Conditions: Healthy
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 99
Healthy volunteers: yes

Brief summary:
The purpose of the study is to learn more about different devices for delivering glucagon during simulations of severe hypoglycemic (low blood sugar) emergencies. The study will be carried out using medical manikins to simulate real life scenarios. No drug will be administered to humans. Part A will last approximately 17 days for Trained Users and Participants with Diabetes (PWD). Part B will last approximately nine (9) days for Untrained Users. Each part will be separated by approximately 7 days.

Detailed description:

Arms:
arm 1: Empty NG device administered to a manikin during simulations of severe hypoglycaemia emergencies. No drug will be administered to humans. arm 2: Commercially available GEK delivered intramuscularly to a manikin during simulations of severe hypoglycaemia emergencies. No drug will be administered to humans.

Interventions: intervention 1: Nasal Glucagon Device (NG) intervention 2: GEK intervention 3: IM Glucagon
Intervention descriptions: intervention 1: NG devices will be provided empty of drug product intervention 2: Used to administer glucagon intramuscularly (IM) intervention 3: Administered IM via GEK

Protocol document:
Prot_001.pdf: 
I8R-MC-IGBM(a) Clinical Pharmacology Protocol
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LY900018
Protocol I8R-MC-IGBM(a)
A Simulation Study Comparing Successful Administration, 
Time to Administer, and User Experience of Ready-to-Use 
Nasal Glucagon with Reconstitutable Injectable Glucagon
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 
nasal glucagon (LY900018), unless such persons are bound by a confidentiality agreement 
with Eli Lilly and Company or its subsidiaries.
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries. 
Nasal Glucagon (LY900018)
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Clinical Pharmacology Protocol Signed and Approved by Lilly:  21 September 2018.
Amendment (a) Electronically Signed and Approved by Lilly on date provided below.
Approval Date: 06-Dec-2018 GMT


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Table of Contents
A Simulation Study Comparing Successful Administration, 
Time to Administer, and User Experience of Ready-to-Use 
Nasal Glucagon with Reconstitutable Injectable Glucagon
Section
Page
Protocol I8R-MC-IGBM(a) A Simulation Study Comparing Successful 
Administration, Time to Administer, and User Experience of Ready-
to-Use Nasal Glucagon with Reconstitutable Injectable Glucagon.......................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................8
2.
Schedule of Activities .......................................................................................................11
3.
Introduction ......................................................................................................................13
3.1.
Study Rationale............................................................................................................13
3.2.
Background..................................................................................................................13
3.3.
Benefit/Risk Assessment..............................................................................................14
4.
Objectives and Endpoints..................................................................................................15
5.
Study Design.....................................................................................................................17
5.1.
Overall Design .............................................................................................................17
5.1.1.
Types of Participants............................................................................................17
5.1.2.
Device Assessment Criteria..................................................................................18
5.1.3.
Detailed Description of Study Procedures ............................................................21
5.1.3.1.
Part A (Trained Users)....................................................................................21
5.1.3.2.
Part B (Untrained Users).................................................................................22
5.1.3.3.
Example Simulation .......................................................................................22
5.1.3.4.
Assessment of Successful Administration.......................................................23
5.1.3.5.
“Memory Decay” Period ................................................................................24
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 ...................................................................................................25
6.
Study Population...............................................................................................................26
6.1.
Inclusion Criteria..........................................................................................................26
6.2.
Exclusion Criteria ........................................................................................................26
6.3.
Lifestyle and/or Dietary Requirements .........................................................................27
6.4.
Screen Failures.............................................................................................................27
7.
Treatment..........................................................................................................................28


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7.1.
Treatment Administered...............................................................................................28
7.1.1.
Packaging and Labeling .......................................................................................28
7.2.
Method of Treatment Assignment ................................................................................28
7.3.
Blinding .......................................................................................................................29
7.4.
Dose Modification........................................................................................................29
7.5.
Preparation/Handling/Storage/Accountability...............................................................29
7.6.
Treatment Compliance .................................................................................................29
7.7.
Concomitant Therapy...................................................................................................29
7.8.
Treatment after the End of the Study............................................................................29
8.
Discontinuation Criteria ....................................................................................................30
8.1.
Discontinuation from Study Treatment.........................................................................30
8.1.1.
Discontinuation of Inadvertently Enrolled Participants.........................................30
8.2.
Discontinuation from the Study....................................................................................30
8.3.
Participants Lost to Follow-up......................................................................................30
9.
Study Assessments and Procedures ...................................................................................31
9.1.
Efficacy Assessments...................................................................................................31
9.2.
Adverse Events ............................................................................................................31
9.2.1.
Serious Adverse Events........................................................................................32
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................33
9.2.2.
Complaint Handling.............................................................................................33
9.3.
Treatment of Overdose.................................................................................................33
9.4.
Safety...........................................................................................................................33
9.5.
Pharmacokinetics .........................................................................................................33
9.6.
Pharmacodynamics ......................................................................................................33
9.7.
Genetics .......................................................................................................................33
9.8.
Biomarkers...................................................................................................................33
9.9.
Health Economics ........................................................................................................33
9.10. Questionnaires .............................................................................................................34
9.10.1.
NASA Task Load Index.......................................................................................34
9.10.2.
Questionnaire Comparing Both Devices...............................................................34
9.10.3.
Device-Specific Questionnaires (NG and GEK) ...................................................34
10.
Statistical Considerations and Data Analysis.....................................................................35
10.1. Sample Size Determination ..........................................................................................35
10.2. Populations for Analyses..............................................................................................35
10.2.1.
Study Participant Disposition ...............................................................................35
10.2.2.
Study Participant Characteristics ..........................................................................35
10.3. Statistical Analyses ......................................................................................................35
10.3.1.
Data Review during the Study..............................................................................37


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10.3.2.
Interim Analyses..................................................................................................37
11.
References ........................................................................................................................38


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List of Tables
Table
Page
Table IGBM.1.
Objectives and Endpoints .......................................................................15
Table IGBM.2.
Example Randomization Schedule - Study IGBM ..................................28


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List of Figures
Figure
Page
Figure IGBM.1.
Illustration of study design for Protocol I8R-MC-IGBM:  Part A............19
Figure IGBM.2.
Illustration of study design for Protocol I8R-MC-IGBM:  Part B............20


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................39
Appendix 2.
Study Governance, Regulatory and Ethical Considerations.....................42
Appendix 3.
Protocol Amendment I8R-MC-IGBM(a) Summary
A Simulation Study Comparing Successful Administration, Time 
to Administer, and User Experience of Ready-to-Use Nasal 
Glucagon with Reconstitutable Injectable Glucagon ...............................45


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1. Protocol Synopsis
Title of Study:
A Simulation Study Comparing Successful Administration, Time to Administer, and User Experience of 
Ready-to-Use Nasal Glucagon with Reconstitutable Injectable Glucagon
Rationale: 
The aim of this study is to compare successful administration rates, time and experience of administering nasal 
glucagon (NG) with those of commercially available glucagon emergency kit (GEK) during a simulated severe 
hypoglycemia emergency.  Two different groups of participants will undergo the simulations.  One group will be 
trained to use each device, in a similar way to the training given to real-life caregivers, close friends or family 
members of a person with diabetes (PWD); the other group will not be given such training, to approximate the real-
life experience of colleagues or acquaintances of a PWD.  During the simulations, both types of participants will 
have to administer treatment to a manikin that represents a person with severe hypoglycemia.
The outcomes from these simulations will be measured quantitatively (the proportion of participants administering a 
successful dose of NG and GEK, and how long it takes) and qualitatively (via user-questionnaires that measure ease 
of use, confidence and other factors). 
Objective(s)/Endpoints:
Objectives
Endpoints
Primary
To test the hypothesis that more Trained Users can 
successfully administer NG than GEK when treating a 
simulated episode of severe hypoglycemia.
The percentage of Trained Users that perform a 
successful administration (complete dose delivered and 
all critical steps completed), both for NG and GEK.
Secondary 
To test the hypothesis that more Untrained Users can 
successfully administer NG than GEK when treating a 
simulated episode of severe hypoglycemia.
The percentage of Untrained Users that perform a 
successful administration (complete dose delivered and 
all critical steps completed), both for NG and GEK.
To compare the average time to successfully 
administer NG, compared with GEK.
The time taken by Trained Users and Untrained Users 
to successfully administer NG or GEK (complete dose 
delivered and all critical steps completed), as measured 
by study site staff.
To compare percentages of users who complete critical 
administration steps for both NG and GEK.
The percentages of Trained Users and Untrained Users 
who complete all of the critical steps for both NG and 
GEK, as assessed by site staff.
To assess the number of simulations that result in 
successful administration of NG.
The percentage of all simulations that result in a 
successful administration of NG, for all users 
combined.


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Objectives
Endpoints
To assess whether, overall, one device (NG or GEK) is 
preferred over the other.
The percentage of participants (Trained Users, PWDs 
and Untrained Users) that prefer one device over the 
other, as recorded in a questionnaire.
To assess overall ease of use of both devices (NG and 
GEK).
The ‘ease of use’ questionnaire ratings given to NG 
and to GEK by Trained Users, PWDs and Untrained 
Users.
Summary of Study Design:
Study I8R-MC-IGBM is a single-center, crossover study assessing the use of NG and GEK during a simulation of a 
severe hypoglycemia episode, with 2 cohorts of participants:  Trained Users (Part A) and Untrained Users (Part B).  
Each participant will take part in 2 simulations, 1 with NG and 1 with GEK.  Quantitative results (whether or not a 
dose is administered successfully, and how long it takes) will be recorded by site staff during each simulation.  
Qualitative results (the opinions of Trained Users, Untrained Users and PWDs) will be captured via questionnaires, 
both during and at the end of the study.
Study Arms and Planned Duration for an Individual Participant:  
In Part A, each Trained User and the accompanying PWD will attend 3 one-day study visits, over the course of 
approximately 2 weeks: 

An initial training visit

Two study visits, each involving a simulation of a severe hypoglycemia emergency, which the Trained 
User will attempt to treat with NG and GEK in turn (in randomized order).
In Part B, each Untrained User will attend 2 study visits over the course of approximately 1 week.  Each visit will 
include 1 simulated severe hypoglycemia emergency, which the participant will attempt to treat with NG and GEK 
in turn (in randomized order).
Number of Participants:
Approximately 72 participants (39 Trained Users and 33 Untrained Users) will be recruited to ensure that 52 
participants (26 Trained Users and 26 Untrained Users) complete the study.  
Trained Users will be recruited such that, of the completers, half (i.e. at least 13) of the accompanying PWDs have 
type 1 diabetes mellitus (T1DM), and half (at least 13) have type 2 diabetes mellitus (T2DM).
Each Trained User will be accompanied at each visit by the PWD with whom they are recruited to the study.
Statistical Analysis:
The McNemar test will be used to assess the primary objective of the study (successful administration of doses in 
Part A of the study, with Trained Users).  The exact-sign test will be used as a sensitivity analysis for the primary 
objective.  


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Successful administration will be assessed for each cohort:

NG (Trained User) versus GEK (Trained User) 

NG (Untrained User) versus GEK (Untrained User)
For Part A (Trained Users), assessment of successful administration will also be stratified between those users who 
have an accompanying PWD with T1DM, and those who have an accompanying PWD with T2DM.
For baseline data, continuous variables will be presented using simple descriptive statistics such as mean, standard 
deviation, median and range.  Categorical variables will be presented as n/N and percentage.
Time to administer a dose will be assessed, making the following comparisons: 

NG (Trained User) versus GEK (Trained User) 

NG (Untrained User) versus GEK (Untrained User)

NG (Trained User) versus NG (Untrained User)

GEK (Trained User) versus GEK (Untrained User)
This analysis, using descriptive statistics, will be assessed for successful and unsuccessful administration combined, 
as well as successful administration only.


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2. Schedule of Activities
Study Schedule Protocol I8R-MC-IGBM:  Part A (Trained Users)
Procedure
Study Visits 
Comments
Visit 1
Visit 2
Visit 3
Day 1
Days 
8-9
Days 
15-17
There must be a gap of at least 7 days between visits. 
Evaluation of Eligibility
X
Prescreening will be conducted by telephone before Visit 1.  For details on evaluation of eligibility, see Section 6. 
Informed Consent
X
Randomization
X
Randomization will be stratified by diabetes type of PWD (T1DM, T2DM).
PWD Trained on Device 
1 by Staff
X
This training should take no longer than 30 minutes, including questions.
“Memory Decay” Period
X
The “memory decay” period will last 55 to 60 minutes and include a short distractor task.  See Section 5.1.3.5.
Participant Trained on 
Device 1 by PWD
X
Site staff should allow up to 30 minutes for the PWD to train the participant.
Simulation
X
X
The simulation at Visit 2 is with Device 1.  The simulation at Visit 3 is with Device 2.  See Table IGBM.2 for 
randomization schedule and Section 5.1.3.3 for details of simulations.
Participant completes 
NASA TLX
X
X
PWD Trained on Second 
Device by Staff
X
This training should take no longer than 30 minutes, including questions.
“Memory Decay” Period
X
The “memory decay” period will last 55 to 60 minutes and include a short distractor task.  See Section 5.1.3.5.
Participant Trained on 
Second Device by PWD
X
Site staff should allow up to 30 minutes for the PWD to train the participant.
Questionnaires 
X
After the simulation at Visit 3, each PWD and Trained User will watch a video showing both simulations.  Then, 
after a delay of 55 to 60 minutes, each PWD and Trained User will answer the comparative and individual-device 
questionnaires.  See Section 5.1.3 for the order of questionnaires and Section 9.10 for detail of questions. 
Safety Assessment/
Follow-up/Early 
Discontinuation
X
X
X
The safety assessment covers any accidents during training or simulations (see Section 9.4), or significant errors 
(e.g. insulin was administered during the simulation instead of glucagon).  For follow-up of discontinued 
participants see Section 8.
Abbreviations:  NASA = National Aeronautics and Space Administration; PWD = person with diabetes; T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus; TLX 
= Task Load Index.


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Study Schedule Protocol I8R-MC-IGBM: Part B (Untrained Users)
Procedure
Visit 1 
Visit 2
Comments
Day 1
Days 8-9
Evaluation of Eligibility
X
Prescreening to be conducted by telephone.  For details on evaluation of eligibility, see Section 6. 
Informed Consent
X
Randomization
X
Simulation with Device 1
X
NASA TLX on Device 1
X
Simulation with Device 2
X
NASA TLX on Device 2
X
Questionnaires
X
After the simulation at Visit 2, each Untrained User will watch a video showing both simulations.  
Then, after a delay of 55 to 60 minutes, each Untrained User will answer the comparative and 
individual-device questionnaires (Section 9.10).
Safety Assessment/ 
Follow-up/Early 
Discontinuation
X
X
The safety assessment covers any accidents during simulations (see Section 9.4), or significant 
errors (e.g. insulin was administered during the simulation instead of glucagon). For follow-up of 
discontinued participants, see Section 8.
Abbreviations: NASA = National Aeronautics and Space Administration; TLX = Task Load Index.


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3. Introduction
3.1.
Study Rationale
The aim of this study is to assess how well different groups of people – those who have received 
training and those who have not – are able to use nasal glucagon (NG), compared with a 
commercially available glucagon emergency kit (GEK) delivered via the intramuscular route, 
during simulations of severe hypoglycemia emergencies.  Assessment of the participants’ 
performance will take 2 forms:

Quantitative:  The proportion of participants who deliver complete doses, and follow all 
critical steps for dose administration, and the time it takes to deliver a dose, as recorded 
by study site staff;

Qualitative:  the user experience, as recorded in questionnaires.  Questions include 
preference for either device, confidence using each device, and ease of use.
In this protocol, participants who are given instructions on each device prior to the simulations 
are referred to as “Trained Users”.  They will be caregivers, family members or people otherwise 
close to a person with diabetes (PWD).  Before each simulation, they will receive training from 
their accompanying PWD in the use of the glucagon rescue devices; this is intended to 
approximate the training that caregivers and relatives are likely to receive from PWDs in real 
life.
Study participants who are not given instructions on each device prior to the simulations are 
referred to as “Untrained Users”.  These are intended to approximate the real-life colleagues or 
acquaintances of a PWD, who may be present during a severe hypoglycemia emergency and 
willing to step in, but are not likely to have received training on the rescue device.
The study involves simulations of severe hypoglycemia emergencies using manikins.  No drug 
will be administered to people.
3.2.
Background
Hypoglycemia, one of the most serious acute complications of diabetes treatment, is defined as 
an abnormally low blood glucose level that exposes the individual to potential harm.  The use of 
glucagon is indicated for the treatment of hypoglycemia in people unable or unwilling to 
consume carbohydrates by mouth, according to American Diabetes Association (ADA) guidance 
(ADA 2018).  ADA guidance identifies a 3-stage classification of hypoglycemia:


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Level
Glycemic criteria
Description
Hypoglycemia alert 
value (level 1)
≤70 mg/dL (3.9 mmol/L)
Sufficiently low for treatment with fast-acting carbohydrate 
and dose adjustment of glucose-lowering therapy
Clinically significant 
hypoglycemia (level 2)
≤54 mg/dL (3.0 mmol/L)
Sufficiently low to indicate serious, clinically important 
hypoglycemia
Severe hypoglycemia 
(level 3)
No specific glucose 
threshold
Hypoglycemia associated with severe cognitive impairment 
requiring external assistance for recovery
Source:  ADA Standards of Medical Care in Diabetes – 2018.
Based on this classification, the ADA recommends that glucagon should be prescribed for all 
individuals at increased risk of clinically significant hypoglycemia (level 2), so that glucagon is 
available should it be needed.  Furthermore, an individual does not need to be a healthcare 
professional to safely administer glucagon.
Nasal glucagon, also known as LY900018, is an investigational drug-device combination 
product intended for the treatment of severe hypoglycemia (level 3 in the ADA guidance), in 
adult and pediatric PWDs.  Nasal glucagon consists of a single-use nasal dosing device that
delivers a fixed 3-mg dose of glucagon powder, absorbed passively through the nasal mucosa.  
Nasal glucagon is being developed as an alternative to commercially available GEKs for 
treatment of severe hypoglycemia, with a needle-free device and fewer steps for administration.
3.3.
Benefit/Risk Assessment
This study does not involve the dosing of study drug to humans.  As such, there is no expected 
benefit to study participants.  During each simulation with a GEK, there is a risk that participants 
may suffer a needle-stick injury, which may also result in accidental administration of the 
marketed comparator product.  Site staff will closely monitor simulations and respond to any 
such safety issues that arise.


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4. Objectives and Endpoints
Table IGBM.1 shows the objectives and endpoints of the study.
Table IGBM.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To test the hypothesis that more Trained Users can 
successfully administer NG than GEK when treating 
a simulated episode of severe hypoglycemia.
The percentage of Trained Users that perform a successful 
administration (complete dose delivered and all critical steps 
completed), both for NG and GEK.  See Section 5.1.3.4 for 
definitions of complete dose and critical steps.
Secondary
To test the hypothesis that more Untrained Users
can successfully administer NG than GEK when 
treating a simulated episode of severe 
hypoglycemia.
The percentage of Untrained Users that perform a successful 
administration (complete dose delivered and all critical steps 
completed), both for NG and GEK.  See Section 5.1.3.4 for 
definitions of complete dose and critical steps.
To compare the average time to successfully 
administer NG, compared with GEK.
The time taken by Trained Users and Untrained Users to 
successfully administer NG or GEK (complete dose 
delivered and all critical steps completed), as measured by 
site staff.
To compare percentages of users who complete 
critical administration steps for both NG and GEK.
The percentages of Trained Users and Untrained Users who 
complete all of the critical steps for both NG and GEK, as 
assessed by site staff.
To assess the number of simulations that result in 
successful administration of NG.
The percentage of all simulations that result in a successful 
administration of NG, for all users combined.
To assess whether, overall, one device (NG or 
GEK) is preferred over the other.
The percentage of participants (Trained Users, PWDs and 
Untrained Users) that prefer one device over the other, as 
recorded in a questionnaire.
To assess overall ease of use of both devices (NG 
and GEK).
The ‘ease of use’ questionnaire ratings given to NG and to 
GEK by Trained Users, PWDs and Untrained Users.


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Objectives
Endpoints
Exploratory
To assess participants’ overall confidence in the use of 
NG and GEK devices.
The ‘confidence’ questionnaire ratings given to NG and 
to GEK by Trained Users, Untrained Users and PWDs.
To compare the time it takes a PWD to teach the use of 
NG and GEK devices.
The average length of time taken by PWDs to teach the 
use of NG and GEK to their associated Trained User, as 
measured by site staff.
To compare participants’ experience of Mental Demand, 
Effort, Frustration and other elements of the NASA Task 
Load Index, following NG and GEK simulations.
Ratings given by Trained Users and Untrained Users in 
the NASA Task Load Index to describe their 
experiences with NG and GEK.
Abbreviations:  GEK = glucagon emergency kit; NASA = National Aeronautics and Space Administration; NG = 
nasal glucagon; PWD = person with diabetes.


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5. Study Design
5.1.
Overall Design
This is a single-center, randomized, crossover study assessing the percentage of successful doses, 
speed, and experience of administering both NG and a commercially available GEK during 
simulations of severe hypoglycemia emergencies.  Participants in the study will administer nasal 
and injectable glucagon devices to manikins.
Study I8R-MC-IGBM (IGBM) is divided into 2 parts, with different types of participants:  
Part A (Trained Users, who will attend all study visits with a PWD) and Part B (Untrained 
Users).  Both parts of the study may be run at the same time.
The study is intended to simulate real-life conditions to capture and document, in a controlled 
setting, any differences in how Trained Users and Untrained Users use NG and GEK, and their 
experience of doing so.
5.1.1. Types of Participants
Participants are defined as follows:

Trained User:  A participant who, during the study, will be given a level of training 
intended to mimic that of a real-life caregiver, relative, or close friend of a PWD.
o
“Trained User” participants must be either related to, or a close friend of, a PWD, 
and therefore already familiar with diabetes and the risk of severe hypoglycemia.  
Each Trained User must be recruited alongside the PWD with whom they are 
familiar, as a “dyad” (a pair of people who have a pre-existing relationship).
o
The Trained User will receive instruction on the use of each device, from the 
PWD, before taking part in the simulation using that device.
o
Trained Users must not have actually administered injectable glucagon (or 
another rescue medication) in the past.  However, they may own a glucagon 
rescue kit, and may have been instructed in its use, as long as such instruction 
occurred at least 2 years before screening.

PWD: The PWD who is the close friend or relative of the Trained User.
o
During the study, the PWD will be trained by site staff on the use of each device, 
and before each simulation, will relay these instructions to the Trained User.
o
The PWD previously may have been instructed in the use of a glucagon rescue 
kit, as long as such instruction occurred at least 2 years before screening.

Untrained User: A participant who will not be given training during the study on either 
device, and who has limited knowledge of severe hypoglycemia and how to treat it.
o
These participants are intended to approximate a real-life colleague or 
acquaintance of a PWD:  someone who is aware of the PWD’s condition and is 


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willing to intervene in an episode of severe hypoglycemia, but has not received 
instructions.  Untrained Users in this study may or may not know a PWD in real 
life.  In any case, they must not have caregiving responsibilities toward a PWD.
o
Untrained Users will participate in the study alone (not as part of a dyad).  
o
Prior to the simulations in this study, Untrained Users will be given basic 
information about severe hypoglycemia and briefly shown an example of each 
rescue device.
5.1.2. Device Assessment Criteria
The criteria for assessing each device include the following:

Dose: Are Trained Users and Untrained Users able to administer a successful dose 
more often in an emergency with one device than the other?

Speed: Are Trained Users and Untrained Users able to deliver a dose faster in an 
emergency with one device than the other?

Accuracy: Do Trained Users and Untrained Users use one device more correctly, i.e. 
perform the critical steps for dose administration, with fewer errors?

Preference: Overall, do Trained Users, PWDs, and Untrained Users prefer one 
device over the other?

Confidence: How confident are Trained Users and Untrained Users in their ability to 
successfully deliver a dose?  How confident are PWDs in the ability of Trained Users 
to successfully deliver a dose?

Ease of Use: How easy do Trained Users and Untrained Users find each device to 
use?  How easy do PWDs think Trained Users find each device?

Task Load:  How do Trained Users and Untrained Users rate each simulation in 
terms of the mental demand, frustration, and other aspects measured using the NASA 
Task Load Index (TLX)?
Study governance considerations are described in detail in Appendix 2.
Figure IGBM.1 (Part A) and Figure IGBM.2 (Part B) illustrate the study design.


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Abbreviations:  GEK = glucagon emergency kit; NASA = National Aeronautics and Space Administration; NG = nasal glucagon; 
PWD = person with diabetes; TLX = Task Load Index.
Figure IGBM.1.
Illustration of study design for Protocol I8R-MC-IGBM: Part A.
Memory 
Decay Period 
(≥7 days)
Visit 1
Visit 2
Visit 3
Memory 
Decay Period 
(≥7 days)
Procedures 
at Each Visit
•
Evaluation of 
Eligibility
•
Informed consent
•
Randomization
•
PWD receives 
training on Device 1
•
PWD trains User on 
Device 1
•
User does simulation 
with Device 1
•
User Completes NASA 
TLX on Device 1
•
PWD receives training 
on Device 2
•
PWD trains User on 
Device 2
•
User does simulation 
with Device 2
•
User Completes NASA 
TLX on Device 2
•
Comparative 
Questionnaire (NG vs 
GEK)
•
Individual-Device 
Questionnaires (NG 
and GEK)
Device Used 
for Each 
Simulation
Device 1 
= GEK
Part A: Trained Users + PWDs
Device 1 
= NG
Device 2 
= NG
Device 2 
= GEK
Visit 1
Visit 2
Visit 3


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Abbreviations:  GEK = glucagon emergency kit; NASA = National Aeronautics and Space Administration; NG = nasal glucagon; 
TLX = Task Load Index.
Figure IGBM.2.
Illustration of study design for Protocol I8R-MC-IGBM:  Part B.
Visit 1
Visit 2
Delay Period 
(≥7 days)
Procedures 
at Each Visit
•
Evaluation of eligibility
•
Informed consent
•
Randomization
•
User shown Device 1
•
Simulation with Device 1
•
User Completes NASA 
TLX on Device 1
•
User shown Device 2
•
Simulation with Device 2
•
User Completes NASA 
TLX on Device 2
•
Comparative 
Questionnaire (NG vs GEK)
•
Individual-Device 
Questionnaires (NG, GEK)
Device Used 
for Each 
Simulation
Device 1 
= GEK
Part B: Untrained Users
Device 1 
= NG
Device 2 
= NG
Device 2 
= GEK
Visit 1
Visit 2


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5.1.3. Detailed Description of Study Procedures
As shown in Figure IGBM.1 and Figure IGBM.2, study procedures will vary between Part A 
(Trained Users) and Part B (Untrained Users).  
Details of each simulation are intended to be included in a study operations manual.  Site staff 
will make a video recording of each simulation, for study participants to review later, before they 
complete questionnaires.  The videos may also be used to validate the site’s evaluation of critical 
steps and other aspects of the simulation.
5.1.3.1.
Part A (Trained Users)
Trained Users will be required to attend the study site on 3 occasions, each time accompanied by 
the PWD with whom they are associated.
At Visit 1, each Trained User and their associated PWD will be evaluated for eligibility, give 
informed consent, and be randomized to 1 of 2 schedules (Table IGBM.2).
Randomization will be stratified by the type of diabetes, i.e. randomization will be performed 
separately for PWDs with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), 
and their accompanying Trained User.  
Following randomization, site staff will instruct the PWD how to use Device 1 (i.e. either NG or 
GEK, depending on the randomization).  This instruction will include a mock administration, 
during which the PWD will actuate the device.  After a “memory decay” period including a 
distractor task (see Section 5.1.3.5), the PWD will relay instructions on how to use Device 1 to 
the Trained User.
At Visit 2, approximately 7 days after Visit 1, each Trained User will take part in a simulation of 
a severe hypoglycemia emergency with a manikin (see Section 5.1.3.3).  The gender of the 
manikin will match the gender of the PWD.  The PWD will not be in the room and will not 
observe the simulation.  Site staff will assess dose administration (successful/unsuccessful; see 
Section 5.1.3.4), and the time taken to administer a dose.
After a short rest period, the Trained User will complete the NASA TLX questionnaire about 
their experience with Device 1.  At around the same time, site staff will instruct the PWD how to 
use Device 2.  After a “memory decay” period including a distractor task (see Section 5.1.3.5), 
the PWD will relay instructions on how to use Device 2 to the Trained User.
At Visit 3, approximately 7 days after Visit 2, each Trained User will take part in a second 
simulation, similar to the first.  They will be asked to treat the manikin with Device 2, again 
observed by site staff only.  The gender of the manikin will again match the gender of the PWD.  
After a short rest period, the Trained User will complete the NASA TLX questionnaire about 
their experience with Device 2.  At around the same time, site staff will assemble a video of both 
simulations (from Visits 2 and 3).  Then both PWD and Trained User will watch the video.  After 
a delay of 55 to 60 minutes, the PWD and Trained User will each complete a questionnaire 
comparing both devices; later they will complete individual questionnaires for both NG and 
GEK, in randomized order (Table IGBM.2).  Details of the questionnaires are in Section 9.10.  


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Participants will be given a device-specific questionnaire only if the Trained User attempted to 
administer that device.  For example, there will be no questionnaire for a simulation if insulin 
was wrongly administered instead of the glucagon device, or if no attempt was made to 
administer a device.  Similarly, participants will be given the comparative questionnaire only if 
the Trained User attempted to administer both NG and GEK during the respective simulations.
5.1.3.2.
Part B (Untrained Users)
Untrained Users will attend the site for 2 visits (Figure IGBM.2).
At Visit 1, after being evaluated for eligibility and giving informed consent, each Untrained User 
will be randomized to 1 of 2 schedules (Table IGBM.2), which will determine the device used at 
each simulation.  Male manikins will be used in each case.
Each Untrained User will be given a brief explanation of diabetes and severe hypoglycemia, and 
briefly shown an example of Device 1 (NG or GEK depending on randomization).  No 
instruction will be given on how to use the device; nor will the Untrained User be allowed time
to read any instructions for using the device.
Each Untrained User will then take part in a simulation (see Section 5.1.3.3) using Device 1.  
Staff will assess successful or unsuccessful treatment (Section 5.1.3.4), and time to successful 
administration (if this occurred within the allotted time).  After a short rest period, the Untrained 
User will complete the NASA TLX questionnaire about their experience.
At Visit 2, approximately 7 days after Visit 1, each Untrained User will be shown an example of 
Device 2.  As at Visit 1, no instruction will be given on how to use the device.  The Untrained
User will take part in a simulation using Device 2, and then complete the NASA TLX.  Site staff 
will assemble a video of both simulations, and the Untrained User will watch it.  After a delay of 
55 to 60 minutes, the Untrained User will fill in a questionnaire comparing both devices, and 
then individual-device questionnaires in randomized order (Table IGBM.2).  Details of the
questionnaires are in Section 9.10.  The Untrained User will be given a device-specific 
questionnaire only if they attempted to administer that device.  For example, there will be no 
questionnaire for a simulation if insulin was wrongly administered instead of the glucagon 
device, or if no attempt was made to administer a device.  Similarly, Untrained Users will be 
given the comparative questionnaire only if they attempted to administer both NG and GEK 
devices during the respective simulations.
5.1.3.3.
Example Simulation
The participant in the simulation (Trained User or Untrained User) will be taken into a room 
where a fully clothed adult manikin is present (e.g. lying face-up on the ground, on a bed, or in a 
chair).  The participant will be told that the manikin represents a PWD experiencing severe 
hypoglycemia.  For Part A, site staff will refer to the manikin using the PWD’s name during the 
simulation.
Near to the manikin will be a backpack, chest of drawers, or other receptacle, appropriate to the 
simulated location (bedroom, office, etc.).  This will contain diabetes supplies (glucometer and 


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strips, alcohol swabs, lancing device, insulin syringe and a vial of insulin) and the glucagon 
device (NG or GEK depending on randomization); it may also contain other everyday items.
The participant will be told to find the PWD’s glucagon device and administer rescue glucagon 
as quickly as possible.  Once the participant finds the device, the timing of the simulation will 
start.  While the participant attempts to administer glucagon, site staff will emphasize the 
urgency of the situation, e.g. by telling the participant that it will be some time before an 
ambulance arrives.  Distracting sounds and events will be incorporated to simulate the stress of a 
real-life situation.  After approximately 15 minutes, site staff will tell the participant that the 
ambulance has arrived, ending the simulation.
5.1.3.4.
Assessment of Successful Administration
The study objectives (Section 4) include an assessment of whether participants are able to 
successfully administer a dose of glucagon to the manikin.  To successfully administer either NG 
or GEK, a participant must complete all of the critical steps for each device, AND administer a 
complete dose, as defined below:
1. Complete All Critical Steps
Device
Critical Steps
NG

Remove device from packaging

Do not test before use

Insert the device tip into one of the manikin’s nostrils 

Push the plunger, keeping the tip inside the nostril, until the green line no longer shows
GEK

Remove device from packaging 

Inject the diluent from the syringe into the vial containing the drug powder

Ensure drug powder is dissolved (by shaking/swirling)

Draw the dissolved drug into the syringe

Inject the drug into the manikin at an appropriate site for intramuscular administration 
(e.g. thigh/buttock/upper arm)
AND
2. Administer a Complete Dose
Device
Complete Dose
NG
Device plunger is pushed until the green line on the plunger is no longer visible.
GEK
90% or more of the glucagon drug solution is administered.


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5.1.3.5.
“Memory Decay” Period
In Part A, there will be a gap of 55 to 60 minutes between PWDs receiving instruction from site 
staff on the use of the device for the next simulation, and the PWDs relaying instructions to their 
accompanying Trained User.  During this “memory decay” period, PWDs will be given a short 
“distractor task”, such as a questionnaire about a topic unrelated to the device or simulation.
5.2.
Number of Participants
Approximately 72 participants (39 Trained Users and 33 Untrained Users) may be enrolled so
that approximately 52 participants (26 Trained Users and 26 Untrained Users) complete the 
study.
Each Trained User must be accompanied during each visit by the PWD with whom they are 
associated (see Section 6.1).  Trained Users will be recruited such that, of completers, half (i.e. at 
least 13) of the accompanying PWDs have T1DM, and half (at least 13) have T2DM.
For purposes of this study, a participant completes the study when all scheduled procedures 
shown in the Schedule of Activities (Section 2) have been completed.
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 participant.
5.4.
Scientific Rationale for Study Design
The use of a crossover design allows a within-participant comparison of NG with GEK.
The use of 2 groups of participants, Trained User and Untrained User, is intended to simulate the 
types of people in the real world who are typically required to administer glucagon in an 
emergency:  caregivers/relatives/close friends of PWDs who have received instruction in how to 
administer glucagon; and colleagues or acquaintances who have not received instruction, but still 
may be willing to step in.
The process of a PWD relaying instructions to the Trained User – rather than the Trained User 
receiving instruction first-hand from site staff – is intended to simulate the real-life tendency for 
PWDs to learn from a medical professional how to use a GEK, and to later relay this information 
to caregivers, relatives and/or close friends.  The “memory decay” period is intended to simulate 
the delay that occurs in relaying these instructions.
A manikin will represent a person experiencing severe hypoglycemia; this allows for better 
control of the variables of each simulation, and avoids ethical issues related to the induction of 
severe hypoglycemia in people.
The PWD will not observe simulations in real time, so as to minimize the risk of their 
intervening or otherwise influencing the Trained User.  This is intended to ensure simulations are 
like-for-like between participants and between devices, which will aid comparison. 
In Part A, the manikin will appear to have the same gender as the PWD, and will be referred to 
with the PWD’s name, to simulate the increased stress and pressure of treating a relative or close 


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friend.  In Part B, this is not a pertinent factor, and manikins will default to being male in 
appearance.
5.5.
Justification for Dose
Not applicable.


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6. Study Population
A generic prescreening by telephone may occur prior to Visit 1 to arrange scheduling of visits for 
both parts.  For Part A (Trained Users), the PWD must declare willingness to attend all study 
visits along with the Trained User.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible for inclusion in the study only if they meet all of the following criteria at 
screening:
For all participants (Trained Users, PWDs and Untrained Users):
[1]
are at least 18 years old at the time of informed consent
[2]
are able to understand the purpose and procedure of the study and to give 
written informed consent to show their own willingness to participate in the 
study
Trained Users only:
[3]
are persons who are not diagnosed with T1DM or T2DM 
[4]
are close friends/relatives of a patient who has been diagnosed with T1DM or 
T2DM and is being treated with insulin
[5]
have not previously administered any rescue medications (e.g. epinephrine, 
glucagon, narcan or seizure medications) 
[6]
agree to not seek out information, or take any training, on how to administer 
either NG or injectable glucagon through the end of the study, except the 
training given as a part of the study
Untrained Users only:
[7]
have not been diagnosed with T1DM or T2DM, and are not a Trained User of 
a person with T1DM or T2DM
[8]
have not previously administered any rescue medications (e.g. epinephrine, 
glucagon, narcan or seizure medications); have not received training to 
administer any such medication; and agree not to take any such training 
through to the end of the study
6.2.
Exclusion Criteria
Participants will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or enrollment:


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All participants (Trained Users, PWDs and Untrained Users):
[9] are study site staff directly affiliated with this study and their immediate 
families.  Immediate family is defined as a spouse, biological or legal
guardian, child or sibling
[10] are Lilly employees or employees of High Point Clinical Trials Center
[11] in the opinion of the investigator or sponsor, are unsuitable for inclusion in the 
study
Trained Users and Untrained Users only (i.e. the participants involved in the 
simulations):
[12] are currently enrolled in a clinical study involving any type of medical 
research judged not to be scientifically or medically compatible with this 
study
[13] have a history of pheochromocytoma, insulinoma or glucagonoma 
[14] are judged by the investigator as being likely to have difficulty performing the 
administration due to physical, cognitive and/or severe psychiatric disorder, 
etc.
[15] are judged by the investigator as being trained or experienced in performing 
rescue drug administration
[16] are judged by the investigator as being trained or experienced in performing 
high-fidelity simulations of drug administration
[17] have used a GEK, attempted to use a GEK, or received instruction in using a 
GEK in the past 2 years
[18] have received formal training in a medical field, and/or worked in this field 
within the prior 5 years; or otherwise are judged by the investigator as being 
trained or experienced as a first responder
PWDs only:
[19]
have received instruction in using a glucagon rescue kit in the past 2 years
[20]
have experienced severe hypoglycemia and been treated with a rescue device 
in the past 2 years.
6.3.
Lifestyle and/or Dietary Requirements
Not applicable.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once, after consultation with the Sponsor.


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7. Treatment
7.1.
Treatment Administered
This study involves a comparison of NG with a commercially available glucagon injection kit, 
administered to a manikin as part of a simulated severe hypoglycemia emergency.  No treatment 
will be administered to humans.
The investigator or designee is responsible for

explaining the correct use of the devices to PWDs

verifying that the simulations are conducted properly

maintaining accurate records of NG and GEK device dispensing and collection

ensuring all devices are destroyed at the end of the study
7.1.1. Packaging and Labeling
Investigational NG devices will be provided empty of drug product, with a mock label, in 
shrink-wrap, and labeled per local regulations.  Commercially available glucagon injection kits 
are labeled according to the country’s regulatory requirements.
In Part A, during the demonstration given by site staff to PWDs, and the demonstrations by 
PWDs to their accompanying Trained User, written Instructions for Use (IFU) will be provided 
for both devices.
For each simulation, GEK devices will be provided sealed, and NG devices provided in shrink-
wrap.
7.2.
Method of Treatment Assignment
Randomization will be performed using a computer-generated randomization schedule, stratified 
by type of participant (Trained Users and Untrained Users).  The randomization of Trained Users 
will be further stratified by whether their accompanying PWDs have either T1DM or T2DM.  
Table IGBM.2 shows the randomization scheme that will be used for both parts of the study, and 
for the order of device-specific questionnaires given after the last simulation.
Table IGBM.2.
Example Randomization Schedule - Study IGBM
Device for Simulation 1 
(“Device 1”); and Device 
Specified in Questionnaire 1
Device for Simulation 2 
(“Device 2”); and Device 
Specified in Questionnaire 2
Schedule I
GEK
NG
Schedule II
NG 
GEK
Abbreviations:  GEK = glucagon emergency kit; NG = nasal glucagon.


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7.3.
Blinding
This is an open-label study.
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 study products received and 
any discrepancies are reported and resolved before use of the study product.
NG shrink-wrap, and GEK container seals, should not be removed prior to simulations.  NG 
shink-wrap should not be removed prior to the device demonstrations given by site staff to 
PWDs.
Only participants enrolled in the study may receive NG and GEK devices and these must only be 
provided by authorized site staff.  All study devices should be stored in an environmentally 
controlled and monitored (manual or automated) area in accordance with the labeled storage 
conditions, where applicable, with access limited to the investigator and authorized site staff.
7.6.
Treatment Compliance
Nasal glucagon and injectable glucagon will be stored at the site throughout the study.  The 
investigator, institution, or the head of the medical institution (where applicable) is responsible 
for study product accountability, reconciliation, and record maintenance (such as receipt, 
reconciliation, and final disposition records).
7.7.
Concomitant Therapy
Not applicable.
7.8.
Treatment after the End of the Study
Not applicable.


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8. Discontinuation Criteria
Site staff will attempt to contact participants who discontinue from the study prematurely for any 
reason, for follow up (for safety assessment and/or to determine why they discontinued).
8.1.
Discontinuation from Study Treatment
Not applicable.
8.1.1. Discontinuation of Inadvertently Enrolled Participants
Not applicable for this study.
8.2.
Discontinuation from the Study
Participants will be discontinued under the following circumstances:

Enrollment in any other clinical study involving an investigational product or enrollment 
in any other type of medical research judged not to be scientifically or medically 
compatible with this study

Participation in the study needs to be stopped for medical, safety, regulatory or other 
reasons consistent with applicable laws, regulations and good clinical practice (GCP)

Investigator Decision
o
the investigator decides that the participant should be discontinued from the study

Participant Decision
o
the participant requests to be withdrawn from the study.
8.3.
Participants Lost to Follow-up
A participant 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 site.  Site staff are expected to make diligent 
attempts to contact participants 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 
(including tolerance limits for timing).
9.1.
Efficacy Assessments
Not applicable.
9.2.
Adverse Events
Because this study involves simulations where participants will handle an injectable kit (the 
GEK), there is a risk of needle-stick injury.
In the event of an accidental needle-stick injury, subjects will be medically managed as 
appropriate, including any laboratory sampling that may be required to manage their safety.
Investigators are responsible for monitoring the safety of participants 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 participant.
The investigator is responsible for the appropriate medical care of participants during the study.
Investigators must document their review of each laboratory safety report, if applicable.
The investigator remains responsible for following, through an appropriate health care option, 
adverse events (AEs) that are serious or otherwise medically important, considered related to the 
study or that caused the participant to discontinue before completing the study. The participant 
should be followed up until the event resolves, stabilizes with appropriate diagnostic evaluation 
or is reasonably explained.  The frequency of follow-up evaluations of the AE is left to the 
discretion of the investigator.
After the informed consent form (ICF) is signed, study site personnel will record, via case report 
form (CRF), the occurrence and nature of each participant’s pre-existing 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, study device or a study procedure, taking into account the 
disease, concomitant treatment or pathologies.  
Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study.


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9.2.1. Serious Adverse Events
A serious adverse event (SAE) is any AE from this study that results in 1 of the following:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (i.e. immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the patient or may require intervention to prevent 1 
of the other outcomes listed in the definition above

when a condition related to the investigational device (e.g. drug delivery system)
necessitates medical or surgical intervention to preclude either permanent impairment of 
a body function or permanent damage to a body structure, the serious outcome of 
“required intervention” will be assigned.
Study site personnel must alert the Lilly clinical research physician (CRP)/clinical 
pharmacologist, or its designee, of any SAE as soon as practically possible.
Additionally, study site personnel must alert Lilly Global Patient Safety, or its designee, of any 
SAE within 24 hours of investigator awareness of the event via a sponsor-approved method.  If 
alerts are issued via telephone, they are to be immediately followed with official notification on 
study-specific SAE forms.  This 24-hour notification requirement refers to the initial SAE 
information and all follow-up SAE information.
Although all AEs are recorded in the CRF after signing informed consent, SAE reporting to the 
sponsor begins after the subject has signed informed consent and handled a device.  However, if 
an SAE occurs after signing informed consent, but prior to handling a device, 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 participants once they have 
discontinued from and/or completed the study (the participant summary CRF has been 
completed).  However, if the investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event reasonably 
possibly related to the study treatment or study participation, the investigator must promptly 
notify Lilly. 
Pregnancy (maternal or paternal exposure to drug 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.


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9.2.1.1.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the label for the GEK, and that the investigator reports as related to this 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.
9.2.2. Complaint Handling
Lilly collects product complaints on drug delivery systems used in clinical trials in order to 
ensure the safety of study participants, monitor quality and to facilitate process and product 
improvements.
Participants should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the drug delivery system so that the situation can be assessed.
9.3.
Treatment of Overdose
Not applicable.
9.4.
Safety
During each simulation with GEK, there is a risk that participants (Trained Users and Untrained 
Users) may suffer a needle-stick injury.  Site staff will closely monitor simulations and respond 
to any such safety issues that arise. 
The Lilly clinical pharmacologist or CRP/scientist will monitor safety data throughout the course 
of the study.
Lilly will review SAEs within time frames mandated by company procedures.  When 
appropriate, the Lilly clinical pharmacologist or CRP will consult with the functionally 
independent Global Patient Safety therapeutic area physician or clinical research scientist.
9.5.
Pharmacokinetics
Not applicable. 
9.6.
Pharmacodynamics
Not applicable.
9.7.
Genetics
Not applicable.
9.8.
Biomarkers
Not applicable.
9.9.
Health Economics
Not applicable.


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9.10. Questionnaires 
As detailed in Section 5.1.3, Trained Users and Untrained Users will complete NASA TLX 
questionnaires soon after each simulation, and all participants (Trained Users, Untrained Users 
and PWDs) will complete further questionnaires at the end of the study. 
As detailed in Sections 5.1.3.1 and 5.1.3.2, the individual (device-specific) and comparative 
questionnaires will be given only for devices that participants actually attempted to administer 
during the simulations.  The NASA TLX will be administered for all participants, whether they 
attempted to administer a glucagon device or not.  
Assuming the comparative questionnaire is given, it will always be given before the device-
specific questionnaires.  The order of the NG- and GEK-specific questionnaires will be 
randomized (Table IGBM.2). 
9.10.1. NASA Task Load Index 
Following each simulation, Trained Users and Untrained Users (but not PWDs) will be asked to 
complete Hart and Staveland’s NASA TLX to gauge their experience during that simulation.  
The NASA TLX is a series of 21-point scales that measure various aspects of carrying out a task.  
Example questions include Mental Demand (“How mentally demanding was the task?”), Effort 
(“How hard did you have to work to accomplish your level of performance?”) and Frustration 
(“How insecure, discouraged, irritated, stressed, and annoyed were you?”). 
9.10.2. Questionnaire Comparing Both Devices 
For Trained Users and Untrained Users, the comparative questionnaire will include questions on 
preference, ease of use and confidence using each device. 
Person with diabetes will receive a differently worded questionnaire that will include questions 
on their preference of device, and their impression of the user experience for ease of use and 
confidence. 
9.10.3. Device-Specific Questionnaires (NG and GEK) 
All participants (Trained Users, Untrained Users and PWDs) will be given a device-specific 
questionnaire for each device (NG and/or GEK) that the participant attempted to administer.  The 
questionnaires will include questions related to ease of use and confidence in using each device, 
without comparing to the other device.  
 


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10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
The sample size is 26 in each of the 2 cohorts (Trained Users and Untrained Users). It is 
assumed that the percentages of successful dosing of NG and GEK will be 90% and 50%,
respectively.  Additionally, a proportion of discordant pairs of 45% is assumed, which reflects a 
moderate within-subject correlation between the 2 treatments.  
These numbers are based on the Yale 2017 study (Yale et al. 2017), where 15 out of 16 (93.8%) 
NG simulations were completely successful and 8/16 (50%) GEK administrations were partially 
successful in the “caregivers” group (the equivalent of the Trained Users group in this study).  
Note that for GEK, the “partial success” rate is used.  In Yale 2017, only 2 out of 16 (12.5%) 
simulations were completely successful for the GEK treatment.  Hence, we are using a best-case 
scenario approach for the successful administration rates of GEK in the current study.  In 
conclusion, the 90% success rate for NG is based on the Yale 2017 NG success rate (15/16, 
93.8%, rounded down) and the 50% success rate for GEK is based on the best-case scenario from 
the Yale 2017 study, i.e. partial administration of GEK in 8/16 (50%) simulations.
Based on these numbers, the sample size will provide 90% statistical power to detect a 
statistically significant difference between success rates of NG and GEK, using the test with a 
2-sided alpha level of 0.05.
Enrollment will be continued per group until 26 Trained Users have been recruited (stratified 
into 13 who have an accompanying PWD with T1DM, and 13 who have a PWD with T2DM) 
and 26 Untrained Users have been recruited.
Participants who are randomized but do not participate in the study simulations may be replaced
to ensure that enough participants may complete the study.
10.2. Populations for Analyses
10.2.1. Study Participant Disposition
A detailed description of participant disposition will be provided at the end of the study. 
10.2.2. Study Participant Characteristics
An individual listing and summary of participant demographics will be provided at the end of the 
study.
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.
The McNemar test will be used to assess the primary objective of the study (Section 4).  The 
exact-sign test will be used as a sensitivity analysis for the primary objective.


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Successful administration will be assessed, for each cohort:

NG (Trained User) versus GEK (Trained User) 

NG (Untrained User) versus GEK (Untrained User)
For Part A (Trained Users), assessment of successful administration will also be stratified
between those users who have an accompanying PWD with T1DM, and those who have an 
accompanying PWD with T2DM.
For baseline data, continuous variables will be presented using simple descriptive statistics such 
as mean, standard deviation, median and range.  Categorical variables will be presented as n/N 
and percentage.
Time to administer a dose will be assessed, making the following comparisons: 

NG (Trained User) versus NG (Untrained User)

GEK (Trained User) versus GEK (Untrained User)

NG (Trained User) versus GEK (Trained User) 

NG (Untrained User) versus GEK (Untrained User)
This analysis, using descriptive statistics, will be assessed for successful and unsuccessful 
administration combined, as well as successful administration only.  Time needed to complete 
glucagon administration will be shown categorically. A graphical presentation of the successful 
administration times may be provided.
To simultaneously model the training effect (Trained Users versus Untrained Users) and the 
treatment effect (NG versus GEK), a generalized estimating equations (GEEs) model will be 
performed, with treatment, training and the treatment-by-training interaction effect as 
independent variables, and the participant as participant identifier. As each Trained User and 
Untrained User will perform both the NG and the GEK administration, the data are paired for the 
device type but not paired for the level of training. Using a GEE model will enable estimation of
both effects simultaneously, and also estimation of the interaction effect, which will test whether 
the difference between devices varies between Trained Users and Untrained Users.  Furthermore, 
the randomization order (NG-GEK versus GEK-NG) can be tested within this model.  Given the 
low sample size of this study and multitude of variables that can be entered, this GEE modeling 
can be exploratory in nature.
Primarily, a GEE model using the binary distribution (success versus no success) and the identity 
link will be produced: this will produce estimated rate differences with 95% confidence 
intervals. In case this model fails to converge, log or logit links can be attempted, to estimate 
relative risks or odds ratios, respectively.
All AEs will be listed, and if the frequency of events allows, safety data will be summarized 
using descriptive methodology.
Additional exploratory analyses of the data will be conducted as deemed appropriate.


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10.3.1. Data Review during the Study
No interim access to data is scheduled to occur.
10.3.2. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the Lilly clinical pharmacologist, CRP/investigator, or designee will consult with the 
appropriate medical director or designee to determine if it is necessary to amend the protocol.


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11.
References
American Diabetes Association. Glycemic targets: standards of medical care in diabetes - 2018. 
Diabetes Care. 2018;41(suppl 1):S55-S64. 
Yale JF, Dulude H, Egeth M, Pichè CA, Lafontaine M, Carballo D, Margolies R, Dissinger E, 
Shames AR, Kaplowitz, N, Zhang MX, Zhang S, Guzman CB. Faster use and fewer failures 
with needle-free nasal glucagon versus injectable glucagon in severe hypoglycemia rescue: a 
simulation study. Diabetes Technol Ther. 2017;19(7):423-432.


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Appendix 1.
Abbreviations and Definitions


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Term
Definition
ADA
American Diabetes Association
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.
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.
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.
Enroll
The act of assigning a participant to a randomization schedule.
Enter
Subjects entered into a study are those who sign the informed consent form.
ERB
ethical review board
GCP
good clinical practice
GEE
generalized estimating equation
GEK
glucagon emergency kit
ICF
informed consent form
ICH
International Council for Harmonisation
IFU
Instructions for Use
informed consent
A process by which a subject 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 subject’s decision to participate. Informed consent is documented by means of a 
written, signed and dated informed consent form.  
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical study, including products already on the market when used or assembled
(formulated or packaged) in a way different from the authorized form, or marketed products 
used for an unauthorized indication, or marketed products used to gain further information 
about the authorized form.


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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.
NG
nasal glucagon
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.
PWD
person with diabetes
Randomize
The process of assigning subjects/patients to an experimental group on a random basis.
SAE
serious adverse event
Screen
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study.  
SUSAR
suspected unexpected serious adverse reaction
T1DM
type 1 diabetes mellitus
T2DM
type 2 diabetes mellitus


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Appendix 2.
Study Governance, Regulatory and Ethical 
Considerations
Informed Consent
The investigator is responsible for

ensuring that the subject 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 subject.  This includes obtaining the 
appropriate signatures and dates on the ICF prior to the performance of any protocol 
procedures.

answering any questions the subject may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the subject’s willingness to 
continue his or her participation in the study.

providing a copy of the ICF to the participant 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 
materials 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 Harmonisation (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.  Lilly or its representatives must approve the ICF 
before it is used at the investigative site.  All ICFs must be compliant with the ICH guideline on 
GCP.
The study site’s ERB(s) should be provided with the following:

the current Investigator’s Brochure and updates during the course of the study

ICF 

relevant curricula vitae


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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 International Ethical Guidelines 
2) applicable ICH GCP Guidelines 
3) applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third-party organization.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Final Report Signature
The investigator or designee will sign the clinical study report for this study, indicating 
agreement with the analyses, results and conclusions of the report.
The sponsor’s responsible medical officer and statistician will sign/approve the final clinical 
study report for this study, confirming that, to the best of his or her knowledge, the report 
accurately describes the conduct and results of the study.
Data Quality Assurance
To ensure accurate, complete and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate.

provide training to instruct the investigators and study coordinators.  This training will 
give instruction on the protocol, the completion of the CRFs and study procedures.

make periodic visits to the study site.

be available for consultation and stay in contact with the study site personnel by mail, 
telephone and/or fax.

review and evaluate CRF data and/or use standard computer edits to detect errors in data 
collection.

conduct a quality review of the database.


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In addition, Lilly or its representatives will periodically check a sample of the subject 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 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 subject/patient personal information collected will be provided in a 
written document to the subject/patient by the sponsor.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety,
regulatory or other reasons consistent with applicable laws, regulations and GCP.


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Appendix 3.
Protocol Amendment I8R-MC-IGBM(a) 
Summary
A Simulation Study Comparing Successful 
Administration, Time to Administer, and User 
Experience of Ready-to-Use Nasal Glucagon with
Reconstitutable Injectable Glucagon
Overview
Protocol I8R-MC-IGBM, A Simulation Study Comparing Successful Administration, Time to 
Administer, and User Experience of Ready-to-Use Nasal Glucagon with Reconstitutable 
Injectable Glucagon, 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:

Section 5.1.3.1 (Detailed Description of Study Procedures, for Part A) now states that the 
PWD will not observe the simulations in real time.  This is to minimize the risk of their 
intervening or otherwise influencing the Trained User.

Section 5.1.3 (Detailed Description of Study Procedures, for both parts A and B) and 
Section 9.10 (Questionnaires) now clarify that the individual device-specific 
questionnaires will only be given if the Trained or Untrained User attempted to 
administer the device in question.  Likewise, the comparative questionnaire will only be 
given if the user attempted to administer both devices during the respective simulations.  
This is to allow for the possibility that a user may wrongly administer insulin instead of a 
glucagon device, or not attempt to administer any device, rendering the questionnaire 
void.

Section 6.4 (Screen Failures) now states that subjects may be rescreened once.

Section 5.1.3.4 (Assessment of Successful Administration) now specifies that, in order to 
achieve a successful administration, users must shake or swirl the GEK vial to ensure the 
drug powder is dissolved. 

In Section 2 (Schedule of Activities) and Section 5.1.3.2 (Detailed Description of Study 
Procedures for Part B), the delay between Untrained Users watching the video and filling 
in the questionnaires has been changed to “55 to 60 minutes”, instead of “at least an 
hour”.  This is to match Part A and ensure each participant’s experience is comparable.

Section 2 (Schedule of Activities) now clarifies that the safety follow-up may also 
address significant errors made during simulations, such as insulin being administered
instead of glucagon.  This is to allow site staff to educate participants in the best way to 
respond to severe hypoglycemia events in the real world.

Other minor editorial changes.


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Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
2.   Schedule of Activities
Study Schedule Protocol I8R-MC-IGBM:  Part A (Trained Users)
Procedure
Study Visits 
Comments
Visit 
1
Visit 
2
Visit 3
Day 1
Days 
8-9
Days 
15-17
There must be a gap of at least 7 days between visits. 
[…]
Safety Assessment/
Follow-up/Early 
Discontinuation
X
X
X
The safety assessment covers any accidents during training or simulations 
(see Section 9.4), or significant errors (e.g. insulin was administered during 
the simulation instead of glucagon).  For follow-up of discontinued 
participants see Section 8.
Study Schedule Protocol I8R-MC-IGBM: Part B (Untrained Users)
Procedure
Visit 1 
Visit 2
Comments
Day 1
Days 8-9
[…]
Questionnaires
X
After the simulation at Visit 2, each Untrained User will watch a 
video showing both simulations.  Then, after a delay of 55 to 60 
minutes, at least an hour, each Untrained User will answer the 
comparative and individual-device questionnaires (Section 9.10)
[…]
Safety Assessment/ 
Follow-up/Early 
Discontinuation
X
X
The safety assessment covers any accidents during simulations (see
Section 9.4), or significant errors (e.g. insulin was administered 
during the simulation instead of glucagon). For follow-up of 
discontinued participants, see Section 8.


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5.1.3.1. Part A (Trained Users)
At Visit 2, approximately 7 days after Visit 1, each Trained User will take part in a 
simulation of a severe hypoglycemia emergency with a manikin (see Section 5.1.3.3).  
The gender of the manikin will match the gender of the PWD.  The PWD will not be in 
the room and will not observe the simulationfrom a separate room.
[…]
At Visit 3, approximately 7 days after Visit 2, each Trained User will take part in a 
second simulation, similar to the first.  They will be asked to treat the manikin with 
Device 2, again observed by site staff onlyand the PWD.
[…]
Details of the questionnaires are in Section 9.10.  Participants will be given a device-
specific questionnaire only if the Trained User attempted to administer that device.  For 
example, there will be no questionnaire for a simulation if insulin was wrongly 
administered instead of the glucagon device, or if no attempt was made to administer a 
device.  Similarly, participants will be given the comparative questionnaire only if the 
Trained User attempted to administer both NG and GEK during the respective 
simulations.
5.1.3.2.   Part B (Untrained Users)
At Visit 2, approximately 7 days after Visit 1, each Untrained User will be shown an 
example of Device 2.  As at Visit 1, no instruction will be given on how to use the device.  
The Untrained User will take part in a simulation using Device 2, and then complete the 
NASA TLX.  Site staff will assemble a video of both simulations, and the Untrained User 
will watch it.  After a delay of 55 to 60 minutes at least an hour, the Untrained User will 
fill in a questionnaire comparing both devices, and then individual-device questionnaires 
in randomized order (Table IGBM.2).  Details of the questionnaires are in Section 9.10.  
The Untrained User will be given a device-specific questionnaire only if they attempted 
to administer that device.  For example, there will be no questionnaire for a simulation if 
insulin was wrongly administered instead of the glucagon device, or if no attempt was 
made to administer a device.  Similarly, Untrained Users will be given the comparative 
questionnaire only if they attempted to administer both NG and GEK devices during the 
respective simulations.
5.1.3.3.   Example Simulation
The participant in the simulation (Trained User or Untrained User) will be taken into a room 
where a fully clothed adult manikin is present (e.g. lying face-up on the ground, on a bed, or in a 
chair).


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5.1.3.4.  Assessment of Successful Administration
1. Complete All Critical Steps
GEK

Remove device from packaging 

Inject the diluent from the syringe into the vial containing the drug powder

Ensure drug powder is dissolved (by shaking/swirling)

Draw the dissolved drug into the syringe

Inject the drug into the manikin at an appropriate site for intramuscular administration 
(e.g. thigh/buttock/upper arm)


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5.4.   Scientific Rationale for Study Design
A manikin will represent a person experiencing severe hypoglycemia; this allows for better 
control of the variables of each simulation, and avoids ethical issues related to the induction of 
severe hypoglycemia in people.
The PWD will not observe simulations in real time, so as to minimize the risk of their 
intervening or otherwise influencing the Trained User.  This is intended to ensure simulations are 
like-for-like between participants and between devices, which will aid comparison.
6.4.   Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) will not
may be rescreened once, after consultation with the Sponsor.
7.2.   Method of Treatment Assignment
Table IGBM.2.
Example Randomization Schedule - Study IGBM
Device for Simulation 1 
(“Device 1”); andor Device 
Specified in Questionnaire 1
Device for Simulation 2 
(“Device 2”); andor Device 
Specified in Questionnaire 2
9.10.   Example QualitativeQuestionnaires
As detailed in Section 5.1.3, Trained Users and Untrained Users will complete NASA TLX 
questionnaires soon after each simulation, and all participants (Trained Users, Untrained Users 
and PWDs) will complete further questionnaires at the end of the study.
As detailed in Section 5.1.3.1 and 5.1.3.2, the individual (device-specific) and comparative 
questionnaires will be given only for devices that participants actually attempted to administer 
during the simulations.  The NASA TLX will be administered for all participants, whether they 
attempted to administer a glucagon device or not. 
Assuming the comparative questionnaire is given, it For the end-of-study questionnaires, the 
questionnaire directly comparing both devices will always be given before the device-specific 
questionnairesfirst.  The order of the NG- and GEK-specific questionnaires will be randomized 
(Table IGBM.2).
9.10.3.  Device-Specific Questionnaires (NG and GEK)
All participants (Trained Users, Untrained Users and PWDs) will be given aanswer 2 device-
specific questionnaires for each device (NG and/or GEK) that the participant attempted to 


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administer, regarding NG and GEK individually.  These questionnaires will include questions 
related to ease of use and confidence in using each device, without comparing to the other device. 

SAP_000.pdf: 
Statistical Analysis Plan I8R-MC-IGBM 
 
A Simulation Study Comparing Successful Administration, Time to Administer, and User 
Experience of Ready-to-Use Nasal Glucagon with Reconstitutable Injectable Glucagon 
 
 
NCT03765502 
 
 
Approval Date: 19-Nov-2018 


Final, 14 Nov 2018
             Page 1 of 15
STATISTICAL ANALYSIS PLAN
A Simulation Study Comparing Successful Administration, Time to Administer, and User 
Experience of Ready-to-Use Nasal Glucagon with Reconstitutable Injectable Glucagon.
Statistical Analysis Plan Status: Final
Statistical Analysis Plan Date: 14-November-2018
Study Drug: LY900018
Sponsor Reference: I8R-MC-IGBM
Covance CRU Study: 1000071-8394076
Clinical Phase I
Approval Date: 19-Nov-2018 GMT


Final, 14 Nov 2018
             Page 2 of 15
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8394076
Sponsor Reference I8R-MC-IGBM
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS .....................................................................................................2
2.
ABBREVIATIONS..............................................................................................................3
3.
INTRODUCTION ...............................................................................................................4
4.
STUDY OBJECTIVES........................................................................................................5
4.1
Primary Objective..........................................................................................................5
4.2
Secondary Objectives ....................................................................................................5
4.3
Exploratory Objectives ..................................................................................................5
5.
STUDY DESIGN.................................................................................................................5
5.1
Types of Participants .....................................................................................................6
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
Adverse Events............................................................................................................10
9.4
Questionnaires.............................................................................................................10
9.5
Statistical Methodology...............................................................................................12
9.6
Other Assessments ......................................................................................................14
10. INTERIM ANALYSES .....................................................................................................14
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ............14
12. REFERENCES ..................................................................................................................14
13. DATA PRESENTATION ..................................................................................................14
13.1 Derived Parameters .....................................................................................................14
13.2 Missing Data ...............................................................................................................15
13.3 Insufficient Data for Presentation ................................................................................15


Final, 14 Nov 2018
             Page 3 of 15
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8394076
Sponsor Reference I8R-MC-IGBM
2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
AE
Adverse event
CRF
Case Report Form
CRU
Clinical Research Unit
CSR
Clinical Study Report
EC
Early Clinical 
e.g.
For example (Latin: exempli gratia)
GEE
Generalized estimating equations
GEK
Glucagon emergency kit
ICH
International Conference on Harmonisation
MedDRA
Medical Dictionary for Regulatory Activities
NA
Not applicable
NASA
National Aeronautics and Space Administration
NG
Nasal glucagon
PWD
Person with diabetes
SAP
Statistical Analysis Plan
SOP
Standard Operating Procedure
SUSAR
Suspected unexpected serious adverse reaction
TFLs
Tables, Figures, and Listings
TLX
Task load index
WHO
World Health Organization


Final, 14 Nov 2018
             Page 4 of 15
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8394076
Sponsor Reference I8R-MC-IGBM
3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
21 September 2018).
This SAP describes the planned analysis of the efficacy and safety 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 analysis 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 simulation 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 
Conference on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials1 and the ICH E3 Guideline entitled Guidance for Industry: 
Structure and Content of Clinical Study Reports2.


Final, 14 Nov 2018
             Page 5 of 15
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8394076
Sponsor Reference I8R-MC-IGBM
4. STUDY OBJECTIVES
4.1
Primary Objective

To test the hypothesis that more Trained Users can successfully administer nasal 
glucagon (NG) than glucagon emergency kit (GEK) when treating a simulated episode of 
severe hypoglycemia.
4.2
Secondary Objectives

To test the hypothesis that more Untrained Users can successfully administer NG than 
GEK when treating a simulated episode of severe hypoglycemia.

To compare the average time to successfully administer NG, compared with GEK, for 
trained and untrained users.

To compare percentages of users who complete critical administration steps for both NG
and GEK, for trained and untrained users.

To assess the number of simulations that result in successful administration of NG.

To assess whether, overall and for trained users, persons with diabetes (PWDs) and 
untrained users, one device (NG or GEK) is preferred over the other.

To assess overall, and for trained users, PWDs and untrained users, ease of use of both 
devices (NG and GEK).
4.3
Exploratory Objectives

To assess participants’ overall confidence in the use of NG and GEK devices.

To compare the time it takes a PWD to teach the use of NG and GEK devices.

To compare participants’ experience of Mental Demand, Effort, Frustration and other 
elements of the National Aeronautics and Space Administration (NASA) Task Load 
Index (TLX), following NG and GEK simulations.
5. STUDY DESIGN
This is a single-center, randomized, crossover study assessing the percentage of simulations with 
dose successfully administered, and other experiences of administering both NG and a 
commercially available GEK during simulations of severe hypoglycemia emergencies. 
Participants in the study will administer nasal and injectable glucagon devices to manikins.
Study I8R-MC-IGBM (IGBM) is divided into 2 parts, with different types of participants: Part A 
(Trained Users, who will attend all study visits with a PWD) and Part B (Untrained Users). Both 
parts of the study may be run at the same time.


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Statistical Analysis Plan 
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The study is intended to simulate real-life conditions to capture and document, in a controlled
setting, any differences in how Trained Users and Untrained Users use NG and GEK, and their
experience of doing so.
5.1
Types of Participants
Participants are defined as follows:

Trained User: A participant who, during the study, will be given a level of training 
intended to mimic that of a real-life caregiver, relative, or close friend of a PWD.
o
“Trained User” participants must be either related to, or a close friend of, a PWD, 
and therefore already familiar with diabetes and the risk of severe hypoglycemia. 
Each Trained User must be recruited alongside the PWD with whom they are 
familiar, as a “dyad” (a pair of people who have a pre-existing relationship).
o
The Trained User will receive instruction on the use of each device, from the
PWD, before taking part in the simulation using that device.
o
Trained Users must not have actually administered injectable glucagon (or
another rescue medication) in the past. However, they may own a glucagon rescue 
kit, and may have been instructed in its use, as long as such instruction occurred at 
least 2 years before screening.

PWD: The PWD who is the close friend or relative of the Trained User.
o
During the study, the PWD will be trained by site staff on the use of each device, 
and at least 7 days before each simulation, will relay these instructions to the 
Trained User.
o
The PWD previously may have been instructed in the use of a glucagon rescue 
kit, as long as such instruction occurred at least 2 years before screening.

Untrained User: A participant who will not be given training during the study on either 
device, and who has limited knowledge of severe hypoglycemia and how to treat it.
o
These participants are intended to approximate a real-life colleague or 
acquaintance of a PWD: someone who is aware of the PWD’s condition and is 
willing to intervene in an episode of severe hypoglycemia, but has not received 
instructions. Untrained Users in this study may or may not know a PWD in real
life. In any case, they must not have caregiving responsibilities toward a PWD.
o
Untrained Users will participate in the study alone (not as part of a dyad). 
o
Prior to the simulations in this study, Untrained Users will be given basic 
information about severe hypoglycemia and briefly shown an example of each 
rescue device.


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Statistical Analysis Plan 
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Covance Clinical Study No. 8394076
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Figure 1 (Part A) and Figure 2 (Part B) illustrate the study design.
Figure 1 - Illustration of study design for Part A.


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Statistical Analysis Plan 
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Figure 2 - Illustration of study design for Part B.
6. TREATMENTS
The following is a list of the study treatment abbreviations that will be used in the TFLs.
Part A (Trained Users who have an accompanying person with T1DM or T2DM)
Study Treatment Name
Abbreviation
Treatment order in TFL
Nasal glucagon
NG
1
Glucagon emergency kit
GEK
2
Part B (Untrained Users)
Study Treatment Name
Abbreviation
Treatment order in TFL
Nasal glucagon
NG
3
Glucagon emergency kit
GEK
4
7. SAMPLE SIZE JUSTIFICATION
The sample size is 26 in each of the 2 cohorts (Trained Users and Untrained Users). It is assumed 
that the percentages of successful dosing of NG and GEK will be 90% and 50%, respectively. 


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Statistical Analysis Plan 
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Covance Clinical Study No. 8394076
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Additionally, a proportion of discordant pairs of 45% is assumed, which reflects a moderate 
within-subject correlation between the 2 treatments.
These numbers are based on the Yale 2017 study3, where 15 out of 16 (93.8%) NG simulations 
were completely successful and 8/16 (50%) GEK administrations were partially or completely
successful in the “caregivers” group (the equivalent of the Trained Users group in this study).
Note that for GEK, the “partial or complete success” rate is used. In Yale 2017, only 2 out of 16 
(12.5%) simulations were completely successful for the GEK treatment. Hence, we are using a 
best-case scenario approach for the successful administration rates of GEK in the current study. 
In conclusion, the 90% success rate for NG is based on the Yale 2017 NG success rate (15/16,
93.8%, rounded down) and the 50% success rate for GEK is based on the best-case scenario from
the Yale 2017 study, i.e. partial administration of GEK in 8/16 (50%) simulations.
Based on these numbers, the sample size will provide 90% statistical power to detect a
statistically significant difference between success rates of NG and GEK, using the test with a
2-sided alpha level of 0.05.
Enrollment will be continued per group until 26 Trained Users have been recruited (stratified
into 13 who have an accompanying PWD with T1DM, and 13 who have a PWD with T2DM)
and 26 Untrained Users have been recruited.
Participants who are randomized but do not participate in the study simulations may be replaced
to ensure that enough participants may complete the study.
8. DEFINITION OF ANALYSIS POPULATIONS
The “Full Analysis Set” will consist of all subjects who participate in at least one training of a 
study device.
The "Per Protocol Population" will consist of all subjects who complete the study without major 
protocol deviations.
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, median, min, 
max, P25, P75 and N 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. 


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Statistical Analysis Plan 
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Covance Clinical Study No. 8394076
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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, type 1 
diabetes mellitus and type 2 diabetes mellitus will be summarized and listed. All other 
demographic variables will be listed only. The demographic variables will also be compared, 
making the following comparisons:

NG (Trained User) versus NG (Untrained User) – two sample t-test

GEK (Trained User) versus GEK (Untrained User) – two sample t-test
9.3
Adverse Events
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the adverse event (AE) will be reported in the listings, only the most severe will be used in the 
summary tables. A pre-existing condition is defined as an AE that starts before the 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 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 21.0 system organ class and preferred term. The summary and frequency AE tables will 
be presented for all causalities and those considered related to the study drug. Any serious AEs
will be listed. 
Associated person AE’s will be listed and summarized by treatment, severity and relationship to 
the study drug.
9.4
Questionnaires
Trained Users and Untrained Users will complete NASA TLX questionnaires soon after each 
simulation, and all participants (Trained Users, Untrained Users and PWDs) will complete 
further questionnaires at the end of the study.
For the end-of-study questionnaires, the questionnaire directly comparing both devices will 
always be given first. The order of the NG- and GEK-specific questionnaires will be randomized.
NASA Task Load Index
Following each simulation, Trained Users and Untrained Users (but not PWDs) will be asked to 
complete Hart and Staveland’s NASA TLX to gauge their experience during that simulation. The 
NASA TLX is a series of 21-point scales that measure various aspects of carrying out a task. 
Example questions include Mental Demand (“How mentally demanding was the task?”), Effort 


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Statistical Analysis Plan 
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Covance Clinical Study No. 8394076
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(“How hard did you have to work to accomplish your level of performance?”) and Frustration 
(“How insecure, discouraged, irritated, stressed, and annoyed were you?”).
Following each simulation, Trained Users and Untrained Users (but not PWDs) will be asked to complete 
Hart and Staveland’s NASA TLX to gauge their experience during that simulation. The NASA TLX 
measures the perceived impact of carrying out a task in 6 dimensions (scales):

Mental Demand (“How mentally demanding was the task?”)

Physical Demand (“How physically demanding was the task?”)

Temporal Demand (“How hurried or rushed was the pace of the task?”)

Performance (“How successful were you in accomplishing what you were asked to do?”)

Effort (“How hard did you have to work to accomplish your level of performance?”) 

Frustration (“How insecure, discouraged, irritated, stressed, and annoyed were you?”).
For each of these scales, the subject assigns as score using a visual analogue scale divided into 
20 segments using 21 hashes. This 21-point scale (0-20) will be converted to a 0-100 point scale 
for the analysis.
Additionally, weights will be calculated for each the scales. This will be carried out using 
comparison cards, on which each scale is compared to the 5 other scales, creating a total of 15 
comparison cards. The subject needs to choose, for each comparison, which scale was the most 
demanding for the task. For each time a scale was selected by the subject, a value of 1 is added to 
its weight. As each scale is compared to the other 5 scales exactly ones, the maximum of the 
weight is 5 (this scale was always selected as being the most demanding) and the minimum is 
zero (this scale was never selected as being the most demanding).
For the analyses, a weighted average of the 100-point-scale scores will be computed in the 
analysis datasets for each subject and administration method (NG / GEK).
Questionnaire Comparing Both Devices
For Trained Users and Untrained Users, the comparative questionnaire will include questions on 
preference, ease of use and confidence using each device.
Person with diabetes will receive a differently worded questionnaire that will include questions 
on their preference of device, and their impression of the user experience for ease of use and 
confidence.
Device-Specific Questionnaires (NG and GEK)
All participants (Trained Users, Untrained Users and PWDs) will answer 2 device-specific 
questionnaires, regarding NG and GEK individually. These will include questions related to ease 
of use and confidence in using each device, without comparing to the other device.
All questionnaire data will be listed and summarized by part and treatment. For Part A (Trained 
Users), summaries will also be stratified between those users who have an accompanying PWD 
with T1DM, those who have an accompanying PWD with T2DM and overall.


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Statistical Analysis Plan 
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Covance Clinical Study No. 8394076
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9.5
Statistical Methodology
The following endpoints will be summarized by treatment using descriptive statistics and listed:

The percentage of Trained Users and Untrained Users that perform a successful
administration

The time taken by Trained Users and Untrained Users to successfully administer NG or 
GEK

The percentages of Trained Users and Untrained Users who complete all of the critical 
steps

The percentage of all simulations that result in a successful administration of NG, for all 
users combined

The average length of time taken by PWDs to teach the use of NG and GEK to their 
associated Trained User,
The McNemar test will be used to assess the percentage of Trained Users that perform a 
successful administration. The exact-sign test will be used as a sensitivity analysis.
Successful administration will be assessed, for each cohort:

NG (Trained User) versus GEK (Trained User)

NG (Untrained User) versus GEK (Untrained User)
Example SAS code for the McNemar test
proc freq data = success;
weight count / zeros;
tables NG_trained*GEK_trained / agree;
exact mcnem;
run;
Example SAS code for the exact-sign test
proc univariate data=success;
  var success_diff;
run;
Where success_diff is 1 if NG is successful and GEK is not, 0 if both treatments are successful 
or not successful and -1 if NG is not successful and GEK is successful.
For Part A (Trained Users), assessment of successful administration will also be stratified
between those users who have an accompanying PWD with T1DM, and those who have an
accompanying PWD with T2DM.
Time to administer a dose will be assessed using summary statistics, making the following 
comparisons:

NG (Trained User) versus NG (Untrained User) – two sample t-test

GEK (Trained User) versus GEK (Untrained User) – two sample t-test


Final, 14 Nov 2018
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Statistical Analysis Plan 
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
NG (Trained User) versus GEK (Trained User) – Paired t-test

NG (Untrained User) versus GEK (Untrained User) – Paired t-test
This analysis, using descriptive statistics and the appropriate t-test, will be assessed for 
successful and unsuccessful administration combined, as well as successful administration only. 
Time needed to complete glucagon administration will be shown categorically based on the 
following categories:

<30 seconds

30 seconds-45 seconds

45 seconds-1 minute

1 minute-1 minute 15 seconds

1 minute 15 seconds-1 minute 30 seconds

1 minute 30 seconds-1 minute 45 seconds

1 minute 45 seconds-2 minutes

2 minutes-2 minutes 15 seconds

2 minute 15 seconds-2 minutes 30 seconds

2minutes 30 seconds-2 minutes 45 seconds 

2 minutes 45 seconds-3 minutes

3-4 minutes

4-5 minutes

5-10 minutes

>10 minutes
A graphical presentation of the successful administration times will be provided using a Kaplan-
Meier plot.
To simultaneously model the training effect (Trained Users versus Untrained Users) and the
treatment effect (NG versus GEK), a generalized estimating equations (GEEs) model will be
performed, with treatment, training and the treatment-by-training interaction effect as
independent variables, and the participant as participant identifier. As each Trained User and
Untrained User will perform both the NG and the GEK administration, the data are paired for the
device type but not paired for the level of training. Using a GEE model will enable estimation of
both effects simultaneously, and also estimation of the interaction effect, which will test whether
the difference between devices varies between Trained Users and Untrained Users. Furthermore,
the randomization order (NG-GEK versus GEK-NG) can be tested within this model. Given the
low sample size of this study and multitude of variables that can be entered, this GEE modelling 
will be exploratory in nature.
Primarily, a GEE model using the binary distribution (success versus no success) and the identity
link will be produced: this will produce estimated rate differences with 95% confidence intervals. 
In case this model fails to converge, log or logit links can be attempted, to estimate relative risks 
or odds ratios, respectively.


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Statistical Analysis Plan 
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Covance Clinical Study No. 8394076
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Example SAS code:
proc genmod data=xx descending;
class  subjid arm trt ftrt ;
model success = arm|trt ftrt / link=identity dist=bin;
repeated subject=subjid;
lsmeans  arm*trt / ilink  diff;
lsmeans  arm / ilink  diff;
lsmeans  trt / ilink  diff;
lsmeans  ftrt / ilink  diff;
run;
where arm = trained or untrained, trt = NG or IM and ftrt = first treatment received
9.6
Other Assessments
All other assessments not detailed in previous sections will be listed but not summarized or 
statistically analyzed.
10.
INTERIM ANALYSES
No interim statistical analyses are planned.
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. Yale JF, Dulude H, Egeth M, Pichè CA, Lafontaine M, Carballo D, Margolies R, Dissinger 
E, Shames AR, Kaplowitz, N, Zhang MX, Zhang S, Guzman CB. Faster use and fewer 
failures with needle-free nasal glucagon versus injectable glucagon in severe hypoglycemia 
rescue: a simulation study. Diabetes Technol Ther. 2017;19(7):423-432.
13.
DATA PRESENTATION
13.1
Derived Parameters
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.


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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 center of the table, 
such as, “No serious adverse events occurred for this study.”