Clinical trial NCT03421379
Conditions: Diabetes Mellitus
Sponsor: Eli Lilly and Company
Start date: 2018-02-21; Completion date: 2018-08-20
Enrollment: 75 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to determine the efficacy and safety of nasal glucagon compared to intramuscular (IM) glucagon for treatment of insulin-induced hypoglycemia in Japanese participants with diabetes mellitus.

Detailed description:

Arms: arm 1: A single dose of 3 milligram (mg) glucagon nasal powder administered intranasally. arm 2: A single dose of 1 mg glucagon hydrochloride solution was administered intramuscular (IM)
Interventions: intervention 1: Glucagon Nasal Powder intervention 2: Glucagon Hydrochloride Solution
Intervention descriptions: intervention 1: Administered intranasally intervention 2: Administered IM

Protocol documents:
Prot_000.pdf: 
I8R-JE-IGBJ(a) Clinical Pharmacology Protocol 
Protocol I8R-JE-IGBJ 
A Phase 3 Study of Nasal Glucagon (LY900018) Compared 
to Intramuscular Glucagon for Treatment of 
Insulin-induced Hypoglycemia in Japanese Patients with 
Diabetes Mellitus 
 
NCT03421379 
 
Approval Date: 05-Dec-2017 
 
 
 


I8R-JE-IGBJ(a) Clinical Pharmacology Protocol
Page 1
LY900018
Protocol I8R-JE-IGBJ
A Phase 3 Study of Nasal Glucagon (LY900018) Compared 
to Intramuscular Glucagon for Treatment of 
Insulin-induced Hypoglycemia in Japanese Patients with 
Diabetes Mellitus
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 (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 (LY900018)
Eli Lilly Japan K.K
Japan
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly:  
26 October 2017
Amendment (a) Electronically Signed and Approved by Lilly on date provided below.
Approval Date: 05-Dec-2017 GMT


I8R-JE-IGBJ(a) Clinical Pharmacology Protocol
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LY900018
Table of Contents
A Phase 3 Study of Nasal Glucagon (LY900018) Compared to 
Intramuscular Glucagon for Treatment of Insulin-induced 
Hypoglycemia in Japanese Patients with Diabetes Mellitus
Section
Page
Protocol I8R-JE-IGBJ A Phase 3 Study of Nasal Glucagon (LY900018) 
Compared to Intramuscular Glucagon for Treatment of Insulin-induced 
Hypoglycemia in Japanese Patients with Diabetes Mellitus.................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................8
2.
Schedule of Activities .......................................................................................................10
3.
Introduction ......................................................................................................................19
3.1.
Study Rationale............................................................................................................19
3.2.
Background..................................................................................................................19
3.3.
Benefit/Risk Assessment..............................................................................................20
4.
Objectives and Endpoints..................................................................................................22
5.
Study Design.....................................................................................................................23
5.1.
Overall Design .............................................................................................................23
5.2.
Number of Participants.................................................................................................24
5.3.
End of Study Definition ...............................................................................................24
5.4.
Scientific Rationale for Study Design...........................................................................24
5.5.
Justification for Dose ...................................................................................................24
6.
Study Population...............................................................................................................25
6.1.
Inclusion Criteria..........................................................................................................25
6.2.
Exclusion Criteria ........................................................................................................27
6.3.
Lifestyle and/or Dietary Requirements .........................................................................29
6.3.1.
Meals and Dietary Restrictions.............................................................................29
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................29
6.3.3.
Activity................................................................................................................29
6.3.4.
Contraception.......................................................................................................30
6.4.
Screen Failures.............................................................................................................30
7.
Treatment..........................................................................................................................31
7.1.
Treatment Administered...............................................................................................31
7.1.1.
Packaging and Labeling .......................................................................................31
7.1.2.
Medical Devices...................................................................................................31
7.2.
Method of Treatment Assignment ................................................................................32


I8R-JE-IGBJ(a) Clinical Pharmacology Protocol
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LY900018
7.2.1.
Selection and Timing of Doses.............................................................................32
7.3.
Blinding .......................................................................................................................32
7.4.
Dose Modification........................................................................................................32
7.5.
Preparation/Handling/Storage/Accountability...............................................................32
7.6.
Treatment Compliance .................................................................................................32
7.7.
Concomitant Therapy...................................................................................................33
7.8.
Treatment after the End of the Study............................................................................33
8.
Discontinuation Criteria ....................................................................................................34
8.1.
Discontinuation from Study Treatment.........................................................................34
8.1.1.
Discontinuation of Inadvertently Enrolled Patients...............................................34
8.2.
Discontinuation from the Study....................................................................................34
8.3.
Discontinuation of the Study ........................................................................................34
8.4.
Patients Lost to Follow-up............................................................................................34
9.
Study Assessments and Procedures ...................................................................................35
9.1.
Efficacy Assessments...................................................................................................35
9.1.1.
Primary Efficacy Assessments .............................................................................35
9.1.2.
Secondary Efficacy Assessments..........................................................................35
9.1.3.
Exploratory Efficacy Assessments .......................................................................35
9.2.
Procedures ...................................................................................................................35
9.2.1.
Insulin-induced Hypoglycemia.............................................................................35
9.2.2.
Glucagon Administration .....................................................................................36
9.2.2.1.
Nasal LY900018 Administration ....................................................................36
9.2.2.2.
Intramuscular Glucagon Administration .........................................................36
9.2.3.
Post Glucagon Administration..............................................................................37
9.2.4.
Procedures for Insufficient Response to Glucagon Administration .......................37
9.2.5.
End of Admission ................................................................................................37
9.3.
Adverse Events ............................................................................................................37
9.3.1.
Serious Adverse Events........................................................................................38
9.3.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................39
9.3.1.2.
Adverse Event Monitoring with a Systematic Questionnaire...........................39
9.3.2.
Complaint Handling.............................................................................................39
9.4.
Treatment of Overdose.................................................................................................40
9.5.
Safety...........................................................................................................................40
9.5.1.
Laboratory Tests ..................................................................................................40
9.5.2.
Vital Signs ...........................................................................................................40
9.5.3.
Electrocardiograms ..............................................................................................40
9.5.4.
Other Tests...........................................................................................................41
9.5.5.
Safety Monitoring ................................................................................................41


I8R-JE-IGBJ(a) Clinical Pharmacology Protocol
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LY900018
9.5.5.1.
Hypoglycemic Event Reporting......................................................................41
9.5.5.2.
Hepatic Safety................................................................................................43
9.6.
Pharmacokinetics .........................................................................................................43
9.6.1.
Bioanalysis...........................................................................................................44
9.7.
Pharmacodynamics ......................................................................................................44
9.7.1.
Immunogenicity Assessments ..............................................................................44
9.8.
Genetics .......................................................................................................................45
9.9.
Biomarkers...................................................................................................................45
9.10. Health Economics ........................................................................................................45
10.
Statistical Considerations and Data Analysis.....................................................................46
10.1. Sample Size Determination ..........................................................................................46
10.2. Populations for Analyses..............................................................................................46
10.2.1.
Study Participant Disposition ...............................................................................46
10.2.2.
Study Participant Characteristics ..........................................................................46
10.2.3.
Treatment Compliance .........................................................................................46
10.3. Statistical Analyses ......................................................................................................46
10.3.1.
Efficacy Analyses ................................................................................................47
10.3.1.1.
Primary Efficacy Analysis ..............................................................................47
10.3.1.2.
Secondary Efficacy Analyses..........................................................................48
10.3.1.2.1.
Plasma Glucose Values.............................................................................48
10.3.1.3.
Exploratory Efficacy Analyses........................................................................48
10.3.1.3.1.
Symptoms of Hypoglycemia.....................................................................48
10.3.2.
Safety Analyses....................................................................................................48
10.3.2.1.
Clinical Evaluation of Safety..........................................................................48
10.3.2.2.
Nasal and Non-nasal Score Questionnaire.......................................................48
10.3.2.3.
Statistical Evaluation of Safety.......................................................................48
10.3.3.
Pharmacokinetic Analyses....................................................................................49
10.3.3.1.
Pharmacokinetic Parameter Estimation...........................................................49
10.3.3.2.
Pharmacokinetic Statistical Inference .............................................................49
10.3.4.
Pharmacodynamic Analyses.................................................................................49
10.3.4.1.
Pharmacodynamic Parameter Estimation ........................................................49
10.3.4.2.
Pharmacodynamic Statistical Inference...........................................................50
10.3.5.
Pharmacokinetic/Pharmacodynamic Analyses......................................................50
10.3.6.
Evaluation of Immunogenicity .............................................................................50
10.3.7.
Data Review During the Study.............................................................................51
10.3.8.
Interim Analyses..................................................................................................51
11.
References ........................................................................................................................52


I8R-JE-IGBJ(a) Clinical Pharmacology Protocol
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LY900018
List of Tables
Table
Page
Table IGBJ.1.
Objectives and Endpoints .......................................................................22
Table IGBJ.2.
Study Treatments....................................................................................31


I8R-JE-IGBJ(a) Clinical Pharmacology Protocol
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LY900018
List of Figures
Figure
Page
Figure IGBJ.1.
Illustration of study design for Protocol I8R-JE-IGBJ.............................23


I8R-JE-IGBJ(a) Clinical Pharmacology Protocol
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LY900018
List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................53
Appendix 2.
Clinical Laboratory Tests........................................................................57
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................58
Appendix 4.
Hepatic Monitoring Tests for Treatment-emergent Abnormality.............61
Appendix 5.
Blood Sampling Summary......................................................................62
Appendix 6.
Nasal and Non-nasal Score Questionnaire...............................................63
Appendix 7.
Edinburgh Hypoglycemia Scale..............................................................65
Appendix 8.
Clarke Hypoglycemia Awareness Survey ...............................................68
Appendix 9.
Protocol Amendment I8R-JE-IGBJ(a) Summary A Phase 3 Study 
of Nasal Glucagon (LY900018) Compared to Intramuscular 
Glucagon for Treatment of Insulin-induced Hypoglycemia in 
Japanese Patients with Diabetes Mellitus................................................71


I8R-JE-IGBJ(a) Clinical Pharmacology Protocol
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LY900018
1. Protocol Synopsis
Title of Study:
A Phase 3 Study of Nasal Glucagon (LY900018) Compared to Intramuscular Glucagon for Treatment of 
Insulin-induced Hypoglycemia in Japanese Patients with Diabetes Mellitus
Rationale:
Nasal glucagon (LY900018) is a powder formulation of human glucagon for the rescue treatment of hypoglycemia 
packaged in a user-friendly, single-use, nasal dosing device that delivers 3 mg glucagon powder for absorption 
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 rescue treatment of hypoglycemia.  
Currently, glucagon in a liquid form lacks physical and chemical stability; thus, marketed products require 
reconstitution of glucagon powder before the product can be administered through intramuscular (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 LY900018 with IM glucagon (IMG), a currently approved product that requires 
reconstitution prior to administration through IM injection, in Japanese patients with type 1 diabetes mellitus 
(T1DM) and patients with type 2 diabetes mellitus (T2DM) who achieve treatment success during controlled 
insulin-induced hypoglycemia.  Treatment success is defined as an increase in plasma glucose (PG) 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 treatments to increase PG.  The nadir is defined as the minimum PG measurement at the time of 
or within 10 minutes following glucagon administration.
Objectives/Endpoints:
Objectives
Endpoints
Primary
To demonstrate that 3 mg LY900018 is non-inferior to 
1 mg IMG for the proportion of patients achieving 
treatment success from insulin-induced hypoglycemia 
using a non-inferiority margin of 10%
The proportion of patients achieving treatment success 
defined as either an increase in PG to >70 mg/dL or an 
increase of >20 mg/dL from nadir within 30 minutes 
after administration of glucagon.  The nadir is defined 
as the minimum PG value at the time of or within 
10 minutes following glucagon administration.
Secondary

To compare the safety and tolerability of 3 mg 
LY900018 with 1 mg IMG

To characterize the PK profile of 3 mg LY900018 
compared to 1 mg IMG

To characterize the PD profile of 3 mg LY900018 
compared to 1 mg IMG

SAE, TEAEs (including gastrointestinal, nasal,
and non-nasal AEs), vital signs 

PK parameters include AUC, Cmax, Tmax

PD parameters include BGmax and Tmax
Abbreviations:  AE = adverse event; AUC = area under the concentration versus time curve; BGmax = maximal 
plasma glucose concentration; Cmax = maximal concentration; IMG = intramuscular glucagon; 
PD = pharmacodynamics; PG = plasma glucose; PK = pharmacokinetics; SAE = serious adverse event; 
TEAE = treatment-emergent adverse event; Tmax = time to maximal concentration.


I8R-JE-IGBJ(a) Clinical Pharmacology Protocol
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LY900018
Summary of Study Design:
Study I8R-JE-IGBJ is a Phase 3, multicenter, randomized, open-label, active comparator, single-dose, 2-treatment, 
2-period crossover study in Japanese patients with T1DM and patients with T2DM.
Treatment Arms and Planned Duration for an Individual Patient:
LY900018:  Single 3-mg dose; nasal administration by study site personnel
IMG (GlucaGen, Novo Nordisk A/S): Single 1-mg dose; IM injection by study site personnel
Patients will undergo a screening examination within 28 days prior to enrollment.  Patients will be administered a 
single dose in Periods 1 and 2, which will be separated by a washout period of 3 to 14 days.  Patients will return for 
a follow-up visit 26 to 30 days after the last study treatment.
Number of Patients:
Seventy five patients may be enrolled in order to have at least 66 patients (at least 30 patients with T1DM and 
T2DM, respectively) complete both periods with evaluable primary outcome. If patients discontinue from the study 
before completion of both periods with evaluable primary outcome for any reason, the patient may be replaced.  
Replacement should not occur beyond 75 patients enrolled, if it is expected to have at least 66 patients complete the 
study.
Statistical Analysis:
A total of 66 completers 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 non-inferiority margin (NIM) of 10%

One-sided alpha level of 0.025

A within-patient correlation of zero between 2 treatment visits
The primary analysis will be a treatment comparison of the percentage of patients, including both T1DM and 
T2DM, who achieve treatment success.  The percentage of patients who achieve treatment success within each 
treatment group and the difference in the percentages between the 2 treatment groups will be computed.  A 2-sided 
95% confidence interval (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.  Non-inferiority of LY900018 will be 
declared if the upper limit of the 2-sided 95% CI constructed on the difference in percentage (IMG - LY900018) is 
less than the NIM of 10%.


I8R-JE-IGBJ(a) Clinical Pharmacology Protocol
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LY900018
2. Schedule of Activities


I8R-JE-IGBJ(a) Clinical Pharmacology Protocol
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LY900018
Study Schedule Protocol I8R-JE-IGBJ
Screening
Period 1
Wash 
out
Period 2
Follow-up/ED
Additional 
Follow-up for 
TE ADAa
Comments
Procedure
Days -28
to -2
Day
-1
Day 1
3 to
14 days
Day
-1
Day 1
Within 
28±2 days 
after last 
study 
treatment
Clinical Assessments
Informed Consent
X
Randomization
X
Admission to CRU
X
X
Admission can be 
rescheduled if PG level is 
not 90 to 250 mg/dL on 
Day 1.
Discharge from CRU
X
X
Patient may be 
discharged 6 hours after 
glucagon administration.  
A patient may remain 
inpatient at the CRU at 
the discretion of the 
investigator.
Medical History
X
Collect Pre-existing
Conditions and Adverse
Events
X
X
X
X
X
X
X
Physical Exam
X
240 min
240 min
X
After screening, medical 
assessment only 
performed to include 
medical review and 
targeted examination, as 
appropriate.


I8R-JE-IGBJ(a) Clinical Pharmacology Protocol
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LY900018
Screening
Period 1
Wash 
out
Period 2
Follow-up/ED
Additional 
Follow-up for 
TE ADAa
Comments
Procedure
Days -28
to -2
Day
-1
Day 1
3 to
14 days
Day
-1
Day 1
Within 
28±2 days 
after last 
study 
treatment
Height and Weight
X
Pre-hypoglycemia 
induction
Pre-hypoglycemia 
induction
X
Height is at screening 
only.  Weight on Day 1 
will be collected before 
the start of the procedure 
to induce hypoglycemia.
Collect Hypoglycemic
Events
X
X
Refer to Section 9.5.5.1.
Collect Concomitant
Medications
X
X
X
X
X
X
X
Review patients’ insulin 
regimens to confirm 
acceptability to undergo 
the procedure to induce 
hypoglycemia.
Meal
X
X
After completion of all 
PK sampling, patients
will be provided a 
carbohydrate-rich meal.  
The investigator will 
ensure the patient’s PG is 
stable.  A prandial insulin 
dose will be administered
if needed.


I8R-JE-IGBJ(a) Clinical Pharmacology Protocol
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LY900018
Screening
Period 1
Wash 
out
Period 2
Follow-up/ED
Additional 
Follow-up for 
TE ADAa
Comments
Procedure
Days -28
to -2
Day
-1
Day 1
3 to
14 days
Day
-1
Day 1
Within 
28±2 days 
after last 
study 
treatment
Insulin infusion to 
Induce Hypoglycemia
X
X
Procedures in Period 2 
will occur at 
approximately the same 
time as those in Period 1. 
Insulin infusion is 
stopped once bedside PG
is <60 mg/dL.
Bedside PG Monitoring
for Safety
X
X
Samples will be collected 
during the hypoglycemia 
induction procedure and 
post study treatment (up
to 120 mins).  Bedside
PG monitoring will be 
conducted no more than 
10 minutes apart while
bedside PG is ≥90 mg/dL 
and no more than 
5 minutes apart when
bedside PG is <90 mg/dL.
Study Treatment 
Administration
X
X
Once bedside PG reaches 
<60 mg/dL, the insulin 
infusion is stopped and 
approximately 5 minutes 
later study drug is 
administered.  
Indicates Time = 0 min.


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LY900018
Screening
Period 1
Wash 
out
Period 2
Follow-up/ED
Additional 
Follow-up for 
TE ADAa
Comments
Procedure
Days -28
to -2
Day
-1
Day 1
3 to
14 days
Day
-1
Day 1
Within 
28±2 days 
after last 
study 
treatment
Injection-Site 
Assessment
Pre-hypoglycemia 
induction, 90 min
Pre-hypoglycemia 
induction, 90 min
Injection-site assessment 
for IMG only.
Nasal Inspection
Pre-hypoglycemia 
induction, 90 min
Pre-hypoglycemia 
induction, 90 min
Nasal inspection both for 
IMG and LY900018.
Vital Signs
(Supine Blood Pressure, 
Pulse Rate, and Body 
Temperature)
X
Pre-hypoglycemia 
induction, 
Predose, 15, 30, 
60, 120, 240 min
Pre-hypoglycemia 
induction, 
Predose, 15, 30, 
60, 120, 240 min
X
Time points may be 
added for each period if 
warranted and agreed 
upon between Lilly and 
the investigator.
Predose time point will be 
between insulin infusion 
stop and study treatment.  
Single 12-lead ECG 
(Local)
X
X
Triplicate 12-lead ECG 
(Central)
Pre-hypoglycemia 
induction (30 and 
15 min prior to 
insulin infusion), 
Predose, 15, 30, 
60, 120, 240 min
Pre-hypoglycemia 
induction (30 and 
15 min prior to 
insulin infusion), 
Predose, 15, 30, 
60, 120, 240 min
Time points may be 
added for Period 1 and 
Period 2 if warranted and 
agreed upon between 
Lilly and the investigator.
Predose time point will be 
between insulin infusion 
stop and study treatment.
Laboratory Tests
Clinical Serology Tests
X
See Appendix 2, Clinical 
Laboratory Tests, for 
details.


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LY900018
Screening
Period 1
Wash 
out
Period 2
Follow-up/ED
Additional 
Follow-up for 
TE ADAa
Comments
Procedure
Days -28
to -2
Day
-1
Day 1
3 to
14 days
Day
-1
Day 1
Within 
28±2 days 
after last 
study 
treatment
Clinical Lab Tests 
(Hematology, Clinical 
Chemistry, and 
Urinalysis)
X
Pre-hypoglycemia 
induction
Pre-hypoglycemia 
induction
X
See Appendix 2, Clinical 
Laboratory Tests, for 
details.  Patients do not 
need to fast for samples at 
screening or follow-up.  
At Periods 1 and 2, 
samples should be 
collected from patients 
who have fasted at least 
8 hours before any study 
procedures.  
HbA1c
X
Pre-hypoglycemia 
induction
See Appendix 2, Clinical 
Laboratory Tests, for 
details.  
Pregnancy Test (Female 
patients of childbearing 
potential only)
X
X
X
X
Serum pregnancy test will 
be performed at 
screening.  Urine 
pregnancy test will be 
performed at every 
admission period and 
follow-up visit if 
applicable.
FSH (Female patients 
only)
X
When needed to confirm 
postmenopausal status.
Ethanol Testing
X
Additional tests can be 
done at the discretion of 
the investigator.


I8R-JE-IGBJ(a) Clinical Pharmacology Protocol
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LY900018
Screening
Period 1
Wash 
out
Period 2
Follow-up/ED
Additional 
Follow-up for 
TE ADAa
Comments
Procedure
Days -28
to -2
Day
-1
Day 1
3 to
14 days
Day
-1
Day 1
Within 
28±2 days 
after last 
study 
treatment
Urine Drug Screen
X
Additional tests can be 
done at the discretion of 
the investigator.
PK (Glucagon)
Pre-hypoglycemia 
induction, 
Predose, 5, 10, 15, 
20, 25, 30, 40, 50, 
60, 90, 120, 240 
min
Pre-hypoglycemia 
induction, 
Predose, 5, 10, 15, 
20, 25, 30, 40, 50, 
60, 90, 120, 240 
min
X
X
Sampling times are 
relative to the time of 
study treatment 
administration (0 min).
Predose time point will be 
between insulin infusion 
stop and study treatment.
Plasma Glucose for PD
Pre-hypoglycemia 
induction, -5, 
Predose, 5, 10, 15, 
20, 25, 30, 40, 50, 
60, 90, 120, 240 
min
Pre-hypoglycemia 
induction, -5, 
Predose, 5, 10, 15, 
20, 25, 30, 40, 50, 
60, 90, 120, 240 
min
-5 mins = stop insulin 
infusion.  Sampling times 
are relative to the time of 
study treatment 
administration (0 min).
Predose time point will be 
between insulin infusion 
stop and study treatment.
Genetic Sample (Stored)
X
Single sample for 
pharmacogenetic analysis 
taken prior to/on Period 1 
Day -1.


I8R-JE-IGBJ(a) Clinical Pharmacology Protocol
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LY900018
Screening
Period 1
Wash 
out
Period 2
Follow-up/ED
Additional 
Follow-up for 
TE ADAa
Comments
Procedure
Days -28
to -2
Day
-1
Day 1
3 to
14 days
Day
-1
Day 1
Within 
28±2 days 
after last 
study 
treatment
Anti-glucagon
Antibodies
Pre-hypoglycemia 
induction
X
X
In the event of drug 
hypersensitivity reactions 
(immediate or 
non-immediate), samples 
will be collected as close 
to event onset as possible, 
at event resolution, and 
30 days following the 
event.  Patients with 
TE ADA at follow-up/ED 
will undergo additional 
follow-up.  Refer to 
Section 9.7.1 for details.
Health Outcome 
Instruments
Clarke Hypoglycemia
Awareness Survey
X
Nasal and Non-nasal
Score Questionnaire
Pre-hypoglycemia 
induction, 15, 30, 
60, 120 min
Pre-hypoglycemia 
induction, 15, 30, 
60, 120 min
Sampling times are 
relative to the time of 
study treatment 
administration (0 min).
Questionnaire will be 
collected in both 
LY900018 and IMG 
treatment groups in both 
periods.


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LY900018
Screening
Period 1
Wash 
out
Period 2
Follow-up/ED
Additional 
Follow-up for 
TE ADAa
Comments
Procedure
Days -28
to -2
Day
-1
Day 1
3 to
14 days
Day
-1
Day 1
Within 
28±2 days 
after last 
study 
treatment
Edinburgh 
Hypoglycemia Scale:  
Experimental
Hypoglycemia
Pre-hypoglycemia 
induction, During 
hypoglycemia 
induction, 
Predose, 15, 30, 
60, 120 min
Pre-hypoglycemia 
induction, During 
hypoglycemia 
induction, 
Predose, 15, 30, 
60, 120 min
Sampling times are 
relative to the time of 
study treatment 
administration (0 min).
During hypoglycemia 
induction will be when 
PG ≤75 mg/dL.
Predose time point will be
between insulin infusion 
stop and study treatment.
Abbreviations: CRU = clinical research unit; ECG = electrocardiogram; ED = early discontinuation; FSH = follicle-stimulating hormone; 
HbA1c = hemoglobin A1c; IMG =intramuscular glucagon; min = minutes; PD = pharmacodynamics; PG = plasma glucose; PK = pharmacokinetics; TE 
ADA = treatment-emergent antidrug antibodies.
a
Samples for immunogenicity, should be collected every 12 weeks (84±7 days) until the titer returns to baseline (ie, returns to within a single 2-fold dilution of 
the baseline titer) or until 1 year after the last dose of study treatment.  A time-matched PK (glucagon) sample may be collected at the follow-up 
immunogenicity assessment(s) if warranted and agreed upon between both the investigator and sponsor.
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.  Plasma 
glucose sample should be collected as close as possible of protocol-specified time point.


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LY900018
3. Introduction
3.1.
Study Rationale
Nasal glucagon (LY900018) is a powder formulation of human glucagon for the rescue treatment 
of hypoglycemia packaged in a user-friendly, single-use, nasal dosing device that delivers 3 mg 
glucagon powder for absorption 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 rescue treatment of hypoglycemia.
Currently, glucagon in a liquid form lacks physical and chemical stability; thus, marketed 
products require reconstitution of glucagon powder before the product can be administered 
through intramuscular (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 I8R-JE-IGBJ (IGBJ) is to compare LY900018 with IM glucagon (IMG)
with respect to the proportion of patients who achieved treatment success during the controlled 
insulin-induced hypoglycemia in Japanese patients with type 1 diabetes mellitus (T1DM) and 
patients with type 2 diabetes mellitus (T2DM).  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 treatments 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 IGBJ are 
similar to the completed Phase 3 Study I8R-MC-IGBC (IGBC) (Rickels et al. 2016) and the 
planned Phase 1 Study I8R-MC-IGBI.
3.2.
Background
Hypoglycemia is a common complication in all patients with T1DM and some patients with 
T2DM who use insulin to reduce blood glucose levels.  Use of sulfonylurea and glinide by 
patients with T2DM may also cause hypoglycemia.  Depending on the severity, hypoglycemia 
causes physical symptoms ranging from weakness, dizziness, and sweating progressing to 
blurred vision, behavioral changes, progressing to unconsciousness, seizures, and coma, and 
possibly to death (American Diabetes Association 2017).  When emergency services are 
available in a timely manner, intravenous (IV) glucose supplementation is also an effective 
treatment.  Glucagon for injection is a globally available product currently indicated for the 
treatment of severe hypoglycemia, and is another important treatment option outside of a clinical 
setting for people who try to rescue patients with severe hypoglycemia.  However, for people 
without enough medical training, the multi-step reconstitution of glucagon and injection 
procedure would be complex and daunting with substantial risk of errors (Polonsky et al. 2016).  
Therefore the needle-free and easy-to-administer formulation of glucagon is desired for patients 
who have a risk of severe hypoglycemia related to anti-diabetes treatments. LY900018 is a 
powder formulation of synthetic human glucagon in a user-friendly, single-use, nasal dosing 


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LY900018
device which delivers 3 mg glucagon powder.  Patients do not need to inhale, as the drug is 
absorbed from the nasal cavity.
Three clinical trials using LY900018 have been completed in non-Japanese 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 3 mg LY900018 and 1 mg 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 3 mg
LY900018 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 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 B001 demonstrated 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 IV insulin under close clinical supervision and were 
administered either LY900018 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 LY900018 and 100% (75 out of 75) of 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 LY900018-treated patient 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 in participants with nadir glucose <50 mg/dL
were 16 minutes in the LY900018 treatment arm and 13 minutes in the IMG treatment arm, 
respectively (Rickels et al. 2016).
3.3.
Benefit/Risk Assessment
There is no anticipated therapeutic benefit for the patients participating in this study.
This study will expose patients to an insulin-induced hypoglycemia meant to simulate 
hypoglycemia in a controlled setting.  The procedure of insulin-induced hypoglycemia targeting 
nadir glucose around 50 mg/dL is adopted from a previously completed trial, specifically 
Study IGBC, which 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 
with frequent glucose monitoring.  Safety provisions have been considered in that IV glucose 
will be administered if the patient experiences signs and symptoms of severe hypoglycemia and 
gauged to require intervention during the experimental procedure, at the discretion of the 
investigator.


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LY900018
Potential risks associated with LY900018, derived from the known risks of currently existing 
injected glucagon therapy and from the safety profile observed from clinical trials conducted for 
LY900018, include nausea, vomiting, allergic reactions, increased blood pressure (BP) and heart 
rate, headache, dysgeusia, and nasal or ocular events (Glucagon G Novo for Injection Package 
Insert, 2016;  Glucagon G Novo for Injection Interview Form, 2015; GLUCAGON for Injection 
ITO Package Insert, 2016; GLUCAGON for Injection ITO Interview Form, 2016).
Nausea and Vomiting:  Glucagon therapy, including LY900018, may cause nausea and vomiting.
Allergic Reactions:  Severe, life-threatening, generalized allergy, including anaphylaxis, can 
occur with glucagon therapy, including LY900018.  Patients who have had hypersensitivity 
reactions to injectable glucagon, or LY900018 or any of its excipients will be excluded from all 
clinical studies.
Increased Blood Pressure and Heart Rate:  Glucagon exerts positive inotropic and chronotropic 
effects.  A temporary increase in both BP and heart rate may occur after the administration of 
glucagon, including LY900018.
Headache and Dysgeusia:  Use of LY900018 may cause headache and altered taste.
Nasal Symptoms:  Use of LY900018 may cause a variety of nasal symptoms, such as runny nose, 
stuffy nose, nasal discomfort, cough, and sneezing.
Ocular Symptoms:  Use of LY900018 may cause a variety of ocular symptoms, such as watery 
eyes, redness of eyes, and itchy eyes.
No additional potential risks of LY900018 were identified in preclinical safety pharmacology 
and toxicity studies (Reno et al. 2015).
More information about the known and expected benefits, risks, serious adverse events (SAEs),
and reasonably anticipated adverse events (AEs) of LY900018 are to be found in the 
Investigator’s Brochure (IB).
More detailed information about the known and expected benefits and risks of GlucaGen® may 
be found in the Summary of Product Characteristics (GlucaGen Summary of Product 
Characteristics, 2015).


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LY900018
4. Objectives and Endpoints
Table IGBJ.1 shows the objectives and endpoints of the study.
Table IGBJ.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To demonstrate that 3 mg LY900018 is non-inferior to 
1 mg IMG for the proportion of patients achieving 
treatment success from insulin-induced hypoglycemia 
using a non-inferiority margin of 10% 
The proportion of patients achieving treatment success 
defined as either an increase in PG to >70 mg/dL or an 
increase of >20 mg/dL from nadir within 30 minutes 
after administration of glucagon.  The nadir is defined as 
the minimum PG value at the time of or within 
10 minutes following glucagon administration.
Secondary

To compare the safety and tolerability of 3 mg 
LY900018 with 1 mg IMG

To characterize the PK profile of 3 mg LY900018 
compared to 1 mg IMG

To characterize the PD profile of 3 mg LY900018 
compared to 1 mg IMG

SAE, TEAEs (including gastrointestinal, nasal, and 
non-nasal AEs), vital signs 

PK parameters include AUC, Cmax, Tmax

PD parameters include BGmax and Tmax
Exploratory

Explore the formation of anti-glucagon antibodies 
to glucagon

To evaluate the recovery from clinical symptoms of 
hypoglycemia

Presence of anti-glucagon antibodies

Hypoglycemia symptoms questionnaire
Abbreviations:  AE = adverse event; AUC = area under the concentration versus time curve; BGmax = maximal 
plasma glucose concentration; Cmax = maximal concentration; IMG = intramuscular glucagon; 
PD = pharmacodynamics; PG = plasma glucose; PK = pharmacokinetics; SAE = serious adverse event; 
TEAE = treatment-emergent adverse event; Tmax = time to maximal concentration.


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LY900018
5. Study Design
5.1.
Overall Design
This is a Phase 3, multicenter, randomized, open-label, active comparator, single-dose, 2-period, 
2-treatment, crossover study in Japanese patients with T1DM and T2DM.  The study consists of 
a screening period; treatment period 1 (Period 1); washout period; treatment period 2 (Period 2);
follow-up period. Figure IGBJ.1 illustrates the study design.  Prior to the study drug 
administration on Period 1 Day 1, patients will be randomly assigned to a treatment sequence
(either LY900018 in Period 1 and IMG in Period 2, or vice versa).
Safety data will be reviewed after the first 6 patients (regardless of type of diabetes) are 
administered LY900018 in Period 2, and the remaining patients will be dosed after confirmation 
of the safety.  The investigator and Lilly clinical research physician (CRP) or scientist will 
review available safety data, including AEs, SAEs, vital signs, electrocardiograms (ECGs), and 
safety laboratory tests, from these patients after they complete Period 2 Day 1. If no clinically 
significant safety findings for treatment or study procedure are noted, the remaining patients will 
be dosed.
In each treatment period, patients will undergo a procedure to induce hypoglycemia using IV 
insulin infusion and serial blood sampling will be conducted to monitor bedside PG for safety.  
The insulin infusion will be stopped once the PG level reaches <60 mg/dL and approximately 
5 minutes later patients will be administered either 3 mg LY900018 or 1 mg IMG (GlucaGen).  
Serial blood sampling will be performed for glucagon (for pharmacokinetics [PK]) and PG (for 
pharmacodynamics [PD]) concentration measurements immediately before and up to 4 hours 
following the administration of glucagon.  In each period, patients will remain in the CRU for at 
least 6 hours after glucagon administration.  All patients will receive a carbohydrate-rich meal 
prior to discharge.  Patients may stay longer as needed, at the discretion of the investigator.
Study governance considerations are described in detail in Appendix 3.
Abbreviations: IM = intramuscular.
Figure IGBJ.1.
Illustration of study design for Protocol I8R-JE-IGBJ.


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LY900018
5.2.
Number of Participants
Seventy five patients may be enrolled in order to have at least 66 patients (at least 30 patients 
with T1DM and T2DM, respectively) complete the study.  For purposes of this study, a 
completer is defined as a patient who completes both periods with evaluable primary outcome.  
If patients discontinue from the study before completion of both periods with evaluable primary 
outcome for any reason, the patient may be replaced to ensure 66 patients complete the study.  
The replacement patients will be assigned the same treatment sequence as the patients to be 
replaced and will complete that treatment sequence in its entirety.  Replacement should not occur
beyond 75 patients enrolled, if it is expected to have at least 66 patients complete the study.
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.
5.4.
Scientific Rationale for Study Design
This study design involves an open-label assessment of 3 mg LY900018 compared to 1 mg of 
the marketed IMG (GlucaGen).  The study will be open label because the different 
administration routes (ie, intranasal and IM) cannot be blinded.  The use of a crossover design 
allows each patient to serve as his or her own control, thereby reducing variability.  The washout 
period of 3 to 14 days is considered sufficient based on the short half-life of LY900018
(t1/2 = approximately 25 minutes). Since the critical role of glucagon in the treatment of severe 
hypoglycemia is to raise the PG level sufficiently to restore cognition to the point where oral 
carbohydrate can be ingested, treatment success is defined either as an increase in PG returning 
to normal level of ≥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 glucose.  It 
is believed that an expected PG nadir of approximately 50 mg/dL (approximately 5 minutes after 
stop of insulin infusion at 60 mg/dL) is low enough to generate clinical symptoms in most 
participants and is high enough to avoid impairment of consciousness.  The primary analysis 
includes both patients with T1DM and T2DM since it is expected that the proportion of 
treatment success is similar between patients with T1DM and T2DM.
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 the 2- and 3-mg LY900018 doses, 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.  
The 1-mg dose of IMG is selected as the approved dose for the rescue treatment of hypoglycemia
in Japan.
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 LY900018 dose will be used to compare 
against 1 mg IMG.


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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 ECG.
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, are 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]
have had a diagnosis of either:
[1a] T1DM based on the World Health Organization (WHO) diagnostic criteria, 
and have been on the following daily insulin therapy for at least 1 year
[A] multiple daily injection of long-acting insulin analog (either insulin 
glargine [U-100 or U-300] or insulin degludec [U-100]) and rapid-acting 
insulin analog (insulin lispro, insulin aspart, or insulin glulisine), or 
[B] continuous subcutaneous insulin infusion (CSII)
Or
[1b] T2DM based on the WHO diagnostic criteria, and have received the
following daily insulin therapy with or without oral anti-hyperglycemic 
medications (OAMs) for at least 1 year
[A] insulin:  long-acting insulin analog (either insulin glargine [U-100 or 
U-300] or insulin degludec [U-100]) alone, or in combination with 
rapid-acting insulin analog (insulin lispro, insulin aspart, or insulin 
glulisine) or CSII
[B] OAM:  up to 3 of the following OAMs in accordance with local 
regulations:  metformin, dipeptidyl peptidase-4 inhibitor, sodium glucose 
cotransporter 2 inhibitor, sulfonylurea (should not be more than half of 
maximum approved doses), glinides, alpha-glucosidase inhibitor, or 
thiazolidine
[2]
male patients: agree to use an effective method of contraception for the 
duration of the study and for 28 days following the last study treatment
[3]
female patients:


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[3a] women of childbearing potential who are abstinent (if this is complete 
abstinence, as their preferred and usual lifestyle) or in a same sex 
relationship (as part of their preferred and usual lifestyle) must agree to 
either remain abstinent or stay in a same sex relationship without sexual 
relationships with males.  Periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods), declaration of abstinence just for 
the duration of a trial, and withdrawal are not acceptable methods of 
contraception.  
[3b] otherwise, women of childbearing potential participating must agree to use 
one highly effective method (less than 1% failure rate) of contraception, or a 
combination of 2 effective methods of contraception for the entirety of the 
study.
[A] women of childbearing potential participating must test negative for 
pregnancy prior to initiation of treatment as indicated by a negative serum 
pregnancy test at the screening visit followed by a negative urine 
pregnancy test within 24 hours prior to exposure.
[B] either one highly effective method of contraception or a combination 
of 2 effective methods of contraception will be used.  The patient may 
choose to use a double barrier method of contraception.  Barrier protection 
methods without concomitant use of a spermicide are not a reliable or 
acceptable method.  Thus, each barrier method must include use of a 
spermicide.  It should be noted that the use of male and female condoms 
as a double barrier method is not considered acceptable due to the high 
failure rate when these methods are combined.
[3c] women not of childbearing potential may participate, and include those who 
are:
[A] infertile due to surgical sterilization (hysterectomy, bilateral 
oophorectomy, or tubal ligation), congenital anomaly such as mullerian 
agenesis
Or
[B] postmenopausal, defined as either:
[i] a woman at least 50 years of age with an intact uterus, not on hormone 
therapy, who has had either:
[a] cessation of menses for at least 1 year, or
[b] at least 6 months of spontaneous amenorrhea with a 
follicle-stimulating hormone >40 mIU/mL; or
[ii] a woman 55 or older not on hormone therapy, who has had at least 
6 months of spontaneous amenorrhea, or
[iii] a woman at least 55 years of age with a diagnosis of menopause prior to 
starting hormone replacement therapy


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[4]
are between 18 and 64 years old for T1DM, or between 20 and 70 years old
for T2DM at the time of informed consent
[5]
have a body mass index of 18.5 to 30.0 kg/m2 for T1DM, or 18.5 to
35.0 kg/m2 for T2DM at the time of screening
[6]
have a hemoglobin A1c value ≤10% at the time of screening
[7]
have clinical laboratory test results within normal reference range (except for 
glycemic parameters) for the population or investigative site, or results with 
acceptable deviations that are judged to be not clinically significant by the 
investigator
[8]
have venous access sufficient to allow for blood sampling and administration 
of insulin for IV administration as per the protocol
[9]
are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures
[10] are able and willing to give 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:
[11] 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
[12] are Lilly employees
[13] are currently enrolled in a clinical trial involving an investigational product or 
any other type of medical research judged not to be scientifically or medically 
compatible with this study
[14] have participated, within the last 4 months, in a clinical trial involving an 
investigational product.  If the previous investigational product has a long 
half-life, 4 months or 5 half-lives (whichever is longer) should have passed
from the last dose of investigational product
[15] have previously completed or withdrawn from this study or any other study 
investigating LY900018, and have previously received LY900018
[16] have known allergies or sensitivity to LY900018, glucagon, related 
compounds, or any components of the formulation, or history of significant 
atopy
[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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LY900018
[18] 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
[19] have received a total daily dose of insulin >1.2 U/kg at the time of screening
[20] have poorly controlled hypertension (ie, supine systolic BP >165 mm Hg or 
supine diastolic BP >95 mm Hg) at screening, or a change in antihypertensive 
medications within 30 days prior to screening
[21] have a history of pheochromocytoma (ie, adrenal gland tumor) or insulinoma
[22] have a history of an episode of severe hypoglycemia (as defined by an episode 
that required third party assistance for treatment) in the 1 month prior to 
screening or have a history of loss of consciousness within the last 2 years 
induced other than by hypoglycemia
[23] have a history of epilepsy or seizure disorder
[24] have a history or presence of cardiovascular, respiratory, hepatic, renal, 
gastrointestinal, endocrine (apart from T1DM or T2DM), hematological, or 
neurological disorders capable of significantly altering the absorption, 
metabolism, or elimination of drugs; of constituting a risk when taking the 
investigational product; or of interfering with the interpretation of data
[25] have known or ongoing psychiatric disorders that, in the opinion of the 
investigator, may preclude the patient from following and completing the 
protocol
[26] regularly use known drugs of abuse and/or show positive findings on urinary 
drug screening
[27] show evidence of human immunodeficiency virus (HIV) infection and/or 
positive HIV antibodies and/or antigen
[28] show evidence of hepatitis C and/or positive hepatitis C antibody
[29] show evidence of hepatitis B and/or positive hepatitis B surface antigen
[30] show evidence of syphilis and/or are positive for syphilis test
[31] are women who are lactating
[32] use of daily systemic beta-blocker, indomethacin, warfarin, anticholinergic 
drugs
[33] have donated 400 mL or more blood in the last 12 weeks (males) or in the last 
16 weeks (females), or any blood donation (including apheresis) within the 
last 4 weeks, or total volume of blood donation within 12 months is 1200 mL 
(males)/800 mL (females) or more at screening


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[34] have an average weekly alcohol intake that exceeds 21 units per week (males 
up to age 65) and 14 units per week (males over 65 and females), or are 
unwilling to stop alcohol consumption from Day -2 to discharge from CRU in 
each period (1 unit = 12 oz or 360 mL of beer; 5 oz or 150 mL of wine; 1.5 oz 
or 45 mL of distilled spirits)
[35] in the opinion of the investigator or sponsor, are unsuitable for inclusion in the 
study
[36] have pre-proliferative and proliferative retinopathy or maculopathy requiring 
treatment or not clinically stable in the last 6 months, or patients with active 
changes in subjective eye symptoms as determined by the investigator if an 
eye exam has not been performed in the last 6 months.  
Note: If an eye examination has been performed no more than 6 months 
before screening, it will not have to be repeated; however, the investigator will 
need to confirm via interview that there is no change in subjective symptoms.
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.
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. Patients should not be given any calorie-containing 
food/drink during insulin-induced hypoglycemia and within 90 minutes of glucagon 
administration unless there is a safety concern. The patients will receive a carbohydrate-rich 
meal after completion of all pharmacokinetic (PK) blood sample collections, at 240 minutes post 
glucagon dose. Patients will be given access to calorie-free water up to 240 minutes post study 
treatment.
While resident in the CRU, patients should 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.
6.3.2. Caffeine, Alcohol, and Tobacco
Patients should refrain from caffeine-containing food/beverages (eg, cola, chocolate drinks, tea,
and coffee) from Day -1 to discharge from CRU in each period.  Patient alcohol intake should 
not exceed 21 units per week (males up to age 65) and 14 units per week (males over 65 and 
females) during the study. Patients must not consume alcohol from Day -2 to discharge from 
CRU in each period. Smoking will not be permitted when resident in the CRU.
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 admission or study visit.


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From the beginning of hypoglycemia induction to 240 minutes post study treatment, patients 
should remain recumbent or sitting on the bed.
6.3.4. Contraception
Male patients must use an effective method of contraception for the duration of the study and for 
28 days following the last study treatment.
Female patients of childbearing potential must use one highly effective method of contraception
(<1% failure rate; such as combined oral contraceptive pill, implanted contraceptives, or 
intrauterine device) or a combination of 2 effective methods of contraception (such as male or 
female condoms with spermicide [not approved in Japan], diaphragms with spermicide [not 
approved in Japan], or cervical sponges) during the study and for 28 days following the last 
study treatment.  The patient may choose to use a double barrier method of contraception.  
Barrier protection methods without concomitant use of a spermicide are not a reliable or 
acceptable method.  Thus, each barrier method must include use of a spermicide.  It should be 
noted that the use of male and female condoms as a double barrier method is not considered 
acceptable due to the high failure rate when these methods are combined.
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 of LY900018 administered once nasally to 1 mg 
glucagon administered IM (comparator).  Table IGBJ.2 shows the study treatment information.
Table IGBJ.2.
Study Treatments
Treatment Name
LY900018
GlucaGen
Dosage Formulation
Dry powder
Dry powder
Dosage Levels
3 mg glucagon
1 mg glucagon
Route of Administration
Intranasal
Intramuscular
Dosing Instructions
Administer a single nasal dose upon 
hypoglycemia onset
Administer a single intramuscular 
injection upon hypoglycemia onset
The procedure for insulin-induced hypoglycemia will require an IV infusion of diluted human 
regular insulin (0.3 U/mL by diluting 15 U human regular insulin [100 U/mL] into 50 mL 
saline).  Details regarding hypoglycemia induction and glucagon administration procedures are 
included in Sections 9.2.1 and 9.2.2, respectively.
The investigator or designee is responsible for:

explaining the correct use of the investigational products to the site personnel

verifying that instructions are followed properly

maintaining accurate records of investigational product dispensing and collection

and returning all unused medication 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 LY900018 and GlucaGen to the clinical site. Study materials will be provided as 
open-label material.
Investigational products must be stored at the investigational site, according to the instructions 
provided on the product label, in a locked and secure place.
Unused investigational products 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 its designee, according to written instruction from the sponsor.
7.1.2. Medical Devices
The manufactured drug product provided for use in the study includes a nasal delivery device as 
part of the investigational drug product.  The device component of the investigational drug 
product is inserted into the nasal cavity to deliver the contained drug constituent.


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7.2.
Method of Treatment Assignment
The treatment sequence to be administered for each enrolled patient will be determined 
according to a randomization table.
7.2.1. Selection and Timing of Doses
The hypoglycemia induction procedure should be initiated at approximately the same time at 
each treatment visit.  Insulin IV infusion will be given until PG is <60 mg/dL. At this point, 
insulin infusion will be stopped and, approximately 5 minutes later, a single glucagon dose 
(LY900018 or IMG) will be administered.  The doses will be administered at approximately the 
same times on each day.  The actual time of all dose administrations 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 patients’ PG concentrations 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 product
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).
7.6.
Treatment Compliance
The investigational product will be administered at the clinical site, and documentation of 
treatment administration will occur at the site.


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7.7.
Concomitant Therapy
Patients on stable concomitant medication at the time of study entry should continue their 
regular, unchanged dose throughout the study.  These medications include stable regimen for 
3 months of the anti-hyperglycemic therapy (for example, insulins and OAMs) as well as 
anti-hypertensive and anti-lipidemic medications.  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).
For patients using basal insulin, the last basal insulin injection should occur no later than 
12 hours prior to the insulin-induced hypoglycemia procedure, and the basal dose should not be 
changed.  Patients may inject basal insulin any time after the last PK sample is collected on 
Day 1 in each period.
For patients using prandial insulin, the last prandial insulin injection should occur no later than 
6 hours prior to the insulin-induced hypoglycemia procedure.  Patients may inject prandial 
insulin after the last PK sample is collected and before the meal on Day 1 in each period.  The 
first prandial insulin dose for an individual patient after insulin-induced hypoglycemia procedure 
should be determined by the investigator based on the PG before meal and carbohydrate intake.
For patients using an insulin pump, a continuous subcutaneous insulin infusion by pump should 
be discontinued prior to procedure to induce hypoglycemia.  Patients may start subcutaneous 
insulin infusion after the last PK sample is collected and before the meal on Day 1 in each period.  
The insulin dose should be determined by the investigator based on the PG before meal and 
carbohydrate intake.
For patients using OAMs, the last dose should occur no later than 12 hours prior to the 
insulin-induced hypoglycemia procedure.  Patients may start OAM after the last PK sample is 
collected on Day 1 in each period.
The following concomitant medications are prohibited to use during the course of the study: 
beta-blocker, indomethacin, warfarin, and anti-cholinergic drugs.
The following concomitant medications that affect gastric motility can be used during the study 
but should be washed out before 7 days of each period and not taken while in the CRU: 
pro-motility medications (eg, metoclopramide, domperidone), opiate medications (eg, morphine),
and medications with anti-emetic effects (eg, promethazine, prochlorperazine).
In general, concomitant medication should be avoided; however, acetaminophen (1 g, maximum 
2 g/24 hours) may be administered at the discretion of the investigator for treatment of 
headaches, etc.  If the need for concomitant medication (other than acetaminophen) arises, 
inclusion or continuation of the patients may be at the discretion of the investigator after 
consultation with a Lilly clinical pharmacologist (CP) or CRP.  Any medication used during the 
course of the study must be documented.
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 must complete AE and 
follow-up procedures as shown in the Schedule of Activities (Section 2).
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, a discussion must occur between the Lilly CP/CRP and the investigator to 
determine if the patient may continue in the study.  If both agree it is medically appropriate to 
continue, the investigator must obtain documented approval from the Lilly CP/CRP to allow the 
inadvertently enrolled patient to continue in the study with or without continued treatment with 
investigational product.
8.2.
Discontinuation from the Study
Patients will be discontinued in 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

investigator decision
o
the investigator decides that the patient should be discontinued from the study for 
any reason.  If this decision is made because of an AE, SAE, or a severe 
hypoglycemia event, appropriate measures are to be taken. Lilly or its designee is 
to be alerted.

patient decision
o
the patient, or legal representative, requests to be withdrawn from the study
8.3.
Discontinuation of the Study
Following the review of the safety data from the first 6 patients to complete Period 2 Day 1, the 
study will be stopped if deemed necessary for patient safety in the opinion of the Investigator and 
sponsor (Section 10.3.7).
8.4.
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.  Site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or were 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.
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 as described in Section 9.2.3 and will be used to assess 
efficacy outcomes.
9.1.1. Primary Efficacy Assessments
The primary efficacy measure is the proportion of patients achieving treatment success, defined 
as either an increase in PG to >70 mg/dL or an increase of >20 mg/dL from nadir within 
30 minutes after administration of glucagon.
9.1.2. Secondary Efficacy Assessments
Secondary efficacy measures will be determined from the pharmacodynamic (PD)
characterization of PG profiles, including evaluation of change from baseline PG concentrations.
9.1.3. Exploratory Efficacy Assessments
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 LY900018 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 Period 1 Day -1 (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. Insulin-induced Hypoglycemia
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 120 minutes following the 
glucagon administration.


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The bedside PG level, measured using a glucose analyzer (Antsense Duo, HORIBA Ltd. or 
equivalent), must be 90 to 250 mg/dL to start the procedure. If the bedside PG is outside of this 
range, the hypoglycemia induction should be rescheduled.
Hypoglycemia will be induced by IV infusion of diluted human regular insulin (0.3 U/mL) at a 
rate of 2 mU/kg/min.  The infusion rate may be adjusted as necessary up to a rate of 
3 mU/kg/min for T1DM or 4 mU/kg/min for T2DM to decrease bedside PG levels <60 mg/dL;
however, the rate of decrease in PG should not exceed 50 mg/dL per 30 minutes. When the 
bedside PG concentration reaches <90 mg/dL, the insulin infusion rate may be decreased to 
approximately 1.0 mU/kg/min at the investigator’s discretion.  Once the bedside PG level is 
<60 mg/dL, the insulin infusion will be stopped.  If the target bedside PG level cannot be 
achieved within 4 hours after the start of insulin infusion, the hypoglycemia induction procedure 
will be terminated before glucagon administration, and the patient may have a carbohydrate-rich 
meal and be discharged from the CRU after medical assessment. Additional safety assessments
may be conducted at the investigator’s discretion.  The patient may be rescheduled for a new 
dosing visit 1 to 7 days later.
For safety monitoring during the hypoglycemia induction procedure, bedside PG levels will be 
measured using the glucose analyzer no more than 10 minutes apart while PG is >90 mg/dL, and 
no more than 5 minutes apart when PG is <90 mg/dL.
Blood samples will be collected at pre-hypoglycemia induction and end of insulin infusion
(5 minutes prior to study treatment) for PG (PD, as measured by central laboratory) and/or 
glucagon (PK) measurements according to the Schedule of Activities (Section 2).
9.2.2. Glucagon Administration
Approximately 5 minutes after the insulin infusion has stopped, glucagon (either 3 mg 
LY900018 or 1 mg IMG) will be administered according to randomization.  Refer to Section 7
for details regarding treatments.
9.2.2.1.
Nasal LY900018 Administration
LY900018 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 (ie, dose is given in the left nostril 
of a patient lying in right lateral recumbency).
The tip of the drug product 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 drug product 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 patient sneezes immediately after administration, document using 
the Nasal and Non-nasal Score Questionnaire (see Appendix 6 for a copy of the questionnaire).
9.2.2.2.
Intramuscular Glucagon Administration
GlucaGen 1 mg for injection will be used as a comparator.  The lyophilized 1 mg glucagon will 
be reconstituted with 1.1 mL diluent according to the instruction.  A dose of 1 mg of glucagon in 


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a concentration of 1 mg/mL will be injected in the deltoid muscle of the patient’s nondominant 
arm with the patient lying in a fully reclined lateral position on the opposite side of the arm being 
administered (ie, dose is given in the left arm of a patient lying in right lateral recumbency if 
right arm is the dominant arm).
9.2.3. Post Glucagon Administration
For 120 minutes after glucagon administration, bedside PG levels will be measured no more than 
5 minutes apart when the PG is <90 mg/dL, and no more than 10 minutes apart when PG is 
>90 mg/dL using a glucose analyzer (Antsense Duo, HORIBA Ltd. or equivalent).  
Blood samples will be collected at predose and various time points post glucagon administration 
for PG (PD, as measured by central laboratory) and/or glucagon (PK) measurements according to 
the Schedule of Activities (Section 2).
To accurately capture the PG profile, the site should not give patients any calorie-containing 
food/drink within 90 minutes of glucagon administration unless there is a safety concern.
9.2.4. Procedures for Insufficient Response to Glucagon 
Administration
If the patient loses consciousness or the bedside PG is declining too fast or symptoms consistent 
with the progression to severe hypoglycemia occur, the investigator may decide to start a glucose 
infusion to prevent a deterioration of the situation.  Following the administration of glucagon, if 
a patient’s bedside PG concentration remains <55 mg/dL at 30 minutes or <60 mg/dL at 
45 minutes postdose, IV glucose may be given as deemed clinically necessary.  If IV glucose is 
given, the time and amount of glucose infusion will be recorded in the CRF.
9.2.5. End of Admission
Before discharge from the CRU, the glucose and insulin dosing and stability of the patient will 
be evaluated by the investigator to ensure patient safety.  Patients will remain at the CRU for at 
least 6 hours following glucagon administration, 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.
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.  The patient should be followed until the event resolves, stabilizes with 


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appropriate diagnostic evaluation, or is reasonably explained.  The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator.
After the informed consent form is signed, study site personnel will record, via CRF, 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, 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, medical 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, medical 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 one 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 one of the other outcomes listed in the definition above

when a condition related to the medical device 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 CRP/CP, or its designee, of any SAE as soon as 
practically possible.
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.  


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Although all AEs are recorded in the CRF 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 patient 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) 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 CRF and reported to Lilly or its designee
within 24 hours as SAEs.
9.3.2. Complaint Handling
Lilly collects product complaints on investigational products used in clinical trials in order to 
ensure the safety of study participants, monitor quality, and to facilitate process and product 
improvements.
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 so that the situation can be assessed.


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9.4.
Treatment of Overdose
For the purposes of this study, an overdose of LY900018 or IMG is considered any dose that is 
higher than the assigned dose.  Refer to the LY900018 IB and GlucaGen Summary of Product 
Characteristics for more information.
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).
Body temperature will be measured as specified in the Schedule of Activities (Section 2) and as 
clinically indicated.
Blood pressure and pulse rate should be measured after at least 5 minutes supine.
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms.  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.  Additional vital signs may be measured during each study 
period if warranted.
9.5.3. Electrocardiograms
For each patient, single and triplicate ECGs should be collected according to the Schedule of 
Activities (Section 2).
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 CRF.
Single ECGs will be collected and stored locally at the investigator’s site.
Triplicate ECGs will be electronically transmitted to a central ECG laboratory designated by 
Lilly.  The central ECG laboratory will perform a basic quality control check (for example, 
demographics and study details) then store the ECGs in a database.  At a future time, the stored 
ECG data may be overread at the central ECG laboratory for further evaluation of machine-read 
measurements or to meet regulatory requirements. Triplicate ECGs collected 30 and 15 minutes 
prior to the start of insulin-induced hypoglycemia on Day 1 of each period will be used to 


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establish a baseline.  The consecutive triplicate ECGs will be obtained at approximately 1-minute 
intervals.
When scheduled at the same time point, ECGs must be recorded before collecting any blood 
samples. Patients must be supine for at least 5 minutes before ECG collection and remain supine 
but awake during ECG collection.  Electrocardiograms may be obtained at additional times,
when deemed clinically necessary.
Single ECGs 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/corrected QT 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.
The machine-read ECG intervals and heart rate may be used for data analysis and report writing 
purposes unless a cardiologist overread of the ECGs is conducted prior to completion of the final 
study report (in which case the overread data would be used).  
9.5.4. Other Tests
Nasal inspections with nasal speculum and injection-site assessments will be conducted 
according to the Schedule of Activities (Section 2).  This inspection will ascertain whether sites 
are normal in appearance prior to and after drug administration.
9.5.5. Safety Monitoring
The Lilly CP 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 CP or 
CRP will periodically review the following data:

trends in safety data

laboratory analytes 

AEs including monitoring of nasal cavity and IM injection site
When appropriate, the Lilly CP or CRP will consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical research scientist.
9.5.5.1.
Hypoglycemic Event Reporting
Episodes of hypoglycemia (plasma glucose ≤70 mg/dL) that occur after the patient’s PG level 
returns to ≥100 mg/dL (at least after 30 minutes post study dose) at post study treatment on 
Day 1, will be described using the following definitions:  


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Documented Glucose Alert Level (Level 1)
Plasma glucose ≤70 mg/dL

Documented symptomatic hypoglycemia:  with typical symptoms of hypoglycemia.

Documented asymptomatic hypoglycemia:  without typical symptoms of 
hypoglycemia.

Documented unspecified hypoglycemia:  with no information about symptoms of 
hypoglycemia available.  (This has also been called unclassifiable hypoglycemia.)
Documented Clinically Significant Hypoglycemia (Level 2)
Similar criterion as for Level 1, except for threshold PG <54 mg/dL

Level 2 documented symptomatic hypoglycemia

Level 2 documented asymptomatic hypoglycemia

Level 2 documented unspecified hypoglycemia
Severe Hypoglycemia (Level 3)
Patient had altered mental status and could not assist in their own care, was semiconscious or 
unconscious, or experienced coma with or without seizures, and the assistance of another person 
was to actively administer carbohydrate, glucagon, or other resuscitative actions.  Plasma 
glucose measurements may not be available during such an event, but neurological recovery 
attributable to the restoration of PG concentration to normal is considered sufficient evidence 
that the event was induced by a low PG concentration (PG ≤70 mg/dL).  
Other Hypoglycemia

Nocturnal hypoglycemia:  Any documented hypoglycemic event (including severe 
hypoglycemia) that occurs at night and presumably during sleep.  This is captured as 
hypoglycemia that occurs between bedtime and waking.  This definition is more 
useful than the commonly used approximately 00:00 to 06:00 definition which does 
not take patients’ individual sleep times into consideration, and is consistent with the 
American Diabetes Association recommendations of reporting events that occur 
during sleep (ADA 2005).  It is also important to collect the actual time when a 
hypoglycemic event occurred to allow further characterization of hypoglycemia 
timing (eg, to allow analysis of frequency of events occurring across a 24-hour 
clock).  Nocturnal hypoglycemia may occur at severity Levels 1, 2, or 3.

Relative hypoglycemia (also referred to as pseudohypoglycemia [Seaquist et al. 
2013]):  An event during which typical symptoms of hypoglycemia occur, that does 
not require the assistance of another person and is accompanied by PG >70 mg/dL.  
The PG value of patients with chronically poor glycemic control can decrease so 
rapidly that patients may report symptoms of hypoglycemia before their PG 
concentration falls below 70 mg/dL.  Events with PG ≤70 mg/dL should not be 
categorized as relative hypoglycemia.  Evaluation and statistical analysis of this 
category is optional.  However, if a patient reports a relative hypoglycemia event 


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where assistance from another person was received or the patient experienced 
significant symptoms, the study team should clarify the circumstances to ensure the 
event is not a severe hypoglycemia event, and report it appropriately.  

Probable symptomatic hypoglycemia:  Symptoms of hypoglycemia were present, but 
PG measurement was not reported.

Overall (or total) hypoglycemia:  This optional category combines most cases of 
hypoglycemia (documented hypoglycemia and probable symptomatic hypoglycemia, 
including severe hypoglycemia).  It does not include relative hypoglycemia.  
Nocturnal and severe hypoglycemia are special cases of documented or probable 
hypoglycemia.  If an event of hypoglycemia falls into multiple subcategories, that 
event should only be counted once in the category of overall (or total) hypoglycemia.
Hypoglycemia episodes will be recorded on specific CRF pages.  Only severe hypoglycemic 
episodes will be reported separately as AEs.  If a hypoglycemic event meets the criteria of 
severe, it needs to be recorded as serious in the CRF (that is, recorded as an SAE).  In the case of 
a hypoglycemic event (other than severe), the actual glucose value, if measured, should be 
recorded in the CRF, with any treatments administered, and not be recorded as an AE.  Cases of 
hypoglycemia may be treated with foods rich in carbohydrate such as fruit, juice, skimmed milk, 
or energy bars.  All episodes of hypoglycemia that are determined by the investigator to 
constitute severe hypoglycemia according to the definition above should be reported as SAEs.
9.5.5.2.
Hepatic Safety
If a study patient experiences elevated alanine aminotransferase (ALT) ≥3× upper limit of 
normal (ULN), alkaline phosphatase (ALP) ≥2× ULN, or elevated total bilirubin (TBL)
≥2× ULN, liver tests (Appendix 4) should be repeated within 3 to 5 days including ALT, 
aspartate aminotransferase, ALP, 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 CP 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 ≥5× ULN on 2 or more consecutive blood tests

elevated serum TBL to ≥2× ULN (except for cases of known Gilbert’s syndrome)

elevation of serum ALP to ≥2× ULN on 2 or more consecutive blood tests 

patient 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 


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glucagon.  Three samples may be collected per patient at additional time points during the study 
if warranted and agreed upon between both the investigator and sponsor.  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 method.
Bioanalytical samples collected to measure investigational product concentrations will be 
retained for a maximum of 1 year following last patient visit for the study.
9.7.
Pharmacodynamics
At times specified in the Schedule of Activities (see Section 2), venous blood samples will be 
collected and used to determine PG concentrations.  
The samples will be stored for up to a maximum of 1 year after last patient visit for the study at a 
facility selected by the sponsor.
9.7.1. Immunogenicity Assessments
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
will be collected to determine antibody production against glucagon.  To interpret the results of 
immunogenicity, a venous blood sample may be collected at the same time points to determine 
the concentrations of glucagon.  All samples for immunogenicity should be taken predose when 
applicable.
In the event of drug hypersensitivity reactions (immediate or non-immediate), additional 
immunogenicity samples will be collected as close to the onset of the event as possible, at the 
resolution of the event, and 30 days following the event.  A PK sample may be collected at these 
same time points(s) if warranted and agreed upon between both the investigator and sponsor.
Treatment-emergent antidrug antibodies (TE ADA) are defined in Section 10.3.6.  If the 
immunogenicity titer at the last scheduled assessment or discontinuation visit meets the 
definition of treatment emergent, then, at the discretion of the sponsor, patients should be called 
back to the site for follow-up immunogenicity assessment(s).  Samples for immunogenicity 
should be collected every 12 weeks until the titer returns to baseline (ie, returns to within a single 
2-fold dilution of the baseline titer) or until 1 year after the last dose of study treatment.  A PK 
sample may be collected at the follow-up immunogenicity assessment(s) if warranted and agreed 
upon between both the investigator and sponsor.  Every attempt should be made to contact 
patients for the follow-up immunogenicity assessment; however, if patients are unwilling or 
unable to return for the visit, this is not considered a protocol violation.  


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Instructions for the collection and handling of blood samples will be provided by the sponsor.  
The actual date and time (24-hour clock time) of each sampling will be recorded.  
Immunogenicity will be assessed by a validated assay designed to detect antidrug antibodies 
(ADA) in the presence of glucagon at a laboratory approved by the sponsor.  Antibodies may be 
further characterized and/or evaluated for their ability to neutralize the activity of glucagon.  
Samples will be retained for a maximum of 15 years after the last patient 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.  
9.8.
Genetics
A blood sample will be collected for pharmacogenetic analysis as specified in the Schedule of 
Activities (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 nasal 
glucagon (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 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 LY900018 or after 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.  
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
Seventy five patients may be enrolled in order to have at least 66 patients (at least 30 patients 
with T1DM and T2DM, respectively) complete the study.  For purposes of this study, a 
completer is defined as a patient who completes both periods with evaluable primary outcome. 
If patients discontinue from the study before completion of both periods with evaluable primary 
outcome for any reason, the patient may be replaced to ensure 66 patients complete the study.  
The replacement patients will be assigned the same treatment sequence as the patients to be 
replaced and will complete that treatment sequence in its entirety.  Replacement should not occur
beyond 75 patients enrolled, if it is expected to have at least 66 patients complete the study.
Assuming a non-inferiority margin (NIM) of 10%, a 98% treatment success rate for both 
treatment groups, and a within-patient correlation of zero, 66 completers will provide at least 
90% power to show non-inferiority between LY900018 and IMG in treatment success from 
insulin-induced hypoglycemia with one-sided alpha level of 0.025 based on the Chi-square test.
The proposed NIM of 10% has been chosen based on the previously completed Phase 3 study 
(Rickels et al. 2016).
10.2. Populations for Analyses
10.2.1. Study Participant Disposition
A detailed description of patient disposition will be provided at the end of the study.
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 demographic characteristics will be recorded, listed,
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.
Efficacy, PK, and PD analyses will be conducted on the full analysis set.  This set includes all 
data from all randomized patients receiving at least one dose of the investigational product 
according to the treatment allocation.  Safety analyses will be conducted for all enrolled patients, 
whether or not they completed all protocol requirements.  If a patient receives a glucose infusion 
to prevent the progression to severe hypoglycemia (see Section 9.2.4), data after IV glucose 


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infusion may be excluded from the efficacy and PD analyses.  Details will be described in the 
statistical analysis plan (SAP).  
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.
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 analysis purposes to 
avoid issues with post-hoc analyses and incomplete disclosures of analyses.  
10.3.1. Efficacy Analyses
10.3.1.1. Primary Efficacy Analysis
The primary objective is to demonstrate that 3 mg LY900018 is non-inferior to 1 mg IMG for the 
proportion (NIM=10%) of Japanese patients with T1DM or T2DM who achieve treatment 
success without receiving additional actions to increase the PG concentration. Treatment success 
is defined as either an increase in PG to ≥70 mg/dL or an increase of ≥20 mg/dL from PG nadir 
within 30 minutes after receiving study treatment.  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 group and the difference in percentages will 
be computed. A 2-sided 95% confidence interval (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.  Non-inferiority of LY900018 will be declared if the upper limit of a 
2-sided 95% CI constructed on the difference in percentages (IMG - LY900018) is less than the 
NIM of 10%.
Primary efficacy analysis will only include patients who complete both treatment visits with
evaluable primary outcome.  The following will be considered as non-evaluable primary efficacy
outcomes and will be 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 who 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.  Additional analysis will be performed if deemed necessary.  The details will 
be provided in the SAP.


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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.  
10.3.1.3. Exploratory Efficacy Analyses
10.3.1.3.1.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 product and protocol procedure AEs will be listed, and, if the frequency of 
events allows, safety data will be summarized using descriptive methodology.
The incidence of symptoms 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.
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 that will be assessed include safety laboratory parameters, vital signs, and 
triplicated ECG parameters.  The parameters will be listed and summarized using standard 
descriptive statistics.  Additional analysis will be performed if warranted upon review of the 
data.  The details will be provided in the SAP.


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10.3.3. Pharmacokinetic Analyses
10.3.3.1. Pharmacokinetic Parameter Estimation
Patients who receive at least 1 dose of study treatment and have measurable glucagon 
concentrations will be included in the PK analysis dataset.  Pharmacokinetic parameter estimates 
for glucagon will be calculated using standard noncompartmental methods of analysis (NCA).  
The primary parameters for PK analysis will be maximal concentration (Cmax), area under the 
concentration versus time curve (AUC), and time to maximal concentration (Tmax) of glucagon.  
Other noncompartmental parameters, such as half-life, apparent clearance, and apparent volume 
of distribution, may be reported.
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).
Parameters will be individually calculated for each patient based on actual time of collection.
10.3.3.2. Pharmacokinetic Statistical Inference
Log-transformed PK parameters (such as Cmax and AUC) 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% CIs.
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.
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


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BGmax
maximal plasma glucose concentration
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 maximal concentration
The following PD parameters will be calculated using change from baseline concentrations of 
PG:
AUEC0-1.5
area under the effect concentration-time curve from time zero (predose) up to 
1.5 hours
BGmax
maximal plasma glucose concentration
Tmax
time to maximal concentration
Baseline PG concentrations will be concentrations from samples obtained immediately prior to 
glucagon dosing (ie, zero hour time point).
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.  The patients who 
receive IV glucose up to 90 minutes postdose will be excluded from the summary statistics.
10.3.4.2. Pharmacodynamic Statistical Inference
The PD parameters (such as BGmax and AUEC) 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% CIs.
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. Evaluation of Immunogenicity
The frequency and percentage of patients with preexisting (baseline) ADA, ADA at any time 
point after baseline, and patients with TE ADA to glucagon may be tabulated. 


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Treatment-emergent ADA are defined as those with a titer 2-fold (1 dilution) greater than the 
minimum required dilution of the assay, if no ADA were detected at baseline; or those with a 
4-fold (2 dilutions) increase in titer compared to baseline, if ADA were detected at baseline. For 
patients with TE ADA, the distribution of maximum titers may be described.  The frequency of 
neutralizing antibodies may also be tabulated.
The relationship between the presence of antibodies to glucagon and efficacy, PK parameters,
PD response, and safety results may be assessed.
10.3.7. Data Review During the Study
Access to safety data is scheduled to occur after the first 6 patients complete Period 2 Day 1.  
The purpose of this review is to initiate remaining patients’ dosing.  The investigator and the 
Lilly sponsor team will make the determination regarding initiation of remaining patients’ dose, 
based upon their review of the data.  
10.3.8. Interim Analyses
Access to the safety data, including AEs, SAEs, vital signs, ECGs, and safety laboratory tests, is 
scheduled to occur after the first 6 patients complete Period 2.  The purpose of the safety reviews 
is to ensure that the study procedures and treatment are safe enough to proceed with the 
remaining patients.  The investigator and the Lilly sponsor team will make the determination to 
proceed with randomization of the remaining patients based upon their review of the safety and 
tolerability data.  
A primary database lock will be conducted after last patient discharge from the CRU. The aim 
of the primary database lock is to enable data analysis to assess the primary/secondary 
objectives, and may include assessment of exploratory objectives.  The primary database lock 
will include all study data, except for immunogenicity data, up to the last patient discharge from 
the CRU.  
If patients need additional follow-up for TE ADA, an additional database lock may be conducted 
to develop the clinical study report.  The database lock may contain all patients’ data up to the
follow-up visit, except for immunogenicity data.  The final database lock is planned after all 
patients complete the follow-up period and additional follow-up for TE ADA (if needed).  


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11.
References
American Diabetes Association; Workgroup on Hypoglycemia. Defining and reporting
hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on
Hypoglycemia. Diabetes Care. 2005;28(5):1245-1249.
American Diabetes Association. Glycemic targets. Diabetes Care. 2017;40(suppl 1):S48-S56.
GlucaGen (glucagon [rDNA origin] for injection) [Summary of Product Characteristics]. 
Bagsvaerd, Denmark: Novo Nordisk; revised 2015. Available at:
https://www.medicines.org.uk/emc/medicine/4258#DOCREVISION. Accessed September 29, 
2017.
Glucagon G Novo for Injection [Package Insert]. Bagsvaerd, Denmark: Novo Nordisk; revised 
2016. Available at: 
http://www.pmda.go.jp/PmdaSearch/iyakuDetail/ResultDataSetPDF/620023_7229402D1036_
1_06. Accessed September 28, 2017.
Glucagon G Novo for Injection [Interview Form]. Bagsvaerd, Denmark: Novo Nordisk; 2015. 
Available at: http://www.info.pmda.go.jp/go/interview/1/620023_7229402D1036_1_007_1F. 
Accessed September 28, 2017.
GLUCAGON for Injection ITO [Package Insert]. Osaka, Japan: Kaigen Pharma Co., Ltd; 2016.
Available at: 
http://www.pmda.go.jp/PmdaSearch/iyakuDetail/ResultDataSetPDF/130616_7229400D1088_
1_11.
GLUCAGON for Injection ITO [Interview Form]. Osaka, Japan: Kaigen Pharma Co., Ltd; 2016. 
Available at: http://www.info.pmda.go.jp/go/interview/1/130616_7229400D1088_1_G07_1F. 
Accessed September 28, 2017.
Polonsky WH, Fisher L, Hessler D, Johnson N.  Emotional distress in the partners of type 1 
diabetes adults: worries about hypoglycemia and other key concerns. Diabetes Technol Ther.
2016;18:292-297.
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.
Reno FE, Normand P, McInally K, Silo S, Stotland P, Triest M, Carballo D, Piché C. A novel 
nasal powder formulation of glucagon: toxicology studies in animal models. BMC Pharmacol 
Toxicol. 2015;16:29.
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, Heller SR, Rodriguez H, 
Rosenzweig J, Vigersky R. Hypoglycemia and diabetes: a report of a workgroup of the 
American Diabetes Association and the Endocrine Society. Diabetes Care. 
2013;36(5):1384-1395


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Appendix 1.
Abbreviations and Definitions
Term
Definition
ADA
antidrug antibodies
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
patient 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
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 plasma glucose concentration
BP
blood pressure
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
Cmax
maximal 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, good clinical practice (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 point, depending on the steps 
required to obtain confirmed results.
CP
clinical pharmacologist


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CRF
case report form
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
CSII
continuous subcutaneous insulin infusion
Durationabove
duration above normal range
Durationbelow
duration below normal range
Durationwithin
duration within normal range
ECG
electrocardiogram
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
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.  
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical 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.


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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.
IM
intramuscular
IMG
intramuscular glucagon
IV
intravenous
NCA
noncompartmental methods of analysis
NIM
non-inferiority margin
OAM
oral anti-hyperglycemic medication
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.
randomize
The process of assigning patients to an experimental group on a random basis.
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PG
plasma glucose
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.  
SUSARs
suspected unexpected serious adverse reactions 
tabove
time to concentrations above normal range
tbelow
time to concentrations below normal range (after tabove)
TBL
total bilirubin
TE ADA
treatment-emergent antidrug antibodies
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 maximal concentration
twithin
time to concentrations within normal range


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T1DM
type 1 diabetes mellitus
T2DM
type 2 diabetes mellitus
ULN
upper limit of normal
WHO
World Health Organization


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Appendix 2.
Clinical Laboratory Tests
Safety Laboratory Tests
Hematologya
Clinical Chemistrya
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Chloride
Mean cell volume 
Calcium
Mean cell hemoglobin 
Phosphorus
Mean cell hemoglobin concentration 
Plasma Glucose
Platelets 
Blood urea nitrogen (BUN)
Leukocytes (WBC)
Uric acid
Cell morphology
Total cholesterol
Relative/% counts of:
Total protein
Neutrophils
Albumin
Lymphocytes
Total bilirubin
Monocytes
Alkaline phosphatase (ALP)
Eosinophils
Aspartate aminotransferase (AST)
Basophils
Alanine aminotransferase (ALT)
Creatinine
Urinalysisa
Gamma-glutamyl transferase (GGT)
Specific gravity
Insulin
pH
Protein
HbA1c c
Glucose
Ketones
Clinical Serology Testb
Bilirubin
Hepatitis B surface antigen
Urobilinogen
Hepatitis C antibody
Blood
HIV
Nitrite
Syphilis
Pregnancy testd
FSHb,e
Ethanol testingb
Urine drug screenb
Abbreviations:  FSH = follicle-stimulating hormone; HbA1c = hemoglobin A1c; HIV = human immunodeficiency 
virus; RBC = red blood cells; WBC = white blood cells.
a
Performed by the local laboratory at screening.  Performed by the sponsor-designated central laboratory at every 
treatment period and follow-up visit.
b
Performed at screening only by the local laboratory.
c
Performed by the local laboratory at screening and by the sponsor-designated central laboratory at other time 
point(s).
d
Female patients of childbearing potential only.  Serum pregnancy test at screening and urine pregnancy tests at 
every treatment period and follow-up visit will be performed by the local laboratory.
e
Female patients only, when needed to confirm postmenopausal status.


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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 informed consent form 
(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 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 must give assurance that the ethical review board (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 good clinical practice (GCP).
The study site’s ERB(s) should be provided with the following:

the current Investigator’s Brochure or Package Insert and updates during the course of the 
study

ICF 

relevant curricula vitae


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LY900018
Regulatory Considerations
This study will be conducted in accordance with the protocol and with:
1) consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) 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 final report coordinating investigator or designee will sign the clinical study report for this 
study, indicating agreement that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.
The investigator with the most enrolled patients will serve as the final report coordinating 
investigator.  If this investigator is unable to fulfill this function, another investigator will be 
chosen by Lilly to serve as the final report coordinating investigator.
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 case report forms (CRFs), and 
study procedures.

make periodic visits to the study site.

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax.


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LY900018

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, 
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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LY900018
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 clinical research 
physician.
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 cells; WBC = white blood cells.
a
Assayed by Lilly-designated 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-JE-IGBJ Sampling Summary
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa,b
27
1
27
Clinical laboratory testsa
9
3
27
Safety glucose monitoringc
1
140d
140
Pharmacokinetics (Glucagon)
4
32e,f
128
Pharmacodynamics (Plasma Glucose)
2
30
60
HbA1c (Period 1)
2
1
2
Anti-glucagon antibody
5
2e
10
Pharmacogenetics
5
1
5
Total
399
a
Additional samples may be drawn if needed for safety purposes.
b Because screening tests are performed at local laboratories at each site, this volume is an estimate and will vary 
depending on the local laboratory’s testing requirements.
c
Sample volume may vary by each clinical research unit.  The number of samples may vary by each patient.
d
Number of samples for safety glucose monitoring calculated assuming samples are collected approximately 
every 3 minutes for 90 minutes during hypoglycemia induction.  Samples collected for 90 minutes + 120 minutes
post glucagon dose = 210 minutes per period/3 = 70 samples per period × 2 periods = 140 samples total.
e
Samples for immunogenicity should be collected every 12 weeks until the titer returns to baseline (ie, returns to 
within a single 2-fold dilution of the baseline titer) or until 1 year after the last dose of study treatment.  A 
time-matched pharmacokinetics (glucagon) sample may be collected at the follow-up immunogenicity 
assessment(s) if warranted and agreed upon between both the investigator and sponsor.
f
Includes 3 additional samples to be drawn if needed.


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LY900018
Appendix 6.
Nasal and Non-nasal Score Questionnaire


I8R-JE-IGBJ(a) Clinical Pharmacology Protocol
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LY900018
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


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LY900018
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


I8R-JE-IGBJ(a) Clinical Pharmacology Protocol
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LY900018
Clarke Hypoglycemia Awareness Survey
1. 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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LY900018
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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LY900018 
Appendix 9. 
Protocol Amendment I8R-JE-IGBJ(a) 
Summary A Phase 3 Study of Nasal Glucagon 
(LY900018) Compared to Intramuscular Glucagon for 
Treatment of Insulin-induced Hypoglycemia in Japanese 
Patients with Diabetes Mellitus 
Overview 
Protocol I8R-JE-IGBJ A Phase 3 Study of Nasal Glucagon (LY900018) Compared to 
Intramuscular Glucagon for Treatment of Insulin-induced Hypoglycemia in Japanese Patients 
with Diabetes Mellitus has been amended.  The new protocol is indicated by Amendment (a) and 
will be used to conduct the study in place of any preceding version of the protocol. 
The overall changes and rationale for the changes made to this protocol are as follows: 
• An exclusion criterion for patients with retinopathy or maculopathy was added due to the 
potential risk of fundal hemorrhage induced by hypoglycemia. 
• The GlucaGen reconstitution volume was changed from 1.0 mL to 1.1 mL in accordance 
with instructions in the Summary of Product Characteristics (2015). 


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LY900018 
Revised Protocol Sections 
Note: 
All deletions have been identified by strikethroughs. 
All additions have been identified by the use of underscore. 
 
The numbering system used for inclusion and exclusion criteria provides a unique number for 
each criterion and allows for efficiency in data collection. 
In case an amendment to the protocol adds a criterion, that criterion will receive the next 
available number, regardless of whether it is an inclusion or exclusion criterion. 
6.2. 
Exclusion Criteria 
[36] have preproliferative and proliferative retinopathy or maculopathy requiring 
treatment or not clinically stable in the last 6 months, or patients with active 
changes in subjective eye symptoms as determined by the investigator if an 
eye exam has not been performed in the last 6 months.   
Note:  If an eye examination has been performed no more than 6 months 
before screening, it will not have to be repeated; however, the investigator will 
need to confirm via interview that there is no change in subjective symptoms. 
9.2.2.2. 
Intramuscular Glucagon Administration 
GlucaGen 1 mg for injection will be used as a comparator.  The lyophilized 1 mg glucagon will 
be reconstituted with 1.01.1 mL diluent according to the instruction. 

SAP_001.pdf: 
I8R-JE-IGBJ Statistical Analysis Plan  
A Phase 3 Study of Nasal Glucagon (LY900018) Compared to Intramuscular Glucagon for 
Treatment of Insulin-induced Hypoglycemia in Japanese Patients with Diabetes Mellitus 
 
NCT03421379 
 
Approval Date: 02-Feb-2018 
 
 
 


Final, 01 Feb 2018
             Page 1 of 26
STATISTICAL ANALYSIS PLAN
A Phase 3 Study of Nasal Glucagon (LY900018) Compared to Intramuscular Glucagon for 
Treatment of Insulin-induced Hypoglycemia in Japanese Patients with Diabetes Mellitus
Statistical Analysis Plan Status:  Final
Statistical Analysis Plan Date:  01 February 2018
Study Drug:  LY900018
Sponsor Reference:  I8R-JE-IGBJ
Covance CRU Study: 1001215- 8376828
Clinical Phase I
Approval Date: 02-Feb-2018 GMT


Final, 01 Feb 2018
             Page 2 of 26
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8376828
Sponsor Reference I8R-JE-IGBJ
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS .....................................................................................................2
2.
ABBREVIATIONS..............................................................................................................4
3.
INTRODUCTION ...............................................................................................................6
4.
STUDY OBJECTIVES........................................................................................................6
4.1
Primary .........................................................................................................................6
4.2
Secondary......................................................................................................................6
4.3
Exploratory Objectives ..................................................................................................7
5.
STUDY DESIGN.................................................................................................................7
6.
TREATMENTS...................................................................................................................8
7.
SAMPLE SIZE JUSTIFICATION .......................................................................................8
8.
DEFINITION OF ANALYSIS POPULATIONS..................................................................9
9.
STATISTICAL METHODOLOGY .....................................................................................9
9.1
General..........................................................................................................................9
9.2
Demographics and Subject Disposition........................................................................10
9.3
Efficacy Assessment....................................................................................................10
9.3.1
Primary Efficacy Analysis ..................................................................................10
9.3.2
Additional Analyses Related to Primary Efficacy Outcome ................................11
9.4
Pharmacokinetic Assessment.......................................................................................12
9.4.1
Pharmacokinetic Analysis...................................................................................12
9.4.2
Pharmacokinetic Statistical Methodology ...........................................................16
9.5
Pharmacodynamic Assessment ....................................................................................16
9.5.1
Pharmacodynamic Analysis................................................................................16
9.5.2
Pharmacodynamic Statistical Methodology ........................................................17
9.5.3
Plasma Glucose Values Statistical Methodology.................................................18
9.6
Safety and Tolerability Assessments............................................................................19
9.6.1
Adverse events ...................................................................................................19
9.6.2
Concomitant medication.....................................................................................19
9.6.3
Clinical laboratory parameters............................................................................20
9.6.4
Vital signs ..........................................................................................................20
9.6.5
Electrocardiogram (ECG)...................................................................................20
9.6.6
Injection-site assessment.....................................................................................21
9.6.7
Hepatic Safety....................................................................................................21
9.6.8
Nasal Inspection.................................................................................................21
9.6.9
Hypoglycemic episodes......................................................................................21
9.6.10
Nasal and Non-nasal Score Questionnaire...........................................................22
9.6.11
Edinburgh Hypoglycemia Scale: Experimental Hypoglycemia ...........................22
9.6.12
Immunogenicity .................................................................................................22


Final, 01 Feb 2018
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8376828
Sponsor Reference I8R-JE-IGBJ
9.6.13
Other assessments...............................................................................................23
9.6.14
Safety and Tolerability Statistical Methodology..................................................23
10. INTERIM ANALYSES .....................................................................................................23
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ............23
12. REFERENCES ..................................................................................................................23
13. DATA PRESENTATION ..................................................................................................24
13.1 Derived Parameters .....................................................................................................24
13.2 Missing Data ...............................................................................................................24
13.3 Insufficient Data for Presentation ................................................................................24
14. APPENDIX........................................................................................................................24
14.1 Appendix 1 Definitions of Nasal/Respiratory/Anosmia AEs ........................................24


Final, 01 Feb 2018
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8376828
Sponsor Reference I8R-JE-IGBJ
2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
AE
Adverse event
AES
All Entered Set Population
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ARS
All Randomized Set Population
AUC
Area under the concentration versus time curve
AUEC
Area under the effect concentration-time curve
AUC(0-4)
Area under the concentration versus time curve from time zero to 4 
hours post-dose
AUC(0-tlast)
Area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable concentration
AUC(0-∞)
Area under the concentration versus time curve from time zero to 
infinity
%AUC(tlast-)
percentage of AUC(0-∞) extrapolated
BGmax
Maximal plasma glucose concentration
BQL
Below the lower limit of quantitation
Clast
Last measureable drug concentration
CL/F
Apparent total body clearance of drug calculated after extra-vascular 
administration
CI
Confidence interval
Cmax
Maximum observed drug concentration
CRF
Case Report Form
CRP
Clinical research physician
CRU
Clinical Research Unit
CSR
Clinical Study Report
CV
Coefficient of variation
EAS
Efficacy Analysis Set Population
EC
Early Clinical 
ECG
Electrocardiogram


Final, 01 Feb 2018
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8376828
Sponsor Reference I8R-JE-IGBJ
e.g.
For example (Latin: exempli gratia)
FAS
Full Analysis Set Population
ICH
International Council on Harmonisation
IM
Intramuscular 
IN
Intranasal 
IMG
Intramuscular glucagon
IV
Intravenous 
KM
Kaplan-Meier
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed model with repeated measures
NG
Nasal glucagon
NIM
Non-inferiority margin
PD
Pharmacodynamic
PK
Pharmacokinetic
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SD
Standard deviation 
TBL
Total bilirubin
TFLs
Tables, Figures, and Listings
T1DM
Type 1 diabetes mellitus
T2DM
Type 2 diabetes mellitus
t1/2
Half-life associated with the terminal rate constant (λz) in non-
compartmental analysis
tmax
Time of maximum observed drug concentration
Tmax
Time to maximum concentration
ULN
Upper limit of normal
Vz/F
Apparent volume of distribution during the terminal phase after 
extra-vascular administration
Vss/F
Apparent volume of distribution at steady state after extra-vascular 
administration
WHO
World Health Organization


Final, 01 Feb 2018
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8376828
Sponsor Reference I8R-JE-IGBJ
3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
26 October 2017 and protocol amendment (a) (final version dated 05 December 2017).
This SAP describes the planned analysis of the safety, tolerability and pharmacokinetic (PK) and 
pharmacodynamic (PD) data from this study. A detailed description of the planned TFLs to be 
presented in the clinical study report (CSR) is provided in the accompanying TFL shell 
document.
The intent of this document is to provide guidance for the statistical and PK analyses of data. In 
general, the analyses are based on information from the protocol, unless they have been modified 
by agreement between Eli Lilly and Company and Covance Early Clinical (EC) Biometrics. A 
limited amount of information concerning this study (e.g., objectives, study design) is given to 
help the reader’s interpretation. This SAP must be signed off prior to first subject administration
for this study. When the SAP and TFL shells are agreed upon and finalized, they will serve as the 
template for this study’s CSR.
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon 
between Eli Lilly and Company and Covance EC Biometrics and identified in the CSR. Any 
minor deviations from the TFLs may not be documented in the CSR.
This SAP is written with consideration of the recommendations outlined in the International 
Council on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials1 and the ICH E3 Guideline entitled Guidance for Industry:
Structure and Content of Clinical Study Reports2.
4. STUDY OBJECTIVES
4.1
Primary
The primary objective is:

To demonstrate that 3 mg LY900018 is non-inferior to 1 mg intramuscular glucagon 
(IMG) for the proportion of patients achieving treatment success from insulin-induced 
hypoglycaemia using a non-inferiority margin of 10%.
4.2
Secondary
The secondary objectives are:

To compare the safety and tolerability of 3 mg LY900018 with 1 mg IMG

To characterize the PK profile of 3 mg LY900018 compared to 1 mg IMG

To characterize the PD profile of 3 mg LY900018 compared to 1 mg IMG


Final, 01 Feb 2018
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8376828
Sponsor Reference I8R-JE-IGBJ
4.3
Exploratory Objectives
The exploratory objectives are:

To explore the formation of anti-glucagon antibodies to glucagon

To evaluate the recovery from clinical symptoms of hypoglycemia
5. STUDY DESIGN
This is a Phase 3, multicenter, randomized, open-label, active comparator, single-dose, 2-period, 
2-treatment, crossover study in Japanese patients with Type 1 diabetes mellitus (T1DM) and 
Type 2 diabetes mellitus (T2DM). The study consists of a screening period; treatment period 1 
(Period 1); washout period; treatment period 2 (Period 2); follow-up period. Figure 1 illustrates 
the study design. Prior to the study drug administration on Period 1 Day 1, patients will be 
randomly assigned to a treatment sequence (either LY900018 in Period 1 and IMG in Period 2, 
or vice versa). 
Safety data will be reviewed after the first 6 patients (regardless of type of diabetes) are 
administered LY900018 in Period 2, and the remaining patients will be dosed after confirmation 
of the safety. The investigator and Lilly clinical research physician (CRP) or scientist will review 
available safety data, including adverse events (AEs), serious adverse events (SAEs), vital signs, 
electrocardiograms (ECGs), and safety laboratory tests, from these patients after they complete 
Period 2 Day 1. If no clinically significant safety findings for treatment or study procedure are 
noted, the remaining patients will be dosed.
In each treatment period, patients will undergo a procedure to induce hypoglycemia using
intravenous (IV) insulin infusion and serial blood sampling will be conducted to monitor bedside
plasma glucose (PG) for safety. The insulin infusion will be stopped once the PG level reaches 
<60 mg/dL and approximately 5 minutes later patients will be administered either 3 mg 
LY900018 or 1 mg IMG (GlucaGen). Serial blood sampling will be performed for glucagon (for 
PK) and PG (for PD) concentration measurements immediately before and up to 4 hours 
following the administration of glucagon. In each period, patients will remain in the Clinical 
Research Unit (CRU) for at least 6 hours after glucagon administration. All patients will receive 
a carbohydrate-rich meal prior to discharge. Patients may stay longer as needed, at the discretion 
of the investigator. Study governance considerations are described in detail in Appendix 3 of the 
protocol.


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Abbreviations:  IM = intramuscular. 
Figure 1. Illustration of study design
6. TREATMENTS
The following is a list of the study treatment abbreviations that will be used in the TFLs.
Study Treatment Name
Treatment order in TFL
3 mg LY900018 glucagon IN
1
1 mg GlucaGen glucagon IM
2
IM = intramuscular; IN = intranasal
7. SAMPLE SIZE JUSTIFICATION
Seventy five patients may be enrolled in order to have at least 66 patients (at least 30 patients 
with T1DM and T2DM, respectively) complete the study. For purposes of this study, a completer 
is defined as a patient who completes both periods with evaluable primary outcome. If patients 
discontinue from the study before completion of both periods with evaluable primary outcome 
for any reason, the patient may be replaced to ensure 66 patients complete the study. The 
replacement patients will be assigned the same treatment sequence as the patients to be replaced 
and will complete that treatment sequence in its entirety. Replacement should not occur beyond 
75 patients enrolled, if it is expected to have at least 66 patients complete the study.
Assuming a non-inferiority margin (NIM) of 10%, a 98% treatment success rate for both 
treatment groups, and a within-patient correlation of zero, 66 completers will provide at least 
90% power to show non-inferiority between LY900018 and IMG in treatment success from 
insulin-induced hypoglycemia with one-sided alpha level of 0.025 based on the Chi-square test. 
The proposed NIM of 10% has been chosen based on the previously completed Phase 3 study 
(Rickels et al. 2016)3.


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8. DEFINITION OF ANALYSIS POPULATIONS
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.
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when subjects are assigned to analysis populations.
9. STATISTICAL METHODOLOGY
9.1
General
Data listings will be provided for all data that is databased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include the arithmetic mean, arithmetic standard deviation (SD), median, 
minimum (and/or 1st quartile), maximum (and/or 3rd quartile) and N; for log-normal data (e.g. 
the PK parameters: area under the concentration versus time curve [AUCs] and the maximum 
observed drug concentration [Cmax]) the geometric mean and geometric coefficient of variation 
(CV%) will also be presented. For categorical data, frequency count and percentages will be 
presented. Data listings will be provided for all subjects up to the point of withdrawal, with any 
subjects excluded from the relevant population highlighted. Summary statistics and statistical 
analyses will generally only be performed for subjects included in the relevant analysis 
population. For the calculation of summary statistics and statistical analysis, unrounded data will 
be used. 
Mean change from baseline is the mean of all individual subjects’ change from baseline values. 
Each individual change from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint. The individual subject’s change from baseline 
values will be used to calculate the mean change from baseline using a SAS procedure such as 
Proc Univariate.
As the study includes T1DM and T2DM patients, the following parameters will be reported by 
diabetes type and the results will be included in (but not limited to) the summary report:


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Subject Disposition
Demographics
Proportion of Treatment Success 
PK parameters
PD parameters
Plasma Glucose values over time
Adverse events
Hypoglycemia
Data analysis will be performed using SAS® Version 9.4 or greater.
9.2
Demographics and Subject Disposition
Subject disposition will be listed. The demographic variables age, sex, race, ethnicity, country of 
enrolment, site ID, body weight, height, body mass index, duration of diabetes (years), baseline 
HbA1c value (%), baseline Clarke Hypoglycemia Awareness status (%) and baseline substance 
use (alcohol) will be summarized and listed. A frequency of previous diabetic therapy will also 
be produced and listed.
Summary outputs and statistical analyses will be produced by diabetes type.
9.3
Efficacy Assessment
9.3.1 Primary Efficacy Analysis
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 nasal glucagon (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.
Primary efficacy analysis will only include patients who complete both treatment visits with
evaluable primary outcome. The analysis will be performed separately for each diabetes type.
The following will be considered as nonevaluable primary efficacy outcome and excluded from 
the analysis related to primary efficacy outcome:


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
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. 
9.3.2 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 diabetic type, and compared using the same method 
as for the primary efficacy analysis specified above.

ARS

Patients in EAS population with nadir glucose <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
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


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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.
9.4
Pharmacokinetic Assessment
9.4.1 Pharmacokinetic Analysis
Pharmacokinetic parameter estimates will be determined using non-compartmental procedures in 
validated software program (Phoenix WinNonlin Version 6.4 or later).
Plasma concentrations of glucagon will be used to determine the following PK parameters 
following LY900018 and GlucaGen administration, when possible:  


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Parameter
Units
Definition
AUC(0-4)
pmol.h/L
area under the concentration versus time curve from time zero to 4 
hours post-dose
AUC(0-tlast)
pmol.h/L
area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable 
concentration
AUC(0-∞)
pmol.h/L
area under the concentration versus time curve from time zero to 
infinity
%AUC(tlast-)
%
percentage of AUC(0-∞) extrapolated
Cmax
pmol/L
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 
non-compartmental analysis
CL/F
L/h
apparent total body clearance of drug calculated after 
extra-vascular administration
Vz/F
L
apparent volume of distribution during the terminal phase after 
extra-vascular administration
Vss/F
L
apparent volume of distribution at steady state after extra-vascular 
administration
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).
Additional PK parameters may be calculated, as appropriate. The software and version used for 
the final analyses will be specified in the clinical study report. 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 non-bolus pre-dose sampling times which will be set to zero.

Cmax and tmax will be reported from observed values. If Cmax occurs at more than one 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 three 
consecutive plasma concentrations above the lower limit of quantification (LLOQ), with 
at least one of these concentrations following Cmax. 


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
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. Half-life 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 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 below the lower limit of 
quantitation (BQL). Plasma concentrations reported as BQL will be set to a value of zero 
when all of the following conditions are met: 

The compound is non-endogenous.

The samples are from the initial dose period for a subject or from a 
subsequent dose period following a suitable wash-out period.

The time points occur before the first quantifiable concentration.

All other BQL concentrations that do not meet the above criteria will be set to missing. 

Also, where two or more consecutive concentrations are BQL towards the end of a 
profile, the profile will be deemed to have terminated and 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 vs. Time Profiles
o
Individual concentrations will be plotted utilizing actual sampling times.
o
The terminal point selections will be indicated on a semi-logarithmic plot.
o
Baseline corrected concentration plots will also be presented
Average Concentration vs. Time Profiles
o
The average concentration profiles will be graphed using scheduled (nominal) 
sampling times. 
o
The average concentration profiles will be graphed using arithmetic average 
concentrations.
o
Quantifiable concentrations will be used to calculate average concentrations.


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o
Concentrations at a sampling time exceeding the sampling time window specified 
in the protocol, or ± 10%, will be excluded from the average concentration 
profiles.
o
Concentrations excluded from the mean calculation will be documented in the 
final study report.
o
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 pharmacokinetic 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 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 one 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.


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Reporting of Excluded Values
Individual values excluded as outliers will be documented in the final report. Approval of the 
final report will connote approval of the exclusion.
9.4.2 Pharmacokinetic Statistical Methodology
The PK parameters will be statistically analysed, listed and summarized by diabetic type and 
overall.
Log-transformed PK parameters (such as Cmax and AUC) 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% confidence intervals (CIs).
Example SAS code:
proc mixed data=test covtest alpha=0.1;
   by parameter;
   class treatment patient period sequence;
   model log_pk = treatment period sequence / ddfm=kr alpha=0.1;
   random patient;
   lsmeans treatment / pdiff cl alpha=0.1;
   ods output lsmeans=lsmeans;
   ods output diffs=diffs;
  ods output covparms=cov;
run;
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.
9.5
Pharmacodynamic Assessment
9.5.1 Pharmacodynamic Analysis
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 
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:


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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.
9.5.2 Pharmacodynamic Statistical Methodology
The PD parameters will be statistically analysed, listed and summarized by diabetic type and 
overall.
The PD parameters (such as BGmax and area under the effect concentration-time curve [AUEC]) 
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. Similar SAS code will be used as in the PK analysis.
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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9.5.3 Plasma Glucose Values Statistical Methodology
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 
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, time points and their interaction 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 modelled 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 treatment*time /solution
ddfm=kr;
repeated time(visit)/subject=patient type=un;
lsmeans treatment*time/cl diff om;
run;
As an exploratory analysis and if there is sufficient data, a subgroup analysis of plasma glucose 
over time by concomitant oral diabetes drug will be performed (with particular focus on 
Sulfonylureas).  The purpose of the analysis is to assess whether the concomitant oral diabetes 


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drug triggers rebound hypoglycaemia or not. For each concomitant oral diabetes drug, the data 
will be summarized by treatment and diabetes type.
9.6
Safety and Tolerability Assessments
9.6.1 Adverse events
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the AE will be reported in the listings, only the most severe will be used in the summary 
tables. A pre-existing condition is defined as an AE that starts before the subject has provided 
written informed consent and is ongoing at consent. A non-treatment emergent AE is defined as 
an AE which starts after informed consent but prior to dosing. A treatment-emergent AE is 
defined as an AE which occurs postdose or which is present prior to dosing and becomes more 
severe postdose.
All AEs will be listed. Treatment-emergent AEs will be summarized by diabetic type, treatment, 
severity and relationship to the study drug. The frequency (the number of AEs, the number of 
subjects experiencing an AE and the percentage of subjects experiencing an AE) of 
treatment-emergent AEs will be summarized by treatment, Medical Dictionary for Regulatory 
Activities (MedDRA) version 20.1 system organ class and preferred term. The summary and 
frequency AE tables will be presented for all causalities and those considered related to the study 
drug. Any serious AEs will be tabulated.
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.
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.
Clinically significant abnormal findings through electrocardiograms (ECGs), nasal inspection, 
injection site inspection, and physical examination will be captured as AEs.
9.6.2 Concomitant medication
Concomitant medication will be coded using the World Health Organization (WHO) drug 
dictionary (Version March 2017). Concomitant medication will be listed. A listing of rescue 
therapy will also be provided for the ARS.


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Statistical Analysis Plan 
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Covance Clinical Study No. 1001215-8376828
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9.6.3 Clinical laboratory parameters
All clinical chemistry and hematology data will be summarized by parameter and treatment, and 
listed. Urinalysis data will be listed. Additionally clinical chemistry, hematology and urinalysis 
data outside the reference ranges will be listed.
Values for any clinical chemistry, hematology and urinalysis values outside the reference ranges 
will be flagged on the individual subject data listings.
9.6.4 Vital signs
Vital signs data will be summarized by treatment together with changes from baseline, where 
baseline is defined as Day 1 predose of each period. Figures of mean vital signs and mean 
changes from baseline profiles by treatment will be presented by treatment. 
Furthermore, values for individual subjects will be listed.
The shift of abnormalities of vital signs from baseline to post treatment will also be summarized 
by treatment group. For this shift analysis, the high limit is 140 mm Hg for systolic blood 
pressure, 90 mm Hg for diastolic blood pressure, and 100 bpm for pulse; the low limit is 
90 mm Hg for systolic blood pressure, 50 mm Hg for diastolic blood pressure, and 50 bpm for 
pulse.
All timepoints will be presented on summary tables and figures.
9.6.5 Electrocardiogram (ECG)
Triplicate ECG data will be obtained directly from the 12-lead ECG traces. These data include 
the PR, QT, QTcB intervals, QRS duration and heart rate, where QTcB is the QT interval 
corrected using Bazett’s formula. In addition, the QT interval corrected using Fridericia’s 
formula (QTcF) will be calculated as follows:


3 60HR
QT
QTcF 
The mean of the triplicate data will be used for subsequent calculations. The ECG data will be 
summarized by treatment together with changes from baseline, where baseline is defined as Day 
1 predose of each period. Figures of mean ECG data and mean changes from baseline will be 
presented by treatment. The frequency of subjects with a maximum increase from baseline in 
QTcF interval will be summarized for each treatment according to the following categories: >30 
ms and >60 ms. In addition, the frequency of subjects with QTcF postdose values, according to 
the following categories: >450 ms, >480 ms and >500 ms, will be summarized by treatment.
All timepoints will be presented on summary tables and figures.
A plasma LY900018 concentration-QT analysis will be performed to assess the changes from 
baseline (Day 1 predose of each period) QTcF interval relative to plasma LY900018. BLQ 


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Statistical Analysis Plan 
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Covance Clinical Study No. 1001215-8376828
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LY900018 concentration data will be imputed to 50% of the LLOQ for the purposes of the 
analysis. The analysis will be performed by plotting change from baseline QTcF against 
LY900018 concentrations, including all post dosing timepoints. The plot will be produced 
separately for each treatment and diabetes type.
A mixed effects analysis model will be performed on the change from baseline QTcF values and 
will include LY900018 concentration as a covariate and subject as a random effect. The results 
of the model and associated 90% CI will be fitted on the plot and the p-value for the slope 
reported.
9.6.6 Injection-site assessment
Injection-site assessment data (erythema, induration, categorical pain, pruritus and edema) will 
be listed and summarized in frequency tables.
9.6.7 Hepatic Safety
If a study patient experiences elevated alanine aminotransferase (ALT) ≥3× upper limit of 
normal (ULN), alkaline phosphatase (ALP) ≥2× ULN, or elevated total bilirubin (TBL) ≥2× 
ULN, liver tests (Protocol Appendix 4) should be repeated to confirm the abnormality and to 
determine if it is increasing or decreasing. 
The subjects’ liver disease history and associated person liver disease history data will be listed. 
Any concomitant medication of acetaminophen/paracetamol will be listed. Results from any 
hepatic monitoring procedures, such as a magnetic resonance elastography scan, and a biopsy 
assessment will be listed, if performed.
Hepatic risk factor assessment data will be listed. Liver related signs and symptoms data will be 
summarized by treatment and listed. Alcohol and recreational drug use data will also be listed.
All hepatic chemistry, hematology, coagulation, and serology data will be listed. Values outside 
the reference ranges will be flagged on the individual subject data listings.
9.6.8 Nasal Inspection
Nasal inspections will be performed for safety monitoring purposes only and will not be 
presented.
9.6.9 Hypoglycemic episodes
Hypoglycemic event data will be listed and summarized by hypoglycemia category, treatment 
and diabetes type as defined in the Protocol (Section 9.5.5.1).
Severe hypoglycemic events will be reported separately as SAEs.


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Statistical Analysis Plan 
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Covance Clinical Study No. 1001215-8376828
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9.6.10 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 the plasma glucose analysis.
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.
9.6.11 Edinburgh Hypoglycemia Scale: Experimental Hypoglycemia
The Edinburgh Hypoglycemia Scale data will be analyzed in the same way as the nasal 
questionnaire data for the ARS.
If a patient receives rescue treatment to raise PG concentrations, measurements taken after the 
rescue will be excluded from the analysis.
9.6.12 Immunogenicity
The frequency and percentage of patients with pre-existing (baseline) ADA, ADA at any time 
point after baseline, and patients with TE ADA to glucagon will be tabulated if available.
Treatment-emergent ADA are defined as those with a titer 2-fold (1 dilution) greater than the 
minimum required dilution of the assay, if no ADA were detected at baseline; or those with a 
4-fold (2 dilutions) increase in titer compared to baseline, if ADA were detected at baseline. For 
patients with TE ADA, the distribution of maximum titers will be tabulated if available. The 
frequency of neutralizing antibodies will also be tabulated if available.
If there is antibody presence, the relationship between the presence (or absence) of antibodies 
and clinical parameters (AEs, efficacy measures, and so on) will be assessed. Likewise, the 
relationship between the presence of antibodies and the PK/PD parameters to LY900018 will be 
assessed.


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Statistical Analysis Plan 
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Covance Clinical Study No. 1001215-8376828
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9.6.13 Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed.
9.6.14 Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.
10.
INTERIM ANALYSES
Access to the safety data, including AEs, SAEs, vital signs, ECGs, and safety laboratory tests, is 
scheduled to occur after the first 6 patients complete Period 2. The purpose of the safety reviews 
is to ensure that the study procedures and treatment are safe enough to proceed with the 
remaining patients. The investigator and the Lilly sponsor team will make the determination to 
proceed with randomization of the remaining patients based upon their review of the safety and
tolerability data.
A primary database lock will be conducted after last patient discharge from the CRU. The aim of 
the primary database lock is to enable data analysis to assess the primary/secondary objectives, 
and may include assessment of exploratory objectives. The primary database lock will include all 
study data, except for immunogenicity data, up to the last patient discharge from the CRU.
If patients need additional follow-up for TE ADA, an additional database lock may be conducted 
to develop the CSR. The database lock may contain all patients’ data up to the follow-up visit, 
except for immunogenicity data. The final database lock is planned after all patients complete the 
follow-up period and additional follow-up for TE ADA (if needed).
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
There were no changes from the protocol specified statistical analyses.
12.
REFERENCES
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998.
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.
3. 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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Covance Clinical Study No. 1001215-8376828
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13.
DATA PRESENTATION
13.1
Derived Parameters
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be 
reported to three significant figures. Observed concentration data, e.g. Cmax, should be reported 
as received. Observed time data, e.g. tmax, should be reported as received. N and percentage 
values should be reported as whole numbers. Median values should be treated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values.
13.2
Missing Data
Missing data will not be displayed in listings.
13.3
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of subjects or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the centre of the table, 
such as, “No serious adverse events occurred for this study.”
14.
APPENDIX
14.1
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


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Statistical Analysis Plan 
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Covance Clinical Study No. 1001215-8376828
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10051712 
Nasal cyst 
Respiratory, thoracic and mediastinal disorders
10052437 
Nasal discomfort 
Respiratory, thoracic and mediastinal disorders
10062209 
Nasal disorder 
Respiratory, thoracic and mediastinal disorders
10028740 
Nasal dryness 
Respiratory, thoracic and mediastinal disorders
10028741 
Nasal inflammation 
Respiratory, thoracic and mediastinal disorders
10051208 
Nasal mucosa atrophy 
Respiratory, thoracic and mediastinal disorders
10057537
Nasal mucosal discolouration 
Respiratory, thoracic and mediastinal disorders
10061305 
Nasal mucosal disorder 
Respiratory, thoracic and mediastinal disorders
10076585
Nasal mucosal erosion 
Respiratory, thoracic and mediastinal disorders
10057358 
Nasal mucosal hypertrophy 
Respiratory, thoracic and mediastinal disorders
10065546 
Nasal mucosal ulcer 
Respiratory, thoracic and mediastinal disorders
10028747 
Nasal necrosis 
Respiratory, thoracic and mediastinal disorders
10051181 
Nasal odour 
Respiratory, thoracic and mediastinal disorders
10028750
Nasal oedema 
Respiratory, thoracic and mediastinal disorders
10028756 
Nasal polyps 
Respiratory, thoracic and mediastinal disorders
10076406 
Nasal pruritus 
Respiratory, thoracic and mediastinal disorders
10028762 
Nasal septum deviation 
Respiratory, thoracic and mediastinal disorders
10028763
Nasal septum disorder 
Respiratory, thoracic and mediastinal disorders
10075027 
Nasal septum haematoma 
Respiratory, thoracic and mediastinal disorders
10028765 
Nasal septum perforation 
Respiratory, thoracic and mediastinal disorders
10028766 
Nasal septum ulceration 
Respiratory, thoracic and mediastinal disorders
10052354 
Nasal turbinate abnormality 
Respiratory, thoracic and mediastinal disorders
10028779
Nasal turbinate hypertrophy 
Respiratory, thoracic and mediastinal disorders
10028780 
Nasal ulcer 
Respiratory, thoracic and mediastinal disorders
10076553 
Nasal varices 
Respiratory, thoracic and mediastinal disorders
10065120 
Oroantral fistula 
Gastrointestinal disorders
10068319 
Oropharyngeal pain 
Respiratory, thoracic and mediastinal disorders
10062321 
Paranasal cyst 
Respiratory, thoracic and mediastinal disorders
10074401 
Paranasal sinus aplasia 
Congenital, familial and genetic disorders
Paranasal sinus discomfort
Respiratory, thoracic and mediastinal disorders
10069702 
Paranasal sinus haematoma 
Respiratory, thoracic and mediastinal disorders
10057392 
Paranasal sinus hypersecretion 
Respiratory, thoracic and mediastinal disorders
10067998
Paranasal sinus mucosal hypertrophy 
Respiratory, thoracic and mediastinal disorders
10072591 
Paranasal sinus necrosis 
Respiratory, thoracic and mediastinal disorders
10034018 
Parosmia 
Nervous system disorders
10064037 
Rhinalgia 
Respiratory, thoracic and mediastinal disorders
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


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Statistical Analysis Plan 
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Covance Clinical Study No. 1001215-8376828
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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