Conditions: Hypoglycemia Diabetes Mellitus, Type 1
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 70
Healthy volunteers: no

Brief summary:
The purpose of this study is to compare a needle-free treatment of hypoglycemia with nasal glucagon (study drug) to a marketed glucagon administered by the intramuscular (IM) route, in participants with type 1 diabetes mellitus (T1DM).

Detailed description:

Arms:
arm 1: Single dose of Nasal Glucagon. arm 2: Single intramuscular (IM) dose of Glucagon.

Interventions: intervention 1: Nasal Glucagon intervention 2: Intramuscular Glucagon
Intervention descriptions: intervention 1: Administered nasally intervention 2: Administered IM

Protocol document:
Prot_000.pdf: 
 
 
Protocol I8R-MC-IGBI(b) 
 
 
Comparison of Glucagon Administered by Either the Nasal(LY900018) or Intra-muscular 
(GlucaGen®) Routes in Adult Patients with Type 1 Diabetes Mellitus During Controlled 
Insulin-Induced Hypoglycemia 
 
 
NCT03339453  
 
 
Approval Date: 12-Oct-2017 
 
 


I8R-MC-IGBI(b) Clinical Pharmacology Protocol
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LY900018
Protocol I8R-MC-IGBI(b)
Comparison of Glucagon Administered by Either the Nasal 
(LY900018) or Intra-muscular (GlucaGen®) Routes in Adult 
Patients with Type 1 Diabetes Mellitus During Controlled 
Insulin-Induced Hypoglycemia
EudraCT Number 2017-000249-33
Confidential Information
The information contained in this protocol 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 
glucagon nasal powder (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.
Glucagon nasal powder (LY900018)
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly: 
08 May 2017
Amendment (a) Electronically Signed and Approved by Lilly:
16 Aug 2017
Amendment (b) Electronically Signed and Approved by Lilly on 
approval date provided below.
Approval Date: 12-Oct-2017 GMT


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Table of Contents
Comparison of Glucagon Administered by Either the Nasal 
(LY900018) or Intra-muscular (GlucaGen®) Routes in Adult 
Patients with Type 1 Diabetes Mellitus During Controlled 
Insulin-Induced Hypoglycemia
Section
Page
Protocol I8R-MC-IGBI(b) Comparison of Glucagon Administered by 
Either the Nasal (LY900018) or Intra-muscular (GlucaGen®) Routes 
in Adult Patients with Type 1 Diabetes Mellitus During Controlled 
Insulin-Induced Hypoglycemia ...........................................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................8
2.
Schedule of Activities .......................................................................................................11
3.
Introduction ......................................................................................................................16
3.1.
Study Rationale............................................................................................................16
3.2.
Background..................................................................................................................16
3.3.
Benefit–Risk Assessment .............................................................................................17
4.
Objectives and Endpoints..................................................................................................19
5.
Study Design.....................................................................................................................20
5.1.
Overall Design .............................................................................................................20
5.2.
Number of Participants.................................................................................................21
5.3.
End of Study Definition ...............................................................................................21
5.4.
Scientific Rationale for Study Design...........................................................................22
5.5.
Justification for Dose ...................................................................................................22
6.
Study Population...............................................................................................................23
6.1.
Inclusion Criteria..........................................................................................................23
6.2.
Exclusion Criteria ........................................................................................................24
6.3.
Lifestyle and/or Dietary Requirements .........................................................................26
6.3.1.
Meals and Dietary Restrictions.............................................................................26
6.3.2.
Alcohol................................................................................................................26
6.3.3.
Activity................................................................................................................26
6.4.
Screen Failures.............................................................................................................26
7.
Treatment..........................................................................................................................27
7.1.
Treatment Administered...............................................................................................27
7.1.1.
Packaging and Labeling .......................................................................................27
7.1.2.
Medical Devices...................................................................................................28


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7.2.
Method of Treatment Assignment ................................................................................28
7.2.1.
Selection and Timing of Doses.............................................................................28
7.3.
Blinding .......................................................................................................................28
7.4.
Dose Modification........................................................................................................28
7.5.
Preparation/Handling/Storage/Accountability...............................................................28
7.6.
Treatment Compliance .................................................................................................29
7.7.
Concomitant Therapy...................................................................................................29
7.8.
Treatment after the End of the Study............................................................................29
8.
Discontinuation Criteria ....................................................................................................30
8.1.
Discontinuation from Study Treatment.........................................................................30
8.1.1.
Discontinuation of Inadvertently Enrolled Patients...............................................30
8.2.
Discontinuation from the Study....................................................................................30
8.3.
Patients Lost to Follow-up............................................................................................30
9.
Study Assessments and Procedures ...................................................................................31
9.1.
Efficacy Assessments...................................................................................................31
9.2.
Procedures ...................................................................................................................31
9.2.1.
Inducing Hypoglycemia .......................................................................................31
9.2.2.
Glucagon Administration .....................................................................................31
9.2.2.1.
Nasal Administration......................................................................................32
9.2.2.2.
Intra-muscular Administration........................................................................32
9.2.3.
Procedures for Insufficient Response to Glucagon 
Administration .....................................................................................................32
9.2.4.
End of Admission ................................................................................................32
9.3.
Adverse Events ............................................................................................................32
9.3.1.
Serious Adverse Events........................................................................................33
9.3.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................34
9.3.1.2.
Adverse Event Monitoring with a Systematic 
Questionnaire .................................................................................................34
9.3.2.
Complaint Handling.............................................................................................34
9.4.
Treatment of Overdose.................................................................................................35
9.5.
Safety...........................................................................................................................35
9.5.1.
Laboratory Tests ..................................................................................................35
9.5.2.
Vital Signs ...........................................................................................................35
9.5.3.
Electrocardiograms ..............................................................................................35
9.5.4.
Other Tests...........................................................................................................36
9.5.5.
Safety Monitoring ................................................................................................36
9.5.5.1.
Hepatic Safety................................................................................................37
9.6.
Pharmacokinetics .........................................................................................................37


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9.6.1.
Bioanalysis...........................................................................................................37
9.7.
Pharmacodynamics ......................................................................................................38
9.7.1.
Exploratory Sample Assessments and Storage......................................................38
9.8.
Genetics .......................................................................................................................38
9.9.
Biomarkers...................................................................................................................39
9.10. Health Economics ........................................................................................................39
10.
Statistical Considerations and Data Analysis.....................................................................40
10.1. Sample Size Determination ..........................................................................................40
10.2. Populations for Analyses..............................................................................................40
10.2.1.
Study Participant Disposition ...............................................................................40
10.2.2.
Study Participant Characteristics ..........................................................................40
10.2.3.
Treatment Compliance .........................................................................................40
10.3. Statistical Analyses ......................................................................................................40
10.3.1.
Efficacy Analyses ................................................................................................41
10.3.1.1.
Primary Efficacy.............................................................................................41
10.3.1.2.
Secondary Efficacy Analyses..........................................................................42
10.3.1.2.1.
Plasma Glucose Values.............................................................................42
10.3.1.2.2.
Symptoms of Hypoglycemia.....................................................................42
10.3.2.
Safety Analyses....................................................................................................42
10.3.2.1.
Clinical Evaluation of Safety..........................................................................42
10.3.2.2.
Nasal and Non-nasal Score Questionnaire.......................................................43
10.3.2.3.
Statistical Evaluation of Safety.......................................................................43
10.3.3.
Pharmacokinetic Analyses....................................................................................43
10.3.3.1.
Pharmacokinetic Parameter Estimation...........................................................43
10.3.3.2.
Pharmacokinetic Statistical Inference .............................................................43
10.3.4.
Pharmacodynamic Analyses.................................................................................44
10.3.4.1.
Pharmacodynamic Parameter Estimation ........................................................44
10.3.4.2.
Pharmacodynamic Statistical Inference...........................................................44
10.3.5.
Pharmacokinetic/Pharmacodynamic Analyses......................................................45
10.3.6.
Data Review during the Study..............................................................................45
10.3.7.
Interim Analyses..................................................................................................45
11.
References ........................................................................................................................46


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List of Tables
Table
Page
Table IGBI.1.
Objectives and Endpoints .......................................................................19
Table IGBI.2.
Treatments Administered........................................................................27


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List of Figures
Figure
Page
Figure IGBI.1.
Illustration of study design for Protocol I8R-MC-IGBI...........................21


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................47
Appendix 2.
Clinical Laboratory Tests........................................................................51
Appendix 3.
Study Governance, Regulatory, and Ethical Considerations....................52
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............55
Appendix 5.
Blood Sampling Summary......................................................................56
Appendix 6.
Nasal and Non-nasal Score Questionnaire...............................................57
Appendix 7.
Edinburgh Hypoglycemia Scale..............................................................59
Appendix 8.
Clarke Hypoglycemia Awareness Survey ...............................................62
Appendix 9.
Protocol Amendment I8R-MC-IGBI(b) Summary: Comparison of 
Glucagon Administered by Either the Nasal (LY900018) or Intra-
muscular (GlucaGen®) Routes in Adult Patients with Type 1 
Diabetes Mellitus During Controlled Insulin-Induced 
Hypoglycemia ........................................................................................65


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1. Protocol Synopsis
Title of Study:
Comparison of Glucagon Administered by Either the Nasal (LY900018) or Intra-Muscular (GlucaGen®) Routes in 
Adult Patients with Type 1 Diabetes Mellitus During Controlled Insulin-Induced Hypoglycemia
Rationale:
LY900018 is an investigational drug–device combination product consisting of a single-use nasal dosing device that 
delivers a fixed 3-mg dose of glucagon powder absorbed through the nasal mucosa. The glucagon component of 
LY900018 is a synthetic single-chain, 29-amino-acid polypeptide identical to human glucagon. LY900018 is being 
developed for the treatment of severe hypoglycemia.
Currently, glucagon in a liquid form lacks physical and chemical stability; thus marketed products require 
reconstitution of glucagon before the product can be administered through subcutaneous or intra-muscular (IM) 
injection.  LY900018 combines stable, synthetic glucagon and a nasal dosing device that for effective use obviates
reconstitution, injection, and moreover, patient inhalation. Because of these advantages, LY900018 may offer a 
significant improvement in the treatment of severe hypoglycemia occurring outside of the hospital setting.
The aim of this study is to compare GlucaGen®, a currently approved product that requires reconstitution prior to 
administration through IM injection, and LY900018 in those patients who achieve treatment success during 
controlled insulin-induced hypoglycemia in patients with type 1 diabetes mellitus (T1DM).  Treatment success is 
defined as an increase in plasma glucose (PG) to ≥70 mg/dL (3.9 mmol/L) or an increase of ≥20 mg/dL from the 
plasma glucose nadir within 30 minutes after receiving glucagon, without the patient receiving additional actions to 
increase PG.  The nadir is defined as the minimum plasma glucose measurement at the time of or within 10 minutes 
following glucagon administration.


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Objectives/Endpoints
Objectives
Endpoints
Primary
To compare LY900018 versus GlucaGen® in the 
percentage of adult patients with T1DM who achieve
treatment success during controlled insulin-induced 
hypoglycemia
The percentage of patients who achieve treatment 
success will be defined as an increase in plasma glucose 
to ≥70 mg/dL or an increase of ≥20 mg/dL from plasma 
glucose nadir within 30 minutes after receiving 
glucagon, without receiving additional actions to 
increase the plasma glucose concentration.  The nadir 
will be defined as the minimum plasma glucose 
concentration at the time of or within 10 minutes 
following glucagon administration.
Secondary
1.
To assess the safety and tolerability of
LY900018 versus GlucaGen®
2.
To characterize the PD profiles of
LY900018 versus GlucaGen®
3.
To characterize the PK profiles of
LY900018 versus GlucaGen®
1.
Summary of AEs, including nasal and non-
nasal AEs; vital signs
2.
The PD parameters include BGmax, Tmax
3.
The PK parameters include AUC, Cmax, Tmax
Abbreviations:  AE = adverse event; AUC = area under the concentration versus time curve; BGmax = maximal 
blood glucose; Cmax = maximal concentration; PD = pharmacodynamics; PK = pharmacokinetics; T1DM = type 
1 diabetes mellitus; Tmax = time to maximal concentration.
Summary of Study Design:
Study I8R-MC-IGBI is a multicenter, randomized, open-label, 2-treatment, 2-period, crossover study conducted in 
adult patients with T1DM.
Treatment Arms and Planned Duration for an Individual Patient:
LY900018:  Single 3-mg dose; nasal administration by study site personnel
GlucaGen® (Novo Nordisk A/S):  Single 1-mg dose; IM injection
Number of Patients:
Approximately 70 patients with T1DM will be enrolled in order to have 66 patients complete both treatment visits
with evaluable primary outcome.
Statistical Analysis: A total of 66 patients are required in the study in order to achieve the primary objective with 
at least 90% power using the following assumptions:

A treatment success rate of 98% for both treatments

A noninferiority margin of 10%

One-sided alpha level of 0.025

A within-patient correlation of zero between 2 treatment visits


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The primary analysis will be a treatment comparison of the percentage of patients who achieve treatment success.  
The percentage of patients who achieve treatment success within each treatment arm and the difference in the 
percentages between 2 treatment arms will be computed.  A 2-sided 95% confidence interval (CI) will be obtained 
from the 1-sample mean of the paired differences in outcome (1=outcome observed; 0=outcome not observed) 
across 2 study visits.  Noninferiority of nasal glucagon (NG) will be declared if the upper limit of the 2-sided 95% 
CI constructed on the difference in percentage (IM glucagon – NG) is less than the noninferiority margin of 10%.


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2. Schedule of Activities


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Study Schedule Protocol I8R-MC-IGBI
Procedure
Screening
Visit 
Period 1 
and Period 
2 
CRU Visits
Follow-up
(or ED)
Visit
Comments
Up to 28
days before 
Period 1
Day 1
28(+2) days 
after last 
dose of study 
drug
Sign informed consent form
X
Written informed consent has to be provided before any trial-related 
activity and may be obtained during a separate informed consent visit 
to the site
Medical history
X
Clarke Hypoglycemia Awareness 
Survey
X
See Appendix 8.
Height
X
Weight
X
X
X
During Periods 1 and 2, body weight will be collected before the start 
of the procedure to induce hypoglycemia
Vital signs (supine blood pressure, 
pulse rate, and body temperature)
X
X
X
See Section 9.5.2; the patient should be at rest for at least 5 minutes 
before vital signs are measured.
During Periods 1 and 2, vital signs should be measured before the start 
of the procedure to induce hypoglycemia and at 45 minutes after 
glucagon administration.
Time points may be added for Period 1 and Period 2 if warranted and 
agreed upon between Lilly and the investigator.
Clinical laboratory tests
X
X
X
See Appendix 2, Clinical Laboratory Tests, for details.
Patients do not need to fast for laboratory samples collected at 
screening or follow-up.  At Period 1 and Period 2 site visits, laboratory 
tests should be collected from patients who have fasted at least 8 hours 
before any study procedures.  All screening, hepatic monitoring and 
study day laboratory tests to be processed at a local laboratory.  
Hepatitis E laboratory tests to be processed at a central laboratory.  
Sample collection for HbA1c
X
X 
(Period 1 
only)
Screening samples and samples collected before the start of the 
procedure to induce hypoglycemia to be processed at local laboratory.


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Pregnancy test 
X
X
X
Serum pregnancy test will be performed at screening and analyzed at a 
local laboratory.  Urine pregnancy test will be performed at admission 
for study Periods 1 and 2 as well as at the follow-up visit and 
processed on site
Physical examination
X
X
X
Physical examinations will be performed before the start of the 
procedure to induce hypoglycemia in Periods 1 and 2 and at the 
follow-up visit.  Patients will review recent insulin demand with site 
personnel prior to inducing hypoglycemia (see Section 7.7).  
12-Lead ECG
X
X
X
See Section 9.5.3; single 12-lead ECGs will be collected for local 
safety assessment.  During Periods 1 and 2, ECGs will be collected 
before the start of the procedure to induce hypoglycemia.  
Electrocardiograms may be obtained at additional times, when deemed 
clinically necessary
Adverse event assessment
X
X
X
See Section 9.3
Admission to CRU
X
The patient should arrive at the CRU at approximately 0700 hours, 
having fasted for at least 8 hours
Discharge from CRU
X
The patient may be discharged 6 hours following the procedure.  A 
patient may remain inpatient at the CRU at the discretion of the 
investigator
Dinner
X 
Following completion of all study procedures, the patient will be 
provided a carbohydrate-rich meal, and the investigator will ensure the 
patient’s plasma glucose is stable 
Nasal inspection 
X
Nasal inspection should be conducted before the procedure to induce 
hypoglycemia and at 90 minutes postglucagon administration
Injection-site inspection (for IM 
glucagon only)
X
The injection site will be inspected before the procedure to induce 
hypoglycemia to confirm injection site is normal and at 90 minutes 
postglucagon administration
Nasal and Non-nasal Score 
Questionnaire 
X
See Appendix 6, Nasal and Non-nasal Score Questionnaire. 
Questionnaire to be completed approximately 30 minutes prior to 
hypoglycemia induction and 15, 30, 60, and 90 minutes postglucagon 
administration


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Edinburgh Hypoglycemia Scale
X
See Appendix 7, Edinburgh Hypoglycemia Scale.This questionnaire 
should be completed when PG ≤75 mg/dL and again at PG ≤60 mg/dL 
after the start of the insulin infusion and at 15, 30, 45, and 60 minutes 
postglucagon administration
Insulin infusion to induce 
hypoglycemia
X
Refer to Sections 9.2 and 7.7 for details regarding this procedure, 
including steps to take before the procedure begins and steps to take if 
there is an insufficient response to glucagon administration.  
Procedures taking place on Period 2 will occur at approximately the 
same time as those for Period 1.
Study drug administration
X
Once PG reaches below 60 mg/dL, the insulin infusion is stopped and 
approximately 5 minutes later study drug is administered
Sample collection for 
measurement of glucagon
X
X
Samples will be collected pre-dose (i.e., immediately prior to glucagon 
administration) and at 5, 10, 15, 20, 25, 30, 40, 50, 60, 90, 120, and 
240 minutes post-glucagon administration at Periods 1 and 2 and once 
at follow-up.  All samples will be processed at a central laboratory.
Sample collection for 
measurement of DPC
X
Samples will be collected from NG-treated patients pre-dose (i.e., 
immediately prior to glucagon administration) and at 10, 20, 30, 40, 
60, 120, and 240 minutes post-glucagon administration.  Three 
additional samples may be collected.  Samples to be processed at a 
central laboratory.
Bedside glucose safety 
measurements (SuperGL 
laboratory analyzer)
X
Samples will be collected throughout the study procedure. During the 
hypoglycemia induction procedure, plasma glucose concentration will 
be measured no more than 10 minutes apart while the plasma glucose 
concentration is ≥100 mg/dL and no more than 5 minutes apart when 
the plasma glucose concentration is <100 mg/dL.  Post-glucagon 
administration, plasma glucose concentration will be measured every 5 
minutes for the first 30 minutes and every 10 minutes up to 90 
minutes.
Sample collection for 
measurement of plasma glucose
X
Samples will be collected pre-dose (i.e., immediately prior to glucagon 
administration) and at 5, 10, 15, 20, 25, 30, 40, 50, 60, and 90 minutes 
post-glucagon administration.  Samples to be processed at a central 
laboratory.
Exploratory sample
X 
(Period 1 
only)
X
Serum samples will be collected prior to the procedure to induce 
hypoglycemia.


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Genetic sample
X
(Period 1 
only)
Abbreviations:  CRU = clinical research unit; DPC = dodecylphosphocholine; ECG = electrocardiogram; ED = early discontinuation; HbA1c = hemoglobin A1c; 
IM = intra-muscular; NG = nasal glucagon; PG = plasma glucose.
Note:  if multiple procedures take place at the same time point, the following order of the procedure should be used: ECG, vital signs and venipuncture.


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3. Introduction
3.1.
Study Rationale
Nasal glucagon (NG; LY900018) is an investigational drug–device combination product 
consisting of a single-use nasal dosing device that delivers glucagon powder for absorption
through the nasal mucosa. Nasal glucagon represents a significant improvement in the evolution 
of the treatment of severe hypoglycemia with glucagon; it 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 [Lilly] and
GlucaGen® HypoKit [Novo Nordisk A/S]).
The aim of this study (Study I8R-MC-IGBI [IGBI]) is to compare the planned commercial drug 
product of NG to GlucaGen, a currently approved product that requires reconstitution prior to 
administration through intra-muscular (IM) injection, in those patients who achieve treatment 
success during controlled insulin-induced hypoglycemia in patients with type 1 diabetes mellitus 
(T1DM).  Treatment success is defined as an increase in plasma glucose (PG) concentration to 
≥70 mg/dL or an increase of ≥20 mg/dL from the PG nadir within 30 minutes after receiving 
glucagon, without the patient receiving additional actions to increase PG.  The nadir is defined as 
the minimum PG concentration at the time of or within 10 minutes following glucagon 
administration. The design and conduct of Study IGBI are similar to the completed Phase 3 
Study I8R-MC-IGBC (IGBC) (Rickels et al. 2016).
3.2.
Background
Glucagon is a widely available product currently indicated for the treatment of severe 
hypoglycemia.  The principal action of glucagon is to increase PG concentration through its 
action in the liver.  Nasal glucagon development has produced robust clinical data in adult 
healthy subjects, adult patients with T1DM and type 2 diabetes mellitus (T2DM), as well as
pediatric patients with T1DM.
Nasal glucagon powder contains 3-mg of glucagon in a ready-to-use, single-use intranasal 
powder delivery device. Glucagon comprises 10% by weight of the powder in the device. The 
formulation also contains beta-cyclodextrin as a filler/bulking agent/absorption enhancer and 
dodecylphosphocholine (DPC) as an absorption enhancer/surfactant.  Beta-cyclodextrin is a 
compendial excipient and DPC is a novel excipient.  The device delivers a single dose to the 
nostril upon actuation.
Three clinical trials using NG have been completed in adults with T1DM and T2DM:  Study
IGBC, Study I8R-MC-IGBA (IGBA), and an actual use study (Study I8R-MC-B002 [B002]).  
Studies IGBC and IGBA demonstrated comparable safety and efficacy between NG and 
injectable glucagon in reversing insulin-induced hypoglycemia in adult patients with T1DM only
(Study IGBA) or patients with T2DM and T1DM (IGBC).  Study B002 was an actual use study 
that evaluated the effectiveness of NG administered by a trained caregiver to patients with 
T1DM experiencing moderate to severe hypoglycemia in a real-world environment of work and 
home.  Study B002 demonstrated that 96% of moderate to severe hypoglycemic events were 


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LY900018
resolved within 30 minutes.  Finally, 2 trials were conducted in pediatric patients with T1DM: 
Study I8R-MC-IGBB (IGBB) and Study I8R-MC-B001 (B001).  Studies IGBB and 
B001demonstrated effectiveness in rescuing pediatric patients from hypoglycemia.
All adult diabetic patients in the 2 inpatient clinical trials (Studies IGBA and IGBC) underwent 
hypoglycemia induction through intravenous (IV) insulin under close clinical supervision and 
were administered either NG or injectable glucagon.
Patients fully recovered from hypoglycemia without additional actions to increase glucose level.  
Specifically, in Study IGBC, at 30 minutes after glucagon dosing, 98.7% (74 out of 75 patients)
of NG and 100% (75 out of 75) of intra-muscular glucagon (IMG)-treated patients achieved 
treatment success (defined as an increase in PG to >70 mg/dL or an increase of >20 mg/dL from 
nadir).  The nadir is defined as the minimum glucose measurement at the time of or within 
10 minutes following glucagon administration. The NG-treated patients who did not meet the 
above criteria did achieve both PG >70 mg/dL and an increase of >20 mg/dL from nadir at 
40 minutes after dosing. Furthermore, the mean time to treatment success was 16 minutes in the 
NG treatment arm and 13 minutes in the IMG treatment arm (Rickels et al. 2016).
3.3.
Benefit–Risk Assessment
Glucagon is generally well tolerated, with mild side effects noted.  These included occasional 
nausea and vomiting; however, these side effects may also occur with hypoglycemia (for 
example, dizziness, fainting, light headedness, blurred vision, headaches, fatigue). Nasal 
glucagon is a needle-free, ready-to-use nasal dosing device for administration into nostrils
requiring no inhalation.  In contrast to other products on the market, this requires no 
reconstitution.  Patients being treated with the investigational product will derive no direct 
benefit from it as treatment will follow an insulin-induced hypoglycemia.
To date, there have been 10 completed clinical studies (8 in adults, 2 in pediatric population) in 
which the safety, efficacy, or effectiveness of NG has been evaluated.  No deaths or serious 
adverse events (SAEs) associated with NG occurred during these studies.  The most frequently 
reported treatment-emergent adverse events (TEAEs) in NG-treated patients represent events 
related to local tolerability including lacrimation increased, headache, rhinorrhea, nasal 
discomfort, nasal congestion, and nasal pruritus, and gastrointestinal disorders including nausea 
and vomiting.  All TEAEs were transient in nature and most resolved within 24 hours of 
exposure. Severe adverse reactions to glucagon are very rare, although generalized allergic 
reactions, urticaria, respiratory distress, and hypotension have been reported in patients who have 
received glucagon.
This study will expose patients with T1DM to an insulin-induced hypoglycemia meant to 
simulate hypoglycemia in a controlled setting. The protocols used to induce the controlled 
hypoglycemia have been adopted from a previously completed trial, specifically Study IGBC,
that demonstrated the safe use of this method.  This is an inpatient procedure in which the 
patients will be under constant supervision of the clinical research unit (CRU) staff.  Safety 
provisions have been considered in that IV glucose will be administered if the patient


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LY900018
experiences signs and symptoms of severe hypoglycemia and gauged to require intervention
during the experimental procedure, at the discretion of the investigator.
No clinically significant safety or tolerability concerns have been identified in patients to date for 
NG up to the highest single dose (6-mg) given in an acute setting.
More information about the known and expected benefits, risks, SAEs, and reasonably 
anticipated adverse events (AEs) of glucagon nasal powder are to be found in the Investigator’s 
Brochure (IB).


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4. Objectives and Endpoints
Table IGBI.1 shows the objectives and endpoints of the study.
Table IGBI.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To compare LY900018 versus GlucaGen® in the 
percentage of adult patients with T1DM who achieve
treatment success during controlled insulin-induced 
hypoglycemia
The percentage of patients who achieve treatment 
success, which will be defined as an increase in plasma
glucose to ≥70 mg/dL or an increase of ≥20 mg/dL 
from plasma glucose nadir within 30 minutes after 
receiving glucagon, without receiving additional 
actions to increase the plasma glucose concentration; 
nadir will be defined as the minimum plasma glucose 
concentration at the time of or within 10 minutes 
following glucagon administration.
Secondary
1.
To assess the safety and tolerability of
LY900018 versus GlucaGen®
2.
To characterize the PD profiles of LY900018
versus GlucaGen®
3.
To characterize the PK profiles of LY900018
versus GlucaGen®
1.
Summary of AEs, including nasal and non-
nasal AEs; vital signs
2.
The PD parameters include BGmax, Tmax
3.
The PK parameters include AUC, Cmax,
Tmax
Exploratory
1.
To characterize the PK profile of the DPC
excipient of LY900018
2.
To assess the occurrence and severity of
hypoglycemia symptoms during controlled
insulin-induced hypoglycemia
3.
To assess the awareness of hypoglycemia
prior to its induction
1.
The PK parameters include AUC, Cmax,
Tmax
2.
The Edinburgh Hypoglycemic Scale will be
used to assess the occurrence and severity of
hypoglycemia symptoms
3.
The Clarke Hypoglycemia Awareness survey
will be used to assess awareness of
hypoglycemia symptoms
Abbreviations:  AE = adverse event; AUC = area under the concentration versus time curve; BGmax = maximal 
blood glucose; Cmax = maximal concentration; DPC = dodecylphosphocholine; PD = pharmacodynamics; PK = 
pharmacokinetics; T1DM = type 1 diabetes mellitus; Tmax = time to maximal concentration.


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5. Study Design
5.1.
Overall Design
This is a Phase 1, multicenter, randomized, open-label, 2-treatment, 2-period, crossover study.  
Figure IGBI.1 illustrates the study design.  In each period, patients with T1DM will undergo a 
procedure to induce hypoglycemia using insulin infusion. The insulin infusion will be used to 
decrease PG and will be stopped once PG <60 mg/dL and it is expected that PG will continue to 
decrease for an additional 15 to 20 mg/dL to its lowest concentration.  Approximately 5 minutes 
after the insulin infusion is stopped, patients will be administered either 3-mg NG (LY900018) 
or 1-mg IMG (GlucaGen) in the deltoid muscle of the nondominant arm by CRU staff members.  
Serial blood sampling will be performed for glucagon and PG concentration assessments 
immediately before and up to 6 hours following administration of glucagon.  Following each test 
period, patients will remain in the CRU for at least 6 hours following the procedure.  All patients
will receive a carbohydrate-rich meal prior to discharge.  Patients may stay longer as needed, at 
the discretion of the investigator.
After a wash-out period of at least 1 day (24 hours) and no more than 7 days, patients will return 
to the clinic and the procedure repeated with each patient crossed over to the alternate glucagon
treatment.
A CRU visit for follow-up or early discontinuation should occur approximately 28±2 days after 
the last dose of study drug.


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Abbreviations:  CRU = clinical research unit; IM = intra-muscular; T1DM = type 1 
diabetes mellitus.
Figure IGBI.1.
Illustration of study design for Protocol I8R-MC-IGBI.
5.2.
Number of Participants
Approximately 70 patients with T1DM may be enrolled to ensure that at least 66 patients 
complete both treatment visits with evaluable primary outcome (see Section 10.3.1.1).
If patients drop out of the study before completion of both periods or completed the study 
without evaluable primary outcome in at least 1 period, replacement patients will be enrolled to 
ensure at least 66 patients are available for the evaluation of primary objective. The replacement 
patients will assume the same treatment sequence as the patients to be replaced and will 
complete that treatment sequence in its entirety.
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of
Activities (Section 2) for the last patient.


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5.4.
Scientific Rationale for Study Design
This study will be used to supplement the comprehensive chemistry, manufacturing control
analytical plan for bridging the planned commercial drug product with the clinical trial drug 
product. Since the existing stores of clinical trial drug product have been exhausted, an indirect 
comparator/bridging study must be performed to demonstrate efficacy comparability.  
This study design involves an open-label assessment of the planned commercial drug product 
compared to the marketed product (GlucaGen) within the T1DM population.  The 2 study 
periods will be separated by a washout period of no less than 1 day (24 hours) and no more than 
7 days due to the short half-life of NG (approximately t1/2 = 25 minutes)   The second of the 2 
study periods will expose the same patients to the alternate study arm (for example, those 
randomly assigned to receive NG LY900018 will receive IM GlucaGen for Period 2).  This 
crossover design will allow each individual patient to act as an internal control.
5.5.
Justification for Dose
Results from studies in both pediatric and adult populations confirm that, while the physiological 
response to glucagon does appear to saturate between 2- and 3-mg NG dose, the lower 2-mg 
dose may not always elicit the maximum response needed in an emergency situation of severe 
hypoglycemia.  The 3-mg dose provides more consistent clinical efficacy compared to the 2-mg 
dose and is similarly well tolerated in both pediatric and adult patients.
Based on LY900018 exposure, efficacy, and safety, the 3-mg dose was selected for the Phase 3 
studies. Therefore, in the current study, the 3-mg NG dose will be used to compare against 1 mg 
of IM GlucaGen.


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6. Study Population
Eligibility of patients for the study will be based on the results of screening medical history, 
physical examination, vital signs, clinical laboratory tests, and electrocardiogram (ECG).  Refer
Section 6.1 and Section 6.2 for full inclusion/exclusion criteria. 
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 28 days prior to enrollment.  Patients who are not enrolled within 
28 days of screening may be subjected to an additional medical assessment and/or clinical 
measurements to confirm their eligibility.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Patients are eligible for inclusion in the study only if they meet all of the following criteria at 
screening and/or enrollment:
[1]
are male or female with a diagnosis of T1DM for at least 2 years and
receiving daily insulin since the time of diagnosis
[1a] for sexually active male patients, who have not been surgically sterilized,
with a female partner of childbearing potential, the female partner must use a 
highly effective method of contraception (for example, surgical sterilization, 
hormonal intrauterine devices [coil], or oral hormone contraceptives, each in 
combination with spermicide-coated condoms); when female partners do not 
use these methods, the male patient must be willing to refrain from sexual 
intercourse from the first dosing until 1 month after the last dosing in the 
trial
[1b] female patients of child-bearing potential must agree to use a highly 
effective method of birth control (highly effective contraception methods are 
considered those with a failure rate <1% undesired pregnancies per year and 
include surgical sterilization, hormonal intrauterine devices [coil], oral 
hormone contraceptives, sexual abstinence, or a surgically sterilized partner) 
throughout the entire duration of this study (from the screening visit until 
study completion)
females of nonchildbearing potential may participate without using highly 
effective contraceptive methods which include those who are 
postmenopausal, defined as women aged <52 years and being amenorrheic 
for more than 1 year with a serum follicle-stimulating hormone (FSH) level 
compatible with postmenopausal status or aged ≥52 years and being 
amenorrheic for less than 1 year and with serum FSH level according to 
local laboratory reference range and not using highly effective contraceptive 
methods or aged ≥52 years being amenorrheic for more than 1 year.


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[2]
are between the ages of 18 to 64 years, inclusive
[3]
have a body weight of at least 50 kg (110 lb)
[4]
have a body mass index of 18.5 to 35 kg/m2, inclusive
[5]
have a hemoglobin A1c (HbA1c) value ≤10%
[6]
have clinical laboratory test results within normal reference range for the
population or investigational site, or results with acceptable deviations that are
judged to be not clinically significant by the investigator
[7]
have venous access sufficient to allow for blood sampling and required
infusions as per the protocol
[8]
are reliable and willing to make themselves available for the duration of the
study and are willing to follow study procedures
[9]
has provided signed informed consent
6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or enrollment:
[10]
are investigative site personnel directly affiliated with this study and their
immediate families.  Immediate family is defined as a spouse, biological or
legal guardian, child, or sibling
[11]
are Lilly employees
[12]
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
[13]
have participated, within the past 30 days, in a clinical study involving an
investigational product
[14]
have previously completed or withdrawn from this study or any other study
investigating LY900018, and have previously received the investigational
product
[15]
have known allergies to LY900018, related compounds or any components of
the formulation, or history of significant atopy
[16]
have a history of hypersensitivity to glucagon or any related products or
severe hypersensitivity reactions (such as angioedema) to any drugs
[17]
have an abnormality in the 12-lead ECG that, in the opinion of the
investigator, increases the risks associated with participating in the study


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[18]
have a supine blood pressure at screening (after at least 5 minutes at rest)
outside the range of 95 to 140 mmHg systolic blood pressure and/or greater
than 90 mmHg for diastolic blood pressure (this excludes white-coat
hypertension, and if repeated measurements are within this range, the subject
may be included in the study); have symptoms of arterial hypotension and/or a
heart rate at rest outside the range of 50 to 90 beats per minute
[19]
have a history of pheochromocytoma (that is, adrenal gland tumor) or
insulinoma
[20]
occurrence of an episode of severe hypoglycemia (defined as requiring the
assistance of another person in the 1 month prior to enrolling in the study)
[21]
have a history of epilepsy or seizure disorder
[22]
have a significant history of or current cardiovascular, respiratory, hepatic,
renal, gastrointestinal, endocrine (apart from T1DM), hematological, or
neurological disorders capable of significantly altering the absorption,
metabolism, or elimination of drugs; of constituting a risk when taking the
study drug; or of interfering with the interpretation of data
[23]
have a significant history of or current psychiatric disorders.
[24]
regularly use known drugs of abuse and/or show positive findings on drug
screening
[25]
show evidence of human immunodeficiency virus (HIV) infection and/or
positive human HIV antibodies
[26]
show evidence of hepatitis C and/or positive hepatitis C antibody
[27]
show evidence of hepatitis B and/or positive hepatitis B surface antigen
[28]
are women who are pregnant according to a positive serum pregnancy test,
actively trying to get pregnant, or are lactating
[29]
have, except for the current regimen of insulin therapy and concomitant
medication (for example, antihypertensive agents, lipid-lowering agents,
contraceptives, and stable treatment with hormone replacement and thyroid
hormone replacement therapy), regular use of or intended use of any
over-the-counter or prescription medications or nutritional supplements that
treat hyperglycemia or insulin resistance or that promote weight loss within
14 days before dosing
[30]
daily use of systemic beta-blocker, indomethacin, warfarin or anticholinergic
drugs.
[31]
have had blood donation or blood loss of more than 500 mL within the past
3 months
[32]
have a significant history of alcoholism or drug abuse as judged by the
investigator, or regularly consume more than 24 g alcohol/day (males) or 12 g
alcohol/day (females)


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[33]
in the opinion of the investigator or sponsor, are unsuitable for inclusion in the
study
[34]
any significant changes in insulin regimen and/or unstable blood glucose
control within the past 3 months prior to screening as assessed by the
investigator
[35]
require daily insulin treatment >1.5 U/kg/body weight.
6.3.
Lifestyle and/or Dietary Requirements
Throughout the study, patients may undergo medical assessments and review of compliance with 
requirements before continuing in the study.  Patients should continue to meet the restrictions 
related to alcohol, caffeine, and medication use.
6.3.1. Meals and Dietary Restrictions
In both treatment periods, patients will fast for at least 8 hours prior to beginning the
hypoglycemia induction procedure.  Once this procedure is completed, the patients will receive a 
carbohydrate-rich meal.  Patients will be given access to calorie-free water during the 
hypoglycemic procedure.
While resident in the CRU, patients may not consume any food or caloric drinks other than that
provided by the CRU.  When not resident in the CRU, patients will be encouraged to follow their 
normal diets.  However, patients are encouraged to consume at least 100 g of carbohydrates 
during the washout period.
6.3.2. Alcohol
Please refer to Section 6.2 regarding excessive alcohol use.  Alcohol use will be prohibited 
during the fasting procedure.  However, alcohol may be consumed during the washout period as 
long as it conforms with the exclusion criteria and does not deviate from habitual patterns of 
consumption.
6.3.3. Activity
Patients are encouraged to maintain their regular exercise habits for the duration of the study.  
However, patients should avoid strenuous exercise 48 hours prior to study days.
During the procedure to induce hypoglycemia, patients should remain recumbent or sitting in the 
CRU until the end of the procedure.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
re-screened.


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7. Treatment
7.1.
Treatment Administered
This study involves a comparison of 3-mg glucagon administered once nasally to 1-mg IMG
(GlucaGen; comparator).  Table IGBI.2 shows the treatment regimens.
Table IGBI.2.
Treatments Administered
Treatment Name
LY900018
GlucaGen
Dosage Formulation
Fine powder
Clear liquid
Unit Dose Strength(s)/Dosage 
Level(s)
3-mg glucagon
1-mg glucagon
Route of Administration
Nasal
Intra-muscular
Dosing instructions
Administer a single nasal dose upon 
hypoglycemia onset
Administer a single intra-muscular 
injection upon hypoglycemia onset
The procedure for insulin-induced hypoglycemia will require an IV infusion of 15-U human 
insulin [100 U/mL] in 49-mL saline.
The investigator or designee is responsible for:

verifying that instructions are followed properly

maintaining accurate records of investigational product dispensation and collection
including documentation of lot or control numbers, as appropriate.

returning all unused medications to Lilly or its designee at the end of the study
7.1.1. Packaging and Labeling
Clinical trial materials will be labeled according to the country’s regulatory requirements.  Lilly 
will supply to the clinical site LY900018 and GlucaGen Hypo Kits as well as insulin lispro U100 
to induce hypoglycemia. Study materials will be provided as open-label material.
All insulin products must be stored at the investigational site, according to the instructions
provided on the product label, in a locked and secure place. 
Unused study materials will remain locked and securely stored, according to the instructions
provided on the product label at the investigational site, until returned to the sponsor or 
destroyed, according to written instruction from the sponsor.


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7.1.2. Medical Devices
The manufactured medical devices provided for use in the study include a nasal delivery device 
as part of the investigational drug–device combination product.  The device component of the 
investigational drug–device product is inserted into the nasal cavity to deliver the contained drug 
constituent.
7.2.
Method of Treatment Assignment
The treatment sequence to be administered for each enrolled patient will be determined 
according to a randomization schedule.
7.2.1. Selection and Timing of Doses
The hypoglycemia induction procedure should be initiated at approximately the same time at 
each treatment visit.  An IV infusion of insulin will be given until PG level of <60 mg/dL is 
reached.  At this point, insulin infusion will be stopped and approximately 5 minutes later, a
single-dose glucagon (NG or IMG) will be administered to the patients by CRU staff.  The actual 
date and time of glucagon administration will be recorded in the patient’s case report form 
(CRF).
7.3.
Blinding
This is an open-label study.  However, the treatment assignment list for all randomized patients 
will not be shared with those responsible for doing either the treatment response assessments or 
making the decision to take additional action to raise the patients’ PG concentration
post-glucagon administration.  The intent is to minimize any potential bias in administering 
additional rescue treatment for hypoglycemia.
7.4.
Dose Modification
Not applicable.
7.5.
Preparation/Handling/Storage/Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained, as communicated by the sponsor, during transit for all investigational products
received and any discrepancies are reported and resolved before use of the study treatment.
Only participants enrolled in the study may receive investigational product or study materials, 
and only authorized site staff may supply or administer investigational product. All 
investigational products should be stored in an 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.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (such as
receipt, reconciliation, and final disposition records).


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7.6.
Treatment Compliance
The investigational product will be administered at the clinical site, and documentation of 
treatment administration will occur at the site.
7.7.
Concomitant Therapy
Patients on stable concomitant medications at the time of study entry should continue their 
regular, unchanged dose throughout the study.  These medications may include a stable regimen 
of insulin therapy (for example, basal and fast-acting insulin) as well as antihypertensive and 
antilipidemic agents.  In addition to the physical examination, investigators should review the 
insulin regimen for all patients enrolled into the study to confirm acceptability to undergo the 
procedure to induce hypoglycemia (see Schedule of Activities; Section 2).
Patients taking multiple daily injections, or a basal/bolus regimen, of insulins should not change 
their basal dose prior to study drug administration.  The last dose of short-acting insulin should 
be administered (by either pump or injection) approximately 6 hours prior to study drug 
administration.  Patients on an insulin pump that is providing a continuous subcutaneous insulin 
infusion will suspend the use of the pump prior to procedure to induce hypoglycemia.
In general, new concomitant medications should be avoided; however, acetaminophen (1 g, 
maximum 2 g/24 hours) may be administered at the discretion of the investigator for treatment of 
headache, etc.  If the need for concomitant medication (other than acetaminophen) arises, 
inclusion or continuation of the patient 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.  All changes in concomitant medications made during the study 
should be recorded.
7.8.
Treatment after the End of the Study
Patients will continue their previous insulin regimen after the study procedure has been 
completed.  


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8. Discontinuation Criteria
Patients discontinuing from the study prematurely for any reason should complete AE and 
follow-up procedures per Section 2 of this protocol.
8.1.
Discontinuation from Study Treatment
8.1.1. Discontinuation of Inadvertently Enrolled Patients
If the sponsor or investigator identifies a patient who did not meet enrollment criteria and was 
inadvertently enrolled, the patient must be discontinued from the study.
8.2.
Discontinuation from the Study
Patients will be discontinued under the following circumstances:

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

Participation in the study needs to be stopped for medical, safety, regulatory, or other
reasons consistent with applicable laws, regulations, and good clinical practice (GCP)

Investigator Decision
o
the investigator decides that the patient should be discontinued from the study
o
if the patient, for any reason, requires treatment with another therapeutic agent
that has been demonstrated to be effective for treatment of the study indication,
discontinuation from the study occurs prior to introduction of the new agent
o
if the patient experiences a severe hypoglycemic event following screening and
prior to study Day 1 or during the washout period between Period 1 and Period 2

Subject Decision
o
the patient requests to be withdrawn from the study.
8.3.
Patients Lost to Follow-up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Study site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or are otherwise 
unable to be followed up by the site.


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9. Study Assessments and Procedures
Section 2 lists the Schedule of Activities, detailing the study procedures and their timing 
(including tolerance limits for timing).
Appendix 2 lists the laboratory tests that will be performed for this study.
Appendix 5 provides a summary of the maximum number and volume of invasive samples, for
all sampling, during the study.
Unless otherwise stated in subsections below, all samples collected for specified laboratory tests 
will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may be 
retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1.
Efficacy Assessments
Plasma glucose levels will be measured prior to the administration of the glucagon product as 
well as at various time points following its administration (see Schedule of Activities; Section 2), 
and will be used to assess efficacy outcome.
Subjective hypoglycemia symptoms will be assessed using a self-reported assessment tool 
(Edinburgh Hypoglycemia Scale; Appendix 7) during the initiation of the hypoglycemia 
induction, as well as at various time points following the administration of either NG or IMG 
(see Schedule of Activities; Section 2).
The ability of the patient to identify hypoglycemic symptoms and describe their frequency will 
be captured at screening visit (see Schedule of Activities; Section 2).  This self-report assessment 
will be done using the Clarke Hypoglycemia Awareness Survey (Appendix 8).
9.2.
Procedures
9.2.1. Inducing Hypoglycemia
The patient will have this procedure after admission to the CRU.  A study investigator, or 
qualified designee, must be present at the bedside for clinical assessments of the patient during 
the insulin infusion and for the 90 minutes following the glucagon administration.
The PG level must be >90 mg/dL to start the procedure. Hypoglycemia will be induced by an IV 
infusion of regular insulin diluted in saline and may be adjusted as necessary to decrease PG 
levels <60 mg/dL.  Once the PG level is <60 mg/dL, the insulin infusion is stopped and 
approximately 5 minutes later NG or IMG is given.  Blood samples are taken for PG
(pharmacodynamics [PD]) and glucagon (pharmacokinetics [PK]) (see Schedule of Activities; 
Section 2).
9.2.2. Glucagon Administration
Either NG or IMG will be given according to the random assignment. The glucagon treatment 
will be administered approximately 5 minutes after the insulin infusion has been stopped.


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9.2.2.1.
Nasal Administration
Nasal glucagon will be administered by CRU staff with the patient lying in a fully reclined 
lateral position on the opposite side of the nostril being administered (that is, dose is given in the 
left nostril of a patient lying in right lateral recumbency).
The tip of the device is gently entered in the nostril to the point where the index and middle 
finger of the administrator are just touching the external nare of the patient. At that point, the 
bottom of the device is pushed with the thumb until the device is engaged, the green band 
disappears, and powder is discharged into the nostril. The drug is absorbed from the nasal 
cavity; thus the patient does not need to inhale after dosing and continues breathing normally 
throughout the process. If a subject sneezes immediately after administration, document using
the Nasal and Non-nasal Score Questionnaire (Appendix 6).
9.2.2.2.
Intra-muscular Administration
The GlucaGen HypoKit contains the necessary supplies to prepare the dose and administer the 
IMG.  A dose of 1-mg of glucagon in a concentration of 1 mg/mL will be injected IM in the 
deltoid muscle of the participant’s nondominant arm with the participant lying in a fully reclined 
lateral position on the opposite side of the arm being administered (that is, dose is given in the 
left arm of a patient lying in right lateral recumbency).
9.2.3. Procedures for Insufficient Response to Glucagon 
Administration
If the PG is declining too fast or symptoms become consistent for the progression to severe
hypoglycemia to occur, the investigator may decide to start a glucose infusion to prevent a 
deterioration of the situation.  Continuous venous access will be used while the patient resides in 
the CRU to enable immediate delivery of IV glucose if needed.  If, following the administration 
of glucagon, a patient’s PG concentration remains <55 mg/dL at 30 minutes or <60 mg/dL at 45
minutes, IV glucose may be given as appropriate to the clinical situation. If IV glucose is given 
or additional glucagon is given, any remaining blood samples for the admission will still be 
collected. 
9.2.4. End of Admission
Before departure from the clinical site, the glucose and insulin dosing and stability of the 
participant will be evaluated by the study physician to ensure the safety of the participant. 
Patients will remain at the CRU for 6 hours following procedure, during which time a 
carbohydrate-rich meal will be provided.  The patient may stay at the CRU longer, at the 
discretion of the investigator. 
9.3.
Adverse Events
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.
The investigator is responsible for the appropriate medical care of patients during the study.


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Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the patient to discontinue the investigational product before 
completing the study.  All AEs will be followed until restoration or until a stable condition has 
been achieved.  The frequency of follow-up evaluations of the AE is left to the discretion of the 
investigator.  The follow-up should not be interrupted, even if there is a reasonable explanation 
for the event.  
After the informed consent form (ICF) is signed, study site personnel will record, via designated 
data collection methods, the occurrence and nature of each patient’s preexisting conditions, 
including clinically significant signs and symptoms of the disease under treatment in the study.  
Additionally, study site personnel will record any change in the condition(s) and the occurrence 
and nature of any AEs.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account the 
disease, concomitant treatment, or pathologies.
A “reasonable possibility” means that there is a potential cause and effect relationship between 
the investigational product, study device and/or study procedure, and the AE.
Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study.
9.3.1. Serious Adverse Events
An SAE is any AE from this study that results in 1 of the following:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in death
or hospitalization but may jeopardize the patient or may require intervention to prevent 1
of the other outcomes listed in the definition above.

when a condition related to the drug delivery system necessitates medical or surgical
intervention to preclude either permanent impairment of a body function or permanent
damage to a body structure, the serious outcome of “required intervention” will be
assigned.
Study site personnel must alert the Lilly clinical research physician (CRP)/clinical 
pharmacologist, or its designee, of any SAE as soon as practically possible.


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Additionally, study site personnel must alert Lilly Global Patient Safety, or its designee, of any 
SAE within 24 hours of investigator awareness of the event via a sponsor-approved method.  If 
alerts are issued via telephone, they are to be immediately followed with official notification on
study-specific SAE forms.  This 24-hour notification requirement refers to the initial SAE 
information and all follow-up SAE information.
Although all AEs are recorded in the designated date collection methods after signing informed 
consent, SAE reporting to the sponsor begins after the patient has signed informed consent and 
has received investigational product.  However, if an SAE occurs after signing informed consent, 
but prior to receiving investigational product, AND is considered reasonably possibly related to a 
study procedure then it MUST be reported.
Investigators are not obligated to actively seek AEs or SAEs in patients once they have 
discontinued from and/or completed the study (the patient summary CRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly.
Pregnancy (maternal or paternal exposure to investigational product) does not meet the definition 
of an AE.  However, to fulfill regulatory requirements any pregnancy should be reported 
following the SAE process to collect data on the outcome for both mother and fetus.
9.3.1.1.
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator reports as related to investigational product or procedure.  Lilly 
has procedures that will be followed for the recording and expedited reporting of SUSARs that 
are consistent with global regulations and the associated detailed guidances.
9.3.1.2.
Adverse Event Monitoring with a Systematic Questionnaire
Before administering the Nasal and Non-nasal Score Questionnaire (see Appendix 6 for a copy
of the questionnaire) and Edinburgh Hypoglycemia Scale (see Appendix 7), study site personnel 
will question the patient about any change in the preexisting condition(s) and the occurrence and 
nature of any AEs.  Study site personnel will explain the possibility to the patient of AEs 
associated with the study and that these AEs will be captured during the study through the use of 
the Nasal and Non-nasal Score Questionnaire and Edinburgh Hypoglycemia Scale.
Nonserious AEs obtained through the questionnaire are recorded and analyzed separately.  
Only SAEs elicited through the Nasal and Non-nasal Score Questionnaire and Edinburgh 
Hypoglycemia Scale are to be recorded as AEs via electronic data entry and reported to Lilly or 
its designee within 24 hours as SAEs.
9.3.2. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical trials in order to ensure the safety of study participants, monitor quality, and to facilitate 
process and product improvements.


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Patients should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product (or drug delivery system) so that the 
situation can be assessed.
9.4.
Treatment of Overdose
Not applicable.
9.5.
Safety
9.5.1. Laboratory Tests
For each patient, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2).
Lilly or its designee will provide the investigator with the results of laboratory tests analyzed by 
a central vendor, if a central vendor is used for the study.
9.5.2. Vital Signs
For each patient, vital sign measurements should be conducted according to the Schedule of 
Activities (Section 2), and following the study-specific recommendations included in the Manual 
of Operations for the study.  
Blood pressure and pulse rate should be measured after at least 5 minutes supine.
If orthostatic measurements are required, patients should be supine for at least 5 minutes and 
stand for at least 2 minutes.
If the patient feels unable to stand, supine vital signs only will be recorded. 
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms.  Additional vital signs may be measured during each study period if 
warranted.
9.5.3. Electrocardiograms
For each patient, ECGs should be collected according to the Schedule of Activities (Section 2)
and the study-specific recommendations included in Manual of Operations for the study.
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
patient receives the first dose of the investigational product should be reported to Lilly, or its 
designee, as an AE via electronic data entry. 
For each patient, a single 12-lead digital ECG will be collected according to the Schedule of 
Activities (Section 2).  Electrocardiograms must be recorded before collecting any blood 
samples.  Patients must be supine for approximately 5 to 10 minutes before ECG collection and 
remain supine but awake during ECG collection.  Electrocardiograms may be obtained at 
additional times, when deemed clinically necessary.  All ECGs recorded should be stored at the 
investigational site.


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Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
patient is still present, to determine whether the patient meets entry criteria at the relevant visit(s) 
and for immediate patient management, should any clinically relevant findings be identified.  
If a clinically significant finding is identified (including, but not limited to, changes in QT/QTc 
interval from baseline) after enrollment, the investigator will determine if the patient can 
continue in the study.  The investigator, or qualified designee, is responsible for determining if 
any change in patient management is needed, and must document his/her review of the ECG 
printed at the time of collection.  Any new clinically relevant finding should be reported as an 
AE.
9.5.4. Other Tests
Blood samples will be collected as specified in the Schedule of Activities (Section 2) and stored
for future exploratory analyses, which may include an assessment of anti-glucagon antibodies. 
Should immunogenicity be assessed, it will be done using a validated assay designed to detect 
antidrug antibodies in the presence of LY900018.  Antibodies may be further characterized 
and/or evaluated for their ability to neutralize the activity of the LY900018.
Samples will be retained for a maximum of 15 years after the last subject visit, or, for a shorter 
period, if local regulations and ethical review boards (ERBs) allow, at a facility selected by the 
sponsor. The duration allows the sponsor to respond to future regulatory requests related to 
LY900018. Any samples remaining after 15 years will be destroyed.
A nasal and injection-site inspection will be conducted in advance of the hypoglycemic induction 
procedure.  This inspection will ascertain whether either sites are normal in appearance prior to 
drug administration. The nasal and inspection-site inspection will also be done 90 minutes
following glucagon administration.
9.5.5. 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 the following data:

trends in safety data

laboratory analytes including HbA1c and electrolytes (see Appendix 2)

adverse events including monitoring of nasal cavity and injection site.
When appropriate, the Lilly clinical pharmacologist or CRP will consult with the functionally 
independent Global Patient Safety therapeutic area physician or clinical research scientist.


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9.5.5.1.
Hepatic Safety
If a study patient experiences elevated alanine aminotransferase (ALT) ≥3X upper limit of 
normal (ULN), alkaline phosphatase (ALP) ≥2X ULN, or elevated total bilirubin ≥2X ULN, 
liver tests (Appendix 4) should be repeated within 3 to 5 days including ALT, aspartate 
aminotransferase, ALP, total bilirubin (TBL), direct bilirubin, gamma-glutamyl transferase, and 
creatinine kinase to confirm the abnormality and to determine if it is increasing or decreasing.  If 
the abnormality persists or worsens, clinical and laboratory monitoring should be initiated by the 
investigator based on consultation with the Lilly clinical pharmacologist or CRP.  Monitoring 
should continue until levels normalize and/or are returning to approximate baseline levels. 
Additional safety data should be collected if 1 or more of the following conditions occur: 

elevation of serum ALT to ≥[5X] ULN on 2 or more consecutive blood tests

elevated serum TBL to ≥[2X] ULN (except for cases of known Gilbert’s
syndrome)

elevation of serum ALP to ≥[2X] ULN on 2 or more consecutive blood tests

patient/subject discontinued from treatment due to a hepatic event or abnormality
of liver tests

hepatic event considered to be an SAE.
9.6.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities (see Section 2), venous blood
samples of approximately 4 mL each will be collected to determine the plasma concentrations of 
glucagon and DPC.  Three samples may be collected per subject at additional time points during 
the study if warranted and agreed upon between both the investigator and sponsor.  DPC samples 
are collected from patients treated with NG only.  Instructions for the collection and handling of 
blood samples will be provided by the sponsor.  The actual date and time (24-hour clock) of each 
sampling will be recorded.
9.6.1. 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 (LC/MS) method.
Concentrations of DPC will be assayed using a validated liquid chromatography with tandem
mass spectrometry (LC/MS) method.  Analyses of samples collected from patients who received 
IMG are not planned.
Bioanalytical samples collected to measure investigational product concentrations will be 
retained for a maximum of 1 year following last patient visit for the study.


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9.7.
Pharmacodynamics
At times specified in the Schedule of Activities (see Section 2), venous blood samples will be 
collected and used to determine the PG concentration. The samples will be stored for up to a 
maximum of 1 year after the last patient visit for the study at a facility selected by the sponsor.
Samples used to assess the secondary objective endpoints will be processed within 1 year 
following last patient visit. Any samples remaining after 1 year will be destroyed.
9.7.1. Exploratory Sample Assessments and Storage
Collection of samples for exploratory research is also part of this study.  Blood samples will be 
collected as specified in the Schedule of Activities (see Section 2). Samples collected and stored 
for exploratory analysis may be used for immunogenicity assessments.
Samples will be retained for a maximum of 15 years after the last patient visit, or for a shorter 
period if local regulations and ERBs allow, at a facility selected by the sponsor.  The duration 
allows the sponsor to respond to future regulatory requests related to the NG (LY900018).  Any 
samples remaining after 15 years will be destroyed.
9.8.
Genetics
A blood sample will be collected for pharmacogenetic analysis as specified in the Schedule of 
Activities (see Section 2), where local regulations allow.
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable exposure or response to 
glucagon nasal powder (LY900018) and to investigate genetic variants thought to play a role in 
diabetes mellitus and related complications.  Assessment of variable response may include 
evaluation of AEs or differences in efficacy.
All samples will be coded with the patient number.  These samples and any data generated can 
be linked back to the patient only by the investigative site personnel.
Samples will be retained for a maximum of 15 years after the last patient visit, or for a shorter 
period if local regulations and/or ERBs/IRBs impose shorter time limits, for the study at a 
facility selected by Lilly or its designee.  This retention period enables use of new technologies, 
response to regulatory questions, and investigation of variable response that may not be observed 
until later in the development of glucagon nasal powder (LY900018) or after glucagon nasal 
powder (LY900018) is commercially available.
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome-wide association studies, multiplex assays, and candidate gene studies.  
Regardless of technology utilized, data generated will be used only for the specific research 
scope described in this section.


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9.9.
Biomarkers
Not applicable.
9.10. Health Economics
Not applicable.


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10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
Assuming a 5% dropout rate, the study will enroll approximately 70 patients to have 66 patients 
completing both treatment visits with evaluable primary outcome.
A total of 66 patients are required in the study in order to achieve the primary objective with at 
least 90% power under the following assumptions:

A treatment success rate of 98% for both treatments

A noninferiority margin of 10%

One-sided alpha level of 0.025

A within-patient correlation of zero between 2 treatment visits
10.2. Populations for Analyses
10.2.1. Study Participant Disposition
Proportion of patients discontinued from the study and the reasons for discontinuation will be 
summarized by treatment group for all randomized patients.
10.2.2. Study Participant Characteristics
The patients’ baseline characteristics and demographics will be obtained at entry and will be 
summarized for all randomized patients.
10.2.3. Treatment Compliance 
No specific study data will be collected for analysis of treatment compliance.
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Eli Lilly and Company 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 statistical analysis plan (SAP) and/or in the clinical study report.  
All data will be entered, verified, and archived at a contract research organization (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 randomized patients who 
received at least 1 dose of the study drug and have evaluable efficacy outcome. 


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Pharmacokinetic/pharmacodynamic analyses will be conducted on data from all randomized 
patients who receive at least 1 dose of the study drug and have evaluable PK/PD. 
Safety analyses will be conducted for all randomized patients who receive at least 1 dose of the 
study drug, whether or not they completed all protocol requirements (see Section 10.3.2.1).
All analyses will be based on the treatment patients actually received (if different from assigned 
treatment).  Unless otherwise specified, all tests of statistical significance for treatment 
comparisons will be evaluated at a nominal level of 0.05 using 2-tailed test procedures, and
confidence intervals (CIs) will be computed as 2-tailed using a 95% significance level.  All tests 
of interactions between treatment group and other covariates will be conducted as 2-sided with 
an alpha level of 0.10.  SAS version 9.2 or higher will be used to perform the analyses.
Additional exploratory analyses of the data will be conducted as deemed appropriate.  Study 
results may be pooled with the results of other studies for population PK analyses purposes to 
avoid issues with post hoc analyses and incomplete disclosures of analyses.
10.3.1. Efficacy Analyses
10.3.1.1. Primary Efficacy
The primary outcome is the treatment success, which is defined as an increase in PG to 
≥70 mg/dL or an increase of ≥20 mg/dL from PG nadir within 30 minutes after receiving 
glucagon, without receiving additional actions to increase the PG concentration.  The nadir is 
defined as the minimum PG concentration at the time of or within 10 minutes following 
glucagon administration.
The primary analysis will be a treatment group comparison of the primary outcome.  The 
percentage of treatment successes in each treatment and the difference in percentages will be 
computed.  A 2-sided 95% CI will be obtained from the 1-sample mean of the paired differences 
in primary outcome (1=outcome observed; 0=outcome not observed) across 2 treatment visits.
Noninferiority of NG will be declared if the upper limit of a 2-sided 95% CI constructed on the 
difference in percentages (IMG – NG) is less than the noninferiority margin of 10%.
The proposed noninferiority margin of 10% has been chosen based on the previously completed 
Phase 3 study (Rickels et al. 2016).
Primary efficacy analysis will only include patients who complete both treatment visits with
evaluable primary outcome.  The following will be considered as nonevaluable primary efficacy 
outcome and excluded from the analysis related to primary efficacy outcome: 

Patients with at least 1 treatment visit in which the lowest PG concentration at the time of
or within 10 minutes following glucagon administration is ≥70 mg/dL;

Patients receive an external measure to raise PG concentration either before glucagon
administration or within the first 10 minutes of glucagon administration.
Plasma glucose concentrations assessed through a central laboratory will be used to assess 
treatment success.  If a central laboratory measurement is missing, the SuperGL (or equivalent) 


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measurement from that time point will be used in general with the following additional
provisions:

Out-of-window blood draws (blood draws taken before/after the midpoint between
consecutive planned measurements) that occur prior to the 30-minute time point will be
included.

Central laboratory PG concentrations and SuperGL (or equivalent) concentrations at the
30-minute time point that are measured more than 35 minutes after administration of
glucagon will be considered missing.

If a PG concentration is missing for both central laboratory and SuperGL (or equivalent)
measurements, the missing value will be imputed using linear interpolation of central
laboratory values.
Additional analysis will be performed if deemed necessary.  The details will be provided in the 
SAP.
10.3.1.2. Secondary Efficacy Analyses
10.3.1.2.1.Plasma Glucose Values
Descriptive statistics will be used to summarize the baseline, various postdose time points, and 
absolute change from baseline in PG values by treatment group.  Additional analysis will be 
performed if deemed necessary.  The details will be provided in the SAP.
If a patient receives additional intervention to raise PG concentrations, measurements taken after 
the time of intervention will be excluded from the analysis.
10.3.1.2.2.Symptoms of Hypoglycemia
Descriptive statistics will be used to summarize the baseline, various postdose time points, and 
absolute change from baseline in total score and each subscale score of Edinburgh 
Hypoglycemia Scale by treatment group. Additional analysis will be performed if deemed 
necessary.  The details will be provided in the SAP.
10.3.2. Safety Analyses
10.3.2.1. Clinical Evaluation of Safety
All investigational products 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 for each treatment 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.  
The number of investigational product-related SAEs will be reported.
Nasal/respiratory and anosmia AEs will be identified using preferred terms and summarized by 
treatment group, the details will be provided in the SAP.


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This section is applicable to spontaneously reported AE.  Events solicited through Nasal and 
Non-nasal Score Questionnaire will be analyzed separately and the details are provided in 
Section 10.3.2.2.
10.3.2.2. Nasal and Non-nasal Score Questionnaire
The scoring for each response to Nasal and Non-nasal Score Questionnaire will follow the scale 
displayed on the questionnaire (‘None’=0, ‘Mild’=1, ‘Moderate’=2, ‘Severe’=3).  The total score 
of the questionnaire will be calculated as the sum of the scores for each question. Descriptive 
statistics will be used to summarize the baseline, various postdose time points, and absolute 
change from baseline in total score of Nasal and Non-nasal Score Questionnaire by treatment 
group.  See Appendix 6 for a copy of the questionnaire. Additional analysis will be performed if 
deemed necessary.  The details will be provided in the SAP.
10.3.2.3. Statistical Evaluation of Safety
Safety parameters will be assessed including safety laboratory parameters, vital signs, and ECG 
parameters.  The parameters will be listed and summarized using standard descriptive statistics.  
Additional analysis will be performed if deemed necessary.  The details will be provided in the 
SAP.
10.3.3. Pharmacokinetic Analyses
10.3.3.1. Pharmacokinetic Parameter Estimation
Pharmacokinetic parameter estimates for glucagon and DPC will be calculated using standard 
noncompartmental methods of analysis (NCA).
The primary parameters for PK analysis will be maximum drug concentration (Cmax), area under 
the concentration versus time curve (AUC), time to maximal concentration (Tmax) of glucagon
and DPC.  Other noncompartmental parameters, such as half-life, apparent clearance, and 
apparent volume of distribution may be reported.
Parameters will be individually calculated for each subject based on actual time of collection.
10.3.3.2. Pharmacokinetic Statistical Inference
Log-transformed PK parameters (such as Cmax and AUC parameters) will be evaluated in a 
linear mixed-effects model with fixed effects for treatment, period, and sequence, and a random 
effect for patient.  The treatment differences will be back-transformed to present the ratios of 
geometric means and the corresponding 90% CI.
The Tmax will be analyzed using the Wilcoxon signed rank test.  Estimates of the median 
difference based on the observed medians, 90% CIs, and p-values from the Wilcoxon test will be 
calculated.
Exploratory analyses may be performed for other PK parameters as deemed appropriate.


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10.3.4. Pharmacodynamic Analyses
10.3.4.1. Pharmacodynamic Parameter Estimation
Pharmacodynamic parameters will be calculated using NCA. Key PD parameters will be derived 
to assess the exposure to glucose and duration of exposure above, below, and within the normal
glucose range. The normal range for PG will be considered to be 70 to 108 mg/dL. Actual 
sampling times will be used for all calculations.
The following PD parameters will be calculated using concentrations of glucose:
AUECabove
area under the effect concentration-time curve above the normal range
AUECbelow
area under the effect concentration-time curve below the normal range
AUECwithin
area under the effect concentration-time curve within the normal range
AUEC0-1.5
area under the effect concentration-time curve from time zero (predose) up 
to 1.5 hours
BGmax
maximal blood glucose
Durationabove
duration above normal range
Durationbelow
duration below normal range
Durationwithin
duration within normal range
tabove
time to concentrations above normal range
tbelow
time to concentrations below normal range (after tabove)
twithin
time to concentrations within normal range
Tmax
time to maximum concentration
The following PD parameters will be calculated using baseline-adjusted concentrations of PG:
AUEC0-1.5
area under the effect concentration-time curve from time zero (predose) up to 
1.5 hours
BGmax
maximal blood glucose
Tmax
time to maximum concentration
Baseline PG concentrations will be calculated from samples obtained immediately prior to 
glucagon dosing (e.g., pre-dose).
Other PD parameters of PG may be calculated if required. Individual concentrations and PD
parameters of PG will be summarized with descriptive statistics by treatment.
10.3.4.2. Pharmacodynamic Statistical Inference
The PD parameters (such as BGmax and AUEC parameters) will be log-transformed prior to 
analysis and a linear mixed-effects model fitted to the data, with treatment, period, and sequence
as fixed effects and patient as a random effect.  For each parameter, the treatment difference will 
be back-transformed to present the ratios of geometric means and the corresponding 90% CI.


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The values of Tmax will be analyzed nonparametrically using the Wilcoxon signed-rank test.  
Median differences and approximate 90% CIs for the difference will be calculated for the 
comparisons of treatments.
Exploratory analyses may be performed for other PD parameters as deemed appropriate.
10.3.5. Pharmacokinetic/Pharmacodynamic Analyses
Exploratory analyses may be performed to evaluate exposure–response relationship if needed.
10.3.6. Data Review during the Study
Trial-level safety review will be conducted during the study by the study team.
10.3.7. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the Lilly clinical pharmacologist, CRP/investigator or designee will consult with the 
appropriate medical director or designee to determine if it is necessary to amend the protocol.
A primary data lock will be conducted after last patient discharge from CRU.  The aim of the 
primary data lock is to enable data analysis to assess the primary/secondary objectives, and may 
include assessment of exploratory objectives.  The primary data lock will include all study data 
up to last patient discharge from CRU.  There will be a final study data lock after all patients 
completed the safety follow-up visit.


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11.
References
Rickels MR, Ruedy KJ, Foster NC, Piché CA, Dulude H, Sherr JL, Tamborlane WV, Bethin KE, 
DiMeglio LA, Wadwa RP, Ahmann AJ, Haller MJ, Nathan BM, Marcovina SM, Rampakakis 
E, Meng L, Beck RW; T1D Exchange Intranasal Glucagon Investigators. Intranasal glucagon 
for treatment of insulin-induced hypoglycemia in adults with type 1 diabetes: a randomized 
crossover noninferiority study. Diabetes Care. 2016;39(2):264-270.


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Appendix 1.
Abbreviations and Definitions


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Term
Definition
AE
adverse event:  Any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product 
that does not necessarily have a causal relationship with this 
treatment.  An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom or disease 
temporally associated with the use of a medicinal (investigational) 
product, whether or not related to the medicinal (investigational) 
product.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AUC
area under the concentration versus time curve
AUEC
area under the effect concentration-time curve
BGmax
maximal blood glucose
CI
confidence interval
Cmax
maximum drug concentration
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 the study-related requirements, GCP requirements,
and the applicable regulatory requirements.
confirmation
A process used to confirm that laboratory test results meet the quality 
requirements defined by the laboratory generating the data and that 
Lilly is confident that results are accurate.  Confirmation will either 
occur immediately after initial testing or will require that samples be 
held to be retested at some defined time points, depending on the 
steps required to obtain confirmed results.
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.
CRU
clinical research unit
DPC
dodecylphosphocholine
ECG
electrocardiogram


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enroll
The act of assigning a patient to a treatment.  Patients who are 
enrolled in the study are those who have been assigned to a 
treatment.
enter
Patients entered into a study are those who sign the informed consent 
form directly or through their legally acceptable representatives.
ERB
ethical review board
FSH
follicle-stimulating hormone
GCP
good clinical practice
HbA1c
hemoglobin A1c
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonization
LC-MS/MS
liquid chromatography with tandem mass spectrometry
IM
intra-muscular
IMG
intra-muscular glucagon
informed consent
A process by which a patient voluntarily confirms his or her 
willingness to participate in a particular study, after having been 
informed of all aspects of the study that are relevant to the patient’s 
decision to participate.  Informed consent is documented by means of
a written, signed, and dated informed consent form.  
investigational product
A pharmaceutical form of an active ingredient or placebo being 
tested or used as a reference in a clinical study, 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.
investigator
A person responsible for the conduct of the clinical study at a study
site.  If a study is conducted by a team of individuals at a study site, 
the investigator is the responsible leader of the team and may be 
called the principal investigator.
IV
intravenous
legal representative
An individual or judicial or other body authorized under applicable 
law to consent, on behalf of a prospective patient, to the patient’s 
participation in the clinical study.
NCA
noncompartmental methods of analysis


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NG
nasal glucagon
non-investigational product
A product that is not being tested or used as a reference in the clinical 
study, but is provided to patients and used in accordance with the 
protocol, such as concomitant or rescue/escape medication for 
preventative, diagnostic, or therapeutic reasons, medication to ensure 
adequate medical care and/or products used to induce a physiological 
response.
open-label
A study in which there are no restrictions on knowledge of treatment 
allocation, therefore the investigator and the study participant are 
aware of the drug therapy received during the study.
PG
plasma glucose
PK/PD
pharmacokinetics/pharmacodynamics
randomize
The process of assigning patients to an experimental group on a 
random basis.
SAE
serious adverse event
SAP
statistical analysis plan
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.
SUSAR
suspected unexpected serious adverse reaction
t1/2
drug half-life
T1DM
type 1 diabetes mellitus
T2DM
type 2 diabetes mellitus
TBL
total bilirubin
TEAE
treatment-emergent adverse event:  Any untoward medical 
occurrence that emerges during a defined treatment period, having 
been absent pretreatment, or worsens relative to the pretreatment 
state, and does not necessarily have to have a causal relationship with 
this treatment.
Tmax
time to maximum concentration
ULN
upper limit of normal


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Appendix 2.
Clinical Laboratory Tests
Laboratory Tests
Hematology
Clinical Chemistry
Hematocrit
Sodium
Hemoglobin
Potassium
Magnesiuma
Erythrocyte count (RBC)
Chloride
Mean cell volume 
Bicarbonate
Mean cell hemoglobin
Glucosed
Mean cell hemoglobin concentration
Blood urea nitrogen (BUN)
Leukocytes (WBC) 
Platelets
Total bilirubin
Differential WBC % of:
Albumin
Neutrophils
Alkaline phosphatase (ALP)
Lymphocytes
Aspartate aminotransferase (AST)
Monocytes
Alanine aminotransferase (ALT)
Eosinophils
Creatinine
Basophils
Phosphorus
HbA1c
Urinalysisb
Other
Specific gravity
Ethanol breath testingc
pH
Urine drug screenc
Leukocyte esterase
Hepatitis B surface antigena
Protein
Hepatitis C antibodya
Glucose
HIVa
Ketones
Pregnancy test (a serum pregnancy test will be done at 
screening, and urine pregnancy tests will be done prior 
to inducing hypoglycemia at the CRU visits in Periods 
1 and 2)
Bilirubin
FSHa for confirmation of postmenopausal status
Urobilinogen
Pharmacogenetics
Blood
Nitrite
Color
Abbreviations:  CRU = clinical research unit; FSH = follicle-stimulating hormone; HIV = human immunodeficiency 
virus; RBC = red blood cell; WBC = white blood cell.
a
Performed at screening only
b
Microscopic examination will be performed only if dipstick test is positive for leukocyte esterase, blood, nitrite,
or protein.
c
Urine drug screen and ethanol level may be repeated prior to admission to the CRU and at other times indicated 
in the Schedule of Activities (Section 2).
d
Random at screening and follow-up visits and fasting procedure visits.


I8R-MC-IGBI(b) Clinical Pharmacology Protocol
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Appendix 3.
Study Governance, Regulatory, and 
Ethical Considerations
Informed Consent
The investigator is responsible for

ensuring that the patient understands the nature of the study, the potential risks and
benefits of participating in the study, and that their participation is voluntary.

ensuring that informed consent is given by each patient or legal representative.  This
includes obtaining the appropriate signatures and dates on the ICF prior to the
performance of any protocol procedures and prior to the administration of investigational
product.

answering any questions the patient may have throughout the study and sharing in a
timely manner any new information that may be relevant to the patient’s willingness to
continue his or her participation in the study.

providing a copy of the ICF to the participant or the participant’s legal representative(s)
and retaining a copy on file.
Recruitment
Lilly or its designee is responsible for the central recruitment strategy for patients.  Individual 
investigators may have additional local requirements or processes.  Study-specific recruitment 
material should be approved by Lilly.
Ethical Review
The investigator or appropriate local representative must give assurance that the ERB was 
properly constituted and convened as required by International Council for Harmonization (ICH)
guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  Lilly or its representatives must approve the ICF 
before it is used at the investigative site(s).  All ICFs must be compliant with the ICH guideline 
on GCP.
The study site’s ERB(s) should be provided with the following:

the current IB and updates during the course of the study

ICF

relevant curricula vitae
Regulatory Considerations
This study will be conducted in accordance with the protocol and with


I8R-MC-IGBI(b) Clinical Pharmacology Protocol
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1) consensus ethics principles derived from international ethics guidelines,
including the Declaration of Helsinki and Council for International
Organizations of Medical Sciences International Ethical Guidelines
2) applicable ICH GCP Guidelines
3) applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third-party organization.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Final Report Signature
The investigator or designee will sign the clinical study report for this study, indicating 
agreement with the analyses, results, and conclusions of the report.
The sponsor’s responsible medical officer and statistician will sign/approve the final clinical 
study report for this study, confirming that, to the best of his or her knowledge, the report 
accurately describes the conduct and results of the study.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate.

provide training to instruct the investigators and study coordinators.  This training will
give instruction on the protocol, the completion of the CRFs, and study procedures.

make periodic visits to the study site.

be available for consultation and stay in contact with the study site personnel through
mail, telephone, and/or fax.

review and evaluate CRF data and/or use standard computer edits to detect errors in data
collection.

conduct a quality review of the database.
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly and/or 
regulatory agencies at any time.  Investigators will be given notice before an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 


I8R-MC-IGBI(b) Clinical Pharmacology Protocol
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applicable regulatory agencies, and applicable ERBs with direct access to the original source 
documents.
Data Collection Tools/Source Data
An electronic data capture system will be used in this study.  The site must define and retain all 
source records and must maintain a record of any data where source data are directly entered into 
the data capture system.
Data Protection
Data systems used for the study will have controls and requirements in accordance with local 
data protection law.
The purpose and use of patient personal information collected will be provided in a written 
document to the patient by the sponsor.
Study and Site Closure
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.


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Appendix 4.
Hepatic Monitoring Tests for Treatment-
Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with Lilly or its designee CRP.  Hepatic 
monitoring tests will be conducted at local laboratory or central laboratory in the case of 
hepatitis E.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin time
WBC
Prothrombin time, INR
Neutrophils
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Conjugated bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear Antibodya
AST
Alkaline Phosphatase Isoenzymesa
GGT
CPK
Anti-smooth Muscle Antibody (or Anti-actin 
Antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized
ratio; RBC = red blood cell; WBC = white blood cell.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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Appendix 5.
Blood Sampling Summary
This 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-IGBI Sampling Summary
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume (mL)
HbA1c
2
2
4
Clinical laboratory testsa
15
4
60
Pharmacokinetics – glucagon
4
27
108
Pharmacokinetics – DPC
4
<11
44
Pharmacodynamics – plasma 
glucose
2
22
44
Exploratory sample
10
2
20
Pharmacogenetics
10
1
10
Bedside plasma glucose 
(SuperGL)
0.5
144 (max)
72
Total
362
Total for clinical purposes 
370
a
Additional samples may be drawn if needed for safety purposes.


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Appendix 6.
Nasal and Non-nasal Score Questionnaire


I8R-MC-IGBI(b) Clinical Pharmacology Protocol
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Nasal and Non-nasal Score Questionnaire
Please select the number that corresponds best to the effects/symptoms you are experiencing at this time, 
or have experienced since last questioning.
0=Not experiencing this (no symptoms at all).
1=Only experiencing a mild case of this and it is easily tolerated.
2=Experiencing a moderate level of this symptom.  It is bothersome but tolerable.
3=Experiencing a severe level of this symptom.  It is hard to tolerate and interferes with your activities.
Symptoms
Scale
0
None
1
Mild
2
Moderate
3 
Severe
1. Runny nose
0
None
1
Mild
2
Moderate
3 
Severe
2. Nasal congestion
(nostrils plugged)
0
None
1
Mild
2
Moderate
3 
Severe
3. Nasal itching
0
None
1
Mild
2
Moderate
3 
Severe
4. Sneezing
0
None
1
Mild
2
Moderate
3 
Severe
5. Watery eyes
0
None
1
Mild
2
Moderate
3 
Severe
6. Itchy eyes
0
None
1
Mild
2
Moderate
3 
Severe
7. Redness of eyes
0
None
1
Mild
2
Moderate
3 
Severe
8. Itching of ears
0
None
1
Mild
2
Moderate
3 
Severe
9. Itching of throat
0
None
1
Mild
2
Moderate
3 
Severe


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Appendix 7.
Edinburgh Hypoglycemia Scale


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Edinburgh Hypoglycemia Scale
Each of the 13 symptoms will have a score of 1 to 7:
1 = not experiencing this (no symptoms at all).
2 = only experiencing a very mild case of this and it is easily tolerated.
3 = only experiencing a mild case of this and it is tolerated.
4 = experiencing a mild to moderate case of this and it is tolerated.
5 = experiencing a moderate case of this and it is tolerated.
6 = experiencing a moderate to severe level of this symptom. It is bothersome but tolerable.
7 = experiencing a severe level of this symptom. It is hard to tolerate. 
Neuroglycopenic symptoms
Cognitive dysfunction
Inability to 
concentrate:
1

2

3

4

5

6

7

No symptom
mild to moderate 
symptom
severe 
symptom
Blurred vision:
1

2

3

4

5

6

7

No symptom
mild to moderate 
symptom
severe 
symptom
Anxiety:
1

2

3

4

5

6

7

No symptom
mild to moderate 
symptom
severe 
symptom
Confusion:
1

2

3

4

5

6

7

No symptom
mild to moderate 
symptom
severe 
symptom
Difficulty speaking:
1

2

3

4

5

6

7

No symptom
mild to moderate 
symptom
severe 
symptom
Double vision:
1

2

3

4

5

6

7

No symptom
mild to moderate 
symptom
severe 
symptom


I8R-MC-IGBI(b) Clinical Pharmacology Protocol
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Neuroglycopenia
Drowsiness:
1

2

3

4

5

6

7

No symptom
mild to moderate 
symptom
severe 
symptom
Tiredness:
1

2

3

4

5

6

7

No symptom
mild to moderate 
symptom
severe 
symptom
Hunger:
1

2

3

4

5

6

7

No symptom
mild to moderate 
symptom
severe 
symptom
Weakness:
1

2

3

4

5

6

7

No symptom
mild to moderate 
symptom
severe 
symptom
Autonomic symptoms
Sweating:
1

2

3

4

5

6

7

No symptom
mild to moderate 
symptom
severe 
symptom
Trembling:
1

2

3

4

5

6

7

No symptom
mild to moderate 
symptom
severe 
symptom
Warmness:
1

2

3

4

5

6

7

No symptom
mild to moderate 
symptom
severe 
symptom


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Appendix 8.
Clarke Hypoglycemia Awareness Survey


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Clarke Hypoglycemia Awareness Survey
Check the category that best describes you: (check one only) 
I always have symptoms when my blood sugar is low
A
I sometime have symptoms when my blood sugar is low
R
I no longer have symptoms when my blood sugar is low
R
2. Have you lost some of the symptoms that used to occur when your blood sugar was low:
Yes
R
No
A
3. In the past six months, how often have you had moderate hypoglycemia episodes? (Episodes 
where you might feel confused, disoriented or lethargic and were unable to treat yourself)
Never
A
Once or twice
R
Every other month
R
Every month
R
More than once a month
R
4. In the past year, how often have you had severe hypoglycemic episodes? (Episodes where 
you were unconscious or had a seizure and needed glucagon or intravenous glucose)
Never
A
5 times
R
10 times
R
1 time
R
6 times
R
11 times
R
2 times
R
7 times
R
12 times 
or more
R
3 times
R
8 times
R
4 times
R
9 times
R


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5. How often in the last month have you had readings <70 mg/dL (3.9 mmol/L) with 
symptoms?
Never
1 time/week
4 to 5 
times/week
1 to 3 times
2 to 3 
times/week
Almost daily
6. How often in the last month have you had readings <70 mg/dL (3.9 mmol/L) without 
symptoms?
Never
1 time/week
4 to 5 
times/week
1 to 3 times
2 to 3 
times/week
Almost daily
If answer to question 5 < answer to question 6
R
If answer to question 6 < answer to question 5
A
7. How low does your blood sugar need to go before you feel symptoms?
60-69 mg/dL;
3.3-3.8 mmol/L
A
50-59 mg/dL;
2.8-3.3 mmol/L
R
40-49 mg/dL;
2.2-2.7 mmol/L
R
Less than 40 mg/dL;
less than 2.2 mmol/L
R
8. To what extent can you tell by your symptoms that your blood sugar is low?
Never
R
Rarely
R
Sometimes
R
Often
A
Always
A
Abbreviations: A = aware; R = reduced awareness. 
Final Score: Total Number of “R” responses. Reduced awareness = 4 or more reduced responses; 
Intermediate = 3 reduced responses; Aware = 2 or fewer reduced responses.


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Appendix 9.
Protocol Amendment I8R-MC-IGBI(b)
Summary: Comparison of Glucagon Administered by 
Either the Nasal (LY900018) or Intra-muscular 
(GlucaGen®) Routes in Adult Patients with Type 1 
Diabetes Mellitus During Controlled Insulin-Induced 
Hypoglycemia
Overview
Protocol I8R-MC-IGBI, Comparison of Glucagon Administered by Either the Nasal (LY900018) 
or Intra-muscular (GlucaGen®) Routes in Adult Patients with Type 1 Diabetes Mellitus During 
Controlled Insulin-Induced Hypoglycemia, has been amended.  The new protocol is indicated by 
Amendment (b) and will be used to conduct the study in place of any preceding version of the 
protocol.
The amendment is in response to regulatory feedback.  The overall changes made to this protocol 
are as follows:

In Section 6.2 (Exclusion Criteria), criterion [23] was revised to exclude patients with 
current stable psychiatric disorders.

In Section 9.2.3 (Procedures for Insufficient Response to Glucagon Administration), text 
was added to clarify that continuous venous access will be used to enable immediate 
delivery of glucose to patients if needed.

In Section 9.3 (Adverse Events), text was added to clarify that all AEs will be 
documented, not just those deemed to have a causal relationship with the investigational 
product or those that are severe or medically important.  In addition, text was added to 
clarify that the follow-up for all AEs should not be interrupted, even if there is a 
reasonable explanation for the event.
Additional clarifications were made to the bedside glucose safety measurement thresholds. 


I8R-MC-IGBI(b) Clinical Pharmacology Protocol
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Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.


I8R-MC-IGBI(b) Clinical Pharmacology Protocol
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Schedule of Activities
Procedure
Screening
Visit 
Period 1 and 
Period 2 
CRU Visits
Follow-up
(or ED)
Visit
Comments
Up to 28
days before 
Period 1
Day 1
28(+2) 
days after 
last dose of 
study drug
Bedside glucose safety 
measurements 
(SuperGL laboratory 
analyzer)
X
Samples will be collected throughout the study procedure. During the hypoglycemia 
induction procedure, plasma glucose concentration will be measured no more than 10 
minutes apart while the plasma glucose concentration is > ≥100 mg/dL and no more than 
5 minutes apart when the plasma glucose concentration is <100 mg/dL.  Post-glucagon 
administration, plasma glucose concentration will be measured every 5 minutes for the 
first 30 minutes and every 10 minutes up to 90 minutes.


I8R-MC-IGBI(b) Clinical Pharmacology Protocol
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6.2. Exclusion Criteria
[23]
have a significant history of or current psychiatric disorders.  However, 
patients may be included if the disease is stable and patient is receiving 
treatment
9.2.3. Procedures for Insufficient Response to Glucagon 
Administration
If the PG is declining too fast or symptoms become consistent for the progression to severe
hypoglycemia to occur, the investigator may decide to start a glucose infusion to prevent a 
deterioration of the situation.  Continuous venous access will be used while the patient resides in 
the CRU to enable immediate delivery of IV glucose if needed.  If, following the administration 
of glucagon, a patient’s PG concentration remains <55 mg/dL at 30 minutes or <60 mg/dL at 45
minutes, IV glucose may be given as appropriate to the clinical situation.  If IV glucose is given 
or additional glucagon is given, any remaining blood samples for the admission will still be 
collected. 
9.3. Adverse Events
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the patient to discontinue the investigational product before 
completing the study. All AEs will be followed until restoration or until a stable condition has 
been achieved. The patient should be followed until the event resolves, stabilizes with 
appropriate diagnostic evaluation, or is reasonably explained. The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator. The follow-up should not be 
interrupted, even if there is a reasonable explanation for the event.


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SAP_001.pdf: 
Statistical Analysis Plan Version 1 I8R-MC-IGBI 
Comparison of Glucagon Administered by Either the Nasal(LY900018) or Intra-muscular 
(GlucaGen®) Routes in Adult Patients with Type 1 Diabetes Mellitus During Controlled 
Insulin-Induced Hypoglycemia 
NCT03339453 
Approval Date: 22-Sep-2017 


I8R-MC-IGBI Statistical Analysis Plan Version 1
Page 1
LY900018
1.
Statistical Analysis Plan
I8R-MC-IGBI:  Comparison of Glucagon Administered by 
Either the Nasal (LY900018) or Intra-muscular 
(GlucaGen®) Routes in Adult Patients with Type 1 
Diabetes Mellitus During Controlled Insulin-Induced 
Hypoglycemia
Confidential Information
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of 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.
Glucagon nasal powder (LY900018) for Severe Hypoglycemia
Study I8R-MC-IGBI is a multicenter, randomized, open-label, 2-treatment, 2-period, 
crossover study conducted in adult patients with type 1 diabetes mellitus.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol I8R-MC-IGBI
Phase 1
Statistical Analysis Plan electronically signed and approved by Lilly on date provided 
below.
Approval Date: 22-Sep-2017 GMT


I8R-MC-IGBI Statistical Analysis Plan Version 1
Page 2
LY900018
2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan I8R-MC-IGBI:  Comparison of Glucagon 
Administered by Either the Nasal (LY900018) or Intra-muscular 
(GlucaGen®) Routes in Adult Patients with Type 1 Diabetes Mellitus 
During Controlled Insulin-Induced Hypoglycemia ..............................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................5
4.
Study Objectives.................................................................................................................6
4.1.
Primary Objective ..........................................................................................................6
4.2.
Secondary Objectives.....................................................................................................6
4.3.
Exploratory Objectives...................................................................................................6
5.
A Priori Statistical Methods ................................................................................................7
5.1.
Sample Size Determination ............................................................................................7
5.2.
General Considerations ..................................................................................................7
5.3.
Patient Disposition .........................................................................................................8
5.4.
Patient Characteristics ....................................................................................................8
5.5.
Concomitant Therapy.....................................................................................................8
5.6.
Treatment Compliance ...................................................................................................9
5.7.
Important Protocol Deviations........................................................................................9
5.8.
Primary Outcome and Methodology...............................................................................9
5.8.1.
Additional Analyses Related to Primary Efficacy Outcome..................................10
5.9.
Secondary Efficacy Outcomes and Analyses ................................................................11
5.9.1.
Plasma Glucose Values ........................................................................................11
5.9.2.
Symptoms of Hypoglycemia ................................................................................12
5.10. Safety Analyses............................................................................................................13
5.10.1.
Adverse Event......................................................................................................13
5.10.2.
Nasal and Non-Nasal Score Questionnaire ...........................................................14
5.10.3.
Vital Signs ...........................................................................................................14
5.10.4.
Other Safety Evaluations......................................................................................15
5.11. Pharmacokinetic Analyses............................................................................................15
5.11.1.
Pharmacokinetic Parameter Estimation ................................................................15
5.11.2.
Pharmacokinetic Statistical Inference...................................................................18
5.12. Pharmacodynamic Analyses.........................................................................................18
5.12.1.
Pharmacodynamic Parameter Estimation..............................................................18
5.12.2.
Pharmacodynamic Statistical Inference ................................................................19
5.13. Pharmacokinetic/Pharmacodynamic Analyses..............................................................20


I8R-MC-IGBI Statistical Analysis Plan Version 1
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LY900018
5.14. Exploratory Objectives Analyses..................................................................................20
5.14.1.
PK Profile of DPC................................................................................................20
5.14.2.
Symptoms of Hypoglycemia ................................................................................20
5.14.3.
Clarke Hypoglycemia Awareness.........................................................................20
5.15. Interim Analyses ..........................................................................................................20
6.
Unblinding Plan................................................................................................................22
7.
References ........................................................................................................................23
8.
Appendices .......................................................................................................................24


I8R-MC-IGBI Statistical Analysis Plan Version 1
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Table of Contents
Appendix
Page
Appendix 1.
Definitions of Nasal/Respiratory/Anosmia AEs ..............................................25


I8R-MC-IGBI Statistical Analysis Plan Version 1
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3.
Revision History
This is the first version of the Statistical Analysis Plan (SAP) for Study I8R-MC-IGBI (IGBI). 


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4.
Study Objectives
4.1.
Primary Objective
To compare LY900018 (nasal glucagon [NG]) versus GlucaGen® (intramuscular glucagon 
[IMG]) in the percentage of adult patients with type 1 diabetes mellitus who achieve treatment 
success during controlled insulin-induced hypoglycemia.
4.2.
Secondary Objectives

To assess the safety and tolerability of LY900018 versus GlucaGen

To characterize the pharmacodynamic (PD) profiles of LY900018 versus GlucaGen

To characterize the pharmacokinetic (PK) profiles of LY900018 versus GlucaGen
4.3.
Exploratory Objectives

To characterize the PK profile of the dodecylphosphocholine (DPC) excipient of 
LY900018

To assess the occurrence and severity of hypoglycemia symptoms during controlled 
insulin-induced hypoglycemia

To assess the awareness of hypoglycemia prior to its induction


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5.
A Priori Statistical Methods
5.1.
Sample Size Determination
Assuming a 5% dropout rate, the study will enroll approximately 70 patients to get 66 patients 
completing both treatment visits with evaluable primary outcome. 
A total of 66 patients are required in the study in order to achieve the primary objective with at 
least 90% power using the following assumptions:

A treatment success rate of 98% for both treatments

A noninferiority margin of 10%

Two-sided alpha level of 0.05

A within-patient correlation of zero between 2 treatment visits
5.2.
General Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly and Company (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 (CSR).  Additional exploratory analyses will be 
conducted, as deemed appropriate.
All data will be entered, verified, and archived at a contract research organization (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.
Five patient populations are defined for the analysis of this study:
1). All Entered Set Population (AES):  All patients who sign inform consent and enter in this 
study
2). All Randomized Set Population (ARS):  All patients who are randomized to study 
treatments 
3). Full Analysis Set Population (FAS):  All randomized patients who receive at least 1 dose 
of study drug 
4). Efficacy Analysis Set Population (EAS): Patients in the FAS and have evaluable primary 
efficacy outcome
5). PK/PD Population:  Patients in the FAS and have evaluable PK/PD.
Unless otherwise specified, efficacy analyses related to primary efficacy outcome will be 
conducted on data from EAS; other efficacy analyses and all safety analyses will be conducted 
on data from FAS; PK/PD analyses will be conducted on data from PK/PD population.  
Unless otherwise specified, baseline is the last nonmissing value collected prior to study drug 
administration.


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Summary statistics will include number of patients, mean, standard deviation (SD), minimum 
(and/or 1st quartile), maximum (and/or 3rd quartile), and median.
All analyses will be based on the treatment patients actually received (if different from assigned 
treatment).  Unless otherwise specified, all tests of statistical significance for treatment group 
comparisons (NG vs IMG) will be evaluated at a nominal level of 0.05 using 2-tailed test 
procedures and confidence intervals (CIs) will be computed as 2-tailed using a 95% significance 
level.  All tests of interactions between treatment groups and other covariates will be conducted 
at a 2-sided with alpha level of 0.10.  SAS version 9.2 or higher will be used to perform the 
analysis.
5.3.
Patient Disposition 
Proportion of patients discontinued from study and reasons for discontinuation will be 
summarized by treatment group for the ARS.
The primary reasons for discontinuation will be listed for the AES.
5.4.
Patient Characteristics
Patient baseline characteristics and demographics will be obtained at entry and will be 
summarized for the ARS.
The following baseline parameters will be included in (but are not limited to) the summary 
report:

Age (years),

Gender (Male, Female),

Race (White, American Indian or Alaska Native, Asian, Black or African American, 
Native Hawaiian or Other Pacific Islander),

Ethnicity (Hispanic, Non-Hispanic),

Body weight (kilograms),

Height (centimeters),

Body mass index (BMI) (kilograms per meters squared),

Duration of diabetes (years),

Baseline HbA1c value (%),

Baseline Clarke Hypoglycemia Awareness status (%) (Aware, Intermediate, Reduced 
awareness, as defined in Study IGBI Protocol, Appendix 8)

Baseline substance use (alcohol) 
5.5.
Concomitant Therapy
A listing and summary of concomitant medications will be provided for the ARS. Concomitant 
medication will be coded using the World Health Organization (WHO) drug dictionary
Enhanced B2 format Version March 2017.


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A listing of rescue therapy will be provided for the ARS.  The listing will include, but not be 
limited to, patient ID, treatment group, rescue therapy date/time, and rescue therapy name/dose.
5.6.
Treatment Compliance
No specific study data will be collected for analysis of treatment compliance.
5.7.
Important Protocol Deviations
Important protocol deviations (IPDs) are defined as deviations from the study protocol that may
significantly compromise the data integrity and patients’ safety.  The details of identification of 
IPDs is provided in a separate document (ie, the trial issue management plan).  A listing and/or
summary of IPDs will be provided by the study manager after primary outcome database lock.
5.8.
Primary Outcome and Methodology
The primary outcome is the treatment success, which is defined as an increase in plasma glucose 
(PG) to ≥70 mg/dL or an increase of ≥20 mg/dL from PG nadir within 30 minutes after receiving 
glucagon, without receiving additional actions to increase the PG concentration.  The nadir is 
defined as the minimum PG concentration at the time of or within 10 minutes following 
glucagon administration.
The primary analysis will be a treatment group comparison of the primary outcome in the EAS.  
The percentage of patients achieving treatment success in each treatment group and the 
difference in percentages will be computed.  A 2-sided 95% CI will be obtained from the 
1-sample mean of the paired differences in primary outcome (1 = outcome observed; 
0 = outcome not observed) across 2 treatment visits.  Noninferiority of NG will be declared if the 
upper limit of a 2-sided 95% CI constructed on the difference in percentages (IMG minus NG) is 
less than the noninferiority margin of 10%.  Specifically, for each patient, the paired difference 
of treatment success between IMG and NG will be calculated and PROC TTEST will be used to 
create the 95% CI of the mean difference.
The proposed noninferiority margin of 10% has been chosen based on the previously completed 
Phase 3 study (Rickels et al. 2016).
Primary efficacy analysis will only include patients who complete both treatment visits with 
evaluable primary outcome.  The following will be considered as nonevaluable primary efficacy 
outcome and excluded from the analysis related to primary efficacy outcome: 

Patients with at least 1 treatment visit in which the nadir PG is ≥70 mg/dL;

Patients receiving an external measure to raise PG concentration either before glucagon 
administration or within the first 10 minutes after glucagon administration.
Plasma glucose concentrations assessed through a central laboratory will be used to assess 
treatment success.  If a central laboratory measurement is missing, the SuperGL (or equivalent) 
measurement from that time point will be used in general with the following additional 
provisions:


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
Out-of-window blood draws (blood draws taken before/after the midpoint between 
consecutive planned measurements) that occur prior to the 30-minute time point will be 
included.

Central laboratory PG concentrations and SuperGL (or equivalent) concentrations at the 
30-minute time point that are measured more than 35 minutes after administration of 
glucagon will be considered missing.

If a PG concentration is missing for both central laboratory and SuperGL (or equivalent) 
measurements, the missing value will be imputed using linear interpolation of central 
laboratory values.
5.8.1. Additional Analyses Related to Primary Efficacy Outcome
For each of the following populations, the proportion of patients achieving treatment success will 
be summarized for each treatment group and compared using the same method as for the primary 
efficacy analysis specified above.

ARS

Patients in EAS population with nadir glucose is <50 mg/dL on both treatment visits.
Among patients who achieve treatment success, the proportion of patients achieving (1) an 
increase in glucose to ≥70 mg/dL, or (2) an increase of ≥20 mg/dL from nadir, or (3) an increase 
in glucose to ≥70 mg/dL and an increase of ≥20 mg/dL from nadir will be summarized for each 
treatment group and compared using the same method as for the primary efficacy analysis
specified above for all 3 populations (ie, EAS, ARS, and EAS with nadir <50mg/dL on both 
treatment visits).
As an additional sensitivity analysis, in the EAS population, the primary efficacy outcome will 
be assessed by comparing the upper limit of a 2-sided 95% CI on the difference in proportions 
obtained from a Poisson regression model using the binary primary outcome, accounting for the 
correlation due to the cross-over design using a generalized estimating equation.  The model will 
include adjustments for nadir glucose level and treatment period.  
Below is the example SAS code computing the treatment difference in proportion of patients 
achieving treatment success and 95% CI using the Poisson regression model:
proc genmod data=a;
  class visit treatment patient;
  model success = treatment visit nadir / dist=poisson link=identity;
  repeated subject=patient / type=un;
  estimate 'success' treatment 1 -1;
  lsmeans treatment / diff cl om;
run;
The time from study drug administration to achieve treatment success will be summarized.  A 
Kaplan-Meier (KM) analysis will be used to analyze the time from study drug administration to 
achieve treatment success.  If both components of the treatment success (ie, an increase in 


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glucose to ≥70 mg/dL and an increase of ≥20 mg/dL), are achieved for a patient, the earlier time 
point will be used. If a patient receives an external measure to raise glucose at any point, right 
censoring will be used.  A treatment group comparison of the time to achieve treatment success 
will be performed using Cox proportional hazard models accounting for the correlation due to 
the crossover design, adjusted for baseline glucose value and treatment period.  Due to the 
discrete time data (5-, 10-, or 30-minute intervals), the exact method will be used.  This method 
averages the Cox proportional hazards likelihood over all possible orderings of tied event times.  
In addition, time to achieving either an increase in glucose to ≥70 mg/dL or an increase of 
≥20 mg/dL from nadir will also be analyzed, separately, using the KM estimator of the survival 
function.  
Below is the example SAS code creating KM life table and curve by treatment group: 
proc lifetest data=b plots=(s) outsurv=kmtable;
  time minutes*censor(1);
  strata treatment;
run;
Below is the example SAS code using proportional hazard model:
proc phreg data=b covs(aggregate);
  id patient;
  class treatment visit;
  model minutes*censor(1)= treatment visit nadir / ties=exact;
run;
For the time to event analysis, if a patient receives additional intervention treatment to raise 
glucose prior to achieving a glucose value ≥70 mg/dL or an increase of ≥20 mg/dL from nadir, 
the remaining time points will be considered as non-events (ie, glucose is not ≥70 mg/dL and 
does not increase ≥20 mg/dL from nadir). 
The time to treatment success analysis will also be repeated in EAS patients with nadir glucose 
value <50 mg/dL.
A complete by-patient listing of primary efficacy data will be created.
5.9.
Secondary Efficacy Outcomes and Analyses
5.9.1. Plasma Glucose Values
Descriptive statistics will be used to summarize the baseline, various postdose time points (15, 
30, 45, 60, and 90 minutes post glucagon administration), and absolute change from baseline in 
PG values by treatment group for the FAS.  
If a patient receives additional intervention to raise PG concentrations, measurements taken after 
the time of intervention will be excluded from the analysis.
For this analysis, baseline is defined as the last nonmissing PG measured at the time of or 
immediately prior to glucagon administration at each treatment visit.  A treatment comparison of 
glucose over the 90 minutes following administration of glucagon will be completed using a 


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linear mixed model with repeated measures (MMRM) that accounts for the correlation due to the 
crossover design and the correlation due to multiple measures.  The baseline score, treatment 
period, and time points will be included as covariates in the model.  Least-square means and 
2-sided 95% confidence limits will be calculated for the difference in PG between treatment 
groups (IMG minus NG) at each time point.  
In the MMRM model, the within-patient errors are modeled as an unstructured variance-
covariance matrix.  If the analysis fails to converge, the following variance-covariance matrix 
will be used (in the order listed) until one converges: 
1. Heterogeneous Toeplitz (TOEPH)
2. Heterogeneous First-order Autoregressive (ARH[1])
3. Heterogeneous Compound Symmetry (CSH)
4. Toeplitz (TOEP)
5. First-order Autoregressive (AR[1])
6. Compound Symmetry (CS)
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom for 
the MMRM models.
Below is the example SAS code performing the MMRM analysis:
proc mixed data=c;
  class  patient time visit treatment;
  model value = treatment time visit baseline /solution ddfm=kr;
  repeated time(visit)/subject=patient type=un;
  lsmeans treatment*time/cl diff om;
run;
5.9.2. Symptoms of Hypoglycemia
Descriptive statistics will be used to summarize the baseline, various postdose time points (15, 
30, 45, and 60 minutes post glucagon administration), and absolute change from baseline in total 
score and each subscale score of Edinburgh Hypoglycemia Scale by treatment group for the 
ARS. 
If a patient receives rescue treatment to raise PG concentrations, measurements taken after the 
rescue will be excluded from the analysis.
For this analysis, baseline is defined as the last nonmissing score collected prior to glucagon 
administration at each treatment visit.
The total score and subscale scores will be compared between treatment groups through a linear 
MMRM accounting for the correlation due to the crossover design and the correlation due to 
multiple measures of the questionnaire.  The MMRM analysis of hypoglycemia symptom score
will be performed using the similar approach as specified in Section 5.9.1.


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5.10. Safety Analyses
5.10.1. Adverse Event
This section is applicable to spontaneously reported adverse events (AEs).  Events solicited 
through Nasal and Non-Nasal Score Questionnaire will be analyzed separately, and details are
provided in Section 5.10.2.
All investigational products and protocol procedure AEs will be listed.
The number of investigational product-related SAEs will be reported.
The summary/figure/listing related to AEs will be created using Medical Dictionary for 
Regulatory Activities (MedDRA) version 18.1.
Where changes in severity are recorded in the case report form, each separate severity of the AE 
will be reported in the listings; only the most severe will be used in the summary tables. A 
preexisting condition is defined as an AE that starts before the patient has provided written 
informed consent and is ongoing at the time of giving consent. A non-treatment-emergent AE is 
defined as an AE that starts after informed consent but prior to dosing. A treatment-emergent 
AE (TEAE) is defined as an AE that occurs postdose or that is present prior to dosing and 
becomes more severe postdose. For AEs with missing severity, the severity will be imputed as 
either mild (if collected prior to study drug administration) or severe (if collected post study drug 
administration).  If an AE occurs or worsens after the glucagon administration of the first
treatment visit but prior to the glucagon administration of the second treatment visit, it will be 
counted as a TEAE of the first treatment.  
Treatment-emergent AEs will be summarized by treatment, 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 for each preferred term within each 
System Organ Class will be summarized by treatment. The summary and frequency AE tables 
will be presented for all causalities and those considered related to the study drug. In these 
analyses, patients experiencing the same AE multiple times will be counted once under each 
specific treatment for the corresponding preferred term and body system.
The following will also be presented by treatment group:

The number and proportion of patients who experienced at least 1 TEAE, serious AE, 
TEAE related to study drug (or study device), died, or discontinued from the study due to 
an AE.
Nasal/respiratory/anosmia AEs will be identified using MedDRA preferred term (see Appendix 1
for the list of preferred terms) and summarized by treatment group. The frequency (the number 
of AEs, the number of patients experiencing an AE, and the percentage of patients experiencing 
an AE) of nasal/respiratory/anosmia TEAEs for each preferred term will be summarized by 
treatment.


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The time needed for resolution of nasal/respiratory/anosmia AEs will be calculated based on the 
start and end date/time reported by the investigator and summarized using descriptive statistics.  
Events that did not resolve will be excluded from calculation of the time to resolution.  This 
analysis will include all AEs (ie, patients experiencing AEs with the same preferred term at 
different time points will be counted multiple times).
Kaplan-Meier curve for each treatment will be produced for time to resolution of 
nasal/respiratory/anosmia AEs.  If the event did not resolve during the study, then it will be 
treated as censored observation at the end of the study.
5.10.2. Nasal and Non-Nasal Score Questionnaire
The scoring for each response to the Nasal and Non-Nasal Score Questionnaire will follow the 
scale displayed on the questionnaire (‘None’=0, ‘Mild’=1, ‘Moderate’=2, ‘Severe’=3).  The total 
score of the questionnaire will be calculated as the sum of the scores for each question. 
Descriptive statistics will be used to summarize the baseline, various postdose time points (15, 
30, 60, and 90 minutes), and absolute change from baseline in total score of Nasal and Non-
Nasal Score Questionnaire by treatment group.  
For this analysis, baseline is defined as the score measured prior to glucagon administration at 
each treatment visit.
The total score will be compared between treatment groups through a linear MMRM that 
accounts for the correlation due to the crossover design and the correlation due to repeated 
measures of the questionnaire.  The MMRM analysis of nasal symptom score will be performed 
using the similar approach as specified in Section 5.9.1.
The number and proportion of patients within each score categories of each question in the Nasal 
and Non-Nasal Score Questionnaire in increasing severity (none, mild, moderate, and severe) at 
each time point and shift of categories from baseline to maximal (and last) postdose severity 
category will be provided by treatment group.
5.10.3. Vital Signs
The vital signs (diastolic blood pressure [DBP], systolic blood pressure [SBP], pulse, and body 
temperature) collected at both pre- and 45 minutes post-glucagon administration at the treatment 
visit will be summarized by treatment group using descriptive statistics. 
The shift of abnormalities of DBP, SBP, and pulse from baseline to post treatment will also be 
summarized by treatment group.  For this shift analysis, the high limit is 140 mm Hg for SBP, 
90 mm Hg for DBP, and 100 bpm for pulse; the low limit is 90 mm Hg for SBP, 50 mm Hg for 
DBP, and 50 bpm for pulse.
All abnormal vital sign findings during the study (including screening, pre- and post- glucagon 
administration at each treatment, and poststudy follow-up) will be listed. 
Additional analysis will be performed if warranted upon review of the data.


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5.10.4. Other Safety Evaluations
Abnormal safety laboratory findings will be listed. 
Clinically significant abnormal findings through electrocardiograms, nasal inspection, injection 
site inspection, and physical examination will be captured as AEs (Section 5.10.1).
5.11. Pharmacokinetic Analyses
5.11.1. Pharmacokinetic Parameter Estimation
Patients who receive glucagon treatment and have measurable glucagon concentrations will be 
included in the PK analysis. The PK parameter estimates will be calculated by standard 
noncompartmental methods of analysis using validated software program (Phoenix WinNonlin 
Version 6.4.1 or later). 
Plasma concentrations of glucagon will be used to determine the following PK parameters, when 
possible: 
Parameter
Units
Definition
AUC(0-tlast)
pg.h/mL
Area under the concentration vs time curve from time zero to time 
t, where t is the last time point with a measurable concentration
AUC(0-∞)
pg.h/mL
Area under the concentration vs time curve from zero to infinity
%AUC(tlast-)
%
Percentage of AUC(0-∞) extrapolated
Cmax
pg/mL
Maximum observed drug concentration
tmax
h
Time of maximum observed drug concentration
t1/2
h
Half-life associated with the terminal rate constant (λz) in 
noncompartmental analysis
CL/F
L/h
Apparent total body clearance of drug calculated after 
extravascular administration
Vz/F
L
Apparent volume of distribution during the terminal phase after 
extravascular administration
Vss/F
L
Apparent volume of distribution at steady state after extravascular 
administration
An alternative AUC measure, such as AUC to a common time point, may be calculated if 
AUC(0-∞) cannot be reliably calculated.
The following PK parameters will also be calculated using baseline-adjusted (ie, change from 
baseline) concentrations of glucagon: AUC, Cmax, and tmax.  
Baseline glucagon concentrations will be concentrations from samples obtained immediately 
prior to glucagon dosing (ie, predose). Any resulting negative concentrations will be considered 
below the lower limit of quantitation (BQL) for the purposes of treatment within PK analysis 
(see BQL handling in subsequent subsections).


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Additional PK parameters may be calculated, as appropriate.  The software and version used for 
the final analyses will be specified in the CSR. Any exceptions or special handling of data will 
be clearly documented within the final study report.
Formatting of tables, figures, and abbreviations will follow the Eli Lilly Global PK/PD/TS Tool: 
Non-Compartmental Pharmacokinetic Style Guide. The version of the tool effective at the time 
of PK analysis will be followed.
General PK Parameter Rules

Actual sampling times will be used in the final analyses of individual PK parameters, 
except for nonbolus predose sampling times, which will be set to zero.

Cmax and tmax will be reported from observed values.  If Cmax occurs at more than 1 time 
point, tmax will be assigned to the first occurrence of Cmax. 

AUC parameters will be calculated using a combination of the linear and logarithmic 
trapezoidal methods (linear-log trapezoidal rule).  The linear trapezoidal method will be 
applied up to tmax and then the logarithmic trapezoidal method will be used after tmax.  
The minimum requirement for the calculation of AUC will be the inclusion of at least 3
consecutive plasma concentrations above the lower limit of quantification, with at least 
one of these concentrations following Cmax.  AUC(0-) values where the percentage of 
the total area extrapolated is more than 20% will be flagged.  Any AUC(0-) value 
excluded from summary statistics will be noted in the footnote of the summary table.

Half-life (t½) will be calculated, when appropriate, based on the apparent terminal log-
linear portion of the concentration-time curve.  The start of the terminal elimination phase 
for each subject will be defined by visual inspection and generally will be the first point 
at which there is no systematic deviation from the log-linear decline in plasma 
concentrations.  The t½ will only be calculated when a reliable estimate for this parameter 
can be obtained comprising of at least 3 data points.  If t½ is estimated over a time 
window of less than 2 half-lives, the values will be flagged in the data listings.  Any t½
value excluded from summary statistics will be documented in the footnote of the 
summary table. 

A uniform weighting scheme will be used in the regression analysis of the terminal log-
linear portion of the concentration-time curve.

The parameters based on observed last quantifiable drug concentration (Clast) will be 
reported.
Individual PK Parameter Rules

Only quantifiable concentrations will be used to calculate PK parameters with the 
exception of special handling of certain concentrations reported BQL.  Plasma 
concentrations reported as BQL will be set to a value of zero when all of the following 
conditions are met: 
o
The samples are from the initial dose period for a subject or from a subsequent dose 
period following a suitable washout period.
o
The time points occur before the first quantifiable concentration.


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
All other BQL concentrations that do not meet the above criteria will be set to missing. 

In addition, where 2 or more consecutive concentrations are BQL toward the end of a 
profile, the profile will be deemed to have terminated; therefore, any further quantifiable 
concentrations will be set to missing for the calculation of the PK parameters unless it is 
considered to be a true characteristic of the profile of the drug.
Individual Concentration versus Time Profiles

Individual concentrations will be plotted utilizing actual sampling times.

The terminal point selections will be indicated on a semilogarithmic plot.
Average Concentration versus Time Profiles

The average concentration profiles will be graphed using scheduled (nominal) sampling 
times. 

The average concentration profiles will be graphed using arithmetic average 
concentrations.

Quantifiable concentrations will be used to calculate average concentrations, including 
predose concentrations.

Concentrations at a sampling time exceeding the sampling time window specified in the 
protocol, or ±10%, will be excluded from the average concentration profiles.

Concentrations excluded from the mean calculation will be documented in the final study 
report.

A concentration average will be plotted for a given sampling time only if 2/3 of the 
individual data at the time point have quantifiable measurements that are within the 
sampling time window specified in the protocol or ±10%. An average concentration 
estimated with less than 2/3 but more than 3 data points may be displayed on the mean 
concentration plot if determined to be appropriate and will be documented within the 
final study report.
Treatment of Outliers during Pharmacokinetic Analysis
Application of this procedure to all PK analyses is not a requirement.  Rather, this procedure 
provides justification for exclusion of data when scientifically appropriate.  This procedure 
describes the methodology for identifying an individual value as an outlier for potential 
exclusion, but does not require that the value be excluded from analysis.  The following 
methodology will not be used to exclude complete profiles from analysis.
Data within an Individual Profile
A value within an individual profile may be excluded from analysis if any of the following 
criteria are met:

For PK profiles during multiple dosing, the concentration of the predose sample exceeds 
all measured concentrations for that individual in the subsequent postdose samples.

For PK profiles during single dosing of nonendogenous compounds, the concentration in 
a predose sample is quantifiable.


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
For any questionable datum that does not satisfy the above criteria, the profile will be 
evaluated and results reported with and without the suspected datum. 
Data between Individual Profiles
1. If n<6, then the dataset is too small to conduct a reliable range test.  Data will be analyzed 
with and without the atypical value, and both sets of results will be reported.  
2. If n6, then an objective outlier test will be used to compare the atypical value to other 
values included in that calculation:
a.
Transform all values in the calculation to the logarithmic domain.
b. Find the most extreme value from the arithmetic mean of the log transformed values 
and exclude that value from the dataset.
c.
Calculate the lower and upper bounds of the range defined by the arithmetic mean 
±3*SD of the remaining log-transformed values.
d. If the extreme value is within the range of arithmetic mean ±3*SD, then it is not an 
outlier and will be retained in the dataset.
e.
If the extreme value is outside the range of arithmetic mean ±3*SD, then it is an 
outlier and will be excluded from analysis.
If the remaining dataset contains another atypical datum suspected to be an outlier and n≥6 
following the exclusion, then repeat step 2 above.  This evaluation may be repeated as many 
times as necessary, excluding only 1 suspected outlier in each iteration, until all data remaining 
in the dataset fall within the range of arithmetic mean ±3*SD of the log-transformed values.
Reporting of Excluded Values
Individual values excluded as outliers will be documented in the final study report.  Approval of 
the final study report will connote approval of the exclusion.
5.11.2. Pharmacokinetic Statistical Inference
Log-transformed PK parameters listed in Section 5.11.1 with the exception of Tmax will be 
evaluated in a linear mixed-effects model with fixed effects for treatment, period, and sequence, 
and a random effect for patient.  The treatment differences will be back-transformed to present 
the ratios of geometric means and the corresponding 90% CI.
The Tmax will be analyzed using the Wilcoxon signed rank test.  Estimates of the median 
difference based on the observed medians, 90% CIs, and p-values from the Wilcoxon test will be 
calculated.
Exploratory analyses may be performed for other PK parameters as deemed appropriate.
5.12. Pharmacodynamic Analyses 
5.12.1. Pharmacodynamic Parameter Estimation
Pharmacodynamic parameters will be calculated using NCA Drug Effect Model in validated 
software program (Phoenix WinNonlin Version 6.4.1 or later) and/or SAS. Key PD parameters 
will be derived to assess the exposure to glucose and duration of exposure above, below, and 


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within the normal glucose range. The normal range for PG will be considered to be 70 to 
108 mg/dL. Actual sampling times will be used for all calculations.
The following PD parameters will be calculated using concentrations of glucose:
Parameter
Definition
AUECabove
Area under the effect concentration-time curve above the normal range
AUECbelow
Area under the effect concentration-time curve below the normal range
AUECwithin
Area under the effect concentration-time curve within the normal range
AUEC0-1.5
Area under the effect concentration-time curve from time zero (predose) up 
to 1.5 hours
BGmax
Maximal blood glucose
Durationabove
Duration above normal range
Durationbelow
Duration below normal range
Durationwithin
Duration within normal range
tabove
Time to concentrations above normal range
tbelow
Time to concentrations below normal range (after tabove)
twithin
Time to concentrations within normal range
Tmax
Time to maximum concentration
The following PD parameters will be calculated using baseline-adjusted (ie, change from 
baseline) concentrations of PG:  AUEC0-1.5, BGmax, and Tmax.
Baseline PG concentrations will be concentrations from samples obtained immediately prior to 
glucagon dosing (ie, time point of 0.00 hour).  
If a patient receives additional intervention to raise PG concentrations, measurements taken after 
the time of intervention will be excluded from the estimation of PD parameters.
Other PD parameters of PG may be calculated if required. Individual concentrations and PD
parameters of PG will be summarized with descriptive statistics by treatment.
5.12.2. Pharmacodynamic Statistical Inference 
The PD parameters (AUEC0-1.5, BGmax) will be log-transformed prior to analysis and a linear 
mixed-effects model fitted to the data, with treatment, period, and sequence as fixed effects and 
patient as a random effect.  For each parameter, the treatment difference will be back-
transformed to present the ratios of geometric means and the corresponding 90% CI.
The values of Tmax will be analyzed nonparametrically using the Wilcoxon signed-rank test.  
Median differences and approximate 90% CIs for the difference will be calculated for the 
comparisons of treatments.
Exploratory analyses may be performed for other PD parameters as deemed appropriate.


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5.13. Pharmacokinetic/Pharmacodynamic Analyses
Exploratory analyses may be performed to evaluate exposure–response relationship if needed.
5.14. Exploratory Objectives Analyses
5.14.1. PK Profile of DPC
Patients who receive glucagon treatment and have measurable DPC concentrations will be 
included in the DPC PK analysis. The NCA methods and similar rules for calculating glucagon 
PK parameters (Section 5.11.1) will be used for DPC PK parameters calculation.
Plasma concentrations of DPC will be used to determine the following PK parameters, when 
possible:  
Parameter
Units
Definition
AUC(0-tlast)
pg.h/mL
Area under the concentration vs time curve from time zero to time 
t, where t is the last time point with a measurable concentration
AUC(0-∞)
pg.h/mL
Area under the concentration versus time curve from zero to 
infinity
%AUC(tlast-)
%
Percentage of AUC(0-∞) extrapolated
Cmax
pg/mL
Maximum observed drug concentration
tmax
H
Time of maximum observed drug concentration
t1/2
H
Half-life associated with the terminal rate constant (λz) in 
noncompartmental analysis
CL/F
L/h
Apparent total body clearance of drug calculated after 
extravascular administration
Vz/F
L
Apparent volume of distribution during the terminal phase after 
extravascular administration
Vss/F
L
Apparent volume of distribution at steady state after extravascular 
administration
An alternative AUC measure, such as AUC to a common time point, may be calculated if 
AUC(0-∞) cannot be reliably calculated.
5.14.2. Symptoms of Hypoglycemia
Specified in Section 5.9.2.
5.14.3. Clarke Hypoglycemia Awareness
Specified in Section 5.4.
5.15. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the Lilly clinical pharmacologist/clinical research physician, investigator, or designee 


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will consult with the appropriate medical director or designee to determine if it is necessary to 
amend the protocol.
A primary outcome database lock will be conducted after last treatment discharge from Clinical 
Research Unit (CRU).  The aim of the primary data lock is to enable data analysis to assess the 
primary/secondary objectives, and may include assessment of exploratory objectives.  The 
primary data lock will include all study data up to last patient discharge from CRU.  There will 
be a final study data lock following the end of study safety follow-up visit. 


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6.
Unblinding Plan 
Study IGBI is an open-label study. Treatment assignment will be unblinded to the study team.  


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7.
References
Rickels MR, Ruedy KJ, Foster NC, Piché CA, Dulude H, Sherr JL, Tamborlane WV, Bethin KE, 
DiMeglio LA, Wadwa RP, Ahmann AJ, Haller MJ, Nathan BM, Marcovina SM, Rampakakis 
E, Meng L, Beck RW; T1D Exchange Intranasal Glucagon Investigators. Intranasal glucagon 
for treatment of insulin-induced hypoglycemia in adults with type 1 diabetes: a randomized 
crossover noninferiority study. Diabetes Care. 2016;39(2):264-270.


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8.
Appendices


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Appendix 1.
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


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MedDRA 
Preferred Term 
Code
MedDRA Preferred Term
MedDRA System Organ Class
10028741
Nasal inflammation
Respiratory, thoracic and mediastinal disorders
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


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MedDRA 
Preferred Term 
Code
MedDRA Preferred Term
MedDRA System Organ Class
10064037
Rhinalgia
Respiratory, thoracic and mediastinal disorders
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.


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