................................................................................................55 
15.3. 
Monitoring ..................................................................................................................56 
15.4. 
Data Safety Monitoring Board ....................................................................................56 
15.5. 
Audits and Inspections ................................................................................................56 
16. 
ETHICAL CONSIDERATIONS................................................................................58 
16.1. 
Conduct .......................................................................................................................58 
16.2. 
Institutional Review Board (IRB) ...............................................................................58 
16.3. 
Subject Information and Consent ...............................................................................58 
16.4. 
Subject Recruitment ....................................................................................................59 
16.5. 
Reporting of Safety Issues and Serious Breaches of the Protocol ..............................59 


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17. 
DEFINITION OF END OF TRIAL ...........................................................................60 
18. 
PROCEDURES FOR MODIFYING THE PROTOCOL OR 
TERMINATING THE STUDY .................................................................................61 
18.1. 
Protocol Modifications and Deviations ......................................................................61 
18.2. 
Study Termination ......................................................................................................61 
19. 
PUBLICATION OF STUDY RESULTS ...................................................................62 
20. 
REFERENCES ...........................................................................................................63 
21. 
APPENDICES ............................................................................................................64 
APPENDIX 1. DRAIZE SCALE ................................................................................................64 
APPENDIX 2. OMNIPOD® WEIGHING PROCEDURES ......................................................65 
 


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LIST OF TABLES 
Table 1: 
Emergency Sponsor Contact Information ....................................................................3 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................18 
Table 3: 
OmniPod® Controller Settings ...................................................................................32 
Table 4: 
Schedule of Assessments and Procedures ..................................................................40 
Table 5: 
Volume of Blood Collections for Study-Specific Testing ..........................................42 
Table 6: 
Clinical and Safety-related Laboratory Tests to be Performed ..................................43 
Table 7: 
Adverse Effects Assessment .......................................................................................46 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and Specialist Terms  
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AAT 
Aspartate Aminotransferase 
BHOB 
 
Beta-hydroxybutyrate 
BP 
Blood Pressure 
CRF 
Case Report Form 
CSI 
Continuous Subcutaneous Infusion 
CZ® 
Daikyo Crystal Zenith® 
DMSO 
Dimethyl sulfoxide 
DSMB 
Data and Safety Monitoring Board 
FFA 
Free Fatty Acids 
GCP 
Good Clinical Practice 
GIR 
Glucose Infusion Rate 
HR 
Heart Rate 
ICF 
Informed Consent Form 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
iv 
Intravenous 
kg 
Kilogram 


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L 
Liters 
LSLV 
Last Subject Last Visit 
MDR 
mg 
Medical Device Report 
Milligram 
mcg 
Microgram 
min 
Minute 
PK 
Pharmacokinetic 
rDNA 
Recombinant 
SAE 
Serious Adverse Event 
SC 
Subcutaneous 


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5. 
STUDY OBJECTIVES AND ENDPOINTS 
5.1. 
Primary Objective 
The primary objective of this study is to determine if CSI-Glucagon™ delivered with an 
OmniPod® pump to subjects with congenital hyperinsulinism can lower the GIR required to 
maintain euglycemia (blood glucose ≥ 70 mg/dL) over 2 days. The endpoint will be assessed by 
comparing the rate of treatment failure between placebo and glucagon during the blinded, 
randomized portion of the study. Treatment failure is defined as <20% GIR reduction at 24 hours 
or <33% GIR reduction at 48 hours from baseline GIR determined prior to randomization. 
5.2. 
Secondary Objectives 
The secondary objectives are to: 
1. Compare average proportional GIR reduction from baseline between CSI-Glucagon™ 
and placebo. 
2. Compare the percentage of subjects in each group that achieve GIR≤ 8 mg/(kg*min) 
during treatment. 
3. Compare the percentage of subjects in each group that achieve daily total caloric intake 
from carbohydrate, combining oral, tube and IV sources ≤ equivalent to 8 mg/(kg*min) 
glucose.  
4. Describe the proportion of subjects in each group that discontinue IV glucose infusion as 
well as the proportion of subjects that discontinue continuous naso-gastric feeds (ability 
of patient to fast for 3 hrs.). 
5. Compare proportional time < 70 mg/dL as well as proportional time in euglycemia 
(≥70 mg/dL and < 180 mg/dL) from CGM assessments. 
6. Compare device performance between the groups, including: 
• weight-based estimate of dose volume delivery 
• infusion site leakage 
• device failures/malfunctions  
7. Assess safety of pump switch out procedure as assessed by occurrence of glucose < 50 
mg/dL by continuous glucose monitoring.  
8. Evaluate the safety and tolerability of CSI-Glucagon™ administered from an OmniPod® 
pump by assessing the following endpoints: 
• Incidence of adverse events (AEs) and serious adverse events (SAEs)  
• Laboratory safety variables 
• Physical examination 
• Vital signs 


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• Local tolerability: Erythema and/or edema formation at site of infusion assessed using 
the Draize scale 


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6. 
BACKGROUND AND RATIONALE 
6.1. 
Indication 
The proposed indication for CSI-Glucagon™ (continuous subcutaneous glucagon infusion) is for 
prevention of severe, chronic hypoglycemia related to congenital hyperinsulinism. 
6.1.1. 
Background 
Congenital hyperinsulinism (CHI) is the result of at least ten different genetic defects that result 
in dysregulated insulin secretion.  It is the most frequent cause of severe, persistent 
hypoglycemia in neonates and children [1, 2].  CHI is characterized by inappropriate secretion of 
insulin resulting in hypoketotic hypoglycemia.  If left untreated, CHI may lead to mild to severe 
forms of neurological damage in 30-40% of affected individuals. Surgical treatment (95-98% 
pancreatectomy) of patients with the diffuse form of CHI leads to diabetes mellitus in some 95% 
individuals by 14 years of age [3]. 
In CHI, the histologic abnormalities in pancreatic structure are heterogeneous, but can be 
grouped into the following two broad categories: 
• Focal adenomatous hyperplasia  
• Diffuse abnormality of the islets 
In the focal form, the histologically abnormal beta cells are limited to 1 or more focal areas, 
whereas in the diffuse form, the β-cell abnormality is distributed throughout the pancreas.  In 
focal CHI, a specific area of the pancreas is affected.  Around 40 to 50 per cent of infants with 
persistent CHI will have the focal form [4].  
Diffuse CHI affects the entire pancreas. It can be inherited in a recessive or dominant manner or 
can occur sporadically.   
The management of diffuse and focal disease is different. Focal disease can now be cured if the 
lesions are located accurately and removed completely. However, diffuse disease will often 
require removal of almost the entire pancreas, if the patient does not respond to medical 
management.  Medical management tools include continuous IV dextrose infusion or 
gastronomy tube feeding.  In addition to diazoxide, which is an FDA approved treatment for 
CHI, a number of medications are used off-label including octreotide and glucagon [1].    
6.1.2. 
Rationale 
Xeris Pharmaceuticals has developed a proprietary form of glucagon that is stable in a non-
aqueous form at room temperature and can be injected subcutaneously. CSI-Glucagon™ 
(continuous subcutaneous glucagon infusion) utilizes Xeris’ biocompatible, non-aqueous peptide 
reformulation technology to ultimately create a concentrated, low volume, stable liquid glucagon 
formulation, pre-mixed and pre-loaded into a vial.  Preclinical studies have demonstrated 
equivalent pharmacology of the Xeris glucagon formulation to aqueous-reconstituted glucagon 
formulations.  


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Xeris' soluble glucagon has been safely evaluated for treatment of severe hypoglycemia in adults 
in a Phase 2 safety/PK/PD study that compared 0.5 and 1 mg doses of Xeris (G-Pen™) to Eli 
Lilly glucagon. In addition, micro doses of the same Xeris formulation, G-Pump™ (glucagon 
infusion) designed for use in insulin pumps, such as the OmniPod®, have been safely evaluated 
along with aqueous-reconstituted Novo GlucaGen® in a Phase 2a safety/PK/PD study, in 
advance of its use for outpatient treatment with artificial pancreas devices.  Summary results of 
this recently completed study are reported in Section 6.4.  
Further, mini doses of the same formulation have been safely administered in a Phase 2a PK/PD 
study, and are currently being evaluated in an outpatient Phase 2a study in adults with type 1 
diabetes, for management of mild to moderate hypoglycemia.  
In 2008 Mohnike et al. reported a retrospective study of nine CHI patients treated with SC 
glucagon (aqueous-reconstituted Novo GlucaGen® or an experimental long-acting glucagon). It 
showed SC glucagon infusion could reduce or eliminate glucose infusion, and reduce or 
eliminate octreotide use, when SC glucagon was continued in 3 children for up to 4 years without 
further symptomatic hypoglycemia, convulsions or unconsciousness.  Most importantly, near 
complete pancreatectomies or resurgeries were avoided in 5 of 9 children [5]. 
The proposed use of soluble glucagon to manage severe, persistent hypoglycemia related to 
hyperinsulinism builds on Xeris’ experience in delivering soluble glucagon with an OmniPod® 
for management of hypoglycemia in patients with type 1 diabetes, and will explore the use of 
soluble glucagon delivered as a continuous basal infusion for medical management of severe, 
persistent hypoglycemia that occurs in neonates and children with congenital hyperinsulinism. 
Availability of CSI-Glucagon™ for medical management of CHI may lead to a significant 
reduction of near total pancreatectomies, subsequent insulin dependence in adolescent years and 
overall reduction in the incidence of severe hypoglycemia in this patient population and the 
attendant permanent neurologic damage and substantive burden of care in families with CHI 
patients. 
6.2. 
Nonclinical Pharmacology and Toxicology Experience with Glucagon 
The 29-amino acid sequence of pancreatic glucagon is identical in humans, cows, pigs, dogs, and 
rats, and is also conserved in biosynthetic versions of glucagon [6].   Glucagon Injection (rDNA 
origin) was approved in 1998 and is currently the subject of two approved NDAs ([NDA 20-928] 
and [NDA 20-918]).  Complete NDA-required pharmacology and toxicology data have been 
reviewed and accepted by the FDA, as described in Lilly Glucagon [rDNA origin] for Injection 
and Novo GlucaGen® (glucagon [rDNA origin] for injection) labeling [7, 8].  Xeris’ drug 
substance is produced by solid-phase peptide synthesis (SPPS), which also conserves the 
glucagon peptide sequence. A summary of this information can be found in Xeris’ current 
Investigator’s Brochure, which will be provided to each investigator participating in this study. 


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6.3. 
Nonclinical Pharmacology and Toxicology Experience with CSI-
Glucagon™ 
6.3.1. 
Nonclinical Pharmacology 
Information on the nonclinical pharmacology, pharmacokinetics and toxicology of CSI-
Glucagon™ (continuous subcutaneous glucagon infusion) is referenced to Xeris’ current 
Investigator’s Brochure.   
6.3.2. 
Description and Composition of Drug Product 
Synthetic glucagon is the drug substance in CSI-Glucagon™.  CGMP grade glucagon is 
manufactured, packaged and released by Bachem AG (Bubendorf, Switzerland), conforms with 
USP standards, and has a Type II DMF filed with the FDA.  CSI-Glucagon™ is a sterile 
subcutaneous injectable non-aqueous formulation supplied in 2 mL Crystal Zenith® pre-filled 
cyclic olefin polymer vials with Flurotec® coated stoppers.  Each 200 μl of CSI-Glucagon™ 
formulation delivers 1 mg of glucagon, with trehalose and DMSO as the only excipients. The 
drug product is stored at controlled room temperature (20-25°C) prior to use.   
6.4. 
Clinical Experience with Glucagon 
6.4.1. 
Clinical Experience with Approved Glucagon Products 
Glucagon has a long history of medical use in the US, and is currently marketed by Eli Lilly & 
Co. as Glucagon for Injection [rDNA origin], and Novo Nordisk as GlucaGen® HypoKit®, both 
RLDs for treatment of severe hypoglycemia.  Glucagon has a rapid onset of action and an 
extremely short half-life, and its safety, efficacy and clinical pharmacology have been well 
established. Prior to the current recombinant products, animal-sourced glucagon was marketed. 
The Agency first approved glucagon for use in humans in 1960. 
Of relevance to the proposed indication in infants up to 1 year of age, animal derived glucagon 
was delivered via IM and IV routes to neonates at doses up to 100 μg/kg with no apparent 
adverse effects [9]. 
Published information on the safety, efficacy, immunogenicity and post-marketing surveillance 
of Lilly glucagon as rescue therapy for severe hypoglycemia is referenced to Xeris’ current 
Investigator’s Brochure.  
6.4.2. 
Clinical Experience with Approved Glucagon Products used Off-label to Treat 
Congenital Hyperinsulinism 
Mohnike et al. reported a retrospective review of nine (9) CHI patient cases where continuous 
subcutaneous (SC) glucagon (reconstituted Novo GlucaGen®) was used as a treatment option (1 
- 3 mg/day), with or without concomitant octreotide [5]. The objectives of using continuous SC 
glucagon were to: 
• Stabilize blood glucose levels for several weeks without the use of high-volume dextrose 
infusions administered via a central catheter, which often causes bloating, and 
• Avoid pancreatectomy or resurgeries (further reduction of pancreatic tissue) in patients 
with diffuse CHI.  


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The clinical outcomes of using continuous SC glucagon to treat CHI patients in this retrospective 
review were reported as follows: 
• Central glucose infusions were reduced significantly or eliminated in all 9 children; 
• SC glucagon was continued in 3 children for 1-4 years without further symptomatic 
hypoglycemia, convulsions or unconsciousness; 
• Glucagon treatment was initiated to manage recurrent hypoglycemia after subtotal 
pancreatectomy in 2 of 9 children; 
• Pancreatectomy or subsequent resurgeries (to remove additional pancreatic tissue and 
further reduce insulin output) were avoided in 5 of the 9 children; 
• Octreotide daily dose was reduced to 8-15 μg/kg/day – considerably lower than if it were 
given alone, without glucagon (15-60 μg/kg/day), which is an important outcome given 
octreotide’s adverse side effects; 
• An experimental, stabilized glucagon (glucagon Technospheres™ suspension) was IRB 
approved and used successfully in 3 children; 
• The value of a stable glucagon solution in treating hypoglycemia in CHI patients was 
demonstrated, even though development of the Technospheres™ stabilized glucagon was 
not continued. 
Thus, significant clinical support exists for basal glucagon administration as a significant 
enhancement in the prevention of severe, persistent hypoglycemia in patients with CHI.  In the 
inpatient setting, continuous subcutaneous glucagon infusion via an OmniPod® infusion pump 
would be preferable to high-volume dextrose or glucose infusion via a central catheter. This is 
because dextrose infusion rates are often so high they can cause fluid overload, especially in 
patients with diffuse disease.  Moreover, IV infusion of dextrose is not sustainable in an 
outpatient setting.  Therefore, to move a patient out of the inpatient setting requires surgery to 
insert a gastronomy tube (G-tube) to enable administration of continuous dextrose or feedings for 
a prolonged period of time. G-tube feeding is not a patient or caregiver-friendly medical 
management tool, and often the tube insertion site can become infected. 
Both of the clinicians who aided Xeris in the design of this study, one of whom will be 
participating as an investigator, have experience using IV glucagon to stabilize CHI patients 
prior to surgery. Over 10 years of clinical use, approximately 100 CHI patients have been 
administered IV doses of glucagon, generally about 1 mg/day, for up to 25 days without 
significant adverse effects observed [10]. Among the approximately 43 cases with evaluable 
data, a mean reduction from baseline in GIR of roughly 50% has been observed. According to 
these clinical experts, IV line blockages due to fibrillation of reconstituted aqueous glucagon 
have been a frequent problem. 
In a more recent study [11], a dose of 2.5-5 µg/kg/hr of glucagon administered by the IV route 
resulted in significant increases in blood glucose concentration in children with hyperinsulinemic 
hypoglycemia. In particular, a dose of 5 µg/kg/hr was positively and significantly correlated with 
blood glucose concentration, so this has been selected as the starting dose for the current study.  
In addition to administration of glucagon to CHI patients via continuous subcutaneous infusion 
[5], infusion pumps have been used to safely and effectively deliver insulin to patients with 
neonatal diabetes. In a review of 18 years of clinical practice, a French endocrinologist reported 
using continuous subcutaneous insulin infusion (CSII) in 17 newborns with neonatal diabetes on 


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a transient (n=8) or permanent basis [12]. In all but one case, CSII was initiated in the first 1-2 
months of life and continued 2 months to 1.7 years in transient cases and up to age 13 in a 
permanent case.  CSII was reported to be free from side effects and to be more effective at 
managing blood glucose, compared to frequent daily injections. 
6.4.3. 
Clinical Experience with XeriSol™ Glucagon 
Information on the clinical trials completed to date in healthy normal volunteers and patients 
with type 1 diabetes given injections or bolus doses via subcutaneous infusion pump of the same 
glucagon formulation as CSI-Glucagon™ is referenced to Xeris’ current Investigator’s Brochure. 
6.4.4. 
Clinical Pharmacology  
For a summary of clinical pharmacology data with glucagon, reference can be made to both the 
Eli Lilly & Co. Glucagon Injection [rDNA origin], and Novo Nordisk GlucaGen® (glucagon 
[rDNA origin] for injection) approved labeling and published literature. 


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7. 
STUDY DESIGN 
7.1. 
Study Overview 
This will be a Phase 2, multi-center, randomized, placebo-controlled, double-blind parallel group 
study with open-label follow-up designed to evaluate the efficacy of CSI-Glucagon™ for the 
prevention of hypoglycemia with lower IV glucose infusion rates when delivered subcutaneously 
to patients up to 1 year of age with congenital hyperinsulinism, using an OmniPod® infusion 
pump.  CSI-Glucagon™ is expected to provide a better inpatient treatment option compared to 
the current standard of care.   
The study will consist of three phases: 
1. Baseline Phase: First is a baseline stabilization phase during which concomitant therapy 
with glucagon, octreotide and diazoxide will be safely weaned and continuous “basal” 
enteric feed will be held constant to the degree possible, with the only factors varying 
being meal size and IV GIR adjusted by a set plasma glucose measurement driven 
algorithm that stays unchanged throughout the end of period 3 and, thus, applies equally 
to both treatment groups. Basal enteric feeding will be held constant to the degree 
possible until the third phase of the study, except for extending the fast after meal feeding 
when the GIR is tapered off. 
2. Blinded, Randomized Treatment Phase: Following the stabilization phase, subjects will 
be randomly assigned to blinded treatment with either glucagon or placebo, which will be 
delivered for up to 2 days with an OmniPod® pump with the controller set to a starting 
basal rate of 5 μg/kg/hr and GIR adjustments used to maintain euglycemia. After 48 
hours of blinded treatment, all subjects will transition to open-label treatment in period 3.  
a. At 24 hours, if GIR reduction from baseline is < 20%, subjects will be 
transitioned early to open-label drug. 
3. Open-label Treatment Phase: The third study period will involve an initial assessment of 
the safety of a pump switch out, followed by use of CSI-Glucagon™ to manage glucose 
with minimal glucose infusions for a maximum of 28 days of cumulative exposure until a 
long-term management plan is in place. All subjects, even those meeting the criteria for 
treatment failure during phase 2, whether they received placebo or CSI-Glucagon™, will 
be eligible for the open-label treatment phase as long as such treatment is deemed to be 
beneficial in the judgement of the attending investigator. 
Following the end of study treatment, IV fluids at pre-study rate will be resumed and glucose 
levels will be managed per standard protocol. 
7.2. 
Interruption and Termination of Dosing 
Dosing may be paused at an investigator’s discretion for any serious adverse event (SAE) which 
occurs in a patient receiving treatment until causality is fully assessed by the Investigator (see 
Section 12.6).  Dosing will be discontinued if the SAE is determined to be probably drug-related, 
but otherwise may continue (or resume) at the discretion of the investigator if Sponsor is in 
agreement. 


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Dosing will be terminated for any subject experiencing a serious device-related injury (see 
Section 12.14. For subjects experiencing a device failure or non-serious device-related injury, 
dosing may continue at the discretion of the investigator if the Sponsor is in agreement. 
If study drug is to be terminated due to an SAE or serious device-related injury, dosing may be 
tapered off, rather than halted abruptly, at the investigator’s discretion, so appropriate 
adjustments to GIR and/or alternative therapy for hypoglycemia can be initiated. 
If possible, dosing should continue uninterrupted during the study, but interruption is permissible 
if necessary for the care of the patient e.g., a PET scan. Dosing should be resumed as soon as 
possible, following the same GIR weaning schedule as at initiation.  


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8. 
ELIGIBILITY CRITERIA AND STUDY ENROLLMENT 
8.1. 
Inclusion Criteria 
Subject eligibility should be reviewed and documented by an appropriately qualified member of 
the investigator’s study team before subjects are included in the study.  Subjects must meet the 
following inclusion criteria to be eligible for enrollment into the study: 
1. Patients diagnosed with hyperinsulinism:  
a. Biochemical; detectable insulin (i.e., ≥1 mU/L) at time of hypoglycemia (i.e. blood 
glucose <50mg/dL), and/or suppressed free fatty acids (FFA), and/or suppressed beta-
hydroxybutyrate (BOHB) and/or glycemic response to glucagon at time of 
hypoglycemia. 
2. Absolute necessity of intravenous glucose to prevent hypoglycemia: 
a. Having failed diazoxide therapy as defined by inadequacy of 5 days maximum dose 
of diazoxide to eliminate the need for IV glucose, not necessarily that diazoxide has 
no effect. 
b. May be on diazoxide and/or octreotide, but these drugs will be weaned off prior to 
randomization. 
c. May be on dextrose feeds. 
3. Patient may be a participant in other study protocols such as observational studies, as 
long as no investigational intervention has taken place within 24 hrs or 5 half-lives of a 
drug prior to screening. 
4. Less than 12 months of age at screening. 
8.2. 
Exclusion Criteria 
1. Patients with history of allergy to glucagon or the excipients in Xeris’ glucagon 
formulation. 
2. Patients currently receiving, or less than 12 hours removed from IV glucagon treatment 
that resulted in a best achievable GIR > 8 mg/(kg*min) prior to the start of study drug. 
3. Patients who are diazoxide naïve. 
4. Patients within five days of starting diazoxide. 
5. Patients on steroids at doses larger than 20 mg/m2/day (hydrocortisone equivalent).  
6. Patients with sepsis. 
7. Patients on alpha or beta agonists for blood pressure support. 
8. Patients who received an investigational drug or a study drug within 5 half-lives of drug. 
9. Patients with body weight less than or equal to 2.3 kg/5.0 lbs. 
10. Patients with a history of pancreatectomy and a IV GIR < 8 mg/(kg*min) after weaning 
of all concomitant therapies. 


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8.3. 
Randomization Criteria 
Randomization will occur at the end of period 1 of the study through a centralized web-based 
system. Subjects will be randomized until the requirements of the interim analysis are achieved 
(see Section 13.4), at which point randomization will be halted, pending the outcome of the 
analysis. 


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9. 
STUDY TREATMENTS 
9.1. 
Allocation to Treatment 
Subjects will be enrolled until 12 evaluable patients fulfilling all final protocol GIR selection 
criteria complete period 2 of the study across all investigational sites, at which point an interim 
analysis will be conducted. The randomization will be adaptive with a minimization procedure to 
balance glucose infusion rate at baseline and non-evaluable patients and subjects not fulfilling all 
final protocol GIR selection criteria will be replaced. The final sample size is tentatively 
projected at 24, but may adapt based on the planned interim analysis (see Section 13.4). 
Each subject will receive a basal subcutaneous infusion from an OmniPod® infusion pump 
placed on the anterior abdomen, 5-10 cm away from the umbilicus as per manufacturer’s 
directions. Based on the prior experience of the investigators in treating CH patients with 
glucagon, the starting basal infusion rate for the subjects will be set at 5 μg/kg/hr, but this can be 
adjusted as necessary for a particular subject based on the GIR determined in period 1.   
9.2. 
Blinding 
Blinding will be achieved through the availability of an indistinguishable placebo.    
9.3. 
Drug Supplies 
9.3.1. 
Drug Product Formulation and Packaging 
CSI-Glucagon™ is a room temperature stable, non-aqueous, injectable liquid formulation of 
glucagon.  The formulation consists of 5 mg/mL synthetic glucagon peptide dissolved in a 
primary DMSO solvent, with trehalose added as stabilizing excipients.  A volume of 1 mL of 
formulation is filled into West Pharmaceutical’s 2 mL Crystal Zenith® pre-filled cyclic olefin 
polymer (plastic) vial with Flurotec® coated stopper.  The drug product is stored at controlled 
room temperature (20-25°C) prior to use. 
The placebo comparator to be used in this study is the vehicle for CSI-GlucagonTM. It contains 
no glucagon, but otherwise has the same composition and is indistinguishable in appearance 
from the test product.  
The CSI-Glucagon™ and matching placebo are packaged, labeled and distributed for Xeris 
under cGMP by MRI Global (Kansas City, MO). 
For use during blinded Period 2, sites will be provided with a supply of active and placebo 
product packaged in identical vials with the same blinded label on each. A separate set of 
unblinded vials of active product will be supplied for use during open-label Period 3. 
9.3.2. 
Drug Delivery Devices 
All OmniPod® devices to be used in the study are FDA approved and will not be modified in 
any way from their original state as provided by the manufacturer.  
All devices will be stored at the hospital pharmacies where the clinical investigation takes place 
or in the investigators’ offices prior to use in the clinical trial. 


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9.3.3. 
Preparation, Dispensing and Administration 
• CSI-Glucagon™ and vehicle will be supplied as 1 mL of non-aqueous solution in 
plastic Crystal Zenith (CZ) 2 mL vials.  Each vial of CSI-Glucagon™ will be used to 
fill a single OmniPod® pump. 
• CSI-Glucagon™ will be transferred to the OmniPod® using the kitted syringe and 
needle. Alternatively, a DMSO-compatible B Braun Injekt F® Low Waste Syringe 1 
mL (supplied by Xeris) may be used along with the fill needle supplied by the pump 
manufacturer.  If CSI Glucagon™ is not transferred into the OmniPod® within one 
hour of being drawn up into the syringe, the syringe, needle and drug should be 
discarded, and a fresh vial, needle and syringe should be used to fill the pod. 
To maintain blinding during the randomized portion of the trial (Period 2), study medications 
will be blinded. The investigator will have the ability to unblind should such be necessary for the 
care of the subject in an emergency situation.  During the open-label portion of the study (Period 
3), study drug may be dispensed by any appropriately trained member of the study staff. During 
Period 3, dosing will be adjusted every 7 days as applicable based on the current body weight of 
the subject. During either period, the OmniPod® pump may be loaded with study drug by the 
pharmacist or other appropriately trained study staff. 
The OmniPod® pump placement and study procedures will be performed by qualified/trained 
site staff who have read the OmniPod® Instructions for Use and following Table 3 for 
conversion of required glucagon flow rate to OmniPod® basal settings for pumping insulin.   
Table 3: 
OmniPod® Controller Settings 
Treatment  
Desired Basal Rate  
OmniPod® Setting 
OmniPod® Setting  
(4 kg infant) 
CSI-Glucagon™ 
2.5 μg/kg/hr 
Infant weight in kg * 0.05 
U/hr 
0.2 U/hr 
5 μg/kg/hr 
Infant weight in kg * 0.1 
U/hr 
0.4 U/hr 
10 μg/kg/hr 
Infant weight in kg * 0.2 
U/hr 
0.8 U/hr 
15 μg/kg/hr 
Infant weight in kg * 0.3 
U/hr 
1.2 U/hr 
20 μg/kg/hr 
Infant weight in kg * 0.4 
U/hr 
1.6 U/hr 
During Period 2 (blinded treatment), each OmniPod® will be used for a maximum of 48 hours. 
During period 3 (open-label), each OmniPod® will be used for up to 3 days, and will then be 
exchanged for a fresh pump. Before placement and after use each, each OmniPod will be 
weighed to the nearest whole mg (see Appendix 2). 
During the first pump switch-out during Period 3 (i.e., after the initial 4 hours), the new 
OmniPod® will be placed on the subject but not immediately activated. To evaluate changes in 
blood glucose during “real-world” use conditions, the existing pump will be deactivated and 


Protocol XSGO-CH01 v1.7 
 
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removed, and blood glucose will be assessed. After 5 minutes, blood glucose will be repeated, 
and then the new pump will be activated. 
9.3.4. 
Device Reliability 
A secondary objective of the study is to assess reliability of the OmniPod® infusion pump. This 
will be accomplished by performing weight-based estimates of dose volume delivery and noting 
episodes of significant infusion site leakage, device failures, malfunctions or occlusions. 
Unless operational considerations at a site preclude it, all OmniPod® infusion pumps should be 
weighed before and after use, following the procedure outlined in Appendix 2. Given the short 
duration, the pump used for the 4-hour “switch out” at the beginning of Period 3 is excluded 
from this requirement. 
If operational considerations make a site unable to weigh OmniPod® pumps, information on 
delivery volume obtained from the PDM should be captured in the EDC each time a pump is 
removed from a subject.  
9.3.5. 
Drug Storage and Drug Accountability 
Unless notified otherwise by the Sponsor, all supplied CSI-Glucagon™ and control vials are to 
be stored at controlled room temperature between 20°C to 25°C (68° to 77°F), and should be 
clear and of a water-like consistency at time of use. 
The investigator or an approved study staff will ensure that the study medications are stored in a 
secure area under recommended storage conditions and in accordance with applicable regulatory 
requirements. 
The site will maintain appropriate documentation of continuous storage conditions and these 
records will be monitored, on an on-going basis by the Xeris or its representative.  Any 
deviations in the storage conditions must be documented (including minimum and maximum 
temperature excursions, as well as estimate of total duration outside the recommended storage 
conditions).  Such deviations must be communicated to the Sponsor as soon as identified by the 
site with appropriate course of action taken regarding the future use of the study medications 
upon consultation with Xeris Pharmaceuticals. 
The investigator must maintain adequate records documenting the receipt, use, loss or other 
disposition of the investigational drug products and supplies, including OmniPods, and will 
return unused products to Xeris at the end of the study, following directions from Xeris. 
9.4. 
Concomitant Medications 
During the screening process, information regarding concomitant medications, such as diazoxide 
or octreotide, prescribed by the referring physician must be documented.  Medications taken 
within 4 weeks of Screening will be documented on the concomitant medication log. Any 
changes to a subject’s concomitant medication regimen during the study will also be documented 
on the concomitant medication log. 


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10. 
STUDY PROCEDURES 
10.1. 
Screening Visit   
Subjects will be screened to confirm they meet the selection criteria for the study.  The 
investigator or study team member will obtain informed consent from each subject’s 
parent/guardian in accordance with the procedures described below (see Section 16.3). 
All subjects will be in-patients. Those less than 1 month of age or with unstable condition will be 
in the neonatal intensive care unit. As such, vital signs will be monitored continuously via 
cardiorespiratory monitoring. All enteric feedings will consist of FDA-approved, hospital-issued 
infant formula or breast milk provided by the mothers. 
Subjects will undergo the following procedures to confirm they meet eligibility criteria for this 
study: 
• Review medical history and medications 
• Length and weight 
• Blood pressure and pulse 
• Physical examination 
• Venous blood draws for tests as outlined in the Schedule of Activities (Table 5)  
• Assessment of inclusion/exclusion criteria by Study investigator 
10.2. 
Treatment and Evaluation Phase 
Subsequent to qualification for the study and receipt of parental consent, the following 
procedures will be completed: 
10.2.1. 
Period 1: Baseline GIR (Day -1)  
During this baseline phase, IV glucagon, octreotide and diazoxide will be safely withdrawn prior 
to randomization of study drug on Day 0. Continuous “basal” enteric feed will be held constant 
during all study periods unless GIR=0. Subjects will consume meals as needed and GIR will be 
adjusted to achieve glucose minimally above 70 mg/dL. 
Determine minimal GIR required to keep glucose >70mg/dL, by weaning the IV glucose Q3H 
pre-feeds (or Q3H if on continuous feeds). During all study periods, point-of-care (POC) blood 
glucose will be monitored by each site’s standard practice, which will involve use of the Nova 
StatStrip® Hospital Glucose Measuring System, ACCU-CHEK Inform II, or an equivalent 
system. At the discretion of the PI, the CGM specified for Period 2 (see 10.2.2) may be placed 
during Period 1. As per standard care practices, blood glucose will be checked every 3 hours at a 
minimum, or more frequently at the discretion of the PI as the clinical situation dictates. 
• Wean IV fluids as follows: 
a. if POC glucose is >70 mg/dL (3.3 mmol/L) and < 90 mg/dL(5 mmol/L), reduce 
the GIR 1 mg/kg/min and check blood glucose in 3 hours.  


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b. if POC glucose is >90 mg/dL (5 mmol/L) and <120 mg/dL (6.7 mmol/L), reduce 
the GIR by 2 mg/kg/min and check blood glucose in 1 hour.  
c. if POC glucose is >120 mg/dL (6.7 mmol/L), reduce GIR by 3 mg/kg/min and 
check blood glucose in 1 hour. 
Note: the intent of the weaning procedure is to achieve minimal GIR at which 
POC glucose drops just below 70 mg/dL. Once POC glucose < 70 mg/dL has 
been achieved at least twice, the subject can transition to Period 2. If operational 
considerations preclude an immediate transition, the GIR will be returned to the 
previous “safe” level that maintained POC glucose > 70 mg/dL until the subject 
can be randomized. The “baseline” GIR will be the average GIR during the 
weaning procedure, minus the first two hours, and excluding the post-weaning 
period of “safe” GIR, if applicable. 
• If GIR cannot be reduced because glucose level is <70 mg/dL (3.9 mmol/L), increase 
GIR by 2 mg/kg/min and check blood glucose in 1 hour. 
• If glucose is <50 mg/dL (2.8 mmol/L), give 200 mg/kg dextrose by IV push, increase 
GIR by 2 mg/kg/min, and check blood glucose in 30 minutes. 
The identified GIR must be achieved twice within ±20% during before proceeding to period 2.  
More frequent or smaller GIR changes may be done at the investigator’s discretion should the 
clinical condition so require.  
10.2.2. 
Period 2: Blinded, Randomized Treatment (Days 0-1) 
Once baseline GIR has been established in Period 1, the following procedures will be completed, 
including initiation of blinded study treatment. 
Day 0 
1. If not inserted during Period 1, insert CGM (Dexcom® G4 Platinum) and calibrate per 
manufacturer. Stabilize for a minimum of 2 hours and confirm CGM is reporting glucose 
values before proceeding to step 2. 
{Note: The CGM will be used for rapid alerts, which will trigger POC assessments of 
blood glucose that will be used to guide clinical decisions.} 
2. Draw blood for  plasma insulin and glucagon levels and immunogenicity testing (as listed 
in Table 5), prior to application of the OmniPod® pump. 
3. Photograph the site of approximate cannula insertion prior to application of the 
OmniPod® pump. 
4. Using the appropriate syringe (see Section 9.3.3), load a fresh OmniPod® pump with 1 
mL CSI-Glucagon™ solution (5 mg/mL concentration) or placebo as per the 
randomization scheme. 
5. Study staff will weigh the loaded pump to the nearest whole mg (see Appendix 2), and 
then apply the OmniPod® pump to the abdomen of the subject (see Section 9.1). 
6. Use the PDM to instruct the pump to insert the cannula and ensure deployment as 
follows:   


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 Listen for an audible “click.” 
 Confirm pink slide insert has moved into the window on the surface of the pump, 
indicating deployment. 
 Use the clear window on one end of the pump to view the inserted cannula. 
7. Once cannula deployment is confirmed, set basal rate at 5 μg/kg/hr. Record time of 
starting the pump; this is t=0.   
8. Monitor POC glucose every hour for the first three hours after study drug start and every 
3 hours thereafter; or more frequently if the CGM shows glucose falling <70 mg/dL (3.9 
mmol/L) or rising above >200 mg/dL (11.1 mmol/L). Additionally, the trajectory of 
change in plasma glucose concentration based on the two most recent POC measurements 
should be used to adjust the frequency of glucose monitoring as needed to prevent plasma 
glucose <70 mg/dL (3.9 mmol/L) or >200 mg/dL (11.1 mmol/L).   
9. Adjust IV fluids as per period 1 with the following additions: 
a. If POC glucose is >70 mg/dL (3.9 mmol/L) and GIR=0, introduce and/or extend the 
fasting period after meal feeding as long as possible, while maintaining POC glucose 
> 70 mg/dL. 
b. If GIR cannot be reduced because glucose level is < 70 mg/dL (3.9 mmol/L), restore 
continuous enteric feeding if that has been suspended, or increase glucose infusion 
rate by 2 mg/kg/min and increase study drug infusion rate by 5 µg/kg/hour (to a 
maximum of 20 µg/kg/hr) and check blood glucose in 1 hour. 
10. If glucose is <50 mg/dL (2.8 mmol/L), give 200 mg/kg dextrose by IV push, increase 
GIR by 2 mg/kg/min, increase study drug infusion rate by 5 µg/kg/hour (to a 
maximum of 20 µg/kg/hr) and check blood glucose in 30 minutes.At 12 hours after start 
of study drug, determine average GIR since the start of blinded therapy, excluding the 
first 2 hours. If average “on treatment” GIR has been reduced by < 20% from the baseline 
value determined in Period 1, take the following actions:  
a. Remove the pump and weigh it. 
b. Replace the pump with a new one at the same flow rate setting as the previous pump 
and a fresh supply of the same blinded study drug. 
c. Monitor POC glucose over the next 12 hours, adjusting GIR using the same rules as 
above for making IV fluid adjustments in the interim. 
{Note: This same procedure should be followed if the pump alarms or if there is an 
acute deterioration in an otherwise stable subject, indicating a possible occlusion.} 
Day 1 
At 24 hours after the initial start of study drug, determine average GIR since the start of blinded 
therapy, excluding the first 2 hours. Then compare the “on treatment” GIR to the baseline value 
determined in Period 1 and calculate the percentage change. Depending on percentage change in 
GIR, follow the procedures under either item 1 or item 2. 
1. At 24 hours if average GIR has been reduced by < 20% from the baseline value 
determined in Period 1, complete the following procedures: 


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a. Draw blood for plasma insulin and glucagon levels as well as CBC and CMP. 
b. Remove and weigh the OmniPod® pump (Appendix 2) and: 
a. Photograph the application site, paying particular attention to the cannula 
insertion site. 
o Assess site for edema and erythema using the Draize scale. Any Draize scores 
>0 should be followed to resolution, including a follow-up photograph. 
c. Proceed to Period 3 (see 10.2.3).  
2. At 24 hours if average GIR has been reduced by ≥ 20% from the baseline value 
determined in Period 1, complete the following procedures: 
a. Continue to adjust the GIR during day 1 as per day 0.  
If GIR=0, continuous enteric feeding has been completely weaned, and plasma 
glucose continues to rise, reduce study drug infusion rate by 2.5 µg/kg/hr every 6 
hours to a minimum of 2.5 µg/kg/hr, as long as the pre-meal blood glucose is >70 
mg/dL (3.9 mmol/L). 
At approximately 48 hours from the start of the first blinded study treatment, 
complete the following: 
b. Draw blood for insulin and glucagon levels as well as CBC and CMP. 
c. Remove the OmniPod® pump, weigh it, and photograph the application site, paying 
particular attention to the cannula insertion site. 
d. Assess site for edema and erythema using the Draize scale. Any Draize scores > 0 
should be followed to resolution, including a follow-up photograph. 
e. Proceed to Period 3 (see 10.2.3). 
10.2.3. 
Period 3: Open-label Treatment  
After 24 hours of the initial start of study drug, subjects with a reduction in average GIR <20% at 
24 hours will be assigned to open-label CSI-Glucagon™. 
After 48 hours of the initial start of study drug, subjects with a reduction in average GIR ≥20% at 
24 hours will be assigned to open-label CSI-Glucagon™. 
After a subject is assigned to open-label CSI-Glucagon™, the following procedures will be 
performed.  
Note: If continuous enteric feed was reduced in period 2 and increased feeding is necessary by 
the algorithm, the same rate as established during period 1 should be the target, and any 
additional demands will be covered with the IV GIR. 
Period 3: 
At the start of open-label treatment: 
1. Photograph the site of approximate cannula insertion prior to application of a new 
OmniPod® pump. 
2. Using the same procedures for loading and weighing the pump, and confirming cannula 
deployment as detailed for Day 0, apply a new OmniPod® pump containing CSI-


Protocol XSGO-CH01 v1.7 
 
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Glucagon™ (5 mg/mL), instruct the pump to insert the cannula and set basal rate of 5 
μg/kg/hr. Record time of starting the pump; this is t=0. 
3. Adjust IV fluids as per the Day 1 procedures. 
4. At 4 hours, remove the OmniPod® pump and: 
a. Photograph the application site, paying particular attention to the cannula insertion 
site. 
b. Assess site for edema and erythema using the Draize scale. Any Draize scores > 0 
should be followed to resolution, including a follow-up photograph. 
5. The investigator should provide an assessment as to whether continued treatment would 
be helpful for clinical care. 
a. If yes, and open-label treatment will be continuing, perform “real-world” pump 
change-out procedure (see Section 9.3.3). 
b. If no, and open label treatment is ending, remove CGM and draw blood for 
immunogenicity testing, plasma insulin and glucagon levels as well as CBC, and 
CMP. Do not perform the “real-world” pump change-out procedure in this case. 
6. If CSI-Glucagon™ treatment is considered helpful for clinical care, therapy may 
continue, including intermittently should procedures, e.g., PET scan, require temporary 
discontinuation, for up to a cumulative 28-day glucagon exposure. 
a. Using the same procedures for loading and weighing the pump, and confirming 
cannula deployment as detailed for Day 0, a new OmniPod® pump containing CSI-
Glucagon™ solution should be placed immediately and again at least every 72 hours, 
including any time the pump alarms due to an occlusion. 
b. Each time a pump is replaced, the safety of pump switch out procedures should be as 
assessed by occurrence of blood glucose < 50 mg/dL. 
c. Each time a pump is removed, including at final termination of therapy, the pump 
should be weighed, and the placement site should be photographed and assessed with 
Draize scales and any reactions followed to resolution. 
d. POC glucose will be assessed every three hours; or more frequently if the CGM 
shows glucose falling <70 mg/dL (3.9 mmol/L) or rising above >200 mg/dL (11.1 
mmol/L). Additionally, the trajectory of change in plasma glucose concentration 
based on the two most recent POC measurements should be used to adjust the 
frequency of glucose monitoring as needed to prevent plasma glucose <70 mg/dL (3.9 
mmol/L) or >200 mg/dL (11.1 mmol/L). 
e. CGM will be utilized for rapid alerts, which will trigger POC assessments of blood 
glucose that will be used to guide clinical decisions. At least 2 hours prior to each 
planned pump change, confirm the CGM sensor is working and place another as 
needed. 
f. Every 2 weeks during treatment, draw blood for immunogenicity testing. 
7. Whenever CSI-Glucagon™ treatment is temporarily paused and when treatment ends: 
a. Draw blood for CBC, CMP, immunogenicity testing and plasma insulin and 
glucagon. 
b. Perform physical exam and measure height and weight. 


Protocol XSGO-CH01 v1.7 
 
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c. Resume IV fluids at pre-study rate and manage glucose as per standard procedures. 
10.2.4. 
Period 4, Post-treatment Immunogenicity Testing 
At 28±14 days after receiving the last dose of glucagon in the study, subjects should have blood 
drawn for immunogenicity testing. Preferably, this will be done at the study site. If travel or 
other considerations preclude the subject returning to the study site, the blood draw may be 
performed at a local hospital, laboratory or clinic, or by home health care professional. In this 
case, the plasma sample will be sent directly to the central lab for testing. Xeris or its designee 
will coordinate with the site and the subject to facilitate collection, processing and shipping of 
this blood sample. 
10.3. 
Subject Withdrawal 
Subjects may withdraw from the study at any time at the parent/guardian’s request or they may 
be withdrawn any time at the discretion of the investigator or sponsor, for safety, behavioral or 
administrative reasons.  In any circumstance, every effort should be made to document the 
subject’s outcome, if possible.  Information regarding the reason for not completing the study 
will be recorded on the appropriate case report forms.  The investigator should inquire about the 
reason for withdrawal and follow-up with the subject regarding any unresolved AEs.  It will be 
documented whether or not each subject completed the clinical study. Any subject who receives 
at least one treatment dose of study medication will be included in the safety analysis.  
If a decision by the investigator or sponsor is made to withdraw a subject, a final examination 
should be scheduled soon after the decision to withdraw is made.  The following assessments 
should be completed if possible at this examination: 
• Update any changes to medical history and concomitant medications. 
• Perform physical examination and measure height and weight. 
• Collect blood pressure and pulse rate measurements. 
• Obtain blood samples as outlined in Schedule of Activities 
If the subject is withdrawn from the study and parent/guardian also withdraws consent, no 
further evaluations should be performed, and no additional data should be collected.  The 
sponsor may retain and continue to use any data collected before such withdrawal of consent.  


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Table 4: 
Schedule of Assessments and Procedures 
Assessment 
Screening 
Period 1: 
Baseline 
GIR 
Period 2: 
Randomized 
treatment 
Period 3: 
Open-Label 
Treatment 
Period 4: 
Post-
Treatment 
Day -1 
Day 0 
Day 1 
Day 2 
Q3D 
 
Informed consent 
x 
— 
— 
— 
— 
— 
 
Demographic data 
x 
— 
— 
— 
— 
— 
 
Medical history 
x 
— 
— 
— 
— 
— 
 
Concomitant medications 
x 
xa 
xa 
xa 
xa 
xa 
 
Review eligibility 
x 
— 
— 
— 
— 
— 
 
Physical exam & weight   
x 
— 
— 
— 
— 
xb 
 
Vital signs (CRM) 
x 
x 
x 
x 
x 
x 
 
Hematology (CBC) 
xc 
— 
— 
— 
xf 
xb 
 
Clinical chemistry (CMP) 
xc 
— 
— 
— 
xf 
xb 
 
Blood glucose (POC) 
x 
x 
x 
x 
x 
x 
 
Immunogenicity 
— 
— 
x 
— 
— 
xd 
xg 
Plasma glucagon/insulin 
— 
— 
x 
x 
x 
— 
 
Wean diazoxide and 
octreotide  
— 
x 
— 
— 
— 
— 
 
Adjust GIR (and 
continuous enteric feed) 
when GIR=0 
— 
x 
x 
x 
x 
x 
 
Insert new CGM sensor 
— 
— 
x 
— 
— 
xe 
 
Photograph planned 
insertion site; weigh & 
place new OmniPod® 
— 
— 
x 
— 
xf 
x 
 
Remove & weigh 
OmniPod®; photograph 
and assess site with Draize 
scales 
— 
— 
— 
x 
@ 
4 hrs 
x 
 
Adverse events  
— 
— 
x 
x 
x 
x 
 
a Update as applicable. 
b Complete only when treatment ends or pauses. 
c Normal clinical care samples drawn within 7 days of the intended start of Period 2 will satisfy this requirement. 
d To be drawn every 2 weeks during open-label treatment, Day 14 and 28 (if applicable), whenever treatment is 
paused, and at the end of open-label treatment. 
e Weekly or as needed. 
f Will be performed on Day 1 if subject is a treatment failure and is switched to open-label treatment at 24 hours.  
g To be drawn at 28 ±14 days post-glucagon treatment. 


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11. 
ASSESSMENTS 
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator who will take all steps necessary to ensure 
the safety and well-being of the subject. When a protocol-required test cannot be performed, the 
investigator will document the reason(s) and any corrective and preventive actions taken to 
ensure that study processes are adhered to as soon as possible.  The study team and the Sponsor 
will be informed of these incidents in a timely fashion. 
For all blood collections, every effort must be made to obtain these samples at the same clock 
time each day. Blood collections and other study procedures should be performed at the time 
periods specified in the Schedule of Activities.  With the exception of blood samples for 
determination of plasma glucagon, and insulin concentrations and immunogenicity testing, all 
biological samples will be assayed at onsite clinical laboratories. Procedures for the proper 
processing, storage and shipment of samples to offsite laboratories will be provided to all 
investigators prior to the start of the study.  
11.1. 
Blood Volume 
There will be 3 PK blood samples of about 2.0 mL each drawn over the first 3 days of treatment, 
plus a 1 mL sample for immunogenicity testing at the start of treatment. Hematology and 
chemistry panels will be collected at Screening, at the end of blinded treatment and at the end of 
open-label treatment. Testing performed as part of routine care may be used to satisfy the 
Screening requirement for hematology and chemistry. The amount of blood drawn on any 
particular day for study-specific procedures will not exceed 5% of estimated blood volume based 
on the weight of the subject (Table 5). All subjects exposed to CSI-Glucagon™ will have 
additional 1 mL blood samples for immunogenicity testing collected at 14 and 28 days of open-
label treatment (if applicable), whenever treatment is paused, at the end of open-label treatment, 
and again at 28 ±14 days following the last dose.  


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Table 5: 
Volume of Blood Collections for Study-Specific Testing 
 
Sample Type 
Hematology 
Chemistry Immunogenicity* PK (insulin 
and 
glucagon)** 
Total 
(mL) 
Volume/Day 
Screen 
1*** 
1*** 
- 
- 
2 
Period 2, Day 0 
- 
- 
1 
2 
3 
Period 2, Day 1 non-
responders 
1 
1 
- 
2 
4 
Period 2, Day 2 
responders 
1 
1 
- 
2 
4 
 
 
 
 
 
 
Period 3, Day 14  
(if applicable) 
- 
- 
1 
- 
1 
Period 3, Day 28 
(if applicable) 
- 
- 
1 
- 
1 
Period 3 Pauses/End 
1 
1 
1 
2 
5 
Post Treatment**** 
- 
- 
1 
- 
1 
*Note: Testing will be repeated whenever CSI-Glucagon™ treatment is temporarily paused, when treatment ends 
and at 28±14 days following the last dose of CSI-Glucagon™. 
**Note: POC glucose samples are not reflected in this table, given the small volume of blood that is needed 
(~1.2 µl/sample) for plasma glucose measurements at bedside. 
*** If not performed within 7 days of the start of study treatment as part of routine clinical care.  
****At 28±14 days after the study treatment ends. 
11.2. 
Clinical Laboratory Tests 
The tests outlined in the Table 6 will be performed at the specified time points described in the 
Schedule of Activities.   


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Table 6: 
Clinical and Safety-related Laboratory Tests to be Performed 
Hematology 
Chemistry 
Central Laboratory 
WBC count 
RBC count 
Hemoglobin 
Hematocrit 
Platelet count 
Glucose 
Creatinine 
Sodium 
Chloride 
Bicarbonate 
Potassium 
Calcium 
Albumin 
Alkaline Phosphatase 
AST/SGOT 
ALT/SGPT 
Glucagon levels 
Insulin levels 
Immunogenicity 
The local clinical laboratory at each site will perform all testing specified in Table 6 with the 
exception of Central Laboratory tests (i.e., plasma glucagon and insulin and immunogenicity 
testing). The investigator must maintain, on file, written evidence that the clinical laboratory to 
be used is certified under the Clinical Laboratory Improvement Act or equivalent certification 
(depending on local regulations).  Further, the investigator must provide Xeris Pharmaceuticals 
or its agent with a copy of the certification, the range of normal values, the effective dates for the 
ranges, and the units of measurement for all laboratory tests requested in the protocol.  If any of 
the laboratory measurements will be transformed and/or categorized in any way, a description of 
the procedures(s) used should be included.  Xeris Pharmaceuticals or its agent must receive these 
documents before the shipment of clinical supplies. 
One central analytical lab will analyze the glucagon and insulin samples, and another the anti-
glucagon samples collected in this study. The procedures for preparing, storing and shipping 
these samples to the central analytical labs will be provided to each investigator prior to 
commencement of the study. 
11.3. 
Vital Signs 
Heart rate and respiration will be measured continuously by cardiorespiratory monitoring. These 
items along with BP and body temperature will be recorded in the CRF once daily at 
approximately the same time of day from Screening to the end of study treatment.  
11.4. 
Photographs 
Digital photographs of study drug infusion sites will be taken at the following times: 
• Prior to the application of each OmniPod® pump, photograph the site of approximate 
cannula insertion. 
• Upon removal of each OmniPod® pump, photograph the application site, paying 
particular attention to the cannula insertion site. 


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 For any insertion sites with Erythema or Edema scores >0 (Draize scale), follow-
up photographs should be taken to document resolution. 
Photographs should be time/date stamped and labeled with the subject ID number and stored on 
a secure, access-restricted computer. Care should be taken not to include the subject’s face or 
other identifying information in the photographs. 


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12. 
SAFETY AND ADVERSE EVENT (AE) REPORTING 
12.1. 
Adverse Events 
All observed or volunteered AEs regardless of treatment group or suspected causal relationship 
to the study treatment will be reported.  For all AEs, the investigator must pursue and attempt to 
obtain information adequate to determine the outcome of the AE and to assess whether it meets 
the FDA criteria for classification as an SAE (see Section 12.4) requiring immediate notification 
to Xeris Pharmaceuticals (see Section 12.9).  For all AEs, follow-up by the investigator is 
required until the event resolves or stabilizes at a level acceptable to the investigator to consider 
it closed, and Xeris Pharmaceuticals should concur with that assessment. 
As part of ongoing safety reviews conducted by the Sponsor, any non-serious adverse event that 
is determined to be serious (according to the FDA definitions of an SAE) will be reported by the 
Sponsor as an SAE.  To assist in the determination of case seriousness, further information may 
be requested from the investigator to provide clarity and understanding of the event in the 
context of the clinical study. 
12.2. 
Reporting Period 
For all AEs, the reporting period to Xeris Pharmaceuticals begins from the time informed 
consent is obtained through the last administration of the investigational product.   
12.3. 
Definition of an Adverse Event 
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and which is not necessarily required to have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign, symptom, or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.  Examples of AEs include: 
• Abnormal test findings 
• Clinically significant symptoms and signs 
• Changes in physical examination findings which are untoward and deemed clinically 
significant by the investigator. 
• Allergy/hypersensitivity 
The criteria for determining whether an abnormal objective test finding may be reported as an 
AE are as follows: 
• Test result is associated with accompanying symptoms,  
• Test result requires additional diagnostic testing or medical/surgical intervention,  
• Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment or other treatment, and/or 
• Test result is considered to be an AE by the investigator or Sponsor. 


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Repeat of a test based on an abnormal result in the absence of the above conditions does not 
constitute an AE.  Any abnormal test result determined to be an error does not require reporting 
as an AE. 
A treatment-emergent AE (TEAE) is an AE that either commenced following initiation of study 
treatment or was present prior to study treatment but increased in frequency or severity following 
initiation of study treatment. 
Standard medical terminology should be used in describing AEs.  Informal descriptions should 
be avoided. 
12.4. 
Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence at any dose which: 
• Results in death 
• Is life-threatening 
• Requires inpatient hospitalization 
• Results in persistent or significant disability 
• Is another important medical event 
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in hospitalization or death.  However, if it is determined that the event may jeopardize the 
subject or may require intervention to prevent an SAE outcome, the important medical event 
should be reported as serious.  Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm or blood dyscrasias or convulsions which do not 
result in hospitalization. All SAEs are reportable to the Sponsor within 24 hrs. of first awareness 
of the event by an investigator (see Section 12.9)  
12.5. 
Severity Assessment 
The investigator will use the adjectives mild, moderate or severe to describe the maximum 
intensity of each AE.    These intensity grades are defined as follows in Table 7 . 
Table 7: 
Adverse Effects Assessment 
MILD 
Does not interfere with subject’s usual function 
MODERATE 
Interferes to some extent (<50%) with subject’s usual function 
SEVERE 
Interferes significantly (≥50%) with subject’s usual function 
The terms “serious” and “severe” are not synonymous.  The term “severe” is often used to 
describe the intensity (severity) of a specific event.  The event itself, however, may be of 
relatively minor medical significance.  This is not the same as “serious,” which is based on 


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subject/event outcome or action criteria.  Accordingly, a severe event is not necessarily a serious 
event. 
12.6. 
Causality Assessment 
The investigator will use the following question when assessing causality of an adverse event to 
study drug, where an affirmative answer designates the event as a suspected adverse reaction: Is 
there a reasonable possibility that the drug caused the event? ‘‘Reasonable possibility’’ means 
that there is evidence to suggest a causal relationship between the drug and the adverse event. 
The investigator’s assessment of causality must be provided for all AEs.  The investigator must 
record the causal relationship in the CRF, as appropriate, and report such an assessment in 
accordance with the serious adverse event reporting requirements, if applicable.  Regardless of 
causality, all SAEs are immediately reportable to the Sponsor (see Section 12.9). 
12.7. 
 Withdrawal Due to Adverse Events 
Withdrawal due to AE should be distinguished from withdrawal due to insufficient response, and 
recorded on the appropriate AE CRF.  When a subject withdraws due to an SAE, the SAE must 
be reported in accordance with the reporting requirements. 
12.8. 
Eliciting Adverse Event Information and Reporting 
The investigator is to report all directly observed AEs and all AEs spontaneously reported by the 
study subject.  Each study subject will be questioned about AEs.  Each AE is to be assessed to 
determine if it meets the criteria for SAEs.  If an SAE occurs, expedited reporting will follow 
appropriate regulations. 
12.9. 
Serious Adverse Event Reporting Requirements 
If an SAE occurs, Xeris Pharmaceuticals is to be notified within 24 hrs. of awareness of the 
event by the investigator, regardless of the investigator’s determination of causality.  In 
particular, if the SAE is fatal or life-threatening, notification to Xeris Pharmaceuticals must be 
informed as soon as possible, irrespective of the extent of available AE information.  This time 
frame also applies to follow-up on previously forwarded SAE reports. 
In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (e.g., an outpatient study subject initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hrs. after learning such event and document the time 
of first awareness of the AE.   
A death occurring during the study, during the per-protocol follow-up period, or within 4 weeks 
after stopping treatment with test drug must be reported to Xeris Pharmaceuticals or its 
designee(s) immediately whether or not it is considered treatment-related.  Initial SAE reports 
must be followed by detailed descriptions.  These should include copies of hospital case records 
and other documents when requested.  Telephone reports must be confirmed promptly either by 
email or overnight courier. 


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12.10. 
Non-Serious Adverse Event Reporting Requirements 
All AEs will be reported on the AE page(s) of the CRF.  AEs should be reported using concise 
medical terminology on the CRFs as well as on the form for collection of the SAE information. 
12.11. 
Sponsor Reporting Requirements to Regulatory Authorities 
AE reporting, including suspected serious unexpected adverse reactions will be carried out in 
accordance with applicable regulations. 
The investigator also must notify the IRB of the occurrence of all SAEs, in writing, as soon as is 
practicable and in accordance with local regulations.  A copy of this notification must be 
provided to Xeris Pharmaceuticals or its designee. 
In the event of an SAE that meets the criteria for expedited reporting, an SAE report will be 
prepared for submission to the FDA and any other applicable authorities by Xeris 
Pharmaceuticals or its designee. 
12.12. 
Pregnancy 
This is not applicable since all subjects are under 1 year of age. 
12.13. 
Subject Monitoring 
Subjects will be monitored for AEs throughout the study by the study unit staff.  The principal 
investigator or designated sub-investigator will be on site for initial pump placement and for the 
subsequent 4 hours.  The principal investigator or designated sub-investigator will also be on call 
for the remainder of the study.  As necessary, a physician will administer treatment for any AEs. 
Safety parameters, including laboratory results, will be assessed by the principal investigator or 
his delegate using the site’s criteria for clinical laboratory acceptance ranges as suggested 
guidelines in making the medical assessment. 
Scheduled safety measurements will be repeated according to appropriate SOPs or upon request 
from a physician.  Any abnormal repeated measurement will be evaluated by a physician and 
repeated if judged necessary.  Further action may be taken on the physician’s request. 
12.14. 
Medical Device Reports 
A reportable medical device report (MDR) is one for which there is a reasonable possibility that 
a device has or may have caused or contributed to a death or serious injury. 
Caused or contributed means that a death or serious injury was or may have been attributed to a 
medical device, or that a medical device was or may have been a factor in a death or serious 
injury, including events occurring as a result of: 
(1) Failure; 
(2) Malfunction; 
(3) Improper or inadequate design; 
(4) Manufacture; 


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(5) Labeling; or 
(6) User error. 
Serious injury means an injury or illness that: 
(1) Is life-threatening, 
(2) Results in permanent impairment of a body function or permanent damage to a body 
structure, or 
(3) Necessitates medical or surgical intervention to preclude permanent impairment of a body 
function or permanent damage to a body structure. 
All reportable MDRs will be reported to Xeris within 24 hours of an investigator’s first 
awareness of the event. For all reportable MDRs, within 10 working days of becoming aware of 
the event, the investigator will complete Med Watch Form FDA 3500A for submission to FDA, 
in the case of a device-related death, or to the device manufacturer, in the case of a device-
related serious injury.   


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13. 
DATA ANALYSIS AND STATISTICAL METHODS 
13.1. 
Sample Size Determination  
This is a parallel group adaptive design with one interim analysis after 6 subjects in each study 
arm have completed their post-treatment success-failure determination.    Depending on the 
comparison of the treatment and placebo failure rates, the study will either be stopped with an 
early claim for treatment efficacy, or continued with either 3 or 6 additional subjects per study 
arm so that the final comparison of failure rates will be based on 9 or 12 subjects per study arm.  
The final sample size will be based on the outcome of the interim analysis.   
The criteria for stopping early at 6 subjects per group or continuing to a final sample size of 9 or 
12 subjects per group was designed so that the type 1 error is no larger than 0.025 for treatment = 
control failure rates at any failure rate.  The overall power for concluding that the treatment 
failure rate is less than control is over 98% if the placebo failure rate is at least 0.9 and the 
treatment rate is no more than 0.1, with early efficacy having a power of 66%.  If the placebo 
failure rate is at least 0.95 and the treatment failure rate is no more than 0.05 then the chance for 
an early efficacy determination is 88%.      
Power and type 1 error levels were computed using Monte Carlo simulations of the study, 10,000 
replications for each determination (R, version 3.1.2).   
13.2. 
Statistical Analyses 
The pharmacodynamic endpoints will be derived from the individual glucose infusion rates 
(GIRs).  
Primary and secondary efficacy analyses will be performed using two cohorts of subjects: 
• Primary cohort defined as all subjects fulfilling final protocol GIR selection criteria 
having average GIR assessments at periods 1, 2.  
• Per-Protocol cohort defined as subjects from the Primary cohort having no major 
protocol violations.   
The primary endpoint will be based on the Primary cohort. The safety analyses will use the 
Safety cohort defined as all subjects receiving either of the treatment regimens.  
13.2.1. 
Primary Endpoint (Pharmacodynamic) 
For each subject, the average GIR will be computed for periods 1 (baseline), 2 (treatment) by 
determining the area under the curve of GIR excluding the first 2 hours versus time and then 
dividing by the time duration for each of the periods excluding the first 2 hours using the last 24 
hours for each period, or if less than 24 hours is available, the available data excluding the first 2 
hours.   
The primary comparison of treatment and placebo will be based on a success-failure 
determination (see Section 5.1).  
This is a parallel group, adaptive design with one interim analysis after 6 subjects in each study 
arm have completed their success-failure determination.  If, at the interim analysis, the observed 


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treatment failure rate is lower than placebo so that the one-tailed p value is less than or equal to 
0.0124 (Fisher's exact test, hypergeometric distribution based on the total number of failures) 
then the study will be stopped due to early treatment efficacy. 
If this interim one-tailed p value is greater than 0.0124 but less than or equal to 0.05, then the 
study will continue and an additional 3 more subjects per study arm will be randomized.  If this 
interim one-tailed p value exceeds 0.05 then the study will continue, and an additional 6 more 
subjects will be randomized.   The final analysis will be based on the observed treatment and 
placebo failure rates using all subjects with a success-failure determination.   If, at the final 
analysis, the observed treatment failure rate is lower than placebo so that the one-tailed p value is 
less than or equal to 0.04 (hypergeometric distribution) then treatment efficacy will be 
established. 
The actual type 1 errors are smaller than the efficacy criteria would suggest because of the small 
sample sizes and the use of Fisher's exact test.  From Monte-Carlo simulations the overall type 1 
error for this design is bounded above by 0.016 for null hypothesis treatment = placebo failure 
rates at ay failure rate using the above criteria.  The type 1 error achieves its maximum at 
treatment = placebo = 0.5, and for this design the maximum is 0.016 as estimated by 10,000 
Monte Carlo replications of the design. 
13.2.2. 
Secondary Endpoints (Pharmacodynamic) 
Secondary analyses will include baseline adjusted analyses of the natural logarithm of GIR to 
obtain confidence bounds on ratio of treatment to placebo mean GIR.    
Other important secondary endpoints will consider the average GIR over the last 24 hours during 
period 2. The chance that this final rate is less than 8 mg/kg/min will be estimated and compared.  
Also, the cumulative glucose infusion will be combined with the total enteric feeding for the last 
24 hours.  The chance that this combined value is less than or equal to the daily equivalent of 8 
mg/kg/min will be estimated and compared. 
Furthermore, the following secondary endpoints will be described: 
• Discontinuation of feeds with ability to fast for 3 hours 
• Discontinuation of Gastrostomy tube (G tube) of glucose infusion 
13.2.3. 
Pharmacokinetics 
Pharmacokinetic (PK) data of steady state glucagon concentrations following continuous 
subcutaneous infusion will be analyzed descriptively.  
13.2.4. 
Device Performance 
The following endpoints related to device performance will be analyzed descriptively. 
• Comparison of target vs. a weight-based estimate of dose volume delivery 
• Infusion site leakage 
• Occlusions 
• Device failures/malfunctions 


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13.2.5. 
Safety/Tolerability 
Safety/tolerability endpoints to be analyzed by treatment period will include: 
• Adverse events (AEs) 
• Laboratory safety variables  
• Physical examination 
• Body weight 
• Vital signs 
• Local tolerability 
13.2.5.1. Adverse events: 
All AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) and 
summarized by system organ class and study drug. A summary table indicating the number and 
the percentage of exposed subjects having at least one AE will be made. 
13.2.5.2. Laboratory safety assessments: 
Laboratory values (biochemistry and hematology) will be flagged if outside the normal range. A 
listing of abnormal values will be presented in an end of text (EOT) listing. The individual 
values will be listed indicating values outside normal range. Laboratory assessments will be 
summarized for each applicable time point. 
13.2.5.3. Physical examination: 
Subjects with any findings in the physical examination evaluation at screening will be listed. 
Changes to physical examination will be recorded as AEs if the Investigator judges these as 
being clinically significant. 
13.2.5.4. Vital signs: 
Vital signs will be summarized by descriptive statistics. 
13.2.5.5. Local Tolerability   
The incidences of erythema and edema will be analyzed with a McNemar’s test. 
13.3. 
Subgroup Analysis 
No subgroup analysis is planned for this study. 
13.4. 
Interim Analysis 
An unblinded interim analysis will be conducted after the 6th subject in each study arm has 
completed period 2.  The objectives of this interim analysis are to: 
1. Stop the study early for overwhelming evidence of early efficacy, as defined above in 
Section 13.2.1. 


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2. Continue the study enrolling either 3 or 6 additional subjects per study arm depending on 
the outcome of the interim analysis (see Section 13.2.1) 
The unblinded statistician not related to the conduct of the study will perform this interim 
analysis according to a DSMB charter that will define the analysis details and the 
communications between the unblinded statistician, the DSMB, and the sponsor. 


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


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15. 
DATA HANDLING, RECORD KEEPING, MONITORING AND 
AUDITS 
15.1. 
Case Report Forms/Electronic Data Record 
As used in this protocol, the term “case report form” (CRF) should be understood to refer to 
either a paper form or an electronic data record, or both.  A complete set of CRFs is required and 
should be completed for each individual subject.  The completed original CRFs are the property 
of Xeris Pharmaceuticals and should not be made available in any form to third parties, except 
for authorized representatives of Xeris Pharmaceuticals or appropriate regulatory authorities, 
without written permission from Xeris Pharmaceuticals. 
The investigator has the responsibility for the collection and reporting of all clinical, safety and 
laboratory data entered on the CRFs and any other data collection forms (source documents) and 
ensuring that these are accurate, authentic, attributable, complete, consistent, legible, 
contemporaneous, enduring and available when required.  The CRFs must be signed by the 
investigator or by an authorized staff member to attest that the data contained in the CRFs is true.   
In many cases, data will be entered directly into electronic CRFs (eCRFs) as part of a web-based 
electronic data collection (EDC) system. When data are entered directly, eCRFs will be 
considered as source documents.  Other electronic data will be uploaded into the EDC system 
directly from downloads of devices or from datasets provided by laboratories that are processing 
blood samples. These electronic data will be considered as source documents. 
Other data will be collected first on paper worksheets or CRFs and then transcribed into the EDC 
system. In such cases, the paper forms will be considered source documents for the electronic 
entries. In some cases, source documents are hospital records or the subject’s chart.  In these 
cases, data collected in the CRFs must match the data in those charts. A document should be 
available that clearly identifies which data are being entered directly into the electronic CRF, and 
which data have a paper source. 
Any corrections to entries made in the CRFs must be dated, initialed and explained (if necessary) 
and should not obscure the original entry. An equivalent electronic process will be utilized for 
changes to eCRFs or other changes to data entered into the EDC system. 
15.2. 
Records Retention 
To enable evaluations and/or audits from regulatory authorities or Xeris Pharmaceuticals, the 
investigator agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records, e.g., CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, and detailed 
records of treatment disposition, and adequate documentation of relevant correspondence (e.g., 
letters, meeting minutes, telephone calls reports).  The records should be retained by the 
investigator according to the International Conference on Harmonisation (ICH), regulations, or 
as specified in the Clinical Study Agreement, whichever is longer.  The investigator must obtain 
Xeris Pharmaceuticals’ written permission before disposing of any records, even if retention 
requirements have been met. 


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15.3. 
Monitoring 
Monitoring and auditing procedures developed by Xeris Pharmaceuticals and/or its designee will 
be implemented to ensure compliance with FDA and ICH GCP and GLP guidelines. 
The Xeris Pharmaceuticals’ designated representative (the 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 review, with the stipulation that subject confidentiality will 
be maintained in accordance with local and federal regulations, including HIPAA requirements.  
The monitor will also be responsible for confirming adherence to the study protocol, inspecting 
CRFs and source documents, and ensuring the integrity of the data.  CRFs will be checked for 
accuracy, completeness, and clarity and will be cross-checked for consistency with source 
documents, including laboratory test reports and other subject records.  Instances of missing or 
uninterpretable data will be resolved in coordination with the investigator. 
The monitor/auditor will also investigate any questions concerning adherence to regulatory 
requirements.  Any administrative concerns will be clarified and followed.  The monitor will 
maintain contact with the site through frequent direct communications with the study site by e-
mail, telephone, facsimile, and mail.  The investigator and all other site personnel agree to 
cooperate fully with the monitor and will work in good faith with the monitor to resolve any and 
all questions raised, and difficulties detected by the monitor. 
15.4. 
Data Safety Monitoring Board 
An independent Data Safety Monitoring Board (DSMB) will have oversight of this study. The 
DSMB is an expert advisory group of physicians who function as a review committee 
independent from the Sponsor, and who function to ensure the safety of subjects enrolled in the 
study. DSMB members will meet periodically, without the Sponsor or study team members 
present, to review and discuss cumulative safety and efficacy data. 
After the review of each Data Report has been completed, the DSMB Chairperson will provide 
the official DSMB recommendation to Sponsor regarding the appropriateness of continuing the 
study, from a safety perspective, as well as any other recommendations relevant to study conduct 
and/or patient safety. 
The operating procedures of the DSMB are based on and are in compliance with the Food and 
Drug Administration’s “Guidance for Clinical Trial Sponsors [on the] Establishment and 
Operation of Clinical Trial Data Monitoring Committees” (March 2006, OMB Control Number: 
0910-0581) and with the European Medicines Agency’s “Guideline on Data Monitoring 
Committees” (January 2006, EMEA/CHMP/EWP/5872/03 Corr). 
15.5. 
Audits and Inspections 
The investigator understands that regulatory authorities, the IRB, and/or Xeris Pharmaceuticals 
or their designees have the right to access all CRFs, source documents, and other study 
documentation for on-site audit or inspection and will retain this right from the start of the study 
to at least 2 years after the last approval of a marketing application or for at least 2 years after 
clinical development of the study drug for the indication being studied has been discontinued.  


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The investigator is required to guarantee access to these documents and to cooperate with and 
support such audits and inspections. 


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16. 
ETHICAL CONSIDERATIONS 
16.1. 
Conduct 
This protocol is written in accordance with the principles established by the 18th World Medical 
Assembly General Assembly (Helsinki, 1964) and amendments and clarifications adopted by the 
29th (Tokyo, 1975), 35th (Venice, 1983), 41st (Hong Kong, 1989), 48th (Somerset West, South 
Africa, 1996), 52nd (Edinburgh, 2000), 53rd (Washington, 2002), 55th (Tokyo, 2004), and 59th 
(Seoul, 2008) General Assemblies.  The investigator will ensure that the study described in this 
protocol is conducted in full conformance with those principles, the protocol, current FDA 
regulations, ICH Good Clinical Practices (GCP) guidelines, Good Laboratory Practices (GLP) 
guidelines, local ethical and regulatory requirements, including the Federal Food, Drug and 
Cosmetic Act, U.S. applicable Code of Federal Regulations (title 21), and IRB/IEC requirements 
relative to clinical studies.  
Should a conflict arise, the investigator will follow whichever law or guideline affords the 
greater protection to the individual subject. The investigator will also ensure thorough familiarity 
with the appropriate administration and potential risks of administration of the study drug, as 
described in this protocol and the Investigator’s Brochure, prior to the initiation of the study. 
16.2. 
Institutional Review Board (IRB) 
The Ethics Committee/IRB must be a properly constituted board or committee operating in 
accordance with 21 CFR Part 56, “Institutional Review Boards.”  This protocol, any protocol 
amendments, the associated informed consent forms, and the informed consent procedures must 
be submitted to the IRB for review and approved before the enrollment of any subject into the 
trial.  Clinical supplies may not be shipped to the investigator until Xeris Pharmaceuticals has 
received a copy of the letter or certificate of approval from the IRB for the protocol and any 
protocol amendments. 
All types of subject recruitment or advertising information must be submitted to Xeris 
Pharmaceuticals or its designee and to the IRB for review and approval prior to implementation.  
IRB approval of any protocol amendments must be received before any of the changes outlined 
in the amendments are put into effect, except when the amendment has been enacted to eliminate 
a potential hazard to study subjects.  In such cases, the chair of the IRB should be notified 
immediately, and the amendment forwarded to the IRB for review and approval. 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, e.g., 
recruitment advertisements from the IRB.  All correspondence with the IRB should be retained 
in the Investigator File.  Copies of IRB approvals should be forwarded to Xeris Pharmaceuticals. 
16.3. 
Subject Information and Consent 
Prior to completing any procedures or collecting any data that are not part of usual care, written 
informed consent will be obtained from the parent/guardian.  For patients who are considered 
potentially eligible for the study based on case history, the study protocol will be discussed with 
the parent/guardian by a study investigator and clinic coordinator.  The parent/guardian will be 


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given the Informed Consent Form to read.  The parent/guardian will be encouraged to discuss the 
study with family members and their personal physician(s) before deciding whether to participate 
in the study.  If the parent/guardian agrees to have the child participate, the Informed Consent 
Form will be signed.  A copy of the consent form will be provided to the parent/guardian and 
another copy will be added to the participant’s chart or retained by the center research staff. The 
signed informed consent document must be available for verification by the study monitors at all 
times. 
All parties will ensure protection of subject personal data and will not include subject names on 
any sponsor forms, reports, publications, or in any other disclosures.  Subject names, address, 
date of birth and other identifiable data will be replaced by a numerical code consisting of a 
numbering system provided by Xeris Pharmaceuticals to de-identify the study subject.  In the 
case of data transfer, Xeris Pharmaceuticals will maintain confidentiality and protection of 
subject personal data. 
The informed consent document used in this study, and any changes made during the course of 
the study, must be prospectively approved by both the IRB and Xeris Pharmaceuticals before 
use.   
16.4. 
Subject Recruitment 
All types of subject recruitment or advertising information must be submitted to Xeris 
Pharmaceuticals or its designee and to the IRB for review and approval prior to implementation.  
Advertisements approved by the IRB may be used as recruitment tools. 
16.5. 
Reporting of Safety Issues and Serious Breaches of the Protocol 
In the event of any prohibition or restriction imposed (i.e., clinical hold), or if the investigator is 
aware of any new information which might influence the evaluation of the benefits and risks of 
the investigational product, Xeris Pharmaceuticals should be notified immediately.  In addition, 
the investigator will inform Xeris Pharmaceuticals immediately of any urgent safety measures 
taken by the investigator to protect study subjects against any immediate hazard, and of any 
serious breaches of this protocol. 


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17. 
DEFINITION OF END OF TRIAL 
LSLV is defined as the date the investigator reviews the last subject’s final safety data and 
determines that no further evaluation is required for the subject to complete the trial. 


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18. 
PROCEDURES FOR MODIFYING THE PROTOCOL OR 
TERMINATING THE STUDY 
18.1. 
Protocol Modifications and Deviations 
The principal investigator and the sponsor’s representative must sign this protocol and its 
amendments (if any) before initiating the study.  The investigator will make all reasonable efforts 
to comply with the written protocol.  Protocol modifications to ongoing studies that affect the 
safety of subjects or that alter the scope of the investigation, the scientific quality of the study, 
the experimental design, dosing, study assessments, the number of subjects exposed to test drug, 
or subject selection criteria must be made only after consultation between Xeris Pharmaceuticals 
and the investigator.  All protocol modifications must be reviewed and approved by the IRB 
before the revised protocol can be implemented.  Emergency revisions that eliminate an apparent 
hazard to subjects do not require preapproval by the IRB.  However, the IRB must be notified in 
writing as soon as possible after the modification has been made.  A copy of this communication 
must be forwarded to Xeris Pharmaceuticals.  All departures from the protocol must be fully 
documented in the source documents and the CRFs of the subjects involved. 
18.2. 
Study Termination 
The study may be prematurely terminated at any time because of a regulatory authority decision, 
change in opinion of the IRB, safety problems, or at the discretion of Xeris Pharmaceuticals or 
the principal investigator.  Circumstances that may warrant premature study termination at a one 
or more clinic sites or overall include, but are not limited, to the following: 
• Determination of unexpected, significant, or unacceptable risk to subjects 
• Failure to enter subjects at an acceptable rate 
• Insufficient adherence to the requirements of the protocol 
• Insufficient provision of complete and evaluable data 
• Plans to modify, suspend, or discontinue development of the study drug 
If the study is prematurely terminated or discontinued, Xeris Pharmaceuticals will promptly 
notify the investigator documenting the reason for study termination, and specific procedures for 
termination will be arranged by the sponsor in coordination with the investigator.  After 
notification, the investigator must remove all participating subjects from ongoing study treatment 
within 7 days.  All study materials must be collected and all CRFs completed to the greatest 
extent possible, and all study materials must be returned to Xeris Pharmaceuticals or its designee 
in a timely manner. 


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


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20. 
REFERENCES 
1. Dunne MJ, Cosgrove KE, Shepherd RM, Aynsley-Green A, Lindley KJ. Hyperinsulinism 
in infancy: from basic science to clinical disease. 2004 Physiol Rev 84:239-275. [Dunne 
2004] 
2. Snider KE, Becker S, Boyajian L, Shyng SL, MacMullen C, Hughes, N, Ganapathy, K, 
Bhatti T, Stanley CA, Ganguly A.  Genotype and Phenotype Correlations in 417 Children 
with Congenital Hyperinsulinism. 2013 February J Endocrine Metab 98(2):E55-E63. 
[Snider 2013] 
3. Beltrand J, Caquard M, Arnoux J-B, Laborde K, Velho G, Verkarre V, Rahier J, Brunelle 
F, Nihoul-Fekette C, Saudubray J-M, Robert J-J, De Lonlay P. Glucose Metabolism in 
105 children and adolescents after pancreatectomy for congenital hyperinsulinism. 2012 
February Diabetes Care 35:198-203. [Beltrand 2012] 
4. Pierro A, Nah SA.  Surgical management of congenital hyperinsulinism of infancy.  2011 
Seminars in Pub Surgery 20:50-53. [Pierro 2011] 
5. Mohnike K, Blankenstein O.,  Pfuetzner A. Potzch S, Schober E, Steiner S, Hardy O.T. 
Hardy, Grimberg, A, Van Waarde WM.  Long-term non-surgical therapy of severe 
persistent congenital hyperinsulinism with glucagon.  Horm Res 2008; 70:59-64. 
[Mohnike 2008]  
6. Eistrup, C., Hjortkjæ, R. K., Pickersgill, N., Virgo, D. M. and Woolley, A. P. A. H. 
(1993), Glucagon Produced by Recombinant DNA Technology: Repeated Dose Toxicity 
Studies, Intravenous Administration to CD Rats and Beagle Dogs for Four Weeks. 
Pharmacology & Toxicology, 73: 103–108. [Eistrup 1993] 
7. Glucagon for Injection [rDNA origin] Prescribing Information.  Eli Lilly and Company, 
revised September 2012. [Lilly 2012] 
8. GlucaGen® (glucagon [rDNA origin] for injection) Prescribing Information.  Novo 
Nordisk, Inc. revised April 2014. [Novo 2014] 
9. Cornblath M, Levin EY, Marqueti BA.Studies of Carbohydrate Metabolism in the 
Newborn. II. The Effect of Glucagon on the Concentration of Sugar in Capillary Blood of 
the Nexbon Infant. Pediatrics 1958: 889-92. [Cornblath 1958] 
10. Lado JJ, Givler S, De Leon DD: The Use of Glucagon in the Treatment of Congenital 
Hyperinsulinism. PES/PAS, San Diego, CA April 2015. [Lado 2015] 
11. Shah P, et al. Pharmacokinetics of Intravenous Glucagon in Children with 
Hyperinsulinaemic Hypoglycaemia. European Society for Paediatric Endocrinology, 
Paris, France September 10-12 2016. [Shah 2016]  
12. Tubiana-Rufi, N. (2007) Insulin Pump Therapy in Neonatal Diabetes.  In Shield JPH and 
Scharfmann R (Eds.), Development of the Pancreas and Neonatal Diabetes (pgs.67-74) 
Basel, Karger. [Tubiana-Rufi] 


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21. 
APPENDICES 
APPENDIX 1. DRAIZE SCALE 
• Draize Scale for Erythema and Edema:  to be used for physical examination 
abnormalities at the infusion site. 
• Investigative Site Instructions: The infusion site should be examined after removal of the 
OmniPod® pump and recorded on the case report form. 
• For any infusion site with an Erythema or Edema Formation score > 0, follow-up 
examinations should be performed until scores equal 0. 
Erythema Formation 
Edema Formation 
Description 
Score 
Description 
Score 
No erythema 
0 
No edema 
0 
Very slight erythema 
Barely perceptible 
1 
Very slight edema  
Barely perceptible 
1 
Well defined erythema 
2 
Well defined edema 
 
2 
Moderate erythema 
3 
Moderate edema 
Raised approx. 1 mm 
3 
Severe erythema 
Beet redness to slight 
eschar formation 
4 
Severe edema 
Raised more than 1 mm and 
beyond exposure area 
4 
 


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APPENDIX 2. OMNIPOD® WEIGHING PROCEDURES 
The following procedures will be followed to load and weigh the OmniPod® pump. 
1. Remove pod from original sealed plastic cover and set cover aside. 
2. Load pod as per protocol: 
a. If placebo group, load with 1 mL vehicle, using the kitted needle and syringe 
b. If active group, load with 1 mL glucagon, using a 1 mL Injekt-F syringe and kitted 
needle 
3. Using PDM, prime pod. 
a. A small amount of fluid may collect under/around the needle shield; blot and discard. 
4. Place pod back into the original opened plastic cover and place in Ziploc baggie labeled 
with the subject’s study ID number. 
a. Add a fresh sterile gauze pad to the baggie. 
5. Weigh baggie and record weight to nearest whole mg. 
6. Take PDM and baggie containing pod with original opened plastic cover and dry gauze 
pad to NICU. 
7. Remove the needle shield and blot any pooled liquid using the gauze pad. 
8. Place pod on patient as per protocol. 
9. Place adhesive backing, needle shield, used gauze pad and original opened plastic cover 
back into the baggie and return it to Pharmacy. 
10. When it is time to remove pod, retrieve plastic baggie from Pharmacy. 
11. Deactivate and remove pod and place in plastic baggie and return baggie to Pharmacy 
with PDM. 
12. Pharmacy will weigh plastic baggie, containing used pod, needle shield, adhesive backing 
and used gauze pad, and record weight to nearest whole mg.   
13. Pharmacy will record reading from PDM regarding the amount of drug infused since 
priming. 
Note: Per the manufacturer, the maximum allowable time between Pod priming and activation is 
1 hour.