Conditions: Type 1 Diabetes
Keywords: Severe Hypoglycemia Nasal Powder Hypoglycemia Rescue Therapy Ready to use Glucagon
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 7
Healthy volunteers: no

Brief summary:
The main purpose of this study is to evaluate the safety and tolerability of a study drug called nasal glucagon (Baqsimi) in pediatric participants with type 1 diabetes (T1D) aged 1 to less than 4 years. Blood tests will be performed to check how much nasal glucagon gets into the bloodstream. Blood sugar will also be measured to understand the effect of the drug on blood sugar levels. The study consists of a screening period up to 35 days before dosing, 1 day when a dose of nasal glucagon will be given and then 2 telephone follow up calls; first follow-up call on the day after the nasal glucagon was given and second call about one week after nasal glucagon was given. The study will last up to 9 days, not including the screening period.

Detailed description:

Arms:
arm 1: Participants received a single dose of 3 mg glucagon powder administered intranasally on day 1.

Interventions: intervention 1: Glucagon Nasal Powder [Baqsimi]
Intervention descriptions: intervention 1: Administered intranasally

Protocol document:
Prot_000.pdf: 
 
 
 
Protocol: I8R-MC-IGBO(a) 
 
 
An Open-Label, Multi-Center, Single-Dose Study to Assess the 
Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of 
Nasal Glucagon in Pediatric Patients With Type 1 Diabetes Aged 1 to 
<4 Years   
 
 
NCT04992312 
 
 
Approval Date: 28-Jul-2022 


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I8R-MC-IGBO(a) 
 
 
1 
Title Page 
Confidential Information 
The information contained in this document is confidential and is intended for the use of clinical investigators. It is the property of 
Eli Lilly and Company or its subsidiaries and should not be copied by or distributed to persons not involved in the clinical 
investigation of nasal glucagon (LY900018), unless such persons are bound by a confidentiality agreement with Eli Lilly and 
Company or its subsidiaries.  
 
Note to Regulatory Authorities: This document may contain protected personal data and/or commercially confidential information 
exempt from public disclosure. Eli Lilly and Company requests consultation regarding release/redaction prior to any public release. 
In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be reproduced or 
otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries. 
 
Protocol Title: An Open-Label, Multi-Center, Single-Dose Study to Assess the Safety, Tolerability, 
Pharmacodynamics, and Pharmacokinetics of Nasal Glucagon in Pediatric Patients with Type 1 
Diabetes Aged 1 to <4 years 
Protocol Number: I8R-MC-IGBO 
Amendment Number: a 
Compound: Nasal glucagon 
Study Phase: 1 
Short Title: A Single-Dose Study to Assess Nasal Glucagon in Pediatric Patients with Type 1 
Diabetes aged 1 to <4 years 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Number(s): IND 110674, NDA 210134 
Approval Date: Protocol Amendment (a) Electronically Signed and Approved by Lilly on date 
provided below. 
Document ID: VV-CLIN-069838 
 
 
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I8R-MC-IGBO(a) 
 
 
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Medical Monitor Name and Contact Information will be provided separately. 
 
 
 
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I8R-MC-IGBO(a) 
 
 
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Protocol Amendment Summary of Changes Table 
 
DOCUMENT HISTORY 
Document 
Date 
Original Protocol 
19-Mar-2021 
Amendment [a]  
This amendment is considered to be nonsubstantial. 
Overall Rationale for the Amendment: 
To revise the existing inclusion criterion for hemoglobin A1c (HbA1c) to align with the observed 
distribution at study sites so that the study can consider a wider patient population as potential 
study participants without impacting study participants’ safety and study data integrity. 
Additional clarifications were made as outlined in the table below. 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.1. 
Synopsis and 
Section 3. 
Objectives and 
Endpoints 
In the first secondary endpoint, 
added predose BG in parenthesis, 
deleted plasma from parenthesis, 
and replaced plasma with blood. 
To provide additional information and 
clarification 
Section 1.3. 
Schedule of 
Activities 
(SoA) 
Included SC injection of insulin 
as an option for MDI users 
Added for consistency with Section 
4.1.4. 
Section 3. 
Objectives and 
Endpoints 
In the exploratory endpoint, 
added predose BG in parenthesis 
and replaced plasma with blood 
To provide additional information and 
clarification 
Section 4.1.4. 
Day 1: 
Predose 
Included SC injection of insulin 
as an option for MDI users 
Added for flexibility in treatment options 
for MDI users 
Section 4.1.5. 
Day 1: Dosing 
NG will be administered within 5 
minutes of baseline BG 
measurement changed as predose 
BG measurement 
Correction to state that NG 
administration to be done within 5 
minutes of predose BG rather than from 
baseline BG 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 5.1. 
Inclusion 
Criteria 
In inclusion criterion 4, increased 
the HbA1c level from ≤9.0 to 
≤9.5% 
To revise the existing inclusion criterion 
for HbA1c to align with the observed 
distribution at study sites so that the 
study can consider a wider patient 
population as potential study participants 
without impacting study participants’ 
safety and study data integrity. 
 
 
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Table of Contents 
1. 
Protocol Summary ..........................................................................................................8 
1.1. 
Synopsis ............................................................................................................................8 
1.2. 
Schema ..............................................................................................................................9 
1.3. 
Schedule of Activities (SoA) ..........................................................................................10 
2. 
Introduction ...................................................................................................................16 
2.1. 
Study Rationale ...............................................................................................................16 
2.2. 
Background .....................................................................................................................16 
2.3. 
Benefit/Risk Assessment ................................................................................................16 
2.3.1. 
Risk Assessment .............................................................................................................17 
2.3.2. 
Benefit Assessment .........................................................................................................19 
2.3.3. 
Overall Benefit: Risk Conclusion ...................................................................................19 
3. 
Objectives and Endpoints ............................................................................................21 
4. 
Study Design ..................................................................................................................22 
4.1. 
Overall Design ................................................................................................................22 
4.1.1. 
Screening.........................................................................................................................22 
4.1.2. 
Predosing-Visit Telephone Reminder .............................................................................22 
4.1.3. 
Day 1: Call/Text on Morning of Dosing .........................................................................23 
4.1.4. 
Day 1: Predose ................................................................................................................23 
4.1.5. 
Day 1: Dosing .................................................................................................................24 
4.1.6. 
Day 1: Postdose...............................................................................................................24 
4.1.7. 
Follow-up ........................................................................................................................24 
4.1.8. 
Rescheduling Visits ........................................................................................................24 
4.2. 
Scientific Rationale for Study Design ............................................................................25 
4.3. 
Justification for Dose ......................................................................................................25 
4.4. 
End of Study Definition ..................................................................................................26 
5. 
Study Population ...........................................................................................................27 
5.1. 
Inclusion Criteria ............................................................................................................27 
5.2. 
Exclusion Criteria ...........................................................................................................28 
5.2.1. 
Additional Exclusion Criteria Prior to Dosing Visit (Day 1) .........................................29 
5.3. 
Lifestyle Considerations .................................................................................................29 
5.3.1. 
Meals and Dietary Restrictions .......................................................................................29 
5.4. 
Screen Failures ................................................................................................................30 
6. 
Study Intervention ........................................................................................................31 
6.1. 
Study Intervention Administered ....................................................................................31 
6.1.1. 
Administration Details ....................................................................................................31 
6.2. 
Preparation/Handling/Storage/Accountability ................................................................31 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................32 
6.4. 
Study Intervention Compliance ......................................................................................32 
6.5. 
Concomitant Therapy .....................................................................................................32 
6.6. 
Dose Modification ..........................................................................................................32 
6.7. 
Intervention after the End of the Study ...........................................................................32 
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................33 
7.1. 
Discontinuation of Study Intervention ............................................................................33 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................33 
7.2.1. 
Discontinuation of Inadvertently Enrolled Participants ..................................................33 
7.3. 
Lost to Follow-up............................................................................................................33 
8. 
Study Assessments and Procedures.............................................................................34 
8.1. 
Efficacy Assessments .....................................................................................................34 
8.2. 
Safety Assessments .........................................................................................................34 
8.2.1. 
Physical Examinations ....................................................................................................34 
8.2.2. 
Vital Signs .......................................................................................................................34 
8.2.3. 
Clinical Safety Laboratory Assessments ........................................................................34 
8.2.4. 
Safety Monitoring ...........................................................................................................35 
8.2.5. 
Monitoring for Hypoglycemia ........................................................................................35 
8.2.6. 
Nasal Inspections ............................................................................................................35 
8.2.7. 
Hepatic Safety Monitoring ..............................................................................................36 
8.3. 
Adverse Events and Serious Adverse Events .................................................................36 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................36 
8.3.2. 
Method of Detecting AEs and SAEs ..............................................................................37 
8.3.3. 
Follow-up of AEs and SAEs ...........................................................................................37 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...............................................................37 
8.3.5. 
Pregnancy ........................................................................................................................37 
8.3.6. 
Rescue Treatment............................................................................................................37 
8.3.7. 
Product Complaints .........................................................................................................38 
8.4. 
Treatment of Overdose ...................................................................................................39 
8.5. 
Pharmacokinetics ............................................................................................................39 
8.5.1. 
Bioanalysis ......................................................................................................................39 
8.6. 
Pharmacodynamics .........................................................................................................39 
8.7. 
Genetics ..........................................................................................................................39 
8.8. 
Biomarkers ......................................................................................................................39 
8.9. 
Immunogenicity Assessments.........................................................................................40 
8.10. 
Health Economics ...........................................................................................................40 
9. 
Statistical Considerations .............................................................................................41 
9.1. 
Statistical Hypotheses .....................................................................................................41 
9.2. 
Sample Size Determination ............................................................................................41 
9.3. 
Populations for Analyses ................................................................................................41 
9.4. 
Statistical Analyses .........................................................................................................41 
9.4.1. 
Primary Endpoint: Safety ................................................................................................42 
9.4.2. 
Secondary Endpoints: Pharmacodynamics and Pharmacokinetics .................................42 
9.4.3. 
Exploratory Endpoint: Efficacy ......................................................................................43 
9.5. 
Interim Analyses .............................................................................................................43 
9.6. 
Data Monitoring Committee ...........................................................................................43 
10. 
Supporting Documentation and Operational Considerations ..................................44 
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10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................44 
10.1.1. Regulatory and Ethical Considerations ...........................................................................44 
10.1.2. Financial Disclosure........................................................................................................44 
10.1.3. Informed Consent Process ..............................................................................................45 
10.1.4. Data Protection................................................................................................................45 
10.1.5. Dissemination of Clinical Study Data.............................................................................46 
10.1.6. Data Quality Assurance ..................................................................................................46 
10.1.7. Source Documents ..........................................................................................................47 
10.1.8. Study and Site Start and Closure ....................................................................................47 
10.1.9. Publication Policy ...........................................................................................................48 
10.1.10. Investigator Information .................................................................................................48 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................49 
10.3. 
Appendix 3: Adverse Events: Definitions, and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .........................................................50 
10.3.1. Definition of AE .............................................................................................................50 
10.3.2. Definition of SAE ...........................................................................................................51 
10.3.3. Recording and Follow-Up of AE and/or SAE ................................................................52 
10.3.4. Reporting of SAEs ..........................................................................................................54 
10.4. 
Appendix 4: Liver Safety: Suggested Actions and Follow-up 
Assessments ....................................................................................................................55 
10.5. 
Appendix 6: Blood Sampling Summary .........................................................................57 
10.6. 
Appendix 7: Abbreviations .............................................................................................58 
11. 
References ......................................................................................................................60 
 
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1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title: An Open-Label, Multi-Center, Single-Dose Study to Assess the Safety, 
Tolerability, Pharmacodynamics, and Pharmacokinetics of Nasal Glucagon in Pediatric Patients 
with Type 1 Diabetes Aged 1 to <4 years 
Short Title: A Single-Dose Study to Assess Nasal Glucagon in Pediatric Patients with Type 1 
Diabetes aged 1 to <4 years 
Rationale: The primary aim of Study I8R-MC-IGBO (IGBO) is to assess the safety and 
tolerability of a 3 mg dose of NG (commercial drug product) in pediatric participants aged 1 to 
<4 years with T1D in an inpatient clinical research facility. 
Objectives and Endpoints  
Objectives 
Endpoints 
Primary 
 
To assess the safety and tolerability of a single dose of 
NG 3 mg in children aged 1 to <4 years with T1D 
Incidence of treatment-emergent adverse events. 
Secondary 
 
To assess the PD of a single dose of NG 3 mg in 
children aged 1 to <4 years with T1D 
Change from baseline (predose BG) of maximum 
blood glucose. Other blood glucose parameters:  
 
BGmax 
 
AUC 
 
TBGmax 
To assess the PK of a single dose of NG 3 mg in 
children aged 1 to <4 years with T1D 
Model-estimated population PK parameters 
 
Overall Design: Study IGBO is a Phase 1, open-label, multi-center study with a primary 
objective of assessing safety and tolerability of a single 3 mg dose of NG in pediatric participants 
aged 1 to <4 years with T1D. 
Participants will attend study visits, including screening, in the company of 1 or more parents or 
legal guardians, and in accordance with local healthcare facility practice. 
The study comprises a single cohort, with each participant receiving a single dose of 3 mg NG.  
Disclosure Statement: This is a single-arm, open-label pediatric study. 
Number of Participants: At least 9 participants with an approximate maximum of 20 may be 
enrolled so that 6 evaluable participants complete the study.  
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Intervention Groups and Duration: 
Each participant is expected to participate in the study for up to approximately 7 weeks, from 
screening through follow-up. 
Data Monitoring Committee: No 
1.2. 
Schema 
 
* Predosing-visit telephone call is not required if screening takes place on Day -1.
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1.3. 
Schedule of Activities (SoA) 
Procedure 
Screening 
Visit 
Predosing-visit 
preparation 
reminder 
(telephone) 
Dosing 
Visit 
Follow-up 
(telephone) 
Second 
Follow-up 
(telephone) 
Comments 
Day -35 to 
Day -1  
Day -1 
Day 1 
Day 2 
Day 9±3 
Informed consent 
X 
 
 
 
 
Provided by parent/legal guardian. Should be obtained 
before any study-related procedures are performed. 
May be obtained during a separate informed consent 
visit to the site. 
Demographics 
X 
 
 
 
 
Full date of birth (day, month, year), sex, and 
ethnicity will be collected, if consistent with local 
regulations. 
Medical history 
X 
 
 
 
 
 
Education on 
specifics of dosing 
visit  
X 
X 
 
 
 
Discussion between site staff and parent/legal 
guardian on the target blood glucose range and 
information for dosing visit. See Section 5.1. 
Eligibility 
X 
 
 
 
 
See Section 5. 
Height 
X 
 
 
 
 
 
Weight 
X 
 
X 
 
 
On Day 1, body weight will be measured predose. 
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Procedure 
Screening 
Visit 
Predosing-visit 
preparation 
reminder 
(telephone) 
Dosing 
Visit 
Follow-up 
(telephone) 
Second 
Follow-up 
(telephone) 
Comments 
Day -35 to 
Day -1  
Day -1 
Day 1 
Day 2 
Day 9±3 
Vital signs (body 
temperature, blood 
pressure, pulse rate) 
X 
 
X 
 
 
See Section 8.2.2. On Day 1, vital signs should be 
measured predose and 45 min postdose. Time points 
may be added on Day 1 if warranted, at the discretion 
of the investigator. 
Clinical laboratory 
tests 
X 
 
 
 
 
See Appendix 2 (Section 10.2) for details. Participants 
do not need to fast for laboratory samples. Laboratory 
tests will be processed at a local laboratory. 
Age-appropriate 
physical examination 
X 
 
 
 
 
 
Adverse event 
assessment 
X 
 
X 
X 
X 
AE assessment at telephone follow-up requires 
conversation with parent/legal guardian about any 
AEs experienced by the participant. 
Concomitant 
medication 
assessment 
X 
 
X 
X 
X 
On Day 1, concomitant medication assessment should 
be conducted predose. 
Pre-admission 
contact from site to 
parent/legal guardian 
 
 
X 
 
 
Contact parent/legal guardian to check BG levels are 
suitable for study procedures. Before participant and 
parent/legal guardian leave home, within 
approximately 2 hours before dosing. 
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Procedure 
Screening 
Visit 
Predosing-visit 
preparation 
reminder 
(telephone) 
Dosing 
Visit 
Follow-up 
(telephone) 
Second 
Follow-up 
(telephone) 
Comments 
Day -35 to 
Day -1  
Day -1 
Day 1 
Day 2 
Day 9±3 
Admission to site 
 
 
X 
 
 
It is recommended that participants have a natural 
overnight fast if possible, assuming morning dosing. 
At a minimum, participants should have no food or 
beverage intake other than water within 3 hours 
before dosing. 
Verification of 
hypoglycemia 
history since 
screening 
 
 
Predose 
 
 
See Section 5.2.1. 
Allocation of 
participant 
enrollment number 
 
 
X 
 
 
Once eligibility is confirmed and participant is ready 
for dosing. 
Baseline glucose 
measurement 
 
 
X 
 
 
See Section 4.1.4. 
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Procedure 
Screening 
Visit 
Predosing-visit 
preparation 
reminder 
(telephone) 
Dosing 
Visit 
Follow-up 
(telephone) 
Second 
Follow-up 
(telephone) 
Comments 
Day -35 to 
Day -1  
Day -1 
Day 1 
Day 2 
Day 9±3 
If necessary to 
achieve target 
glucose level, adjust 
basal rate or 
administer a small 
bolus via insulin 
pump; or for MDI, 
infuse a small 
correction bolus of 
insulin diluted in 
normal saline 
through IV or by SC 
injection 
 
 
Predose 
 
 
At PI’s discretion. See Section 4.1.4. 
Nasal inspection  
X 
 
Predose, 
90 min 
 
 
Visual nasal inspections. On Day 1, the predose 
inspection, administration of NG, and postdose 
inspection (90 min) should all be done by the same 
person. 
Return insulin pump 
basal rate to pre-
study settings  
 
 
Postdose 
 
 
For pump users only. If basal rate was adjusted to 
achieve target blood glucose on the study day, the 
basal rate must be returned to participant’s normal 
rate prior to discharge. 
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Procedure 
Screening 
Visit 
Predosing-visit 
preparation 
reminder 
(telephone) 
Dosing 
Visit 
Follow-up 
(telephone) 
Second 
Follow-up 
(telephone) 
Comments 
Day -35 to 
Day -1  
Day -1 
Day 1 
Day 2 
Day 9±3 
NG administration 
 
 
X 
 
 
Nasal glucagon will be administered only if a 
participant’s baseline glucose level is within target 
range. See Section 4.1.4. 
Sample collection for 
measurement of 
plasma glucagon 
(pharmacokinetics) 
 
 
10, 30, 60 
min 
 
 
Time points are relative to NG administration.  
Bedside glucose 
safety measurements  
 
 
X 
 
 
Measured using a point-of-care blood glucose testing 
device: either CGM, if applicable, via IV cannulation, 
or using an approved BG meter. See Section 8.2.4.1. 
Blood glucose readings will be taken every 5 to 10 
min for the first 30 min after dosing, and then every 
20 min up to 90 min. Additional measurements may 
be taken at investigator’s discretion. 
When a planned bedside safety sample coincides with 
a PD sample, the PD sample may be used for bedside 
safety assessment. 
Sample collection for 
measurement of 
plasma glucose 
(pharmacodynamics) 
 
 
P, 10, 30, 
60, 90 min 
 
 
Measured with study-approved rapid glucose analyzer 
(Section 8.6). Timings are relative to NG 
administration.  
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Procedure 
Screening 
Visit 
Predosing-visit 
preparation 
reminder 
(telephone) 
Dosing 
Visit 
Follow-up 
(telephone) 
Second 
Follow-up 
(telephone) 
Comments 
Day -35 to 
Day -1  
Day -1 
Day 1 
Day 2 
Day 9±3 
Meal 
 
 
X 
 
 
Following completion of all study procedures, the 
participant will be provided a meal including 
carbohydrates, and the investigator will ensure the 
participant’s plasma glucose is stable prior to 
discharge.  
Discharge from site 
 
 
X 
 
 
Participants may be discharged after 4 hours postdose 
safety monitoring is complete. If required, a 
participant may remain in clinic for further 
observation, at the discretion of the investigator. 
Abbreviations: AE = adverse event; BG = blood glucose; CGM = continuous glucose monitoring; IV = intravenous; MDI = multiple daily injection; NG = nasal 
glucagon; P = predose; PD = pharmacodynamics; PI = principal investigator; SC = subcutaneous. 
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2. 
Introduction 
2.1. 
Study Rationale 
The primary aim of Study I8R-MC-IGBO (IGBO) is to assess the safety and tolerability of a 
3 mg dose of NG (commercial drug product) in pediatric participants aged 1 to <4 years with 
T1D in an inpatient clinical research facility. 
2.2. 
Background 
NG (also known as Baqsimi; LY900018) is a drug-device combination product consisting of a 
single-use nasal dosing device that delivers glucagon powder for absorption through the nasal 
mucosa. NG provides the same single-chain, 29-amino-acid polypeptide as human glucagon and 
the recombinant DNA-produced glucagon used in currently marketed glucagon emergency kits 
(Glucagon Emergency Kit [Eli Lilly and Company] and GlucaGen® HypoKit [Novo Nordisk 
A/S]). It is approved for use as a treatment for severe hypoglycemia in adults and pediatric 
patients with diabetes mellitus aged ≥4 years. It has not been studied in children aged <4 years. 
The principal action of NG is to increase BG concentration through the action of glucagon in the 
liver.  
The formulation contains 3 mg of glucagon, as well as beta-cyclodextrin (a compendial excipient 
that works as a filler/bulking agent/absorption enhancer), and dodecylphosphocholine (a novel 
excipient that works as an absorption enhancer/surfactant). 
The same drug-device combination product that is approved for use in patients aged 4 years and 
older will be used in this study in pediatric participants aged 1 to <4 years. 
2.3. 
Benefit/Risk Assessment 
NG is administered by inserting the tip of the device into the nostril and pushing the plunger, 
which actuates the device to deliver the NG powder into the nasal mucosa. The tip of the device 
is of similar size with similar drug product volume to other currently marketed devices approved 
and used for pediatric intranasal spray administration in patients aged <4 years including 
Nasacort® (Children’s Nasacort USPI, 2015), Narcan® Nasal Spray (Narcan Nasal Spray PIL, 
2020), Sterimar™ (Sterimar Package Insert, 2019), and Calpol® Saline Nasal Spray (Calpol PIL, 
2010). 
Due to the insertion of the device into the nostril, there is some risk of local nasal discomfort, 
irritation, and possibly trauma. To minimize these risks, NG will be administered by healthcare 
professionals who have been trained on the use of the device and to limit the device insertion 
depth based on the size and distensibility of the external nare for the individual participant.  
NG has been approved as safe and effective for the treatment of severe hypoglycemia in patients 
with diabetes aged ≥4 years. As part of the clinical development program it was tested in the 
pediatric population aged between 4 and <17 years in 1 clinical trial and 1 actual-use study. A 
description and outcomes of these studies are provided in Section 2.3.1.2. The results of this 
current study will provide information that may contribute toward the approval for the treatment 
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of severe hypoglycemia with NG in pediatric patients with diabetes aged 1 to <4 years, allowing 
an additional glucagon formulation treatment option for this population. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of NG may be found in the IB and Baqsimi Package Insert (2019). 
2.3.1. 
Risk Assessment 
Risks related to IGBO study procedures, and how they will be mitigated, are described in 
Section 2.3.1.1. A summary of glucagon safety is in Section 2.3.1.2. 
2.3.1.1. 
Risks and Safety Considerations in Study IGBO 
Baseline glucose target level 
Prior to dosing, each participant’s baseline glucose level should be within a target range of 70 to 
140 mg/dL for NG to be administered. This range is based on premeal target glucose values 
recommended by the ISPAD (DiMeglio et al. 2018) of 70 to 130 mg/dL, with a +10 mg/dL 
allowance for the upper limit. 
Refer to the Study Operations Manual for detailed instructions. 
This study avoids the induction of hypoglycemia (defined as BG <70 mg/dL; Abraham et al. 
2018), to ensure there is no more than a minimal increase in medical risk for the pediatric 
population. 
The investigator may consider rescue medication to pre-empt or treat clinically significant or 
severe hypoglycemia if indicated by the baseline BG level. 
If a participant’s baseline BG level is 
 <70 mg/dL, the investigator will determine whether to proceed with dosing or to use 
rescue treatment (Section 8.3.6).  
 <54 mg/dL (clinically significant hypoglycemia [Level 2]), site will halt study drug 
procedure and use rescue therapy to raise BG level. 
If rescue therapy is administered, the participant should remain at the site until stable based on 
investigator observation and clinical judgment. The visit may be rescheduled for a subsequent 
day at the investigator’s discretion, and according to the Manual of Operations. 
If the participant does not return to the site for a subsequent visit in which required study 
procedures are completed, the participant must be discontinued from the study. 
Blood sampling 
The number and volume of blood samples for each participant have been minimized to reduce 
the potential risks and lower the burden of study procedures for pediatric participants. 
Glucose safety monitoring  
Though hypoglycemia is not induced in this study, there is the potential for a participant to 
experience hypoglycemia. Participants’ BG level will be monitored at the bedside during and 
after NG administration, and the investigator may consider use of glucose or glucagon to 
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I8R-MC-IGBO(a) 
 
 
18 
pre-empt or treat severe hypoglycemia. See Section 8.2.4.1 for details on this bedside glucose 
safety monitoring, and Section 8.3.6 for detail of the rescue procedure. 
Needle punctures 
There is a small risk associated with needle punctures for blood sampling, which in some 
instances may cause bleeding, bruising, discomfort, infections, and/or pain. Use of 
age-appropriate equipment will be used to minimize risks associated with these procedures. In 
addition, use of local anesthetics (e.g., Emla® cream) consistent with local prescribing 
information is permitted during the study visit to ease discomfort associated with venipuncture. 
To minimize venipuncture and adhere to blood volume restrictions, laboratory tests have been 
minimized. 
2.3.1.2. 
Historical Summary of Glucagon Safety 
Injectable glucagon 
There has been extensive patient exposure to recombinant glucagon with injectable 
administration for approximately 20 years. Side effects noted are generally mild and include 
nausea and vomiting. Generalized allergic reactions, including urticaria, respiratory distress, and 
hypotension, have been reported in patients who received glucagon by injection. It is 
contraindicated in patients with known hypersensitivity to it, or in patients with known 
pheochromocytoma or insulinoma.  
Inclusion and exclusion criteria in this study were designed to mitigate these risks. 
Nasal glucagon 
NG was approved in the US and Europe in 2019 for the emergency treatment of severe 
hypoglycemia in patients with diabetes aged 4 years and above.  
The NG development program demonstrated that NG is safe in both adult and pediatric patients 
aged ≥4 years. The program included 10 studies in adults (healthy subjects and patients with 
diabetes) and 2 studies in pediatric patients with T1D. This program demonstrated that NG has a 
comparable safety profile to recombinant glucagon, with the exception of additional effects 
related to its nasal route of administration. The most commonly reported AEs in the NG 
development program were vomiting, headache, nausea, and “upper respiratory tract irritation” 
(rhinorrhea, nasal discomfort, nasal congestion, cough, and epistaxis), watery eyes, redness of 
eyes, sneezing, and itchy nose, throat, and eyes. 
The NG formulation in Study IGBO is the commercial drug product, which was also used in 
adult Studies I8R-MC-IGBI and I8R-MC-IGBJ. Study IGBI was a multi-center, randomized, 
open-label, 2-treatment, 2-period, single-dose, crossover study in adult patients with T1D that 
compared glucagon administered through either the nasal route (NG) or the intra-muscular route 
(GlucaGen) in the recovery from hypoglycemia induced by a controlled insulin infusion. Study 
IGBJ was a Phase 3, multi-center, randomized, open-label, active comparator, single-dose, 2-
period, 2-treatment, crossover study of NG (LY900018) compared to intramuscular glucagon for 
treatment of insulin-induced hypoglycemia in adult Japanese patients with diabetes mellitus. 
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Summary of NG safety in pediatric patients 
NG was assessed in pediatric patients in Studies I8R-MC-IGBB and I8R-MC-B001 (B001). In 
total in these studies, 58 patients aged 4 to <18 years received at least 1 dose of NG. 
Study IGBB evaluated PK, PD, safety, and tolerability of NG 2 mg and 3 mg in pediatric 
patients aged 4 to <17 years with T1D. In this study, 36 patients with T1D received NG 3 mg, 
23 received NG 2 mg, and 24 received weight-based intramuscular glucagon.  
The following table summarizes adverse reactions that occurred in pediatric patients in Study 
IGBB at an incidence of ≥2%, following NG 3 mg administration. 
Adverse Reaction 
NG 3 mg 
n = 36 
% 
Vomiting 
30.6 
Headache 
25.0 
Nausea 
16.7 
Upper Respiratory Tract Irritationa  
16.7 
Abbreviations: n = number of patients; NG = nasal glucagon. 
a 
Upper respiratory tract irritation: nasal discomfort, nasal congestion, sneezing. 
Source: Baqsimi Package Insert, 2019. 
Nasal and ocular symptoms were also solicited in Study IGBB through a patient questionnaire. A 
list of these symptoms and their incidence rates is included in the Baqsimi Package Insert (2019). 
Study B001 is a real-world study that evaluated the effectiveness and ease-of-use of NG 3 mg in 
pediatric patients aged 4 to <18 years with T1D. In this study, 22 patients received at least 1 dose 
of NG 3 mg.  
AEs solicited through the Hypoglycemia Episode Questionnaire and the Nasal Score 
Questionnaire were low to moderate in severity. The most common AEs were nasal discomfort 
(92.9%), watery eyes (85.7%), headache (71.4%), runny nose (64.3%), nasal congestion 
(50.0%), sneezing (50%), and redness of eyes (42.9%), with approximately 60% of events 
resolving within 1 hour.   
Three patients who discontinued from Study B001 due to a clinical event reported severe nasal 
discomfort and 1 patient withdrew consent for reasons not related to a clinical event. 
2.3.2. Benefit Assessment 
There is no anticipated therapeutic benefit for the participants in Study IGBO. 
Study IGBO is expected to help meet an unmet need by contributing to the development of an 
additional rescue therapy with alternate route of administration for the treatment of severe 
hypoglycemia in children aged 1 to <4 years. 
2.3.3. Overall Benefit: Risk Conclusion 
Considering the measures taken to minimize risk to participants of this study, the potential risks 
identified in association with NG are justified by the contribution of data that may inform further 
development and provide the benefit of an additional rescue therapy for severe hypoglycemia 
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that does not require dose adjustment and provides an alternate route of administration for the 
T1D pediatric population aged between 1 and <4 years. 
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3. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
To assess the safety and tolerability of a single dose of 
NG 3 mg in children aged 1 to <4 years with T1D 
Incidence of treatment-emergent adverse events 
Secondary 
 
To assess the PD of a single dose of NG 3 mg in 
children aged 1 to <4 years with T1D 
Change from baseline (predose BG) of maximum 
blood glucose. Other blood glucose parameters:  
 
BGmax 
 
AUC 
 
TBGmax 
To assess the PK of a single dose of NG 3 mg in 
children aged 1 to <4 years with T1D 
Model-estimated population PK parameters 
Exploratory 
 
To assess the efficacy of a single dose of NG 3 mg in 
children aged 1 to <4 years with T1D 
The proportion of participants achieving treatment 
success defined as an increase of blood glucose 
≥20 mg/dL (1.11 mmol/L) from baseline (predose BG) 
within 30 min postdose 
Abbreviations: AUC = area under the concentration-time curve; BGmax = maximum observed blood glucose; NG = 
nasal glucagon; PD = pharmacodynamics; PK = pharmacokinetics; T1D = type 1 diabetes; TBGmax = time of 
maximum observed blood glucose. 
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4. 
Study Design 
4.1. 
Overall Design 
Study IGBO is a Phase 1, open-label, multi-center study with a primary objective of assessing 
safety and tolerability of a single 3 mg dose of NG in pediatric participants aged 1 to <4 years 
with T1D. 
Participants will attend study visits, including screening, in the company of 1 or more parents or 
legal guardians, and in accordance with local healthcare facility practice. For simplicity, the term 
“parent/legal guardian” will be used in the singular throughout this protocol.  
The study comprises a single cohort, with each participant receiving a single dose of 3 mg NG. 
At least 9 participants with an approximate maximum of 20 may be enrolled so that 6 evaluable 
participants complete the study. See Section 9.4 for definitions of evaluable participants. 
For the purposes of this study, a participant completes the study after the conclusion of the 
second follow-up telephone call on Day 9 (±3). 
Study governance considerations are described in detail in Appendix 1, Section 10.1. 
Section 1.2 illustrates the study design. 
4.1.1. 
Screening 
The screening visit will take place as shown in the SoA. 
In addition to screening tests, the screening visit will include an information session for the 
participant’s parent/legal guardian on the target BG range for dosing day, including  
 the target range for the participant’s BG on dosing day 
 how the parent/legal guardian can help achieve this target BG level, including 
o the recommendation that participants have a natural overnight fast if possible, 
assuming morning dosing. At a minimum, participants should have no food or 
beverage intake other than water within 3 hours before dosing 
o parent/legal guardian participation in a predosing-visit telephone reminder on 
Day -1 (if required – see Section 4.1.2), and responding to contact from site on the 
morning of dosing to verify that the BG level is likely to be in a range appropriate 
for the scheduled visit. 
4.1.2. 
Predosing-Visit Telephone Reminder 
On Day -1, site staff will telephone the participant’s parent/legal guardian to give a reminder 
about the procedure for dosing day, including 
 the recommendation that participants have a natural overnight fast if possible, assuming 
morning dosing. At a minimum, participants should have no food or beverage intake 
other than water within 3 hours before dosing,  
 the target BG level, and 
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 that site staff will be in contact on the morning of dosing to determine whether the 
participant’s BG level is likely to be in the required range for dosing. 
Note that this postscreening call may be omitted if the screening visit was on Day -1.  
4.1.3. 
Day 1: Call/Text on Morning of Dosing  
On Day 1, before each participant is expected to leave their home to travel to the site, site staff 
will call or send a text message to the parent/legal guardian soliciting 
 a measurement of the participant’s BG level and  
 the participant’s physical status to participate and attend the visit. 
The BG measurement can be taken either via the participant’s own CGM device or using an 
appropriate glucometer, and will be used to determine whether the baseline BG level is likely to 
be within the target range at the time of dosing at the site.  
Based on this information, the PI may decide to proceed or reschedule the visit (Section 4.1.8).  
4.1.4. 
Day 1: Predose 
For the dosing visit (Day 1), it is recommended that participants have a natural overnight fast if 
possible, assuming morning dosing. At a minimum, participants should have no food or beverage 
intake other than water within 3 hours before dosing. 
At the study site, BG will be measured to determine if the participant’s baseline BG level is 
within the target range of 70 to 140 mg/dL (Section 2.3.1.1), and confirm ability to proceed with 
dosing and other study procedures.  
If BG is  
 below the target range, rescue treatment may be considered (Section 8.3.6).  
 above the target range, the investigator may choose to 
o in the case of pump users, increase the basal insulin rate of the participant’s 
insulin pump, or initiate a small bolus dose, to achieve target BG  
o in the case of MDI users: administer a small correction bolus via SC injection 
of insulin or IV infusion of insulin diluted in normal saline to achieve target 
BG  
o wait and allow BG to decrease to target level if BG is already decreasing, or 
o reschedule the visit (Section 4.1.8). 
If a bolus dose of insulin is administered via the pump, or insulin is administered to patients on 
MDI, the dose level will be based on PI discretion.  
The basal rate or insulin infusion may be adjusted at the discretion of investigator during study 
procedures as necessary to protect participant safety. 
For pump users only, if the investigator adjusts the pump basal rate setting, it may be returned to 
pre-study settings after 90 minutes postdose and all PK and PD samples have been collected, at 
the discretion of investigator. The basal rate setting must be returned to participant’s usual 
setting prior to discharge. Additionally, site staff must confirm the basal settings with the 
parent/legal guardian before the participant is discharged. 
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4.1.5. 
Day 1: Dosing 
NG will be administered within 5 minutes of predose BG measurement by site staff with the 
participant in a recumbent or semi-recumbent position. 
The tip of the device is gently inserted in the nostril. At that point, the plunger of the device is 
pushed firmly until the green line is no longer showing, which indicates that the dose is 
complete. The drug is absorbed from the nasal cavity; thus the participant does not need to inhale 
after dosing.  
If a participant sneezes immediately after administration, site staff should document this in the 
eCRF. All postdose assessments, including PK and PD sampling, would still occur in this case. 
4.1.5.1. 
Suspected Administration Failure 
If site staff are not able to successfully dose – e.g., due to device malfunction, or the child 
forcefully moving their head away – there will be a 30-minute period during which safety and 
PD blood sampling will proceed. At 30 minutes, if PD and safety sampling show that the 
participant’s BG levels are in the target range (Section 2.3.1.1), a second dose may proceed, at 
the discretion of the PI and participant’s parent/legal guardian.  
4.1.6. 
Day 1: Postdose 
After dosing, bedside glucose safety measurements will be taken with either the participant’s 
own CGM device, or with an approved point-of-care glucometer using capillary blood samples, 
as described in Section 8.2.4.1. 
Venous blood samples will be taken for PK measurements. 
Following study procedures, participants will be given a meal including carbohydrates, and 
discharged. Discharge may be delayed if the investigator determines that further observation is 
needed. 
4.1.7. 
Follow-up 
Site staff will conduct 2 follow-up telephone calls with the parent/legal guardian to discuss any 
potential side effects or AEs: 
 on Day 2 
 on Day 9 (±3 days). 
4.1.8. 
Rescheduling Visits 
A participant’s dosing visit may be rescheduled, up to a maximum of 2 times, if 
 based on the Day 1 communication prior to the participant traveling to site (Section 4.1), 
the PI determines that the participant’s BG level is unlikely to be within the target range 
in time for dosing, or 
 a participant’s baseline BG level, as measured on site prior to dosing, is outside the target 
range and may not be achieved within a time frame suitable for completion of all required 
visit procedures (Section 4.1.4), or  
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 a participant has an acute illness such as influenza, ear or respiratory infection, or other 
illness that in the opinion of the investigator would hinder completion of visit procedures. 
Note that if the device malfunctions and no dose is delivered, rescheduling is not required and 
dosing may proceed with another device. See Section 4.1.5.1. 
The dosing visit should be within 35 days of the screening visit. If this is not possible, additional 
time may be allowed between screening and Day 1 with documented approval from the sponsor.  
The dosing day will always be designated as Day 1 and subsequent study days numbered 
accordingly.  
In the event of rescheduled dosing visits, site staff may repeat as needed the postscreening 
communication prior to the participant traveling to site. 
4.2. 
Scientific Rationale for Study Design 
NG 3 mg has demonstrated similar safety and PD responses across all completed adult and 
pediatric studies (age range 4 to <17 years) in which injectable glucagon was used as an active 
comparator. Based on these data, Study IGBO was designed without an active comparator, to 
eliminate unnecessary procedures and minimizes distress and discomfort for study participants.  
4.3. 
Justification for Dose 
NG is approved for use in patients with diabetes aged 4 years and above, at a dose level of 3 mg. 
A single dose of 3 mg NG was supported by the safety, tolerability, efficacy, and PK data 
generated during the NG development program. 
For pediatric patients with diabetes, the selection of a 3 mg dose was based on results from Study 
IGBB. In that study 
 NG 3 mg was administered to all age groups (4 to <8, 8 to <12, and 12 to <17 years). In 
each group, NG 3 mg rapidly produced a maximal BG increase, similar to that of 
injectable glucagon doses (0.5 or 1 mg depending on the patient’s weight); 
 NG 2 mg and 3 mg were administered to the 2 younger age groups (4 to <8 and 8 to <12 
years). NG 3 mg produced a slightly higher glucose response than NG 2 mg; 
 NG 3 mg in pediatric patients showed similar tolerability and safety to NG 2 mg, and to 
weight-based injectable glucagon doses. 
Although 3 mg NG in 1- to <4-year-old participants is expected to result in higher systemic 
glucagon concentrations than those observed with 3 mg NG in older pediatric patients, this 
transient high systemic exposure is expected to be safe. This expectation is based on published 
data with intravenous-administered glucagon in adults (Graf et al. 1999), which showed 
exposures that were multiples higher than the projected maximum exposure following NG 
administration in pediatric patients aged 1 to <4 years, with no safety concerns.  
Additionally, this transient high glucagon concentration is expected to ensure that the maximum 
PD effect of BG excursion is produced, as desired for an emergency-use product. 
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4.4. 
End of Study Definition 
The end of the study is the date of the second follow-up telephone call shown in the SoA 
(Section 1.3) for the last participant. 
 
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5. 
Study Population 
Eligibility of participants for the study will be based on the results of screening medical history, 
physical examination, vital signs, and clinical laboratory tests. 
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented. 
Screening may occur up to 35 days prior to enrollment. At the investigator’s discretion, with 
documented approval from the sponsor, participants who have not attended a dosing visit within 
35 days of screening may be subjected to an additional medical assessment and/or clinical 
measurements to reconfirm their eligibility. Laboratory tests previously collected for the 
screening visit may be used to reconfirm eligibility. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply at 
screening: 
Age 
1. Are aged 1 to <4 years, at the time of the ICF being signed and throughout their 
participation in the study. 
Type of participant and disease characteristics 
2. have a diagnosis of T1D based on medical history for at least 6 months as previously 
demonstrated by either documented presence of autoimmune antibodies (glutamic acid 
decarboxylases; insulin-associated tyrosine phosphatase antibody; insulin autoantibody; 
islet cell antibody) as per medical records, or diagnosis by an endocrinologist (pediatric 
or adult), or a physician with expertise in treating pediatric patients with T1D 
3. have been receiving insulin therapy via MDI, or continuous subcutaneous insulin infusion 
using a pump, and have been stable on the therapy and route of administration for at least 
3 months prior to screening 
4. have a hemoglobin A1c level of ≤9.5% at screening 
5. have venous access sufficient to allow for blood sampling as per the protocol 
6. are in good general health with no conditions that could influence the outcome of the 
trial, and in the judgment of the investigator are a good candidate for the study based on 
review of available medical history, physical examination, and clinical laboratory 
evaluations with no prior history of choanal atresia, nasal/pharyngeal blockage, or 
anomaly. 
Availability and informed consent 
7. participant and their parent/legal guardian are reliable and willing to be available for the 
duration of the study, and to follow study procedures 
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8. the participant’s parent/legal guardian can provide written informed consent on behalf of 
the participant. 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
9. have presence or history of hypersensitivity to glucagon or any related products; or 
severe hypersensitivity reactions, such as angioedema, to any medication 
10. have presence or history of any of the disorders in the following list, that in the opinion of 
the investigator, could significantly alter the absorption, metabolism, or elimination of 
drugs; constitute a risk when taking the investigational product; or interfere with the 
interpretation of data: 
 cardiovascular, 
 respiratory, 
 hepatic, 
 renal, 
 gastrointestinal, 
 endocrine (other than T1D), 
 hematological, or  
 neurological disorders 
 suspected low glycogen stores due to chronic low carbohydrate intake or inadequate 
diet. 
11. have a history of pheochromocytoma (i.e., adrenal gland tumor) or insulinoma 
12. have a history of epilepsy or seizure disorder 
13. have 1 or more congenital anomalies to the anatomy of the nose, or require changes to the 
anatomy of the nose (e.g., are eligible for nasal pharyngeal surgery) 
14. have history or presence of laryngopharyngeal reflux 
15. have an abnormal blood pressure and/or pulse rate as determined by the investigator 
16. in the 3 months before screening, have had an episode of severe hypoglycemia, defined 
as a hypoglycemia event with severe cognitive impairment (including coma and 
convulsions) requiring assistance by another person to actively administer carbohydrates, 
glucagon, or take other corrective actions (Abraham et al. 2018) 
17. have clinically significant multiple or severe drug allergies, or intolerance to topical 
corticosteroids, or severe posttreatment hypersensitivity reactions (including, but not 
limited to, erythema multiforme major, linear immunoglobulin A dermatosis, toxic 
epidermal necrolysis, or exfoliative dermatitis) 
18. have a history of human immunodeficiency virus infection and/or positive human 
immunodeficiency virus antibodies 
19. have a history of hepatitis C and/or positive hepatitis C antibody  
20. have a history of hepatitis B and/or positive hepatitis B surface antigen 
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Prior/concomitant therapy 
21. are regularly administered a systemic beta-blocker, indomethacin, warfarin, or drugs 
classified as anticholinergics, or corticosteroids; or regular use of other medications, 
pending discussion between the investigator and the study clinical pharmacologist or 
CRP 
22. are using closed-loop insulin therapy, UNLESS such a device is set to ‘open 
loop/manual’ mode and the automated low glucose suspend or predictive low glucose 
suspend are disabled on the day of the dosing visit until all PK and PD samples have been 
collected. 
Prior/concurrent clinical study experience 
23. are currently enrolled in a clinical study involving an investigational product or any other 
type of medical research judged not to be scientifically or medically compatible with this 
study 
24. have participated, within the past 30 days, in a clinical study involving an investigational 
product. If the previous investigational product has a long half-life, 5 half-lives or 
30 days (whichever is longer) should have passed. 
Other exclusions 
25. are related to either a Lilly employee; an employee of a third-party organization involved 
in this study; or investigative site staff directly affiliated with this study 
26. in the opinion of the investigator or sponsor, the participant or their parent/legal guardian 
is unsuitable for inclusion in the study. 
5.2.1. 
Additional Exclusion Criteria Prior to Dosing Visit (Day 1) 
27. have had an episode of severe hypoglycemia, or have had glucagon administered, during 
the period between the screening visit and the dosing visit. An episode of severe 
hypoglycemia is defined as a hypoglycemia event with severe cognitive impairment 
(including coma and convulsions) requiring assistance by another person to actively 
administer carbohydrates, glucagon, or take other corrective actions (Abraham et al. 
2018). 
5.3. 
Lifestyle Considerations 
5.3.1. 
Meals and Dietary Restrictions 
It is recommended that participants have a natural overnight fast if possible, assuming morning 
dosing. 
At a minimum, participants should have no food or beverage intake other than water within 
3 hours before dosing. 
 
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5.4. 
Screen Failures 
Screen failures are defined as participants whose parent/legal guardian consented for them to 
participate in the clinical study but who are not subsequently enrolled in the study. A minimal set 
of screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials publishing requirements and 
to respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) or were 
required to unexpectedly discontinue from the study during screening or lead-in period (e.g., due 
to enrollment pause related to the coronavirus disease-19 or other public health emergency) may 
be re-screened once, at the investigator and sponsor’s discretion. In the case of rescreening, the 
participant’s previous screening blood chemistry results may be used if they were taken within 
the previous 6 months. 
Re-screened participants should be assigned a new participant number. Each time re-screening is 
performed, a new informed consent must be signed. 
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6. 
Study Intervention 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to/used by a study participant 
according to the study protocol. 
6.1. 
Study Intervention Administered 
Intervention Name 
Nasal glucagon 
Type  
Drug-Device 
Dose Formulation 
Powder 
Dosage Level(s) 
3 mg glucagon 
Route of Administration 
Nasal 
Use 
Experimental  
investigational medicinal 
product/noninvestigational 
medicinal product 
investigational medicinal product 
Sourcing 
Provided centrally by the sponsor 
Packaging and Labeling 
Nasal glucagon will be provided in nasal delivery 
devices labeled as required per country requirement 
Name(s) or Alias(es) 
Baqsimi; LY900018 
6.1.1. 
Administration Details 
See Section 4.1.5 for an overview of NG administration. Further detail is in the NG Instructions 
for Use. 
6.2. 
Preparation/Handling/Storage/Accountability 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study interventions received and any discrepancies are reported 
and resolved before use of the study intervention. 
Only participants enrolled in the study may receive study intervention and only authorized site 
staff may supply or administer study intervention. All study interventions must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the investigator and authorized site 
staff. 
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The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records). 
Unused study materials will remain locked and securely stored until returned to the sponsor or 
destroyed, according to written instruction from the sponsor. Further guidance and information 
for the final disposition of unused study materials are provided in the Pharmacy Manual. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
Not applicable as this is a single-arm study. 
6.4. 
Study Intervention Compliance 
Participants will receive study intervention directly from the investigator or designee, under 
medical supervision. The date and time of each dose administered in the clinic will be recorded 
in the source documents and in the eCRF. The dose of study intervention and study participant 
identification will be confirmed at the time of dosing by a member of the study site staff other 
than the person administering the study intervention. 
6.5. 
Concomitant Therapy 
Participants on stable concomitant medications at the time of study entry, as defined in 
Section 5.2, Exclusion Criterion 21, should continue their regular, unchanged dose throughout 
the study.  
For participants using CGM, concomitant medications or supplements in doses that may interfere 
with CGM measurements according to the label should not be taken within 48 hours prior to the 
dosing visit. 
In general, new concomitant medications should be avoided; however, acetaminophen or similar 
medication may be administered at the discretion of the investigator postdosing for treatment of 
pain or discomfort. If the need for other concomitant medication arises, inclusion or continuation 
of the participant may be at the discretion of the investigator in consultation with a Lilly clinical 
pharmacologist. Any medication used during the course of the study must be documented in the 
eCRF. All changes in concomitant medications made during the study should be recorded in the 
eCRF. 
6.6. 
Dose Modification 
Dose modification is not allowed in this study. 
Due to the design of the NG drug-device, a full 3 mg dose of NG is administered when the tip of 
the device is inserted into the nostril and the plunger is pressed firmly. It is not possible to 
modify the dose with the current drug-device. 
6.7. 
Intervention after the End of the Study 
Participants will continue their previous insulin regimen after all study procedures have been 
completed. 
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
7.1. 
Discontinuation of Study Intervention 
Not applicable as this is a single-dose study. 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
A participant may withdraw from the study 
 at any time at his/her own request  
 at the request of his/her designee (e.g., parent/legal guardian) 
 at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons 
 due to enrollment in any other clinical study involving an investigational 
product, or enrollment in any other type of medical research judged not to be 
scientifically or medically compatible with this study 
 if their baseline BG is below 54 mg/dL as described in Section 2.3.1.1. 
If consent is withdrawn for disclosure of future information, the sponsor may retain and continue 
to use any data collected before such a withdrawal of consent. If a participant is withdrawn from 
the study, their parent/legal guardian may request destruction of any samples taken and not 
tested, and the investigator must document this in the site study records. 
7.2.1. 
Discontinuation of Inadvertently Enrolled Participants 
If the sponsor or investigator identifies a participant who did not meet enrollment criteria and 
was inadvertently enrolled, then safety follow-up should be performed as outlined in Section 1.3 
(Schedule of Activities), Section 8.2 (Safety Assessments), and Section 8.3 (Adverse Events and 
Serious Adverse Events) of the protocol. Such participants would be classified as discontinued. 
7.3. 
Lost to Follow-up 
A participant will be considered lost to follow-up if the participant’s parent/legal guardian is 
unable to be contacted by the study site for follow-up telephone calls. Site staff are expected to 
make diligent attempts to contact participants’ parent/legal guardian for follow-up.  
Discontinuation of specific sites or of the study as a whole is handled as part of Appendix 1 
(Section 10.1). 
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8. 
Study Assessments and Procedures 
Study procedures and their timing are summarized in the SoA. Protocol waivers or exemptions 
are not allowed. 
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study intervention. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
Investigators or relevant clinical staff will provide age-appropriate explanations to all children 
prior to any assessment or procedure as appropriate. Investigators should assess and monitor 
physical pain and distress at each visit. Clinical staff trained or experienced in pediatric 
phlebotomy should perform blood draws at the clinic. 
Use of local anesthetics (e.g., Emla cream) and other techniques to promote viable ease in blood 
sampling consistent with local prescribing information are permitted during the study visit to 
ease discomfort associated with venipuncture. Owing to blood volume restrictions, laboratory 
tests have been minimized. 
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
8.1. 
Efficacy Assessments 
Efficacy of NG may be assessed as an exploratory objective, based on PD parameters. See 
Section 9.4.3. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
8.2.1. 
Physical Examinations 
An age-appropriate physical examination will be conducted. 
8.2.2. 
Vital Signs 
For each participant, vital sign measurements will be conducted according to the SoA 
(Section 1.3). 
Blood pressure and pulse rate should be measured with the participant sitting and relaxed when 
possible. Blood pressure measurements should be determined using a correctly sized cuff. 
Additional vital signs may be measured for participant safety at the dosing visit, at the discretion 
of the investigator. 
8.2.3. 
Clinical Safety Laboratory Assessments 
For each participant, laboratory tests detailed in Section 10.2 should be conducted according to 
the SoA (Section 1.3). 
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8.2.4. 
Safety Monitoring 
The Lilly clinical pharmacologist or CRP/scientist will monitor safety data throughout the course 
of the study. 
Lilly will review SAEs within time frames mandated by company procedures. The Lilly clinical 
pharmacologist or CRP will periodically review vital signs, safety, and AEs.  
8.2.4.1. 
Bedside Glucose Safety Monitoring 
During and after dosing, BG levels will be measured at the bedside for safety monitoring using 
an approved point-of-care glucometer. This will be 1 of 2 types, as follows: 
 If the participant has been using an approved CGM in accordance with the device label 
for at least 1 month prior to the dosing visit, this CGM may be used for safety 
monitoring. 
 If the participant has not been using an approved CGM, plasma BG levels for safety will 
be measured using a study-approved point-of-care glucometer. 
In both cases, refer to the Study Operations Manual for details. 
Timings of BG measurements are shown in the SoA (Section 1.3). 
8.2.5. 
Monitoring for Hypoglycemia 
Severe hypoglycemia will be described using the following ISPAD definition (Jones 2018): 
Severe hypoglycemia in children: because children have limited ability to detect and/or 
self-treat hypoglycemia, severe hypoglycemia in children is an event in which children have 
severe cognitive impairment, and require external assistance, are semiconscious or unconscious, 
or in coma with or without convulsions, and requires another person to actively administer 
carbohydrates, glucagon, or take other corrective action. 
The determination of a hypoglycemic event as an episode of severe hypoglycemia, as defined 
above, will be made by the investigator based on the medical need of the participant to have had 
hypoglycemia-induced cognitive dysfunction and is not predicated on the report of a participant 
simply having received assistance. 
All episodes of severe hypoglycemia must be recorded in the eCRF and reported as SAEs. 
Use of intravenous glucagon to preempt or treat severe hypoglycemia is described in 
Section 8.3.6. 
8.2.6. 
Nasal Inspections 
A visual nasal inspection will be conducted as specified in the SoA (Section 1.3), and more 
frequently if deemed necessary by the investigator. The same investigator that conducts the 
predose inspection should perform the postdose inspection for consistency. Refer to the Study 
Operations Manual for further details on this procedure. 
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8.2.7. 
Hepatic Safety Monitoring 
If clinically applicable, the investigator may obtain additional laboratory tests during the study to 
confirm any hepatic abnormalities that may occur. Specific tests and follow-up procedures are 
provided in Section 10.4 (Appendix 4). 
8.3. 
Adverse Events and Serious Adverse Events 
AEs will be reported by the investigative site staff, or the participant’s parent/legal guardian. 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention, study device, or device 
constituent, or study procedures, or that caused the participant to discontinue the study (see 
Section 7). 
A non-SAE that can be attributed or related to study device or device constituent, where the 
device complaint/deficiency/problem was anticipated, is also referred to as an adverse device 
effect. 
An SAE attributable or related to an anticipated study device or device constituent 
complaint/deficiency/problem is also referred to as a serious adverse device effect. 
An SAE attributable or related to an unknown or unanticipated device or device constituent 
complaint/deficiency/problem is also referred to as an unanticipated adverse device effect; or 
unanticipated serious adverse device effect in certain countries. 
A “reasonable possibility” means that there is a cause and effect relationship between the 
investigational device product, i.e., study device or device constituent, and/or study procedure 
and the SAE. 
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study intervention. 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs will be collected from the signing of the ICF until the completion of the second 
follow-up phone call. 
AEs that begin before the start of study intervention but after signing of the ICF will be recorded 
on the Adverse Event eCRF. 
Although all AEs after signing the ICF are recorded by the site in the CRF/electronic data entry, 
SAE reporting to the sponsor begins after the participant’s parent/legal guardian has signed the 
ICF and the participant has received study drug. However, if an SAE occurs after signing the 
ICF, but prior to receiving NG, it needs to be reported ONLY if it is considered reasonably 
possibly related to study procedures. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 3. The investigator will 
submit any updated SAE data to the sponsor within 24 hours of it being available. 
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Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the investigator must promptly notify the 
sponsor. 
8.3.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Section 10.3 (Appendix 3). 
Care will be taken not to introduce bias while detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant, participant’s parent/legal guardian, and 
investigator assessment are the preferred method to inquire about AE occurrences. 
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow up with each 
participant’s parent/legal guardian at subsequent visits/contacts. All SAEs will be followed up 
until resolution, stabilization, the event is otherwise explained, or the participant is lost to follow-
up (as defined in Section 7.3). Further information on follow-up procedures is provided in 
Section 10.3 (Appendix 3). 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a study 
intervention under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRBs/IECs, and investigators. 
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the sponsor will review and then file 
it and will notify the IRB/IEC, if appropriate according to local requirements. 
8.3.5. 
Pregnancy 
Not applicable for this study. 
8.3.6. 
Rescue Treatment 
Rescue treatment may be considered to preempt or treat clinically significant or severe 
hypoglycemia based on BG measures taken at baseline (Section 2.3.1.1), or as part of bedside 
glucose safety monitoring during and after dosing (Section 8.2.4.1). 
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8.3.6.1. 
Criteria for Considering Rescue Treatment 
In general, the investigator may decide to start a glucose infusion if a participant’s BG level is 
declining rapidly, or their symptoms become consistent with progression to clinically significant 
or severe hypoglycemia. 
In addition, specific BG thresholds for considering rescue treatment at baseline and during 
bedside glucose safety monitoring are as follows: 
Baseline criteria for rescue 
If a participant’s baseline BG level is 
 <70 mg/dL, the investigator will determine whether to proceed with dosing or to use 
rescue treatment. 
 <54 mg/dL (clinically significant hypoglycemia [Level 2]), site will halt study drug 
procedure and use rescue therapy to raise BG level. Such participants’ visits may be 
rescheduled for a subsequent visit. 
8.3.6.2. 
Rescue Procedure 
Oral or intravenous glucose or glucagon may be given as appropriate to the clinical situation. If 
NG was administered, any remaining blood samples will be collected, if possible, according to 
the SoA.  
Further details will be provided to the site in the Study Operations Manual. 
8.3.7. Product Complaints 
A product complaint is any written, electronic, or oral communication that alleges a deficiency 
related to the identity, quality, durability, reliability, safety, effectiveness, or performance of a 
Lilly product after it is released to the study. When the ability to use the product safely is 
impacted, the following are also product complaints:  
a. Deficiencies in labeling information, and 
b. Use errors for device or combination products due to ergonomic design elements of the 
product. 
The sponsor collects product complaints on investigational products, medical devices, and drug 
delivery systems used in clinical studies to ensure the safety of study participants, monitor 
quality, and to facilitate process and product improvements.  
Complaints are also collected on comparators and other materials supplied, as required and 
instructed for the study.  
Participants’ parent/legal guardian will be instructed to contact the investigator as soon as 
possible if they have a complaint or problem with the investigational product, medical device, or 
delivery system, so that the situation can be assessed. 
Product complaints will be reported by the investigator to the sponsor per instructions provided 
on the study-specific Product Complaint Form.  
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With each complaint related to a medical device or delivery system, the investigator will assess 
and indicate on the complaint form whether the product complaint could have led to an SAE had 
precautions not been taken. 
8.4. 
Treatment of Overdose 
For the purposes of this study, an overdose of NG is considered any dose higher than the planned 
3 mg dose. 
In case of suspected overdosing, serum potassium levels may decrease and should be monitored 
and corrected if needed. If the participant develops a marked increase in blood pressure, blood 
pressure medication appropriate to the child’s age may be administered, e.g., phentolamine 
mesylate for children aged 3+ years (OraVerse USPI, 2018; Baqsimi USPI, 2019).  
Refer to the Product Label for additional details. 
8.5. 
Pharmacokinetics 
At the times specified in the SoA, venous blood samples of approximately 2 mL each will be 
collected to determine the plasma concentrations of glucagon. 
Instructions for the collection and handling of blood samples will be provided by the sponsor. 
The actual date and time (24-hour clock time) of each sampling will be recorded. Sites may use 
topical anesthetics to minimize pain or discomfort associated with sample collection. 
8.5.1. 
Bioanalysis 
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor. 
Concentrations of glucagon will be assayed using a validated liquid chromatography with 
tandem mass spectrometry method. 
Bioanalytical samples collected to measure investigational product concentrations will be 
retained for a maximum of 1 year following last participant visit for the study. 
8.6. 
Pharmacodynamics 
At the times specified in the SoA, blood samples will be collected for use in a study-approved 
rapid glucose analyzer (YSI or equivalent) to determine the plasma concentrations of glucose.  
Instructions for the collection and handling of blood samples will be provided by the sponsor. 
The actual date and time (24-hour clock time) of each sampling will be recorded. 
8.7. 
Genetics 
Genetics will not be evaluated in this study. 
8.8. 
Biomarkers 
Biomarkers will not be evaluated in this study. 
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8.9. 
Immunogenicity Assessments 
Not applicable. 
8.10. 
Health Economics 
Not applicable. 
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9. 
Statistical Considerations 
9.1. 
Statistical Hypotheses 
Not applicable. 
9.2. 
Sample Size Determination 
At least 9 participants with an approximate maximum of 20 may be enrolled so that 6 evaluable 
participants complete the study. 
The sample size is customary for Phase 1 studies evaluating safety, tolerability, PD, and PK, and 
is not powered on the basis of statistical hypothesis testing. 
The sample size assumes a 33% dropout rate. 
Participants who are enrolled but not administered treatment may be replaced to ensure that 
enough participants may complete the study. 
9.3. 
Populations for Analyses 
A detailed description of participant disposition will be provided. 
The participants’ baseline characteristics and demographics will be obtained at entry and will be 
summarized for all enrolled participants who proceed to the dosing visit. 
9.4. 
Statistical Analyses 
Statistical analysis of this study will be the responsibility of Lilly or its designee. 
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol. Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the SAP and/or in the clinical study report. 
All data will be entered, verified, and archived at a CRO external to Lilly and/or at Lilly. Data 
listings, summaries, and analyses will be performed by a CRO and/or by Lilly under the 
guidance and approval of statisticians at Lilly. 
Unless otherwise specified, efficacy analyses will be conducted on all enrolled participants who 
receive the study drug and have an evaluable efficacy outcome (based on PD parameters, see 
Section 9.4.3). 
PK and PD analyses will be conducted on data from all enrolled participants who receive the 
study drug and have evaluable PK or PD data. See Section 9.4.2 for definitions of evaluable PD 
and PK data. 
Safety analyses (Section 9.4.1) will be conducted for all enrolled participants who receive at least 
1 dose of the study drug, whether or not they complete all protocol requirements. 
Additional exploratory analyses of the data will be conducted as deemed appropriate. 
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9.4.1. 
Primary Endpoint: Safety 
9.4.1.1. 
Clinical Evaluation of Safety 
All investigational product and protocol procedure AEs will be listed, and if the frequency of 
events allows, safety data will be summarized using descriptive methodology. 
The incidence of symptoms will be presented by severity and by association with investigational 
product as perceived by the investigator. Symptoms reported to occur prior to enrollment will be 
distinguished from those reported as new or increased in severity during the study. Each 
symptom will be classified by the most suitable term from the Medical Dictionary for Regulatory 
Activities. 
The number of investigational product-related SAEs will be reported. 
Nasal/respiratory and anosmia AEs will be identified using preferred terms and summarized. The 
details will be provided in the SAP. 
9.4.1.2. 
Statistical Evaluation of Safety 
Safety parameters that will be assessed include safety laboratory parameters and vital signs. The 
parameters will be listed or summarized using standard descriptive statistics. Additional analysis 
will be performed if warranted upon review of the data. Details will be provided in the SAP. 
9.4.2. 
Secondary Endpoints: Pharmacodynamics and Pharmacokinetics 
9.4.2.1. 
Pharmacodynamics 
9.4.2.1.1. Pharmacodynamic Parameter Estimation 
Due to limited number of PG measurements (5 time points), a limited number of PD parameters 
will be estimated. The primary PD parameter is change from baseline of BGmax. In addition, 
other PG parameters, BGmax, AUC, and TBGmax may also be estimated. Actual sampling times 
will be used for all calculations. 
Baseline PG concentrations will be calculated from samples obtained immediately prior to 
glucagon dosing (e.g., predose). 
Other PD parameters of PG may be calculated if required. Individual concentrations and PD 
parameters of PG will be summarized using descriptive statistics. 
9.4.2.1.2. Pharmacodynamic Statistical Summary  
The PD parameters (such as change from baseline of BGmax, BGmax, AUC parameters, and 
TBGmax) will be summarized using standard descriptive statistics.  
Evaluable PD data are defined as having baseline and at least 1 postbaseline measure. For 
rescued participants, data after the rescue would be excluded from the analysis.  
See Section 9.4.3 for details on the exploratory efficacy objective based on PD parameters. 
Exploratory analyses may be performed for other PD parameters as deemed appropriate. 
 
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9.4.2.2. 
Pharmacokinetics 
9.4.2.2.1. Pharmacokinetic Parameter Estimation 
Glucagon concentration data after NG administration will be analyzed using a population PK 
approach via nonlinear mixed-effects modeling with the NONMEM software due to limited 
number of PK samples collected in this study. Model-estimated population PK parameters will 
be reported. Additional population PK analysis may be performed by combining data from this 
study with data from other NG studies. 
Evaluable PK outcome is defined as having at least 1 postbaseline measure. For rescued 
participants, data after the rescue would be excluded from the analysis.  
9.4.3. 
Exploratory Endpoint: Efficacy 
PG levels will be measured prior to the administration of glucagon, as well as at various time 
points after administration (SoA, Section 1.3), and may be used to assess efficacy of NG. 
Efficacy of NG will be assessed in terms of “treatment success.” This is defined as an increase of 
PG ≥20 mg/dL (1.11 mmol/L) from baseline within 30 minutes postdose. The proportion of 
participants achieving treatment success will be calculated. 
A Kaplan-Meier curve will be constructed for the time-to-achieve treatment success. 
Evaluable efficacy outcome is defined as having baseline and at least 1 postbaseline measure 
within 30 minutes after dose administration. For rescued participants, data after the rescue would 
be excluded from the analysis. 
The details will be provided in the SAP. 
9.5. 
Interim Analyses 
After 3 patients have completed the study, participant enrollment will be paused and an interim 
analysis will be conducted, evaluating the data relating to the primary and secondary objectives 
(Section 9.4). 
After this interim analysis, if there are no safety concerns, study enrollment will resume. 
The SAP will describe the planned interim analyses in greater detail. 
9.6. 
Data Monitoring Committee 
Not applicable. 
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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
 The investigator will be responsible for reporting cases of suspected child 
abuse and/or neglect according to local regulations including local medical 
association (e.g., American Academy of Pediatrics, EU Academy of 
Pediatrics) or Health Department guidelines). 
 This study will be conducted in accordance with the protocol and with the 
following: 
○ Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences International Ethical Guidelines 
○ Applicable ICH GCP Guidelines 
○ Applicable laws and regulations 
 The protocol, protocol amendments, ICF, IB, and other relevant documents 
(e.g., advertisements) must be submitted to an IRB/IEC by the investigator 
and reviewed and approved by the IRB/IEC before the study is initiated. 
 Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 
 The investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/IEC 
o Notifying the IRB/IEC of SAEs (and/or unanticipated adverse device 
effects) or other significant safety findings as required by IRB/IEC 
procedures 
o Providing oversight of the conduct of the study at the site and 
adherence to requirements of 21 Code of Federal Regulations, ICH 
guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations 
 Investigator sites are compensated for participation in the study as detailed in 
the clinical trial agreement. 
10.1.2. 
Financial Disclosure 
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
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certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3. 
Informed Consent Process 
 The investigator or his/her representative will explain the nature of the study, including 
the risks and benefits, to the participant’s parent/legal guardian and answer all questions 
regarding the study. 
 The participant’s parent/legal guardian must be informed that participation in this study is 
voluntary. The participant’s legally acceptable representative, parent, or legal 
guardian will be required to provide a statement of informed consent that meets the 
requirements of 21 Code of Federal Regulations 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act requirements, where applicable, and 
the IRB/IEC or study center. 
 The medical record must include a statement that consent from the legally 
acceptable representative, parent(s), or legal guardian was obtained before the participant 
was enrolled in the study and the date the written consent was obtained. The medical 
record should also describe how the clinical investigator determined that the person 
signing the ICF was the participant’s legally acceptable representative, parent(s), or legal 
guardian. The site staff obtaining the informed consent must also sign the ICF.  
 The participant’s legally acceptable representative, parent(s), or legal guardian must be 
reconsented to the most current version of the ICF(s) during their child’s participation in 
the study.  
 A copy of the ICF(s) must be provided to the participant’s legally acceptable 
representative, parent(s), or legal guardian. 
Prior to rescreening, the legally acceptable representative, parent(s), or legal guardian must sign 
a new ICF prior to any further study procedures.  
Assent from study participants is not required due to the very young age of the participants. 
10.1.4. 
Data Protection 
● Participants will be assigned a unique identifier by the sponsor. Any participant 
records, datasets, or samples that are transferred to the sponsor will contain the 
identifier only; participant names or any information that would make the 
participant identifiable will not be transferred. 
● The participant’s legally acceptable representative, parent(s), or legal guardian 
must be informed that the participant’s personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the legally acceptable representative, parent(s), or legal 
guardian who will be required to give consent for their data to be used as 
described in the informed consent.  
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● The participant’s legally acceptable representative, parent(s), or legal guardian 
must be informed that the participant’s medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by 
the sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
● The sponsor has processes in place to ensure data protection, information security, 
and data integrity. These processes include appropriate contingency plan(s) for 
appropriate and timely response in the event of a data security breach. 
10.1.5. 
Dissemination of Clinical Study Data 
The sponsor will disclose a summary of study information, including tabular study results, on 
publicly available websites where required by local law or regulation. 
10.1.6. 
Data Quality Assurance 
All participant data relating to the study will be recorded on eCRF unless transmitted to the 
sponsor or designee electronically (e.g., PK data). The investigator is responsible for verifying 
that data entries are accurate and correct by physically or electronically signing the eCRF. 
The investigator must maintain accurate source documentation that supports all information 
entered in the eCRF. Source data may include laboratory tests, medical records, and clinical 
notes. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality such 
as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities, and requirements, including handling of noncompliance issues and monitoring 
techniques are provided in the Monitoring Plan. 
The sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
The sponsor assumes accountability for actions delegated to other individuals (e.g., CRO). 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site staff are accurate, complete, and verifiable from source documents; 
that the safety and rights of participants are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study agreements, 
ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for the time period outlined in the clinical trial agreement unless 
local regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No records 
may be transferred to another location or party without written notification to the sponsor. 
In addition, the sponsor or its representatives will periodically check a sample of the participant 
data recorded against source documents at the study site. The study may be audited by the 
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sponsor or its representatives, and/or regulatory agencies at any time. Investigators will be given 
notice before an audit occurs. 
Data capture system 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor. 
An electronic data capture system will be used in this study for the collection of CRF data. The 
investigator maintains a separate source for the data entered by the investigator or designee into 
the sponsor-provided electronic data capture system. The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF. 
Data collected via the sponsor-provided data capture system(s) will be stored at a third party. The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture system(s). Prior to decommissioning, the investigator will receive an archival 
copy of pertinent data for retention. 
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and reports will be provided to the investigator for review 
and retention. Data will subsequently be transferred from the central vendor to the sponsor data 
warehouse. 
Data from complaint forms submitted to the sponsor will be encoded and stored in the global 
product complaint management system. 
10.1.7. 
Source Documents 
Source documents are defined in Section 10.1.6. 
● Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
● Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies 
must be explained. The investigator may need to request previous medical records 
or transfer records, depending on the study. Also, current medical records must be 
available. 
10.1.8. 
Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
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Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to 
● failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines 
● inadequate recruitment of participants by the investigator 
● discontinuation of further study intervention development 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of the 
reason for termination or suspension, as specified by the applicable regulatory requirements. The 
investigator shall promptly inform the participant’s parent/legal guardian, and assure appropriate 
participant therapy and/or follow-up. 
10.1.9. 
Publication Policy 
In accordance with the sponsor’s publication policy, the results of this study will be submitted 
for publication by a peer-reviewed journal if the results are deemed to be of significant medical 
importance. 
10.1.10. 
Investigator Information 
Physicians with experience in pediatric clinical studies, and in treating pediatric patients with 
diabetes, will participate as investigators in this clinical trial. 
 
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10.2. 
Appendix 2: Clinical Laboratory Tests 
The following tests will be performed by the local laboratory. 
● Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol. 
● Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
Investigators must document their review of each laboratory safety report.  
Safety Laboratory Tests 
Hematology 
Clinical Chemistry 
Hematocrit 
Sodium 
Hemoglobin 
Potassium 
Erythrocyte count (RBC) 
Chloride 
Mean cell volume  
Glucose 
Mean cell hemoglobin  
Blood urea nitrogen (BUN) 
Mean cell hemoglobin concentration  
Albumin 
Leukocytes (WBC)  
Total bilirubin 
Platelets 
Alkaline phosphatase (ALP) 
Differential WBC % of: 
Aspartate aminotransferase (AST) 
Neutrophils 
Alanine aminotransferase (ALT) 
Lymphocytes 
Creatinine 
Monocytes 
Magnesium 
Eosinophils 
Bicarbonate 
Basophils 
Phosphorus 
 
HbA1c 
Abbreviations: HbA1c = glycated hemoglobin; RBC = red blood cell; WBC = white blood cell. 
 
 
 
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10.3. 
Appendix 3: Adverse Events: Definitions, and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of AE 
AE Definition 
 An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered 
related to the study intervention. 
 NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention.  
 
Events Meeting the AE Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., electrocardiogram, radiological scans, vital sign 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not related to 
progression of underlying disease). 
 Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition. 
 New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdose should be reported regardless of sequelae. 
 The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as an AE or SAE if they fulfill the definition of an AE or SAE. Also, “lack of 
efficacy” or “failure of expected pharmacological action” also constitutes an AE or 
SAE. 
 
Events NOT Meeting the AE Definition 
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
 The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
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 Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.  
10.3.2. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 In general, hospitalization signifies that the participant has been admitted to hospital 
for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during hospitalization 
are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious. 
 Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
 The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
 This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
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f. 
Other situations: 
 Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent 1 of the other 
outcomes listed in the above definition. These events should usually be considered 
serious. 
 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse. 
10.3.3. 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
 When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
 The investigator will then record all relevant AE/SAE information in the CRF. 
 It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the sponsor or designee in lieu of completion of the AE/SAE CRF page. 
 There may be instances when copies of medical records for certain cases are requested 
by the sponsor or designee. In this case, all participant identifiers, with the exception of 
the participant number, will be redacted on the copies of the medical records before 
submission to the sponsor or designee. 
 The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to 1 of the following categories:  
 Mild: An event that is easily tolerated by the participant, causing minimal discomfort, 
and not interfering with everyday activities. 
 Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. 
 Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
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Assessment of Causality 
 The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
 The investigator will consider any AEs, SAEs, and clinically important laboratory 
abnormalities as related to the study intervention unless there is clear evidence that the 
event is not related. 
 The investigator will use clinical judgment to determine the relationship. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
 The investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment. 
 For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
 There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor or designee. 
However, it is very important that the investigator always make an assessment of 
causality for every event before the initial transmission of the SAE data to the sponsor 
or designee. 
 The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment. 
 The causality assessment is 1 of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AEs and SAEs 
 The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor 
or designee to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
 If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide the sponsor or designee with a copy of any 
postmortem findings including histopathology. 
 New or updated information will be recorded in the originally completed CRF. 
 The investigator will submit any updated SAE data to the sponsor or designee within 
24 hours of receipt of the information. 
 
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10.3.4. 
Reporting of SAEs 
SAE Reporting via Paper CRF 
 Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the sponsor or designee. 
 Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames. 
 Contacts for SAE reporting can be found in the SAE Report. 
 
 
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10.4. 
Appendix 4: Liver Safety: Suggested Actions and Follow-up 
Assessments  
At the PI’s discretion, in the event of suspected hepatic impairment of a study participant, close 
or comprehensive monitoring may be conducted. 
Close hepatic monitoring 
Laboratory tests (Appendix 2, Section 10.2), including ALT, AST, ALP, TBL, as well as direct 
bilirubin, gamma glutamyltransferase, and creatine kinase, should be conducted. 
These should be repeated within 48 to 72 hours to confirm the abnormality and to determine if it 
is increasing or decreasing, if 1 or more of these conditions occur: 
If a participant with baseline results of ...  
develops the following elevations: 
ALT or AST <1.5x ULN 
ALT or AST ≥3x ULN 
ALP <1.5x ULN 
ALP ≥2x ULN 
TBL <1.5x ULN 
TBL ≥2x ULN (except for patients with Gilbert’s syndrome) 
ALT or AST ≥1.5x ULN 
ALT or AST ≥2x baseline 
ALP ≥1.5x ULN 
ALP ≥2x baseline 
TBL ≥1.5x ULN 
TBL ≥2x baseline (except for patients with Gilbert’s syndrome) 
If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation with 
the Lilly-designated medical monitor. At a minimum, this evaluation should include physical 
examination and a thorough medical history, including symptoms, recent illnesses (e.g., heart 
failure, systemic infection, hypotension, or seizures), recent travel, history of concomitant 
medications (including over-the-counter), herbal and dietary supplements, history of alcohol 
drinking and other substance abuse.  
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a frequency of 
1 to 3 times weekly, based on the participant’s clinical condition and hepatic biochemical tests. 
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if the 
participant’s clinical condition and laboratory results stabilize. Monitoring of ALT, AST, ALP, 
and TBL should continue until levels normalize or return to approximate baseline levels. 
Comprehensive hepatic evaluation  
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
one or more of these conditions occur: 
If a participant with baseline 
results of...  
develops the following elevations: 
ALT or AST <1.5x ULN 
ALT or AST ≥3x ULN with hepatic signs/symptoms*, or  
ALT or AST ≥5x ULN 
ALP <1.5x ULN 
ALP ≥3x ULN 
TBL <1.5x ULN 
TBL ≥2x ULN (except for patients with Gilbert’s syndrome) 
ALT or AST ≥1.5x ULN 
ALT or AST ≥2x baseline with hepatic signs/symptoms*, or 
ALT or AST ≥3x baseline 
ALP ≥1.5x ULN 
ALP ≥2x baseline 
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TBL ≥1.5x ULN 
TBL ≥1.5x baseline (except for patients with Gilbert’s syndrome)  
 * Hepatic signs/symptoms are severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, fever, rash, and/or 
eosinophilia >5%. 
At a minimum, this evaluation should include physical examination and a thorough medical 
history, as outlined above, as well as tests for prothrombin time-international normalized ratio; 
tests for viral hepatitis A, B, C, or E; tests for autoimmune hepatitis; and an abdominal imaging 
study (e.g., ultrasound or computed tomography scan).  
Based on the participant’s history and initial results, further testing should be considered in 
consultation with the Lilly-designated medical monitor, including tests for hepatitis D virus, 
cytomegalovirus, Epstein-Barr virus, acetaminophen levels, acetaminophen protein adducts, 
urine toxicology screen, Wilson’s disease, blood alcohol levels, urinary ethyl glucuronide, and 
serum phosphatidylethanol. Based on the circumstances and the investigator’s assessment of the 
participant’s clinical condition, the investigator should consider referring the participant for a 
hepatologist or gastroenterologist consultation, magnetic resonance cholangiopancreatography, 
endoscopic retrograde cholangiopancreatography, cardiac echocardiogram, or a liver biopsy.  
Additional hepatic data collection (hepatic safety CRF) in study participants who have 
abnormal liver tests during the study  
Additional hepatic safety data collection in hepatic safety CRF should be performed in study 
participants who meet 1 or more of the following 5 conditions: 
1. Elevation of serum ALT level to ≥5x ULN on 2 or more consecutive blood tests (if 
baseline ALT <1.5x ULN) 
➢ In participants with baseline ALT level ≥1.5x ULN, the threshold is ALT level 
≥3x baseline on 2 or more consecutive tests 
2. Elevation of TBL level to ≥2x ULN (if baseline TBL level <1.5x ULN) (except for cases 
of known Gilbert’s syndrome) 
➢ In participants with baseline TBL level ≥1.5x ULN, the threshold should be TBL 
level ≥2x baseline 
3. Elevation of serum ALP level to ≥2x ULN on 2 or more consecutive blood tests (if 
baseline ALP <1.5x ULN) 
➢ In participants with baseline ALP level ≥1.5x ULN, the threshold is ALP level 
≥2x baseline on 2 or more consecutive blood tests 
4. Hepatic event considered to be an SAE 
5. Discontinuation of study drug due to a hepatic event  
Note: the interval between the  consecutive blood tests should be at least 2 days. 
 
 
 
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10.5. 
Appendix 6: Blood Sampling Summary 
The following table summarizes the approximate number of venipunctures and blood volumes 
for all blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.  
Protocol I8R-MC-IGBO Sampling Summary for full sampling 
 
Purpose 
Blood Volume per 
Sample (mL) 
Number of Blood 
Samples 
Total Volume 
(mL) 
Screening chemistry and 
hematologya 
3 
1 
3 
Bedside point-of-care glucose 
monitoringb 
- 
9 
0.01 
Pharmacokinetics (plasma 
glucagon) 
2 
3 
6 
Pharmacodynamics (plasma 
glucose) 
0.1 
5 
0.5 
Blood discard for cannula patency 
1 
5 
5 
Total 
 
 
14.51 
Total for clinical purposes [rounded up to the nearest 10 mL] 
20 
a Additional samples may be drawn if needed for safety purposes.  
b Applies only to participants for whom a point-of-care blood glucometer will be used, i.e., this is not needed for 
participants who are using their own continuous glucose monitoring equipment (see Section 8.2.4.1). The volume 
of each glucose measurement using a point-of-care blood glucometer is estimated at 0.3 to 1.5 µL (0.0003 to 
0.0015 mL; ADA 2020). 
 
 
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10.6. 
Appendix 7: Abbreviations 
Term 
Definition 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BG 
blood glucose 
BGmax 
maximum observed BG 
CGM 
continuous glucose monitoring 
complaint 
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system. 
compliance 
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements. 
CRF 
case report form 
CRO 
contract research organization 
CRP 
clinical research physician: Individual responsible for the medical conduct of the study. 
Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician, or other medical officer. 
eCRF 
electronic case report form 
enroll 
The act of assigning a participant to a treatment. Participants who are enrolled in the 
study are those who have been assigned to a treatment. 
enter 
Participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives. 
GCP 
good clinical practice 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
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informed consent 
A process by which a participant, or their parent or legal guardian, voluntarily confirms 
their willingness to participate in a particular study, after having been informed of all 
aspects of the study that are relevant to the decision to participate. Informed consent is 
documented by means of a written, signed, and dated informed consent form. 
interim analysis 
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked. 
investigational 
product 
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form. 
IRB 
Institutional Review Board 
ISPAD 
International Society for Pediatric and Adolescent Diabetes 
IV 
intravenous 
MDI 
multiple daily injection 
NG 
nasal glucagon 
participant 
Equivalent to CDISC term “subject”: an individual who participates in a clinical trial, 
either as recipient of an investigational medicinal product or as a control 
PG 
plasma glucose 
PI 
principal investigator 
PK/PD 
pharmacokinetics/pharmacodynamics 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
screen 
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study.  
SoA 
schedule of activities 
T1D 
type 1 diabetes 
TBGmax 
time of maximum observed blood glucose 
TBL 
total bilirubin 
ULN 
upper limit of normal 
 
 
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11. 
References 
Abraham MB, Jones TW, Naranjo D, et al. ISPAD Clinical Practice Consensus Guidelines 2018: 
assessment and management of hypoglycemia in children and adolescents with diabetes. 
Pediatr Diabetes. 2018;19(Suppl. 27):178-192. https://doi.org/10.1111/pedi.12698 
[ADA] American Diabetes Association. Diabetes Forecast 2020 consumer guide – meters. 
Accessed March 15, 2021. http://main.diabetes.org/dforg/pdfs/2020/2020-cg-blood-glucose-
meters.pdf?utm_source=Offline&utm_medium=Print&utm_content=meters&utm_campaign=
DF&s_src=vanity&s_subsrc=meters 
Baqsimi United States Package Insert [USPI]. Indianapolis, IN: Eli Lilly and Company; 2020. 
Accessed March 15, 2021. http://pi.lilly.com/us/baqsimi-uspi.pdf 
Calpol Saline Nasal Spray Product Information Leaflet [PIL]. Dublin: Johnson & Johnson 
(Ireland) Ltd; 2010. Accessed March 15, 2021. 
https://www.boots.com/wcsstore/ExtendedSitesCatalogAssetStore/Product_PatientLeaflets/A0
0000322-10097250.P-Calpol_S&C_Saline_Nasal_Spray.pdf 
Children’s Nasacort [USPI]. Paris, France: Sanofi SA; 2015. Accessed March 15, 2021. 
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2683ce6a-c4d2-4d51-9bb6-
d842581ebdd8 
DiMeglio LA, Acerini CL, Codner E, et al. ISPAD Clinical Practice Consensus Guidelines 2018: 
glycemic control targets and glucose monitoring for children, adolescents, and young adults 
with diabetes. Pediatr Diabetes. 2018;19(Suppl 27):105-114. 
https://onlinelibrary.wiley.com/doi/full/10.1111/pedi.12737 
Graf CJ, Woodworth JR, Seger ME, et al. Pharmacokinetic and glucodynamic comparisons of 
recombinant and animal-source glucagon after IV, IM, and SC injection in healthy volunteers. 
J Pharm Sci. 1999;88(10):991-995. https://doi.org/10.1021/js99007p 
Jones TW. Defining relevant hypoglycemia measures in children and adolescents with type 1 
diabetes. Pediatr Diabetes. 2018;19(3):354-355. doi:10.1111/pedi.12600 
Narcan Nasal Spray [PIL]. Plymouth Meeting, PA: Adapt Pharma Inc; 2020. Accessed March 
15, 2021. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=724df050-5332-4d0a-
9a5f-17bf08a547e1&audience=professional 
OraVerse [USPI]. Louisville, CO: Septodont Inc; 2018. Accessed March 15, 2021. 
https://www.drugs.com/pro/oraverse.html 
Sterimar Blocked Nose Baby [PIL]. Levallois Perret, France: Sofibel SAS; 2019. Accessed 
March 15, 2021. https://www.laboratoribaldacci.it/wp-content/uploads/2019/02/Foglietto-
illustrativo_Sterimar-Baby.pdf 
Approved on 28 Jul 2022 GMT


Signature Page for VV-CLIN-069838 v1.0
Signature Page for VV-CLIN-069838 v1.0
Approval
Medical Director
28-Jul-2022 14:43:40 GMT+0000
Approval
Statistician
28-Jul-2022 17:20:54 GMT+0000
Approved on 28 Jul 2022 GMT
PPD
PPD

SAP_001.pdf: 
 
 
 
Statistical Analysis Plan: I8R-MC-IGBO (Final Version 1.0) 
 
 
An Open-Label, Multi-Center, Single-Dose Study to Assess the 
Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of 
Nasal Glucagon in Pediatric Patients With Type 1 Diabetes Aged 1 to 
<4 Years   
 
 
NCT04992312 
 
 
Approval Date: 20-Oct-2021 


Final Version 1.0, 13OCT2021
             Page 1 of 17
STATISTICAL ANALYSIS PLAN
An Open-Label, Multi-Center, Single-Dose Study to Assess the Safety, Tolerability,
Pharmacodynamics, and Pharmacokinetics of Nasal Glucagon in Pediatric Patients with 
Type 1 Diabetes Aged 1 to <4 years
Statistical Analysis Plan Status: Final
Statistical Analysis Plan Version: 1.0
Statistical Analysis Plan Date: 13OCT2021
Investigational Medicinal Product: Nasal glucagon
Protocol Reference: I8R-MC-IGBO
Labcorp Study: 1001215-8442739
Clinical Phase I
Approval Date: 20-Oct-2021 GMT


Final Version 1.0, 13OCT2021
             Page 2 of 17
Statistical Analysis Plan 
CONFIDENTIAL
Labcorp Study: 1001215-8442739
Protocol Reference: I8R-MC-IGBO
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS ............................................................................................... 2
2.
ABBREVIATIONS........................................................................................................ 4
3.
INTRODUCTION ......................................................................................................... 5
4.
STUDY OBJECTIVES.................................................................................................. 5
Primary Objective.................................................................................................... 5
Secondary Objectives .............................................................................................. 5
Exploratory Objective.............................................................................................. 5
5.
STUDY ENDPOINTS ................................................................................................... 6
Primary Endpoint .................................................................................................... 6
Secondary Endpoints............................................................................................... 6
Exploratory Endpoint .............................................................................................. 6
6.
STUDY DESIGN........................................................................................................... 6
7.
TREATMENT ............................................................................................................... 7
8.
SAMPLE SIZE JUSTIFICATION ................................................................................. 7
9.
DEFINITION OF ANALYSIS POPULATIONS............................................................ 8
10. STATISTICAL METHODOLOGY ............................................................................... 8
General.................................................................................................................... 8
Demographics and Patient Disposition..................................................................... 9
Pharmacokinetic Assessment................................................................................... 9
10.3.1
Pharmacokinetic Analysis............................................................................... 9
10.3.2
Pharmacokinetic Statistical Methodology ....................................................... 9
Pharmacodynamic Assessment ................................................................................ 9
10.4.1
Pharmacodynamic Analysis............................................................................ 9
10.4.2
Pharmacodynamic Statistical Methodology .................................................. 10
Efficacy Assessment.............................................................................................. 10
Safety and Tolerability Assessments...................................................................... 10
10.6.1
Adverse events ............................................................................................. 10
10.6.2
Glucose Monitoring and Hypoglycemia........................................................ 11
10.6.3
Concomitant medication............................................................................... 11
10.6.4
Vital signs .................................................................................................... 12
10.6.5
Hepatic Monitoring ...................................................................................... 12
10.6.6
Nasal Inspection ........................................................................................... 12
10.6.7
Other assessments......................................................................................... 12
10.6.8
Safety and Tolerability Statistical Methodology............................................ 12


Final Version 1.0, 13OCT2021
             Page 3 of 17
Statistical Analysis Plan 
CONFIDENTIAL
Labcorp Study: 1001215-8442739
Protocol Reference: I8R-MC-IGBO
11. INTERIM ANALYSES ............................................................................................... 12
12. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ...... 12
13. REFERENCES ............................................................................................................ 13
14. DATA PRESENTATION ............................................................................................ 13
Derived Parameters ............................................................................................... 13
Missing Data ......................................................................................................... 13
Insufficient Data for Presentation .......................................................................... 13
15. APPENDICES ............................................................................................................. 14
Appendix 1: Document History...................................................................................... 14
Appendix 2: Definitions of Nasal/Respiratory/Anosmia AEs.......................................... 15


Final Version 1.0, 13OCT2021
             Page 4 of 17
Statistical Analysis Plan 
CONFIDENTIAL
Labcorp Study: 1001215-8442739
Protocol Reference: I8R-MC-IGBO
2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
AE
Adverse event
AUC
Area under the concentration versus time curve
BG
Blood glucose
BGmax
Maximum observed blood glucose
CGM
Continuous glucose monitoring
Cmax
Maximum observed drug concentration
CRF
Case Report Form
CSR
Clinical Study Report
ICH
International Conference on Harmonisation
MedDRA
Medical Dictionary for Regulatory Activities
NG
Nasal glucagon
PD
Pharmacodynamic
PG
Plasma Glucose
PK
Pharmacokinetic
SAP
Statistical Analysis Plan
SD
Standard deviation 
SOP
Standard Operating Procedure
T1D
Type 1 diabetes
TBGmax
Time of maximum observed blood glucose
TEAE
Treatment-emergent adverse event
TFLs
Tables, Figures, and Listings
WHO
World Health Organization


Final Version 1.0, 13OCT2021
             Page 5 of 17
Statistical Analysis Plan 
CONFIDENTIAL
Labcorp Study: 1001215-8442739
Protocol Reference: I8R-MC-IGBO
3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
19 March 2021).
This SAP describes the planned analysis of the safety, tolerability, pharmacokinetic (PK), and 
pharmacodynamic (PD) data from this study. A detailed description of the planned TFLs to be 
presented in the clinical study report (CSR) is provided in the accompanying TFL shell 
document.
The intent of this document is to provide guidance for the statistical and PK analyses of data. In
general, the analyses are based on information from the protocol, unless they have been modified 
by agreement with Eli Lilly and Company. A limited amount of information concerning this 
study (e.g., objectives, study design) is given to help the reader’s interpretation. For open-label 
studies, this SAP must be signed off prior to first patient visit for this study. When the SAP and 
TFL shells are agreed upon and finalized, they will serve as the template for this study’s CSR.
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon with
Eli Lilly and Company and identified in the CSR. Any minor deviations from the TFLs may not 
be documented in the CSR.
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials1 and the ICH E3 Guideline entitled Guidance for Industry: Structure 
and Content of Clinical Study Reports2.
4. STUDY OBJECTIVES
Primary Objective
The primary objective is to assess the safety and tolerability of a single dose of nasal glucagon 
(NG) 3 mg in children aged 1 to <4 years with type 1 diabetes (T1D).
Secondary Objectives
The secondary objectives are:

To assess the PD of a single dose of 3 mg NG in children aged 1 to <4 years with T1D

To assess the PK of a single dose of 3 mg NG in children aged 1 to <4 years with T1D.
Exploratory Objective
The exploratory objective is to assess the efficacy of a single dose of 3 mg NG in children aged 1 
to <4 years with T1D.


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5. STUDY ENDPOINTS
Primary Endpoint
The primary endpoint is the incidence of treatment-emergent adverse events (TEAEs).
Secondary Endpoints
The secondary endpoints are:

Change from baseline of maximum blood (plasma) glucose

The following plasma glucose (PG) parameters:
o
maximum observed blood glucose (BGmax)
o
area under the concentration-time curve (AUC)
o
time of maximum observed blood glucose (TBGmax)

Model-estimated population PK parameters
Exploratory Endpoint
The exploratory endpoint is the proportion of patients achieving treatment success defined as an 
increase of PG ≥20 mg/dL (1.11 mmol/L) from baseline within 30 min postdose
6. STUDY DESIGN
Study IGBO is a Phase 1, open-label, multi-center study with a primary objective of assessing
safety and tolerability of a single 3 mg dose of NG in pediatric patients aged 1 to <4 years with 
T1D.
Patients will attend study visits, including screening, in the company of 1 or more parents or
legal guardians, and in accordance with local healthcare facility practice. 
The study comprises a single cohort, with each patient receiving a single dose of 3 mg NG. At 
least 9 patients with an approximate maximum of 20 may be enrolled so that 6 evaluable patients 
complete the study. 
For the purposes of this study, a patient completes the study after the conclusion of the second 
follow-up telephone call on Day 9 (±3).
A study schema can be seen in Figure 1.


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Figure 1: Study Schema for IGBO
7. TREATMENT
The following is a list of the study treatment that will be used in the TFLs.
Study Treatment Name
Treatment order in TFL
3 mg nasal glucagon
1
8. SAMPLE SIZE JUSTIFICATION
At least 9 patients with an approximate maximum of 20 may be enrolled so that 6 evaluable
patients complete the study.


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The sample size is customary for Phase 1 studies evaluating safety, tolerability, PD, and PK, and
is not powered on the basis of statistical hypothesis testing.
The sample size assumes a 33% dropout rate.
Patients who are enrolled but not administered treatment may be replaced to ensure that enough 
patients may complete the study. Patients that do not have at least 1 PD postbaseline measure
may also be replaced.
9. DEFINITION OF ANALYSIS POPULATIONS
The “Efficacy” population will consist of all patients who received at least one dose of NG, and 
have baseline and at least 1 postbaseline PG measure within 30 minutes after dose 
administration. For rescued patients, data after the rescue would be excluded from the analysis.
The “Safety” population will consist of all patients who received at least one dose of NG, 
whether or not they complete all protocol requirements.
The “Pharmacokinetic” population will consist of all patients who received at least one dose of 
NG and have evaluable PK data. For rescued patients, data after the rescue would be excluded 
from the analysis.
The “Pharmacodynamic” population will consist of all patients who received at least one dose of 
NG and have evaluable PD data. For rescued patients, data after the rescue would be excluded 
from the analysis.
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when patients are assigned to analysis populations.
10.
STATISTICAL METHODOLOGY
General
Data listings will be provided for all data that is databased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include the arithmetic mean, arithmetic standard deviation (SD), median, 
min, max and n; for log-normal data (e.g. the PK parameters: AUCs and maximum observed 
drug concentration [Cmax]) the geometric mean and geometric coefficient of variation will also be 
presented. For categorical data, frequency count and percentages will be presented. Data listings 
will be provided for all patients up to the point of withdrawal, with any patients excluded from 
the relevant population highlighted. Summary statistics and statistical analyses will generally 
only be performed for patients included in the relevant analysis population. For the calculation of 
summary statistics and statistical analysis, unrounded data will be used. 
Mean change from baseline is the mean of all individual patients’ change from baseline values. 
Each individual change from baseline will be calculated by subtracting the individual patient’s 
baseline value from the value at the timepoint. The individual patient’s change from baseline 


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values will be used to calculate the mean change from baseline using a SAS procedure such as 
Proc Univariate.
Data analysis will be performed using SAS® Version 9.4 or greater.
Demographics and Patient Disposition
Patient disposition will be listed. The demographic variables age, sex, race, ethnicity, country of 
enrolment, site ID, body weight, height, screening glycated hemoglobin, and duration of T1D
will be summarized and listed. All other demographic variables will be listed only.
Pharmacokinetic Assessment
10.3.1
Pharmacokinetic Analysis
Glucagon concentration data after NG administration will be analyzed using a population PK
approach via nonlinear mixed-effects modeling with the NONMEM software due to limited
number of PK samples collected in this study. Model-estimated population PK parameters will
be reported. Additional population PK analysis may be performed by combining data from this
study with data from other NG studies.
Evaluable PK outcome is defined as having at least 1 postbaseline measure. 
Pharmacokinetic concentrations of plasma glucagon by timepoint will be summarized by 
descriptive statistics and listed. Mean and individual concentration over time plots will also be 
produced.
Derivation of the PK parameters will be done by Eli Lilly and Company. Eli Lilly and Company 
will also be responsible for all PK parameter TFLs.
10.3.2
Pharmacokinetic Statistical Methodology
No inferential statistical analyses are planned
Pharmacodynamic Assessment
10.4.1
Pharmacodynamic Analysis
Due to limited number of PG measurements (5 time points) from the glucose analyzer, a limited 
number of PD parameters will be estimated. The primary PD parameter is change from baseline 
of BGmax. In addition, other PG parameters, AUC and TBGmax, may also be estimated. Actual 
sampling times will be used for all calculations.
PG AUC will be calculated using the trapezoidal rule. If the first (predose) or last (90 minutes) 
timepoints are missing, an AUC will not be derived.
Baseline PG concentrations will be calculated from samples obtained immediately prior to 
glucagon dosing (e.g., predose).


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Other PD parameters of PG may be calculated if required. 
Derivation of the PD parameters will be done by Labcorp. Labcorp will also be responsible for 
all PD TFLs.
10.4.2
Pharmacodynamic Statistical Methodology
The PG PD parameters, as well as the change from baseline for BGmax, where baseline is defined 
as Day 1 Predose, will be summarized and listed.
Individual concentrations of PG, together with changes from baseline (predose), will also be 
summarized by timepoint using descriptive statistics and listed. Mean, mean changes from 
baseline, and individual concentration over time plots will be produced.
No inferential statistical analyses are planned
Efficacy Assessment
Plasma glucose levels will be measured prior to the administration of glucagon, as well as at 
various time points after administration and will be used to assess the efficacy of NG.
Efficacy of NG will be assessed in terms of “treatment success”, in which treatment success is 
defined as an increase of PG≥20 mg/dL (1.11 mmol/L) from baseline within 30 minutes 
postdose. The proportion of patients achieving treatment success will be calculated, summarized, 
and listed. Rescued patients, data after the rescue would be excluded from the analysis, see 
Section 10.6.2 for further information on rescued patients.
The time to treatment success will be summarized and listed.
A Kaplan-Meier curve will be constructed for the time-to-achieve treatment success. 
Safety and Tolerability Assessments
10.6.1
Adverse events
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the adverse event (AE) will be reported in the listings, only the most severe will be used in the 
summary tables. A pre-existing condition is defined as an AE that starts before the patient has 
provided written informed consent and is ongoing at consent. A non-TEAE is defined as an AE 
which starts after informed consent but prior to dosing. A TEAE is defined as an AE which 
occurs postdose or which is present prior to dosing and becomes more severe postdose. 
All AEs will be listed. Treatment-emergent AEs will be summarized by severity and relationship 
to the study drug. The frequency (the number of AEs, the number of patients experiencing an AE
and the percentage of patients experiencing an AE) of TEAEs will be summarized by Medical 
Dictionary for Regulatory Activities (MedDRA) version 24.0 system organ class and preferred 
term. The summary and frequency AE tables will be presented for all causalities and those 
considered related to the study drug by the investigator. Any serious AEs will be listed.


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Nasal/respiratory and anosmia AEs (see Appendix 2) will be summarized.
Discontinuations due to AEs will be listed.
10.6.2
Glucose Monitoring and Hypoglycemia
At baseline, during, and after dosing, blood glucose (BG) levels will be measured at the bedside 
for safety monitoring using an approved point-of-care glucometer. The bedside glucose 
measurements will be performed for safety monitoring only and will not be databased.
Severe hypoglycemica in children events will be listed and summarized. Severe hypoglycemia in 
children is defined3 as follows:

Severe hypoglycaemia in children: because children have limited ability to detect 
and/or self-treat hypoglycemia, severe hypoglycemia in children is an event in which 
children have severe cognitive impairment, and require external assistance, are 
semiconscious or unconscious, or in coma with or without convulsions, and requires 
another person to actively administer carbohydrates, glucagon, or take other corrective 
action
The determination of a hypoglycemic event as an episode of severe hypoglycemia, as defined 
above, will be made by the investigator based on the medical need of the patient to have had 
hypoglycemia-induced cognitive dysfunction and is not predicated on the report of a patient
simply having received assistance.
Further information on patients that experience a hypoglycemic event will be collected using a 
hypoglycaemia event CRF form, this data will be listed and summarized.
A glucose infusion alternative glucagon therapy, or oral carbohydrate may be used for rescue 
treatment if a patient’s BG level is declining rapidly, or their symptoms become consistent with 
progression to clinically significant or severe hypoglycemia. A separate listing will be presented 
for the use of rescue medication used for severe hypoglycaemia.
The following steps will be taken based on the patient’s baseline BG level:

If BG < 70 mg/dL, the investigator will determine whether to proceed with dosing or to 
use rescue treatment.

If BG < 54 mg/dL (clinically significant hypoglycemia [Level 2]), site will halt study 
drug procedure and use rescue therapy to raise BG level. Such patients’ visits may be 
rescheduled for a subsequent visit
10.6.3
Concomitant medication
Concomitant medication will be coded using the WHO drug dictionary (Version March 2021). 
Concomitant medication will be listed.


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10.6.4
Vital signs
Vital signs data will be listed for individual patients.
Changes from baseline (Day 1 predose) will be calculated for vital signs.
10.6.5 Hepatic Monitoring
If a patient experiences elevated laboratory parameters, as detailed in Section 10.4 of the 
protocol, additional tests will be performed to confirm the abnormality. Additional safety data 
may be collected if required, as defined in the protocol. Where applicable, the following will be 
presented.
The patients’ liver disease history and associated person liver disease history data will be listed. 
Any concomitant medications that have potential for hepatotoxicity, including acetaminophen 
will be listed. Results from any hepatic monitoring procedures, such as a magnetic resonance 
elastography scan, and biopsy assessments will be listed, if performed.
Hepatic risk factor assessment data will be listed. Liver related signs and symptoms data will be 
summarized by treatment and listed. Alcohol and recreational drug use data will also be listed.
All hepatic chemistry, hematology, coagulation, and serology data will be listed. Values outside 
the reference ranges will be flagged on the individual patient data listings.
10.6.6
Nasal Inspection
AEs found during Nasal inspection will be summarized and listed by pre-dose and 90 min post-
dose respectively. TEAEs found during nasal inspection will also be summarized and listed. 
10.6.7
Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed.
10.6.8
Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.
11.
INTERIM ANALYSES
After 3 patients have completed the study, patient enrollment will be paused and an interim
analysis will be conducted, evaluating the data relating to the primary and secondary objectives
After this interim analysis, if there are no clinically significant safety concerns, study enrollment 
will resume.
12.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
There were no changes from the protocol specified statistical analyses.


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13.
REFERENCES
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998.
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.
3. Jones TW. Defining relevant hypoglycemia measures in children and adolescents with type 1
diabetes. Pediatr Diabetes. 2018;19(3):354-355. doi:10.1111/pedi.12600
14.
DATA PRESENTATION
Derived Parameters
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be 
reported to three significant figures. Observed concentration data, e.g. BGmax, should be reported 
as received. Observed time data, e.g. TBGmax, should be reported as received. N and percentage 
values should be reported as whole numbers. Median values should be treated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values.
Missing Data
Missing data will not be displayed in listings.
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of patients or data for presentation. If this
occurs, the blank TFL shell will be presented with a message printed in the center of the table, 
such as, “No serious adverse events occurred for this study.”


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15.
APPENDICES
Appendix 1: Document History
Status and Version
Date of Change
Summary/Reason for Changes
Final Version 1.0
NA
NA; the first version.
NA = not applicable


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Appendix 2: Definitions of Nasal/Respiratory/Anosmia AEs
MedDRA 
Preferred Term 
Code
MedDRA Preferred Term
MedDRA System Organ Class
10001315
Administration site reaction
General disorders and administration site 
conditions 
10069773
Administration related reaction
Injury, poisoning and procedural complications
10049153
Allergic sinusitis
Respiratory, thoracic and mediastinal disorders
10002653
Anosmia
Nervous system disorders
10071399
Chronic eosinophilic rhinosinusitis
Respiratory, thoracic and mediastinal disorders
10071380
Chronic hyperplastic eosinophilic 
sinusitis
Respiratory, thoracic and mediastinal disorders
10010588
Congenital perforated nasal septum
Congenital, familial and genetic disorders
10011224
Cough
Respiratory, thoracic and mediastinal disorders
10013789
Dry throat
Respiratory, thoracic and mediastinal disorders
10076417
Empty nose syndrome
Injury, poisoning and procedural complications
10068957
Eosinophilic rhinitis
Respiratory, thoracic and mediastinal disorders
10015090
Epistaxis
Respiratory, thoracic and mediastinal disorders
10020039
Hiccups
Respiratory, thoracic and mediastinal disorders
10050515
Hyposmia
Nervous system disorders
10049419
Increased upper airway secretion
Respiratory, thoracic and mediastinal disorders
10067068
Intranasal hypoaesthesia
Respiratory, thoracic and mediastinal disorders
10051660
Intranasal paraesthesia
Respiratory, thoracic and mediastinal disorders
10072926
Maxillary sinus pseudocyst
Respiratory, thoracic and mediastinal disorders
10075834
Nasal adhesions
Respiratory, thoracic and mediastinal disorders
10062771
Nasal cavity mass
Respiratory, thoracic and mediastinal disorders
10074617
Nasal cavity toxicity
Respiratory, thoracic and mediastinal disorders
10028735
Nasal congestion
Respiratory, thoracic and mediastinal disorders
10076524
Nasal crusting
Respiratory, thoracic and mediastinal disorders
10051712
Nasal cyst
Respiratory, thoracic and mediastinal disorders
10052437
Nasal discomfort
Respiratory, thoracic and mediastinal disorders
10062209
Nasal disorder
Respiratory, thoracic and mediastinal disorders
10028740
Nasal dryness
Respiratory, thoracic and mediastinal disorders
10028741
Nasal inflammation
Respiratory, thoracic and mediastinal disorders


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MedDRA 
Preferred Term 
Code
MedDRA Preferred Term
MedDRA System Organ Class
10051208
Nasal mucosa atrophy
Respiratory, thoracic and mediastinal disorders
10057537
Nasal mucosal discolouration
Respiratory, thoracic and mediastinal disorders
10061305
Nasal mucosal disorder
Respiratory, thoracic and mediastinal disorders
10076585
Nasal mucosal erosion
Respiratory, thoracic and mediastinal disorders
10057358
Nasal mucosal hypertrophy
Respiratory, thoracic and mediastinal disorders
10065546
Nasal mucosal ulcer
Respiratory, thoracic and mediastinal disorders
10028747
Nasal necrosis
Respiratory, thoracic and mediastinal disorders
10051181
Nasal odour
Respiratory, thoracic and mediastinal disorders
10028750
Nasal oedema
Respiratory, thoracic and mediastinal disorders
10028756
Nasal polyps
Respiratory, thoracic and mediastinal disorders
10076406
Nasal pruritus
Respiratory, thoracic and mediastinal disorders
10028762
Nasal septum deviation
Respiratory, thoracic and mediastinal disorders
10028763
Nasal septum disorder
Respiratory, thoracic and mediastinal disorders
10075027
Nasal septum haematoma
Respiratory, thoracic and mediastinal disorders
10028765
Nasal septum perforation
Respiratory, thoracic and mediastinal disorders
10028766
Nasal septum ulceration
Respiratory, thoracic and mediastinal disorders
10052354
Nasal turbinate abnormality
Respiratory, thoracic and mediastinal disorders
10028779
Nasal turbinate hypertrophy
Respiratory, thoracic and mediastinal disorders
10028780
Nasal ulcer
Respiratory, thoracic and mediastinal disorders
10076553
Nasal varices
Respiratory, thoracic and mediastinal disorders
10065120
Oroantral fistula
Gastrointestinal disorders
10068319
Oropharyngeal pain
Respiratory, thoracic and mediastinal disorders
10062321
Paranasal cyst
Respiratory, thoracic and mediastinal disorders
10074401
Paranasal sinus aplasia
Congenital, familial and genetic disorders
Paranasal sinus discomfort
Respiratory, thoracic and mediastinal disorders
10069702
Paranasal sinus haematoma
Respiratory, thoracic and mediastinal disorders
10057392
Paranasal sinus hypersecretion
Respiratory, thoracic and mediastinal disorders
10067998
Paranasal sinus mucosal hypertrophy
Respiratory, thoracic and mediastinal disorders
10072591
Paranasal sinus necrosis
Respiratory, thoracic and mediastinal disorders
10034018
Parosmia
Nervous system disorders
10064037
Rhinalgia
Respiratory, thoracic and mediastinal disorders


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MedDRA 
Preferred Term 
Code
MedDRA Preferred Term
MedDRA System Organ Class
10039085
Rhinitis allergic
Respiratory, thoracic and mediastinal disorders
10039088
Rhinitis atrophic
Respiratory, thoracic and mediastinal disorders
10059235
Rhinitis hypertrophic
Respiratory, thoracic and mediastinal disorders
10039094
Rhinitis perennial
Respiratory, thoracic and mediastinal disorders
10039096
Rhinitis ulcerative
Respiratory, thoracic and mediastinal disorders
10067770
Rhinolithiasis
Respiratory, thoracic and mediastinal disorders
10039101
Rhinorrhoea
Respiratory, thoracic and mediastinal disorders
10048908
Seasonal allergy
Immune system disorders
10075540
Silent sinus syndrome
Respiratory, thoracic and mediastinal disorders
10040740
Sinus barotrauma
Injury, poisoning and procedural complications
10040742
Sinus congestion
Respiratory, thoracic and mediastinal disorders
10062244
Sinus disorder
Respiratory, thoracic and mediastinal disorders
10040747
Sinus headache
Nervous system disorders
10040748
Sinus perforation
Respiratory, thoracic and mediastinal disorders
10040749
Sinus polyp
Respiratory, thoracic and mediastinal disorders
10040750
Sinus polyp degeneration
Respiratory, thoracic and mediastinal disorders
10064770
Sinusitis noninfective
Respiratory, thoracic and mediastinal disorders
10041232
Sneezing
Respiratory, thoracic and mediastinal disorders
10043521
Throat irritation
Respiratory, thoracic and mediastinal disorders
10070488
Upper-airway cough syndrome
Respiratory, thoracic and mediastinal disorders
10047145
Vasomotor rhinitis
Respiratory, thoracic and mediastinal disorders
Abbreviations:  MedDRA = Medical Dictionary for Regulatory Activities


Leo Document ID = 654edab8-df29-4a0f-952d-4fe986e4bfc8
Approver: 
Approval Date & Time: 18-Oct-2021 16:18:26 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 18-Oct-2021 22:01:01 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 19-Oct-2021 14:17:17 GMT
Signature meaning: Approved
Approver:
Approval Date & Time: 20-Oct-2021 16:02:37 GMT
Signature meaning: Approved
PPD
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