Conditions: Healthy
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 23
Healthy volunteers: yes

Brief summary:
The purpose of this study is to determine how the body handles LY3185643 and rGlucagon and what effects LY3185643 and rGlucagon have on the body. This study will also help to determine if LY3185643 is safe and well-tolerated.

This study will last at least 35 days, not including screening.

Detailed description:

Arms:
arm 1: LY3185643 administered subcutaneous (SC) arm 2: rGlucagon administered subcutaneous (SC)

Interventions: intervention 1: LY3185643 intervention 2: rGlucagon
Intervention descriptions: intervention 1: Administered SC intervention 2: Administered SC

Protocol document:
Prot_000.pdf: 
Protocol (a) I8Z-MC-APCA 
 
A Randomized, 9-Way, Single-Dose, Crossover Study to Evaluate the Pharmacokinetics, 
Pharmacodynamics, Safety, and Tolerability of LY3185643 and rGlucagon in Healthy Subjects 
NCT02951780 
Approval Date: 08-Dec-2016 
 
 
 


I8Z-MC-APCA(a) Clinical Pharmacology Protocol
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LY3185643
Protocol I8Z-MC-APCA(a)
A Randomized, 9-Way, Single-Dose, Crossover Study to 
Evaluate the Pharmacokinetics, Pharmacodynamics, 
Safety, and Tolerability of LY3185643 and rGlucagon in 
Healthy Subjects
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 
LY3185643, 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.  
LY3185643
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly: 
17 August 2016
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly on date 
provided below.
Approval Date: 08-Dec-2016 GMT


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Table of Contents
A Randomized, 9-Way, Single-Dose, Crossover Study to Evaluate the 
Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of 
LY3185643 and rGlucagon in Healthy Subjects
Section
Page
Protocol I8Z-MC-APCA(a) A Randomized, 9-Way, Single-Dose, 
Crossover Study to Evaluate the Pharmacokinetics, 
Pharmacodynamics, Safety, and Tolerability of LY3185643 and 
rGlucagon in Healthy Subjects............................................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................8
2.
Schedule of Activities .......................................................................................................11
3.
Introduction ......................................................................................................................14
3.1.
Study Rationale............................................................................................................14
3.2.
Background..................................................................................................................14
3.2.1.
Clinical Experience..............................................................................................15
3.3.
Benefit/Risk Assessment..............................................................................................16
4.
Objectives and Endpoints..................................................................................................17
5.
Study Design.....................................................................................................................18
5.1.
Overall Design .............................................................................................................18
5.2.
Number of Participants.................................................................................................20
5.3.
End of Study Definition ...............................................................................................20
5.4.
Scientific Rationale for Study Design...........................................................................20
5.5.
Justification for Dose ...................................................................................................21
6.
Study Population...............................................................................................................22
6.1.
Inclusion Criteria..........................................................................................................22
6.2.
Exclusion Criteria ........................................................................................................23
6.3.
Lifestyle and/or Dietary Requirements .........................................................................25
6.3.1.
Meals and Dietary Restrictions.............................................................................25
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................25
6.3.3.
Activity................................................................................................................25
6.4.
Screen Failures.............................................................................................................26
7.
Treatment..........................................................................................................................27
7.1.
Treatment Administered...............................................................................................27
7.1.1.
Packaging and Labeling .......................................................................................28
7.2.
Method of Treatment Assignment ................................................................................28


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7.2.1.
Selection and Timing of Doses.............................................................................28
7.3.
Blinding .......................................................................................................................28
7.4.
Dose Modification........................................................................................................28
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............................................................................30
8.
Discontinuation Criteria ....................................................................................................31
8.1.
Discontinuation from Study Treatment.........................................................................31
8.1.1.
Discontinuation of Inadvertently Enrolled Subjects..............................................31
8.2.
Discontinuation from the Study....................................................................................31
8.3.
Subjects Lost to Follow-Up..........................................................................................32
9.
Study Assessments and Procedures ...................................................................................33
9.1.
Efficacy Assessments...................................................................................................33
9.2.
Adverse Events ............................................................................................................33
9.2.1.
Serious Adverse Events........................................................................................34
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................34
9.2.2.
Complaint Handling.............................................................................................35
9.3.
Treatment of Overdose.................................................................................................35
9.4.
Safety...........................................................................................................................35
9.4.1.
Laboratory Tests ..................................................................................................35
9.4.2.
Physical Examination...........................................................................................35
9.4.3.
Vital Signs ...........................................................................................................35
9.4.4.
Electrocardiograms ..............................................................................................35
9.4.4.1.
Continuous 12-Lead ECG Monitoring ............................................................36
9.4.4.1.1.
Recordings for Data Analysis....................................................................36
9.4.4.2.
Telemetry.......................................................................................................37
9.4.5.
Safety Monitoring ................................................................................................37
9.4.6.
Immunogenicity Assessments ..............................................................................37
9.5.
Pharmacokinetics .........................................................................................................38
9.5.1.
Bioanalysis...........................................................................................................38
9.6.
Pharmacodynamics ......................................................................................................38
9.6.1.
Glucodynamic Samples........................................................................................38
9.7.
Genetics .......................................................................................................................38
9.8.
Biomarkers...................................................................................................................39
9.9.
Health Economics ........................................................................................................39
10.
Statistical Considerations and Data Analysis.....................................................................40
10.1. Sample Size Determination ..........................................................................................40


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10.2. Populations for Analyses..............................................................................................40
10.2.1.
Study Participant Disposition ...............................................................................40
10.2.2.
Study Participant Characteristics ..........................................................................40
10.3. Statistical Analyses ......................................................................................................40
10.3.1.
Safety Analyses....................................................................................................40
10.3.1.1.
Clinical Evaluation of Safety..........................................................................40
10.3.1.2.
Statistical Evaluation of Safety.......................................................................41
10.3.2.
Pharmacokinetic Analyses....................................................................................41
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................41
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................41
10.3.3.
Pharmacodynamic Analyses.................................................................................41
10.3.3.1.
Pharmacodynamic Parameter Estimation ........................................................41
10.3.3.2.
Pharmacodynamic Statistical Inference...........................................................41
10.3.4.
Evaluation of Immunogenicity .............................................................................42
10.3.5.
Interim Analyses..................................................................................................42
11.
References ........................................................................................................................43


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List of Tables
Table
Page
Table APCA.4.1.
Objectives and Endpoints .......................................................................17
Table APCA.5.1.
Treatment Sequences..............................................................................20
Table APCA.7.1.
Investigational Product Regimens...........................................................27


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List of Figures
Figure
Page
Figure APCA.5.1.
Study design...........................................................................................19


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................44
Appendix 2.
Clinical Laboratory Tests........................................................................47
Appendix 3.
Study Governance, Regulatory, and Ethical Considerations....................48
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............51
Appendix 5.
Blood Sampling Summary......................................................................52
Appendix 6.
Protocol Amendment I8Z-MC-APCA(a)
A Randomized, 9-Way, Single-Dose, Crossover Study to Evaluate 
the Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability 
of LY3185643 and rGlucagon in Healthy Subjects .................................53


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1. Protocol Synopsis
Title of Study:  A Randomized, 9-Way, Single-Dose, Crossover Study to Evaluate the Pharmacokinetics, 
Pharmacodynamics, Safety, and Tolerability of LY3185643 and rGlucagon in Healthy Subjects
Rationale: The availability of insulin pumps and continuous glucose monitors has transformed diabetes care by 
allowing continuous infusion of insulin with bolus doses administered based on food intake.  Hypoglycemia may 
result from excessive insulin administration in relation to food intake, disease state, or physical activity.  
Hypoglycemia may be life-threatening; this is a risk with any insulin administration, and may be of concern with 
automated systems.
An artificial pancreas device system (APDS) may provide better control of blood sugar with less episodes of 
hypoglycemia.  A bihormonal APDS combines automated delivery of both insulin and glucagon.  Pilot studies using 
investigational, bihormonal APDSs have demonstrated that delivery of small doses of glucagon in response to 
declining glucose levels reduces the frequency of hypoglycemia.  Glucagon opposes the effects of insulin in the liver 
and increases blood glucose levels.
The current commercial glucagon (recombinant glucagon [rGlucagon]) preparations are only available as 
lyophilized powder that must be reconstituted with a diluent before administration.  The current Lilly formulation of 
rGlucagon also has poor solubility in aqueous buffers at or near physiological pH values and poor chemical and 
physical stability when formulated at low and high pH.
LY3185643 is a glucagon analog with improved solubility that is being developed for use in a bihormonal APDS.  
The current study is designed to assess the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of 
LY3185643 and compare these to rGlucagon.
Objectives/Endpoints:
Primary Objective
Endpoints
The primary objective of this study is to evaluate the PK 
and PD profiles of LY3185643 and rGlucagon after 
single doses of study treatment
Cmax, AUC, and terminal half-life of LY3185643 and 
rGlucagon
Cmax and AUC (change from predose) of blood glucose
and C-peptide
Secondary Objective
Endpoints
To evaluate the safety and tolerability of LY3185643 
after single doses of study treatment
Adverse events
Abbreviations:  AUC = area under the concentration versus time curve; Cmax = maximum concentration; 
PD = pharmacodynamic; PK = pharmacokinetic; rGlucagon = recombinant glucagon.
Summary of Study Design:  This study is a Phase 1, single-center, subject- and investigator-blind, randomized, 
9-way, 3-period crossover study in healthy subjects to evaluate the PK and PD of LY3185643 and rGlucagon after 
subcutaneous (SC) administration.
Up to 37 healthy men and women may be enrolled to target approximately 18 subjects to complete the study.  Each 
subject will receive 3 doses on each of 3 dosing days (total of 9 doses: 5 doses of LY3185643 and 4 doses of 
rGlucagon) administered SC.  Doses will be administered in a 9-way complete crossover design in 3 periods, and 
subjects will be randomized to predefined treatment sequences.


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Each study period will consist of 3 days (Days -1 to 2). Subjects should return for the next period with a minimum 
of 3 days between treatment periods.
Blood samples will be collected for the determination of concentrations of LY3185643, glucagon, glucose, 
C-peptide, and for immunogenicity.  Safety data will include clinical examinations, vital signs, electrocardiograms 
(ECGs; including telemetry), clinical laboratory tests, and a record of adverse events (AEs).
Treatment Arms and Duration:  Each subject will be randomized to 1 of 9 treatment sequences comprising single 
SC doses of LY3185643 or rGlucagon.  Subjects will receive 9 doses total during 3 treatment periods (3 doses per 
period).  Each treatment period will consist of 3 days with a minimum of 3 days between each period. A follow-up 
visit will be required at least 30 days after completing the last dose of study treatment.
Number of Subjects: Up to 37 subjects may be enrolled so that approximately 18 subjects complete the study.
Statistical Analysis:  PK and PD analyses will be conducted on the full analysis set.  This set includes all data from
all randomized subjects receiving at least 1 dose of the investigational product and with a baseline and at least 
1 postbaseline measurement for each dose according to the treatment the subjects actually received.  Safety analyses 
will be conducted for all enrolled subjects whether or not they completed all protocol requirements.
Sample Size:  The sample size is customary for Phase 1 studies evaluating safety, PK, and/or PD parameters and is 
considered sufficient to evaluate the primary objective of this study.
Safety:  All investigational product and protocol procedure AEs will be listed, and if the frequency of events allows, 
safety data will be summarized using descriptive methodology.  Other safety parameters that will be assessed 
include safety laboratory parameters, vital signs, and ECG parameters.  The safety parameters will be listed and 
summarized using standard descriptive statistics.
Pharmacokinetics:  PK parameter estimates for LY3185643 and rGlucagon will be calculated by standard 
noncompartmental methods of analysis.  The primary parameters for analysis will be maximum drug concentration 
(Cmax) and area under the concentration versus time curve (AUC).  Other noncompartmental parameters, such as 
half-life, apparent clearance, and apparent volume of distribution, may be reported.  Population PK and 
exposure-response analyses may be performed using PK and glucose data.
PK parameters for LY3185643 and rGlucagon will be summarized for each dose group.  PK parameter estimates 
will be evaluated to delineate effects of dose proportionality.
Pharmacodynamics:  The PD time-action and response of LY3185643 and rGlucagon will be compared to establish 
the relative potency between LY3185643 and rGlucagon.  The primary PD response variables of interest include 
time to Cmax (Tmax), Cmax, and change from baseline to each time point, and incremental AUCs for glucose and
C-peptide.  A dose-proportionality parameter will also be estimated to establish the relative potency between 
LY3185643 and rGlucagon.  Partial AUC for glucose over appropriate time intervals will be calculated using the 
trapezoidal rule.
Parameters will be analyzed using a nonlinear mixed-effects model with period, treatment (LY3185643 or 
rGlucagon), and dose (within treatment) as fixed effects, baseline glucose as a covariate, and subject as a random 
effect.  A conversion factor will be defined in the model for each parameter to estimate the relative potency of 
LY3185643 to rGlucagon.  In addition, a conversion factor will be estimated between LY3185643 and rGlucagon 


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for multiple parameters simultaneously using a similar mixed nonlinear model approach to account for the 
correlation between parameters for the same subject.
All PD parameters including the baseline-corrected parameters will be summarized by dose group and tabulated.  
Summary statistics will be provided.  The individual observed and mean (by dose group) time profile of the 
PD measurements after dosing will be plotted.
Immunogenicity:  The frequency of antibody formation to LY3185643 will be determined.  If a neutralization assay 
is performed, the frequency of neutralizing antibodies will be determined.  The relationship between the presence (or 
absence) of antibodies and AEs will be assessed.  Likewise, the relationship between the presence of antibodies and 
the PK parameters and PD response to LY3185643 will be assessed.
Interim Analysis:  No interim analyses are planned for this study.
The Lilly study team is unblinded, and the investigator will remain blinded until the study is completed.  Data may 
be analyzed while the trial is ongoing, but no changes to the study design are planned.  An assessment committee 
will not be formed.


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2. Schedule of Activities


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Study Schedule Protocol I8Z-MC-APCA 
 
Screen 
Periods 1, 2, 3a 
FU/ETb 
 
Procedure 
Up to 
Day -28 
Day -1
Day 1c 
Day 2 
 
Comments 
Informed consent 
X 
 
 
 
 
 
Admission to CRU 
 
X 
 
 
 
 
Discharge from CRU 
 
 
 
X 
 
 
Carbohydrate-rich 
meal 
 
X 
 
 
 
Subjects will be provided a meal approximately 10:00 PM 
and will remain fasted until completion of the study 
procedures on Day 1. 
Treatment 
administration 
 
 
X (3 doses) 
 
 
Subjects will receive 3 doses of study treatment, each 
separated by at least 4 hours (for example, 8:00 AM, 
12:00 PM, 4:00 PM). 
Medical history 
X 
 
 
 
 
 
Height 
X 
 
 
 
 
 
Weight 
X 
X 
 
 
X 
 
AEs/concomitant 
medications 
X 
 
X 
X 
X 
Collected throughout the study. 
Vital signs (minutes) 
X 
 
-20 (±10), 15 (±5), 30 (±5), 
45 (±5), 60 (±5), 90 (±15), 
120 (±15), 180 (±15), 210 (±15) 
X 
X 
Supine blood pressure and/or pulse rate may be measured 
as clinically indicated.  Sampling times are relative to the 
time of each study drug administration. 
Clinical laboratory 
tests 
X 
 
Any time before the first dose 
 
X 
Period 1 only.  See Appendix 2, Clinical Laboratory Tests, 
for details. 
Pregnancy test 
X 
X 
 
 
X 
Urine pregnancy tests will be performed.  See Appendix 2, 
Clinical Laboratory Tests, for details. 
Physical examination/ 
medical assessment 
X 
 
 
X 
X 
Physical examination at screening.  Thereafter, medical 
assessment and targeted examination, as appropriate. 
12-lead ECG 
(minutes) 
X 
 
-20 (±10) 
 
X 
Single ECGs will be collected for safety.  Predose ECGs 
must be recorded before collecting any blood for safety or 
PK tests. 
ECG telemetry 
 
X 
X 
 
 
The ECG waveform and cardiac rhythm will be monitored 
continuously using an ECG telemetry monitor during the 
inpatient stay at the CRU, from the night of Day -1 to 
4 hours after the last dose on Day 1 for all 3 periods. 
 


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Study Schedule Protocol I8Z-MC-APCA
Screen
Periods 1, 2, 3a
FU/ETb
Procedure
Up to 
Day -28
Day -1
Day 1c
Day 2
Comments
Continuous ECG 
monitoring 
X
15 ECGs will be extracted from the continuous ECG 
recording at -5, 30, 60, 120, and 180 minutes postdose for 
each Day 1 dose administration.
PK samples:  
LY3185643 or 
glucagon (minutes)
0 (predose), 15 (±2.5), 30 (±2.5), 
60 (±5), 120 (±10), 180 (±10)
Sampling times are relative to the time of each study drug 
administration.  
Glucose samples 
(minutes)
-5 (±2.5), 0 (predose), 5 (±1), 
10 (±1), 15 (±2.5), 22 (±2.5), 
30 (±2.5), 45 (±5), 60 (±5), 
75 (±5), 90 (±5), 105 (±5), 
120 (±5), 150 (±5), 180 (±5)
Blood concentrations using YSI glucose analyzer.  
Sampling times are relative to the time of each study drug 
administration.
PD samples:  
C-peptide, glucose 
(minutes)
-5 (±2.5), 0 (predose), 5 (±1), 
15 (±2.5), 30 (±2.5), 60 (±5), 
120 (±5)
Sampling times are relative to the time of each study drug 
administration.
Immunogenicity 
(LY3195643 
antibodies) samples
Any time before the first dose
X
Period 1 and Period 3 only.  Prior to the first dose only.
Abbreviations:  AE = adverse event; CRU = clinical research unit; ECG = electrocardiogram; ET = early termination; FU = follow-up; PD = pharmacodynamics; 
PK = pharmacokinetics.
Note:  The site should schedule activities as appropriate. In cases where several study procedures are scheduled at the same time, the order of priority for these 
procedures will be as follows:  PK samples, PD samples, vital signs, ECG, clinical laboratory samples.
a
Each treatment period will consist of 3 days (Days -1 to 2).  Subjects should return for the next period with a minimum of 3 days between treatment periods.
b
FU/ET visit will occur at least 30 days after completing the last dose of study treatment.
c
Study drug will be administered 3 times on Day 1 in each period.  Day 1 activities will be performed 3 times on Day 1 with the sampling times corresponding 
to each study drug administration.


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3. Introduction
3.1.
Study Rationale
The Diabetes Control and Complications Trial (DCCT) and its observational Epidemiology of 
Diabetes Interventions and Complications (EDIC) follow-up study demonstrated that intensive 
therapy (that lowers glycemia) reduced renal and cardiovascular disease, the predominant causes 
of early mortality in patients with type 1 diabetes mellitus (T1DM) (Nathan et al. 2005;
DCCT/EDIC Research Group et al. 2011).
The availability of insulin pumps and continuous glucose monitors has transformed diabetes care 
by allowing continuous infusion of insulin with bolus doses administered based on food intake.  
Hypoglycemia may result from excessive insulin administration in relation to food intake, 
disease state, or physical activity.  Hypoglycemia may be life-threatening; this is a risk with any 
insulin administration, and may be of concern with automated systems.
An artificial pancreas device system (APDS) may provide better control of blood sugar with less 
episodes of hypoglycemia. A bihormonal APDS combines automated delivery of both insulin 
and glucagon. Pilot studies using investigational, bihormonal APDSs have demonstrated that 
delivery of small doses of glucagon in response to declining glucose levels reduces the frequency 
of hypoglycemia (Russell et al. 2012).  Glucagon is a 29-aminoacid peptide hormone produced 
in the pancreas that stimulates glucagon receptors in the liver, resulting in the breakdown of 
stored glycogen into glucose. Glucagon opposes the effects of insulin in the liver and increases 
blood glucose levels.
The current commercial glucagon (recombinant glucagon [rGlucagon]) preparations are only 
available as lyophilized powder that must be reconstituted with a diluent before administration. 
The current Lilly formulation of rGlucagon also has poor solubility in 
 
 
LY3185643 is a glucagon analog with improved solubility that is being developed for use in a 
bihormonal APDS.  The current study is designed to assess the pharmacokinetic (PK) and 
pharmacodynamic (PD) profiles of LY3185643 and compare these to rGlucagon.  Understanding 
the relative potency of these molecules, as well as any differences in time-action profiles, will be 
used to direct modifications of APDS control algorithms that have been developed based on 
rGlucagon pharmacology.  These modified control algorithms will be tested in future studies 
using LY3185643 in an investigational, bihormonal APDS.
3.2.
Background
LY3185643 is a selective glucagon analog with potency similar to rGlucagon based on 
nonclinical studies (in vitro and in vivo). LY3185643 administration resulted in dose-dependent 
increases in blood glucose levels in the 
 in vivo following subcutaneous 
(SC) dosing in a similar time pattern as rGlucagon. Peak glucose level was attained at 
30 minutes and the glucose level returned to baseline at approximately 60 minutes 
postadministration as observed with rGlucagon.
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The PK of LY3185643 was evaluated in rats and dogs. Exposure increased with increase in 
dose. LY3185643 exposure in dogs was generally dose proportional. No consistent sex 
differences in systemic exposure were observed in rats or dogs. The time to maximum drug 
concentration (Tmax) ranged from approximately 
 in dogs. The half-life (t1/2) of 
LY3185643 following SC administration in dogs ranged from approximately 
.
Development of LY3185643 was supported by repeat-dose nonclinical studies in both rats and 
dogs receiving daily SC injections for approximately 1 month. No adverse findings were 
reported following the 1-month nonclinical toxicology studies in both rats and dogs.  
Administration of LY3185643
 decreased blood pressure and increased heart 
rate (refer to the LY3185643 Investigator’s brochure [IB]), consistent with the acute effects of 
native and/or recombinant glucagon peptides previously described in dogs (CDER 1998; Eistrup 
et al. 1993). No other LY3185643-related cardiovascular changes were noted. The reported 
changes in animal physiology were consistent with the pharmacologically-related changes 
associated with repeated administration of native and/or recombinant glucagon peptide described 
previously (Root 1954; CDER 1998; Eistrup et al. 1993).
Further, signs of injection-site inflammation were observed in dogs at all doses which were 
attributed of the frequency of repeat SC administration; however, there were no local tolerance 
issues observed in the nonclinical repeat-dose studies.
3.2.1. Clinical Experience
LY3185643 has been administered SC to 27 healthy subjects as single doses of 0.01 mg,
0.03 mg, 0.05 mg, 0.06 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.48 mg, and 0.72 mg (n = 3 subjects for 
each dose level). Preliminary PK data available for doses up to 0.2 mg show dose-dependent 
increases in LY3185643 exposures. Over the dose range of 0.01 to 0.2 mg, the median time to 
peak concentrations ranged between 0.5 to 1.25 hours, mean peak concentrations ranged between 
0.13 to 4.25 ng/mL, and mean terminal t1/2 ranged between 0.5 to 0.75 hours. LY3185643 
concentrations decreased below the limit of quantification by 4 hours postdose. Dose-dependent 
increases in glycemic response were observed up to 0.2-mg dose level. Maximum mean blood 
glucose elevations of up to 180 mg/dL were observed at doses above 0.2 mg of LY3185643.
Peak glucose concentrations were reached between 0.5 to 2 hours postdose, and glycemic effects 
lasted for up to 3 hours postdose.  This transient glycemic effect at high LY3185643 
concentrations is consistent with rGlucagon findings and likely reflects a feedback inhibition of 
hepatic glucose output in response to exogenous glucagon administration (Mighiu et al. 2013).
Adverse events (AEs) included nausea, vomiting, light headed, headache, dizziness, vasovagal 
episode, erythema at injection site, loose stools, feeling hot and cold, abrasion of right leg, 
increased appetite, right thigh ache, drowsiness, feels sleepy, feels faint, decreased alertness, and 
dehydration.  The most common (67% of 36 reported events) AEs were nausea (n=10), vomiting
(n=6), headache (n=3), dizziness (n=3), and light headedness (n=2). No serious AEs (SAEs)
were noted.
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3.3.
Benefit/Risk Assessment
AEs seen after LY3185643 administration in a single-dose study, Study I7U-MC-GAHA 
(Study GAHA), were consistent with AEs reported with currently marketed glucagon such as 
nausea and vomiting. Tolerability issues in Study GAHA were mild-to-moderate and dose
dependent. No clinically significant safety or tolerability concerns were identified in 27 subjects 
who received single doses of LY3185643 up to 0.72 mg in Study GAHA.
 
 However, no arrhythmias were observed with LY3185643 administration, 
 
  
Nevertheless, continuous telemetry will be performed during dosing periods in the current study.
Potential risks are considered to be monitorable and manageable at the planned dose range of 
10 to 200 µg (0.01 to 0.2 mg) for LY3185643 in healthy subjects for this proposed study, which 
will be conducted in a Phase 1 clinical research unit (CRU).  Because of the short half-life of 
LY3185643, any pharmacologic effects are anticipated to be short-lived.
No benefit to study subjects is anticipated.  More information about the known and expected 
benefits, risks, SAEs and reasonably anticipated AEs of LY3185643 are to be found in the IB; 
known and expected benefits, and risks of rGlucagon may be found in the package insert for 
rGlucagon (Glucagon for injection prescribing information, 2012).
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4. Objectives and Endpoints
Table APCA.4.1 shows the objectives and endpoints of the study.
Table APCA.4.1.
Objectives and Endpoints
Primary Objective
Endpoints
The primary objective of this study is to evaluate the PK 
and PD profiles of LY3185643 and rGlucagon after 
single doses of study treatment
Cmax, AUC, and terminal half-life of LY3185643 and 
rGlucagon
Cmax and AUC (change from predose) of blood glucose 
and C-peptide
Secondary Objective
Endpoints
To evaluate the safety and tolerability of LY3185643 
after single doses of study treatment
Adverse events
Exploratory Objective
Endpoints
To evaluate immunogenicity of LY3185643 after 
multiple single doses of study treatment
Anti-LY3185643 antibodies
Abbreviations:  AUC = area under the concentration versus time curve; Cmax = maximum concentration; 
PD = pharmacodynamic; PK = pharmacokinetic; rGlucagon = recombinant glucagon.


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5. Study Design
5.1.
Overall Design
This study is a Phase 1, single-center, subject- and investigator-blind, randomized, 9-way,
3-period crossover study in healthy subjects to evaluate the PK and PD of LY3185643 and 
rGlucagon after SC administration.
Up to 37 healthy men and women may be enrolled to target approximately 18 subjects to 
complete the study. Each subject will receive 3 doses on each of 3 dosing days (total of 9 doses:
5 doses of LY3185643 and 4 doses of rGlucagon) administered SC. Doses will be administered 
in a 9-way complete crossover design in 3 periods, and subjects will be randomized to predefined 
treatment sequences.  Completers are defined as subjects who have received all 9 doses.
Subjects will be required to attend the CRU on at least 5 occasions:

1 screening visit (may occur up to 28 days before randomization)

3 treatment periods

1 follow-up visit (at least 30 days after completing the last dose of study 
treatment)
Each study period will consist of 3 days (Days -1 to 2).  Subjects should return for the next 
period with a minimum of 3 days between treatment periods.
On Day -1, subjects will be admitted to the CRU. Subjects will be provided a carbohydrate-rich 
meal in the evening at approximately 10:00 PM and will remain fasted until completion of the 
study procedures on Day 1.
On Day 1, study drug will be administered SC as follows:

Dose 1:  morning of Day 1

Dose 2:  approximately 4 hours after administration of the first dose

Dose 3:  approximately 4 hours after administration of the second dose
Blood samples will be collected for the determination of concentrations of LY3185643, 
glucagon, glucose, C-peptide, and for immunogenicity as shown in the Schedule of Activities
(Section 2).
Safety data will include clinical examinations, vital signs, electrocardiograms (ECGs; including 
telemetry), clinical laboratory tests, and a record of AEs.
All study procedures will end approximately 4 hours after the third dose. Subjects will be 
provided dinner and stay overnight in the CRU for observation. Subjects will be discharged the 
following day (Day 2) after completion of all assessments as shown in the Schedule of Activities
(Section 2).
Figure APCA.5.1 illustrates the study design.


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Period 1
Periods 2 and 3
Summary
Abbreviations:  CRU = clinical research unit; D/C = discharge.
Figure APCA.5.1.
Study design.
Approximately 18 subjects are expected to complete the study.  Each subject will be randomized 
to 1 of 9 treatment sequences comprising single SC doses of LY3185643 or rGlucagon 
(Table APCA.5.1).
Subjects who discontinue may be replaced to target at least 18 completers; the replacement 
subject will be assigned the treatment sequence of the discontinued subject and complete all 
3 treatment periods (total of 9 doses).


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Table APCA.5.1.
Treatment Sequences
Cohorta
Treatment Period 1
Treatment Period 2
Treatment Period 3
A
Dose 1
Dose 9
Dose 7
Dose 6
Dose 4
Dose 8
Dose 5
Dose 3
Dose 2
B
Dose 2
Dose 7
Dose 8
Dose 4
Dose 5
Dose 9
Dose 6
Dose 1
Dose 3
C
Dose 3
Dose 8
Dose 9
Dose 5
Dose 6
Dose 7
Dose 4
Dose 2
Dose 1
D
Dose 4
Dose 6
Dose 2
Dose 3
Dose 9
Dose 1
Dose 8
Dose 7
Dose 5
E
Dose 5
Dose 4
Dose 3
Dose 1
Dose 7
Dose 2
Dose 9
Dose 8
Dose 6
F
Dose 6
Dose 5
Dose 1
Dose 2
Dose 8
Dose 3
Dose 7
Dose 9
Dose 4
G
Dose 7
Dose 1
Dose 4
Dose 9
Dose 2
Dose 6
Dose 3
Dose 5
Dose 8
H
Dose 8
Dose 2
Dose 5
Dose 7
Dose 3
Dose 4
Dose 1
Dose 6
Dose 9
I
Dose 9
Dose 3
Dose 6
Dose 8
Dose 1
Dose 5
Dose 2
Dose 4
Dose 7
Note:  This is an example table; subjects will be assigned a treatment sequence according to the actual treatment 
schedule provided to the site.
Dose assignment:  Dose 1 = 10 µg LY3185643; Dose 2 = 25 µg LY3185643; Dose 3 = 50 µg LY3185643; 
Dose 4 = 100 µg LY3185643; Dose 5 = 200 µg LY3185643; Dose 6 = 10 µg rGlucagon; Dose 7 = 25 µg
rGlucagon; Dose 8 = 50 µg rGlucagon; Dose 9 = 200 µg rGlucagon.
a
In each cohort, LY3185643 and rGlucagon will be administered.
The Schedule of Activities (Section 2) details the procedures and tests occurring at specific times 
during the study.
5.2.
Number of Participants
Up to 37 subjects may be enrolled so that approximately 18 subjects complete the study.
Subjects who receive all 9 doses of study treatment will be considered as completing the study.
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last subject.
5.4.
Scientific Rationale for Study Design
A population of healthy subjects is selected based upon the likelihood of less physiologic 
variability in the absence of disease states that may affect multiple organ systems and the 
absence of other confounding factors such as concomitant medications.  Furthermore, studies 
with native glucagon suggest that the PD responses being assessed in this study are similar 
between healthy subjects and subjects with diabetes who form the eventual patient population for 
this treatment (Nielsen et al. 1997; Matsuda et al. 2002).
Three doses of LY3185643 and/or rGlucagon will be administered on Day 1 of each study 
period; each dose will be separated by at least 4 hours.  A 4-hour dosing cycle is considered 
appropriate because previous clinical data support that a 4-hour observation period is a sufficient 
amount of time to obtain both the PK and PD profiles.  The study drug concentrations will be 
below the quantification limits by 4 hours and the glycemic levels will return back to baseline 
within 4 hours postdose. A previous study used a similar design with up to 4 doses given over 
the course of a single day and showed that this dosing schedule was well tolerated and that the 
PD response was not attenuated or refractory to repeat dosing (Blauw et al. 2016).


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The use of a crossover design allows each subject to serve as his or her own control, thereby 
reducing variability.
The currently marketed glucagon product, rGlucagon, will be administered to provide a
comparison of its PK/PD profile to the PK/PD profile of LY3185643.
5.5.
Justification for Dose
The approved rGlucagon doses for hypoglycemia recovery are 0.5 and 1 mg administered
parenterally. Small bolus doses of rGlucagon ranging between 5 to 50 µg are administered in the 
bihormonal APDS (Russell et al. 2014). In vitro binding affinity data and clinical glucose 
response indicate that the potency of rGlucagon and LY3185643 are similar. Thus, a dose range 
of 10 to 200 µg (0.01 mg to 0.2 mg) for both LY3185643 and rGlucagon was selected for 
evaluation of PK/PD to enable the dosing of LY3185643 in APDS. This dose range is supported 
by preclinical and clinical safety/tolerability data.
In a single dose-escalation safety/tolerability study (Study I7U-MC-GAHA [Study GAHA]), 
LY3185643 was safely administered to healthy subjects within a dose range of 0.01 to 0.72 mg. 
The proposed doses of LY3185643 in the current study are within that range and the proposed 
top dose of 0.2 mg is approximately 4-fold lower than the 0.72-mg dose administered in 
Study GAHA.


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6. Study Population
Eligibility of subjects for study enrollment will be based on the results of screening medical 
history, physical examination, vital signs, clinical laboratory tests, and ECG.
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented.
Screening may occur up to 28 days before enrollment.  Subjects who are not enrolled within 
28 days of screening may be subjected to an additional medical assessment and/or clinical 
measurements to confirm their eligibility.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Subjects are eligible for inclusion in the study only if they meet all of the following criteria at 
screening and/or enrollment:
[1]
are overtly healthy males or females, as determined by medical history and 
physical examination
[1a] male subjects:
Male subjects with female partners of childbearing potential will be required to use a 
condom in conjunction with a spermicidal gel, foam, cream or suppository.  In addition, 
the female partner will be requested to use an additional effective form of contraception, 
which can be any of the following:

female condom with spermicide

diaphragm with spermicide

cervical sponge

cervical cap with spermicide

combined oral contraceptive pill and mini-pill

NuvaRing

implantable contraceptives

injectable contraceptives (such as Depo-Provera®)

intrauterine device (such as Mirena® and ParaGard®)

total abstinence
Men who have had a vasectomy with appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate are not required to use contraception.  Male subjects 


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with a female partner meeting the definition of a woman not of childbearing potential will 
not be required to use contraception.
[1b] female subjects:
women not of childbearing potential may participate without using contraception, and 
include those who are:
a) infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy, or 
tubal ligation), congenital anomaly such as mullerian agenesis; or
b) postmenopausal – postmenopausal is defined as women with an intact uterus who 
have not taken hormones or oral contraceptives within 1 year, who have had either 
cessation of menses for at least 1 year, or 6 to 12 months of spontaneous 
amenorrhea with follicle-stimulating hormone consistent with menopause 
(>40 mIU/mL)
[2]
are between 21 and 60 years of age at the time of screening, inclusive
[3]
have a body mass index of 18.0 to 30.0 kg/m2, inclusive, at screening
[4]
have clinical laboratory test results within normal reference range for the 
population or investigative site, or results with acceptable deviations that are 
judged to be not clinically significant by the investigator
[5]
have venous access sufficient to allow for blood sampling as per the protocol
[6]
are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures
[7]
are able and willing to give signed informed consent
6.2.
Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or enrollment:
[8] are investigative site personnel directly affiliated with this study and their 
immediate families.  Immediate family is defined as a spouse, biological or 
legal guardian, child, or sibling
[9] are Lilly employees
[10] are currently enrolled in a clinical trial involving an investigational product or 
any other type of medical research judged not to be scientifically or medically 
compatible with this study
[11]
have participated, within the last 30 days, in a clinical trial involving an 
investigational product.  If the previous investigational product has a long 
half-life, 3 months or 5 half-lives (whichever is longer) should have passed
[12]
have previously completed or withdrawn from this study or any other study 
investigating LY3185643, and have previously received the investigational 
product


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LY3185643
[13]
have known allergies to LY3185643 or rGlucagon, related compounds, or any 
components of the formulation, or history of significant atopy
[14]
have a history or ECG evidence of heart block, or any abnormality in the 
12-lead ECG that, in the opinion of the investigator, increases the risks 
associated with participating in the study
[15]
have an abnormal blood pressure as determined by the investigator
[16]
have a history of recurring symptomatic postural hypotension irrespective of 
the decrease in blood pressure, or asymptomatic postural hypotension at 
screening as defined as a decrease in systolic blood pressure ≥20 mm Hg 
within 3 minutes when changing from supine to standing position
[17]
have a history of vasovagal response such as fainting
[18]
have a significant history of or current cardiovascular, respiratory, hepatic, 
renal, gastrointestinal, endocrine, hematological, or neurological disorders 
capable of significantly altering the absorption, metabolism, or elimination of 
drugs; of constituting a risk when taking the investigational product; or of 
interfering with the interpretation of data
[19]
have a history of/current insulinoma and/or pheochromocytoma
[20]
have known or ongoing psychiatric disorders
[21]
have a history of drug abuse
[22]
show evidence of human immunodeficiency virus (HIV) infection and/or 
positive human HIV antibodies
[23]
show evidence of hepatitis C and/or positive hepatitis C antibody
[24]
show evidence of hepatitis B and/or positive hepatitis B surface antigen
[25]
intend to use over-the-counter or prescription medication within 7 and 
14 days, respectively, before dosing (apart from vitamin/mineral supplements, 
occasional paracetamol, hormone replacement therapy, or thyroid-replacement 
therapy).  If this situation arises, inclusion of an otherwise suitable subject 
may be at the discretion of the investigator and sponsor
[26]
have had systemic exposure to glucocorticoids within 3 months before entry 
into the study (including oral or intra-articular glucocorticoids, or potent 
topical steroids applied to >20% of body surface area)
[27]
have any chronic diseases or illness that interfere with glucose metabolism
[28]
have known presence of hereditary problems of glycogen storage disease, 
and/or galactose
[29]
have had lymphoma, leukemia, or any malignancy within the past 5 years 
except for basal cell or squamous epithelial carcinomas of the skin that have 
been resected with no evidence of metastatic disease for 3 years


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LY3185643
[30]
consume more than 10 cigarettes per day or the equivalent, or are unable or 
unwilling to refrain from nicotine use while in residence at the CRU
[31]
have donated blood of 450 mL or more in the last 3 months or provided any 
blood donation within the last month before screening
[32]
have an average weekly alcohol intake that exceeds 14 units per week or are 
unwilling to stop alcohol consumption from 24 hours before dosing until the 
completion of each trial period (1 unit = 12 oz or 360 mL of beer; 5 oz or 
150 mL of wine; 1.5 oz or 45 mL of distilled spirits)
[33]
in the opinion of the investigator or sponsor, are unsuitable for inclusion in the 
study
6.3.
Lifestyle and/or Dietary Requirements
Throughout the study, subjects may undergo medical assessments and review of compliance with 
requirements before continuing in the study.
6.3.1. Meals and Dietary Restrictions
At approximately 10:00 PM on Day-1 of each study period, subjects will be provided with a 
mixed meal containing at least 100 g of carbohydrate and at least 600 calories total.  Subjects 
should be encouraged to consume the entire meal.
For all treatment periods, subjects are expected to fast for approximately 8 hours before the first 
dose until 4 hours after the last dose.  Water can be consumed freely during this period.
When at home, subjects will be encouraged to follow normal, unrestricted diet that contains at 
least 150 g of carbohydrate daily (in the form of simple sugars, starch, or complex 
carbohydrates) and refrain from strenuous exercise for at least 3 days before admission to the 
CRU.
6.3.2. Caffeine, Alcohol, and Tobacco
No alcohol will be allowed at least 24 hours before each dose and throughout the duration of 
each CRU visit.
No tobacco smoking or use of smokeless tobacco will be permitted while subjects are resident in 
the CRU.
Subjects should refrain from caffeine-containing food/beverages (for example, cola, chocolate, 
Milo, tea, and coffee) for at least 12 hours before each dose and throughout the duration of each 
CRU visit.
6.3.3. Activity
Subjects will be encouraged to maintain their regular exercise; however, they should not 
undertake vigorous or prolonged exercise at least 3 days before admission to the CRU.  After 
dosing, subjects should remain recumbent or sitting in the CRU.


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6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened.


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7. Treatment
7.1.
Treatment Administered
LY3185643 and rGlucagon will be supplied by Lilly or its representative in accordance with 
current good manufacturing practices and will be supplied with lot numbers.
Each vial of investigational product will contain 1 mg/mL of LY3185643 or rGlucagon (Lilly 
USA, LLC).  LY3185643 or rGlucagon may be diluted for SC administration.  Additional 
information can be found in the pharmacy instructions including detailed instructions for the 
preparation of the investigational products.  rGlucagon will be reconstituted from the lyophilized 
commercial product on the day of use and will be administered within the time limits defined in 
the pharmacy instructions.
Table APCA.7.1 shows the treatment regimens.
Table APCA.7.1.
Investigational Product Regimens
Product:
LY3185643 
rGlucagon
(recombinant glucagon)
Dose range:
10 to 200 µg
10 to 200 µg
Route of administration:
subcutaneous injection
subcutaneous injection
The investigator or designee is responsible for:

explaining the correct use of the investigational product to the site personnel

verifying that instructions are followed properly

maintaining accurate records of investigational product dispensing and collection

returning all unused medication to Lilly or its designee at the end of the study
Note: In some cases, sites may destroy the material if, during the investigative site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical trial materials.
Subjects will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
Study treatment will be drawn up into a 0.3-mL insulin syringe with a 6-mm/31 G needle to 
ensure all injections are delivered to a consistent depth target into the SC space.  Each syringe 
will be labelled appropriately and dispensed to qualified site personnel for administration.
The doses will be administered SC in the CRU by qualified site personnel (as designated by the 
investigator). Injection sites selected should be approximately 5 cm from the umbilicus and the 
treatment administered SC with the needle applied at approximately 90 degrees without pinching 
the skinfold.  Each injection in a given study period will be administered into a different 
quadrant of the anterior abdominal wall (that is, left upper quadrant, left lower quadrant, and 
right upper quadrant) and the site of injection for each dose will be recorded.  As far as it is 


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practical, the same staff will administer the injections.  Please refer to the pharmacy binder for 
detailed instructions.
7.1.1. Packaging and Labeling
LY3185643 will be packaged by Lilly or its representative in a 2-mL vial.
rGlucagon will be packaged by Lilly or its representative in a 1-mL vial.
These clinical trial materials will be labeled in accordance with local regulatory requirements.
7.2.
Method of Treatment Assignment
Randomization tables with treatment codes for allocation of LY3185643 or rGlucagon will be 
prepared by the statistician for the study and provided to the site pharmacists involved in dose 
preparation.  The pharmacist will provide treatment to the blinded site staff who will administer 
the study drugs.
7.2.1. Selection and Timing of Doses
The doses will be administered in the CRU during the treatment period on Day 1 only. The 
actual time of all dose administrations will be recorded in the subject’s case report form (CRF).
7.3.
Blinding
This study is subject- and investigator-blind.  Blinding will be maintained throughout the 
conduct of the trial until all data are cleaned to an acceptable level of quality and locked.
Emergency codes will be available to the investigator.  A code, which reveals the treatment 
group for a specific study subject, may be opened during the study only if the subject’s
well-being requires knowledge of the subject’s treatment assignment.
If a subject’s study treatment assignment is unblinded, the subject must be discontinued from the 
study unless the investigator obtains specific approval from a Lilly clinical pharmacologist or 
clinical research physician (CRP) for the study participant to continue in the study.  During the 
study, emergency unblinding should occur only by accessing the study subject’s emergency 
code.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a subject’s treatment assignment is warranted for medical management of the event.  Subject’s
safety must always be the first consideration in making such a determination.  If the investigator 
decides that unblinding is warranted, the investigator should make every effort to contact the 
Lilly clinical pharmacologist or CRP before unblinding a study subject’s treatment assignment
unless this could delay emergency treatment of the subject.  If a study subject’s treatment 
assignment is unblinded, Lilly must be notified immediately.
Upon completion of the study, all codes must be returned to Lilly or its designee.
7.4.
Dose Modification
There will be no dose modifications of LY3185643 and rGlucagon.


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7.5.
Preparation/Handling/Storage/Accountability
All clinical trial material provided to the investigator will be stored in a secure place and 
allocated and dispensed by appropriately trained persons.  The allocation and dispensing of the 
investigational products will be fully documented and verified by a second person. Detailed 
records of the amounts of the investigational product received, dispensed, and remaining at the 
end of the study will be maintained.
Only participants enrolled in the study may receive investigational product and only authorized 
site staff may supply or administer study treatment. All study treatments should be stored in an
environmentally controlled and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the investigator and authorized site staff.
The investigator is responsible for study treatment accountability, reconciliation, and record 
maintenance (such as receipt, reconciliation and final disposition records).  The investigator site 
will be permitted to destroy the investigational material after written approval is obtained from 
the sponsor.
7.6.
Treatment Compliance
Every attempt will be made to select subjects who have the ability to understand and comply 
with instructions.  Noncompliant subjects may be discontinued from the study.
The investigational product will be administered at the CRU and documentation of treatment 
administration will occur at the site.
The specifications in this protocol for the timings of safety, PK, and PD sampling are given as 
targets to be achieved within reasonable limits.  Modifications may be made to the time points 
based upon the safety and PK information obtained.  The scheduled time points may be subject 
to minor alterations; however, the actual time must be correctly recorded in the CRF.  Failure to 
obtain samples due to clinical issues, such as problems with venous access, technical difficulty 
with obtaining samples, or subject no show for planned procedural visits will not be considered a 
protocol deviation but the site will still be required to notify the sponsor in writing.
Any major modifications that might affect the conduct of the study, subject safety, and/or data 
integrity will be detailed in a protocol amendment.
7.7.
Concomitant Therapy
Subjects should not use over-the-counter or prescription medication within 7 and 14 days, 
respectively, before each dosing (apart from vitamin/mineral supplements, occasional 
paracetamol, hormone replacement therapy, or thyroid-replacement therapy).
If the need for concomitant medication arises, inclusion or continuation of the subject may be at 
the discretion of the investigator and, if possible, after consultation with a Lilly clinical 
pharmacologist or CRP.  Any additional medication used during the course of the study must be 
documented.


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7.8.
Treatment after the End of the Study
LY3185643 and rGlucagon will not be made available to subjects after conclusion of the study.


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8. Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
Discontinuation of the investigational product for abnormal liver tests should be considered by 
the investigator when a subject meets one of the following conditions after consultation with the 
Lilly designated medical monitor:

alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5X upper 
limit of normal (ULN)

ALT or AST >3X ULN along with one of the following criteria
o
sustained for more than 2 weeks or
o
total bilirubin level >2X ULN or
o
prothrombin time >1.5X ULN or
o
appearance of fatigue, nausea, vomiting, right upper-quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%)

alkaline phosphatase (ALP) >3X ULN

ALP >2.5X ULN and total bilirubin level >2X ULN

ALP >2.5X ULN with the appearance of fatigue, nausea, vomiting, right quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%)
Subjects who discontinue the investigational product early will have procedures performed as 
shown in the Schedule of Activities (Section 2).
8.1.1. Discontinuation of Inadvertently Enrolled Subjects
If the sponsor or investigator identifies a subject who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Lilly clinical pharmacologist/CRP
and the investigator to determine if the subject may continue in the study.  If both agree it is 
medically appropriate to continue, the investigator must obtain documented approval from the 
Lilly clinical pharmacologist/CRP to allow the inadvertently enrolled subject to continue in the 
study with or without continued treatment with investigational product.
8.2.
Discontinuation from the Study
Subjects will be discontinued in the following circumstances:

enrollment in any other clinical trial 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


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
investigator decision
o
the investigator decides that the subject should be discontinued from the study

subject decision
o
the subject, or designee (for example, parents or legal guardian) requests to be 
withdrawn from the study
Subjects who discontinue the study early will have end-of-study procedures performed as shown 
in the Schedule of Activities (Section 2).
8.3.
Subjects Lost to Follow-Up
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact subjects 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).
Appendix 2 lists the laboratory tests that will be performed for this study.
Appendix 5 provides a summary of the maximum number and volume of invasive samples for all 
sampling during the study.
Unless otherwise stated in subsections below, all samples collected for specified laboratory tests 
will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may be 
retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
Investigators must document their review of each laboratory safety report.
9.1.
Efficacy Assessments
This section is not applicable for this study.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of subjects 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 subject.
The investigator is responsible for the appropriate medical care of subjects during the study.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the subject to discontinue the investigational product before 
completing the study.  The subject should be followed until the event resolves, stabilizes with 
appropriate diagnostic evaluation, or is reasonably explained.  The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator.
After the informed consent form (ICF) is signed, study site personnel will record, via CRF, the 
occurrence and nature of each subject’s preexisting conditions, including clinically significant 
signs and symptoms of the disease under treatment in the study.  Additionally, site personnel will 
record any change in the condition(s) and the occurrence and nature of any AEs.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment or a study procedure, taking into account the disease, 
concomitant treatment, or pathologies.
A “reasonable possibility” means that there is a cause and effect relationship between the 
investigational product and/or study procedure and the AE.
Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study.


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If a subject’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via CRF.
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

events considered significant by the investigator based upon appropriate medical 
judgment
Study site personnel must alert Lilly, 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 begins 
after the subject has signed informed consent and has received investigational product.  
However, if an SAE occurs after signing informed consent, but before receiving investigational 
product, AND is considered reasonably possibly related to a study procedure then it MUST be 
reported.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued from and/or completed the study (the subject summary CRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has
been discharged from the study and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to investigational product or procedure.  
United States 21 CFR 312.32 and European Union Clinical Trial Directive 2001/20/EC and the 
associated detailed guidances or national regulatory requirements in participating countries 
require the reporting of SUSARs.  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.


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9.2.2. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical trials in order to ensure the safety of study participants, monitor quality, and to facilitate 
process and product improvements.
Subjects should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
9.3.
Treatment of Overdose
For the purposes of this study, an overdose of LY3185643 is considered any doses higher than 
the doses assigned through randomization.  An overdose of rGlucagon is considered as any dose 
higher than 1 mg (the upper limit of the approved dosage in the prescribing information).  Refer 
to the IB for LY3185643 and the prescribing information for rGlucagon (2012) for management 
of inadvertent treatment overdose.
9.4.
Safety
9.4.1. Laboratory Tests
For each subject, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2).
9.4.2. Physical Examination
Physical examinations and routine medical assessments will be conducted as specified in the 
Schedule of Activities (Section 2).
9.4.3. Vital Signs
For each subject, vital signs measurements should be conducted according to the Schedule of 
Activities (Section 2).
Blood pressure and pulse rate should be measured after at least 5 minutes supine.
If orthostatic measurements are required, subjects should be supine for at least 5 minutes and 
stand for at least 3 minutes.
If the subject feels unable to stand, supine vital signs only will be recorded.
Additional vital signs may be measured during each study period if warranted at the discretion of 
the investigator.
9.4.4. Electrocardiograms
For each subject, ECGs should be collected according to the Schedule of Activities (Section 2).
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
subject receives the first dose of the investigational product should be reported to Lilly, or its 
designee, as an AE via CRF.


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9.4.4.1.
Continuous 12-Lead ECG Monitoring
Continuous 12-lead ECG monitoring does not allow bedside printing or viewing of ECGs 
extracted from the signal recorded.  Thus, for subject safety, ECGs must be recorded by a local, 
static 12-lead ECG device at the times specified in the Schedule of Activities (Section 2).  These 
safety ECGs will not be transmitted to a central ECG laboratory.  Safety ECGs must be 
interpreted by the investigator or qualified designee soon after the time of collection.  This 
review will be documented and provides information for immediate subject management.  If the 
ECG shows a clinically significant quantitative or qualitative change from baseline, the 
investigator or qualified designee will assess the subject for symptoms (for example, palpitations, 
near syncope, syncope) and determine if the subject can continue in the study.  The investigator 
or qualified designee is responsible for subject management.  If the investigator determines that 
the changes identified in the ECG are clinically relevant, an applicable AE should be recorded on 
the subject CRF.
9.4.4.1.1. Recordings for Data Analysis
Continuous 12-lead recordings will be performed according to the Schedule of Activities
(Section 2). Patients must be in a quiet atmosphere without significant external stimulation (for 
example, TV, internet, etc.), remain in a supine position for at least 5 to 10 minutes before the 
specified ECG collection times, and remain supine but awake during ECG collection and for at 
least 10 minutes afterward.  Subjects should be encouraged to remain still, if possible, during this 
time.
Digital recordings of all periods of continuous ECG recordings in individual subjects will be 
transferred to a central ECG laboratory designated by Lilly.  The ECG laboratory will perform 
quality control checks for the time points of interest (for example, acquisition quality for ability 
to measure/interpret, demographics, and study details) and extract 15 unique 10-second ECGs at 
the times listed in the Schedule of Activities (Section 2).
The ECG laboratory will then store the recording as well as the extracted 10-second ECGs, and a 
cardiologist at the central ECG laboratory will conduct a full overread (including the 
measurement of all intervals) on one of the replicates that was extracted.  For each set of 
replicates, the cardiologist will determine the RR and QT intervals and heart rate on the ECGs 
that were not fully overread.  No reports will be issued from the central ECG laboratory back to 
the sites for any ECGs.
All data from the overreads will be placed in a Lilly or clinical research organization (CRO)
database for analytical and study report purposes.
It is recognized that the ECG interpretations by the investigator (or qualified designee) and the 
cardiologist at the central ECG laboratory may be different.  Interpretation of the ECG by the 
investigator (or qualified designee) will be used for study entry and immediate subject 
management.  Interpretations of the ECG at the central laboratory will be used for data analysis 
and report-writing purposes.


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9.4.4.2.
Telemetry
The ECG waveform and cardiac rhythm will be monitored continuously using an ECG telemetry 
monitor during the inpatient stay at the CRU, from the night of Day -1 to 4 hours after the last 
dose on Day 1, for all 3 periods.  Telemetry data from Day -1 up to approximately 1 hour before
dosing will be reviewed by the investigator before administration of the first dose on Day 1.  
Subjects will not be dosed if any exclusion criteria are observed (for example, Exclusion 
Criterion [14]).  Any other observations, such as changes in the ECG waveform and rhythm,
should be evaluated by the investigator and the decision to dose will be at the investigator’s 
discretion.  Any confirmed abnormalities/events assessed to be clinically significant by the 
investigator during monitoring should be recorded in the medical record and reported as a 
preexisting condition or AE on the AE CRF page.
9.4.5. Safety Monitoring
The Lilly clinical pharmacologist or CRP will monitor safety data throughout the course of the 
study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly clinical 
pharmacologist or CRP will consult with the functionally independent Global Patient Safety 
therapeutic area physician or clinical research scientist when appropriate and periodically 
review:

trends in safety data

laboratory analytes

AEs
If a study subject experiences elevated ALT ≥3X ULN, ALP ≥2X ULN, or elevated total 
bilirubin ≥2X ULN, clinical and laboratory monitoring should be initiated by the investigator.  
Details for hepatic monitoring depend upon the severity and persistence of observed laboratory 
test abnormalities.  To ensure subject safety and compliance with regulatory guidance, the 
investigator is to consult with the Lilly designated CRP regarding collection of specific 
recommended clinical information and follow-up laboratory tests (Appendix 4).
9.4.6. Immunogenicity Assessments
At the visits and times specified in the Schedule of Activities (Section 2), blood samples for 
immunogenicity testing will be collected to determine antibody production against the
investigational product.  Justification for the lack of paired PK samples is based on the short t1/2
of LY3185643 (less than 1 hour) and the long delay between the dose administration and 
sampling times.
Additional samples may be collected if there is a possibility that an AE is immunologically 
mediated.  Immunogenicity will be assessed by a validated assay designed to detect anti-drug 
antibodies in the presence of the investigational product.  Antibodies may be further 
characterized and/or evaluated for cross-reactive binding to native glucagon and/or their ability 
to neutralize the activity of the investigational product.


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Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and Ethical Review Boards (ERBs) allow, at a facility selected by the 
sponsor.  The duration allows the sponsor to respond to future regulatory requests related to the 
investigational product.  Any samples remaining after 15 years will be destroyed.
9.5.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
of approximately 4 mL each will be collected to determine the plasma concentrations of
LY3185643 or glucagon.  Instructions for the collection and handling of blood samples will be 
provided by the sponsor.  The actual date and time (24-hour clock time) of each sampling will be 
recorded.
9.5.1. Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.
Concentrations of LY3185643 will be assayed 
 
Concentrations of glucagon will be assayed using a validated LC/MS method.
Bioanalytical samples collected to measure investigational product concentrations will be 
retained for a maximum of 1 year following last subject visit for the study.
9.6.
Pharmacodynamics
At the times specified in the Schedule of Activities (Section 2), venous blood samples will be
collected and used to determine the PD effects of LY3185643 or rGlucagon.  Blood will be 
collected to evaluate blood glucose and C-peptide (both analyzed at a central laboratory
designated by the sponsor).
The sample(s) will be stored for up to a maximum of 1 year after the last subject visit for the 
study at a facility selected by the sponsor.
9.6.1. Glucodynamic Samples
Blood samples (approximately 0.2 mL each) will be obtained for the measurement of glucose at 
the times specified in the Schedule of Activities (Section 2) using a validated method (YSI 
glucose analyzer) that will be readily available at the investigative site during the inpatient 
periods in order to provide real-time glucose measurement.  Repeat samples for 
counter-checking of apparent spurious results may be taken where indicated.  Samples will be 
disposed of upon confirmation of results.
9.7.
Genetics
This section is not applicable for this study.
CCI


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9.8.
Biomarkers
This section is not applicable for this study.
9.9.
Health Economics
This section is not applicable for this study.


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10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
The sample size is customary for Phase 1 studies evaluating safety, PK, and/or PD parameters 
and is considered sufficient to evaluate the primary objective of this study.
Subjects who discontinue the study may be replaced so that at least 18 subjects complete the 
study.  Replacement subjects will be assigned the treatment sequence of the subject that 
discontinued the study.
10.2. Populations for Analyses
10.2.1. Study Participant Disposition
A detailed description of subject disposition will be provided at the end of the study.
10.2.2. Study Participant Characteristics
The subject’s age, sex, weight, body mass index, height, race/subrace, or other demographic 
characteristics will be recorded and summarized.
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Eli Lilly and Company.
PK and PD analyses will be conducted on the full analysis set. This set includes all data from all 
randomized subjects receiving at least 1 dose of the investigational product and with a baseline 
and at least 1 postbaseline measurement for each dose according to the treatment the subjects 
actually received.  Safety analyses will be conducted for all enrolled subjects whether or not they 
completed all protocol requirements.
Additional exploratory analyses of the data will be conducted as deemed appropriate.  Study 
results may be pooled with the results of other studies for population analysis purposes.
10.3.1. Safety Analyses
10.3.1.1. Clinical Evaluation of Safety
All investigational product and protocol procedure AEs will be listed, and if the frequency of 
events allows, safety data will be summarized using descriptive methodology.
The incidence of symptoms for each treatment will be presented by severity and by association 
with investigational product as perceived by the investigator.  Symptoms reported to occur 
before first dose will be distinguished from those reported as new or increased in severity during 
the study.  Each symptom will be classified by the most suitable term from the medical 
regulatory dictionary.
The number of investigational product-related SAEs will be reported.


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10.3.1.2. Statistical Evaluation of Safety
Safety parameters that will be assessed include safety laboratory parameters, vital signs, and 
ECG parameters.  The ECG parameters that will be assessed include the ECG heart rate and the 
following intervals: QT, RR, PR, and QT corrected for heart rate (QTc) using Fridericia’s 
formula (QTcF).  The safety parameters will be listed and summarized using standard descriptive 
statistics.  Any additional analyses will be detailed in the statistical analysis plan.
10.3.2. Pharmacokinetic Analyses
10.3.2.1. Pharmacokinetic Parameter Estimation
PK parameter estimates for LY3185643 and rGlucagon will be calculated by standard 
noncompartmental methods of analysis.
The primary parameters for analysis will be maximum drug concentration (Cmax) and area under 
the concentration versus time curve (AUC).  Other noncompartmental parameters, such as t1/2, 
apparent clearance, and apparent volume of distribution, may be reported. Population PK and 
exposure-response analyses may be performed using PK and glucose data.
10.3.2.2. Pharmacokinetic Statistical Inference
PK parameters for LY3185643 and rGlucagon will be summarized for each dose group. PK
parameter estimates will be evaluated to delineate effects of dose proportionality.
10.3.3. Pharmacodynamic Analyses
The PD time-action and response of LY3185643 and rGlucagon will be compared to establish 
the relative potency between LY3185643 and rGlucagon.
10.3.3.1. Pharmacodynamic Parameter Estimation
The primary PD response variables of interest include Tmax, Cmax, and change from baseline to 
each time point, and incremental AUCs for glucose and C-peptide.  A dose-proportionality 
parameter will also be estimated to establish the relative potency between LY3185643 and 
rGlucagon.  Partial AUC for glucose over appropriate time intervals will be calculated using the 
trapezoidal rule.  The AUC for each subject after each dose will also be baseline-adjusted.  
Baseline for each dose will be defined as the average of predose values for that dose.
10.3.3.2. Pharmacodynamic Statistical Inference
PD parameters of interest may be transformed before statistical analysis if deemed necessary.  
Unless specified otherwise, parameters will be analyzed using a nonlinear mixed-effects model 
with period, treatment (LY3185643 or rGlucagon), and dose (within treatment) as fixed effects, 
baseline glucose as a covariate, and subject as a random effect.  The use of other influencing 
variables as covariates will be explored as detailed in the statistical analysis plan.
A conversion factor will be defined in the model for each parameter to estimate the relative
potency of LY3185643 to rGlucagon.  In addition, a conversion factor will be estimated between 
LY3185643 and rGlucagon for multiple parameters simultaneously using a similar mixed 
nonlinear model approach to account for the correlation between parameters for the same 
subject.  Model details will be discussed in the statistical analysis plan.


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All PD parameters including the baseline-corrected parameters will be summarized by dose 
group and tabulated.  Summary statistics will be provided.  The individual observed and mean 
(by dose group) time profile of the PD measurements after dosing will be plotted.
10.3.4. Evaluation of Immunogenicity
The frequency of antibody formation to LY3185643 will be determined.  If a neutralization assay 
is performed, the frequency of neutralizing antibodies will be determined.  The relationship 
between the presence (or absence) of antibodies and AEs will be assessed.  Likewise, the 
relationship between the presence of antibodies and the PK parameters and PD response to 
LY3185643 will be assessed.
10.3.5. 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.
The Lilly study team is unblinded, and the investigator will remain blinded until all data 
collection has been completed.  Data may be analyzed while the trial is ongoing, but no changes 
to the study design are planned.  An assessment committee will not be formed.


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11.
References
Blauw H, Wendl I, DeVries JH, Heise T, Jax T; PCDIAB consortium. Pharmacokinetics and 
pharmacodynamics of various glucagon dosages at different blood glucose levels. Diabetes 
Obes Metab. 2016;18(1):34-39.
[CDER] Center for Drug Evaluation and Research. NDA 020928, Glucagon (glucagon 
recombinant), review and evaluation of pharmacology and toxicology data, original summary. 
1998. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/98/20928.pdf.
Accessed August 8, 2016.
Eistrup C, Hjortkjaer RK, Pickersgill N, Virgo DM, Woolley AP. Glucagon produced by 
recombinant DNA technology: repeated dose toxicity studies, intravenous administration to 
CD rats and beagle dogs for four weeks. Pharmacol Toxicol. 1993;73(2):103-108.
DCCT/EDIC Research Group, de Boer IH, Sun W, Cleary PA, Lachin JM, Molitch ME, 
Steffes MW, Zinman B. Intensive diabetes therapy and glomerular filtration rate in type 1 
diabetes. N Engl J Med. 2011;365(25):2366-2376.
Glucagon for injection (rDNA origin) prescribing information. Indianapolis, IN: Lilly USA, 
LLC; revised 2012. Available at: http://pi.lilly.com/us/rglucagon-pi.pdf. Accessed July 20, 
2016.
Matsuda M, DeFronzo RA, Glass L, Consoli A, Giordano M, Bressler P, DelPrato S. Glucagon 
dose-response curve for hepatic glucose production and glucose disposal in type 2 diabetic 
patients and normal individuals. Metabolism. 2002;51(9):1111-1119.
Mighiu PI, Yue JT, Filippi BM, Abraham MA, Chari M, Lam CK, Yang CS, Christian NR, 
Charron MJ, Lam TK. Hypothalamic glucagon signaling inhibits hepatic glucose production. 
Nat Med. 2013;19(6):766-772.
Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ, Raskin P, Zinman B; 
Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and 
Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and 
cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353(25):2643-
2653.
Nielsen MF, Wise S, Dinneen SF, Schwenk WF, Basu A, Rizza RA. Assessment of hepatic 
sensitivity to glucagon in NIDDM: use as a tool to estimate the contribution of the indirect 
pathway to nocturnal glycogen synthesis. Diabetes. 1997;46(12):2007-2016.
Root MA. Effect of chronic administration of glucagon to rats and rabbits. Proc Soc Exp Biol 
Med. 1954;87(1):108-110.
Russell SJ, El-Khatib FH, Nathan DM, Magyar KL, Jiang J, Damiano ER. Blood glucose control 
in type 1 diabetes with a bihormonal bionic endocrine pancreas. Diabetes Care. 
2012;35(11):2148-2155.
Russell SJ, El-Khatib FH, Sinha M, Magyar KL, McKeon K, Goergen LG, Balliro C, 
Hillard MA, Nathan DM, Damiano ER. Outpatient glycemic control with a bionic pancreas in 
type 1 diabetes. N Engl J Med. 2014;371(4):313-325.


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Appendix 1.
Abbreviations and Definitions
Term
Definition
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
APDS
artificial pancreas device system
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
blinding
A procedure in which one or more parties to the trial are kept unaware of the treatment 
assignment(s).  Unless otherwise specified, blinding will remain in effect until final 
database lock.
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the subject is not, or vice versa, or when the sponsor is aware of the treatment 
but the investigator and/his staff and the subject are not.  A double-blind study is one in 
which neither the subject nor any of the investigator or sponsor staff who are involved in 
the treatment or clinical evaluation of the subjects are aware of the treatment received.
CIOMS
Council for International Organizations of Medical Sciences
Cmax
maximum drug concentration
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the trial-related requirements, good clinical practice requirements, and the 
applicable regulatory requirements.
confirmation
A process used to confirm that laboratory test results meet the quality requirements defined 
by the laboratory generating the data and that Lilly is confident that results are accurate.  
Confirmation will either occur immediately after initial testing or will require that samples 
be held to be retested at some defined time point, depending on the steps required to obtain 
confirmed results.
CRF
case report form


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CRP
Clinical Research Physician:  Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research scientist, 
global safety physician or other medical officer.
CRU
clinical research unit
DCCT
Diabetes Control and Complications Trial
ECG
electrocardiogram
EDIC
Epidemiology of Diabetes Interventions and Complications
enroll
The act of assigning a subject to a treatment.  Subjects who are enrolled in the trial are those 
who have been assigned to a treatment.
enter
Subjects entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ERB
Ethical Review Board
GCP
good clinical practice
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonization
informed consent
A process by which a subject voluntarily confirms his or her willingness to participate in a 
particular trial, after having been informed of all aspects of the trial 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.
interim analysis
An interim analysis is an analysis of clinical trial data, separated into treatment groups, that 
is conducted before the final reporting database is created/locked.
Investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical trial, including products already on the market when used or assembled 
(formulated or packaged) in a way different from the authorized form, or marketed products 
used for an unauthorized indication, or marketed products used to gain further information 
about the authorized form.
investigator
A person responsible for the conduct of the clinical trial at a trial site.  If a trial is conducted 
by a team of individuals at a trial site, the investigator is the responsible leader of the team 
and may be called the principal investigator.
LC/MS
liquid chromatography with tandem mass spectrometry
Legal 
representative
An individual or judicial or other body authorized under applicable law to consent, on 
behalf of a prospective subject, to the subject’s participation in the clinical trial.


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Non-
investigational 
product
A product that is not being tested or used as a reference in the clinical trial, but is provided 
to subjects and used in accordance with the protocol, such as:  concomitant or rescue/escape 
medication for preventative, diagnostic, or therapeutic reasons, medication to ensure 
adequate medical care, and/or products used to induce a physiological response.
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
QTc
QT corrected for heart rate
QTcF
QTc using Fridericia’s formula
rGlucagon
recombinant glucagon
SAE
serious adverse event
SC
subcutaneous(ly)
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 trial.
SUSARs
suspected unexpected serious adverse reactions
t1/2
half-life
T1DM
type 1 diabetes mellitus
Tmax
time to maximum drug concentration
ULN
upper limit of normal


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Appendix 2.
Clinical Laboratory Tests
Laboratory Tests
Hematologya
Clinical Chemistrya
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume 
Chloride
Mean cell hemoglobin
Calcium
Mean cell hemoglobin concentration
Phosphorus
Leukocytes (WBC)
Magnesium
Absolute counts of:
Glucose (fasting)
Neutrophils
Blood urea nitrogen
Lymphocytes
Total cholesterol
Monocytes
Total protein
Eosinophils
Albumin
Basophils
Total bilirubin
Platelets
Alkaline phosphatase
Aspartate aminotransferase
Urinalysisa
Alanine aminotransferase
Specific gravity
Creatinine
pH
Gammaglutamyl transferase
Protein
Glucose
Hepatitis B surface antigenc
Ketones
Hepatitis C antibodyc
Bilirubin
HIVc
Urobilinogen
Pregnancy testd
Blood
FSHe
Nitrite
Thyroid-stimulating hormonef
Leukocytes
Microscopyb
Abbreviations:  FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cells; 
WBC = white blood cells.
a
Results will be validated by the local laboratory at the time of initial testing.
b
If clinically indicated, per investigator’s discretion.
c
Performed at screening only. Tests may be waived if they have been performed within 6 months before
screening and the corresponding reports are available for review.
d
Only for females. Test will be performed at screening, at every admission to the clinical research unit, and at the 
follow-up or early termination visit.
e
For women only when needed to confirm postmenopausal status.
f
Only for subjects who are being treated with thyroxine or have a history of thyroid disease.


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Appendix 3.
Study Governance, Regulatory, and 
Ethical Considerations
Informed Consent
The investigator is responsible for:

ensuring that the subject understands the potential risks and benefits of participating in 
the study

ensuring that informed consent is given by each subject or legal representative.  This 
includes obtaining the appropriate signatures and dates on the informed consent form 
(ICF) before the performance of any protocol procedures and before the administration 
of investigational product

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 trial
Ethical Review
The investigator or appropriate local representative must give assurance that the ethical review 
board (ERB) was properly constituted and convened as required by International Conference on 
Harmonization (ICH) guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  Lilly or its representatives must approve the ICF 
before it is used at the investigative site(s).  All ICFs must be compliant with the ICH guideline 
on good clinical practice (GCP).
The study site’s ERB(s) should be provided with the following:

the current IB for LY3185643 and the prescribing information for rGlucagon and updates 
during the course of the study

ICF

relevant curricula vitae
Regulatory Considerations
This study will be conducted in accordance with:
1) consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International
Organizations of Medical Sciences (CIOMS) International Ethical guidelines
2) applicable ICH GCP guideline
3) applicable laws and regulations


I8Z-MC-APCA(a) Clinical Pharmacology Protocol
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LY3185643
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 case report forms (CRFs), and 
study procedures

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax

review and evaluate CRF data and/or use standard computer edits to detect errors in data 
collection

conduct a quality review of the database
In addition, Lilly or its representatives will periodically check a sample of the 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 laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to the original source 
documents.


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LY3185643
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.
Study and Site Closure
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.


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Appendix 4.
Hepatic Monitoring Tests for Treatment-
Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with subjects in consultation with Lilly or its designee clinical research 
physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin time
WBC
Prothrombin time, INR
Neutrophils, segmented
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Conjugated bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
Alanine aminotransferase
Anti-nuclear antibodya
Aspartate aminotransferase
Gammaglutamyl transferase
Anti-smooth muscle antibody (or anti-actin antibody)a
Creatinine phosphokinase
Abbreviations:  Ig = immunoglobulin; INR = international normalized ratio; RBC = red blood cells; WBC = white 
blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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Appendix 5.
Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.  Fewer 
venipunctures and blood draws may actually occur, but this will not require a protocol 
amendment.
Protocol I8Z-MC-APCA Sampling Summary
Purpose
Maximum Blood Volume 
per Sample (mL)
Maximum Number 
of Blood Samples
Maximum Total 
Volume (mL)
Screening testsa
17
1
17
Clinical laboratory testsa
11
2
22
Pharmacokinetics
4
54
216
Blood discard for cannula patency
0.25
135
33.75
Pharmacodynamics (glucose)
0.2
135
27
Pharmacodynamics (glucose and 
C-peptide)
2.5
63
157.5
Immunogenicity
7
3
21
Total
494.25
Total for clinical purposes [rounded up to nearest 10 mL]
500
a
Additional samples may be drawn if needed for safety purposes.


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Appendix 6.
Protocol Amendment I8Z-MC-APCA(a)
A Randomized, 9-Way, Single-Dose, Crossover Study to 
Evaluate the Pharmacokinetics, Pharmacodynamics, 
Safety, and Tolerability of LY3185643 and rGlucagon in 
Healthy Subjects
Overview
Protocol I8Z-MC-APCA(a) [A Randomized, 9-Way, Single-Dose, Crossover Study to Evaluate 
the Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of LY3185643 and 
rGlucagon in Healthy Subjects] 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:

Minor typographical errors addressed.

Inclusion of descriptions of effective birth control methods, as suggested by the 
FDA.

The Exclusion Criteria for systemic exposure to glucocorticoids within 3 months 
to include the use of oral or intra-articular glucocorticoids, or extensive use 
topical steroids, as suggested by the FDA.

Increase in the sample size as a result of higher than expected subject drop-out rate 
among early participants.

Deletion of word Holter, since the site uses Mortara surveyor system.

Clarification of the duration of telemetry (text is now consistent with the 
information in the Schedule of Activities).

Deletion of the phrase LY3185643 antibodies listed in the Clinical Laboratory 
Tests table.  These blood samples remain listed in the Schedule of Activities.


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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.
Section 1.
Synopsis
Summary of Study Design:  This study is a Phase 1, single-center, subject- and investigator-blind, randomized, 
9-way, 3-period crossover study in healthy subjects to evaluate the PK and PD of LY3185643 and rGlucagon after 
subcutaneous (SC) administration.
Up to 2737 healthy men and women may be enrolled to target approximately 18 subjects to complete the study.  
Each subject will receive 3 doses on each of 3 dosing days (total of 9 doses:  5 doses of LY3185643 and 4 doses of 
rGlucagon) administered SC.  Doses will be administered in a 9-way complete crossover design in 3 periods, and 
subjects will be randomized to predefined treatment sequences.
Number of Subjects:  Up to 27 37 subjects may be enrolled so that approximately 18 subjects complete the study.


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LY3185643
Section 2.
Schedule of Activities
Study Schedule Protocol I8Z-MC-APCA
Screen
Periods 1, 2, 3a
FU/ETb
Procedure
Up to 
Day -28
Day -1
Day 1c
Day 2
Comments
Continuous ECG
Holter monitoring 
(24-hour)
X
15 ECGs will be extracted from the continuous ECG
Holter recording at -5, 30, 60, 120, and 180 minutes 
postdose for each Day 1 dose administration.
Immunogenicity 
(LY3195643 
antibodies) samples
Any time before the first dose
X
Period 1 and Period 3 only.  Prior to the first dose only.


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5.1.
Overall Design
Up to 2737 healthy men and women may be enrolled to target approximately 18 subjects to 
complete the study.  Each subject will receive 3 doses on each of 3 dosing days (total of 9 doses:  
5 doses of LY3185643 and 4 doses of rGlucagon) administered SC.  Doses will be administered 
in a 9-way complete crossover design in 3 periods, and subjects will be randomized to predefined 
treatment sequences.  Completers are defined as subjects who have received all 9 doses.
5.2.
Number of Participants
Up to 2737 subjects may be enrolled so that approximately 18 subjects complete the study.
Section 6.1.
Inclusion Criteria
[1a] male subjects:
agree to use an effective method of contraception for the duration of the study
Male subjects with female partners of childbearing potential will be required to use a 
condom in conjunction with a spermicidal gel, foam, cream or suppository.  In addition, 
the female partner will be requested to use an additional effective form of contraception, 
which can be any of the following:
•
female condom with spermicide
•
diaphragm with spermicide
•
cervical sponge
•
cervical cap with spermicide
•
combined oral contraceptive pill and mini-pill
•
NuvaRing
•
implantable contraceptives
•
injectable contraceptives (such as Depo-Provera®)
•
intrauterine device (such as Mirena® and ParaGard®)
•
total abstinence
Men who have had a vasectomy with appropriate post-vasectomy documentation of the absence 
of sperm in the ejaculate are not required to use contraception.  Male subjects with a female 
partner meeting the definition of a woman not of childbearing potential will not be required to 
use contraception.
[1b] female subjects:
women not of childbearing potential may participate without using contraception, and 
include those who are:


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LY3185643
Section 6.2.
Exclusion Criteria
[26]  have used had systemic exposure to glucocorticoids within 3 months before entry into the 
study, or (including oral or intra-articular glucocorticoids, or potent topical steroids applied to 
>20% of body surface area)
Section 9.4.4.1.
Continuous 12-Lead Holter ECG Monitoring
Continuous 12-lead HolterECG monitoring does not allow bedside printing or viewing of ECGs 
extracted from the signal recorded.  Thus, for subject safety, ECGs must be recorded by a local, 
static 12-lead ECG device at the times specified in the Schedule of Activities (Section 2).  These 
safety ECGs will not be transmitted to a central ECG laboratory.  Safety ECGs must be 
interpreted by the investigator or qualified designee soon after the time of collection.  This 
review will be documented and provides information for immediate subject management.  If the 
ECG shows a clinically significant quantitative or qualitative change from baseline, the 
investigator or qualified designee will assess the subject for symptoms (for example, palpitations, 
near syncope, syncope) and determine if the subject can continue in the study.  The investigator 
or qualified designee is responsible for subject management.  If the investigator determines that 
the changes identified in the ECG are clinically relevant, an applicable AE should be recorded on 
the subject CRF.
Section 9.4.4.1.1.
Holter Recordings for Data Analysis
Continuous 12-lead Holter recordings (H12+ ) will be performed according to the Schedule of 
Activities (Section 2).  Patients must be in a quiet atmosphere without significant external 
stimulation (for example, TV, internet, etc.), remain in a supine position for at least 5 to 10 
minutes before the specified ECG collection times, and remain supine but awake during ECG 
collection and for at least 10 minutes afterward.  Subjects should be encouraged to remain still, if 
possible, during this time.
Digital recordings of all periods of continuous ECG recordings in individual subjects will be 
transferred to a central ECG laboratory designated by Lilly.  The ECG laboratory will perform 
quality control checks for the time points of interest (for example, acquisition quality for ability 
to measure/interpret, demographics, and study details) and extract 15 unique 10-second ECGs at 
the times listed in the Schedule of Activities (Section 2).
The ECG laboratory will then store the 24-hour recording as well as the extracted 10-second 
ECGs, and a cardiologist at the central ECG laboratory will conduct a full overread (including 
the measurement of all intervals) on one of the replicates that was extracted.  For each set of 
replicates, the cardiologist will determine the RR and QT intervals and heart rate on the ECGs 
that were not fully overread.  No reports will be issued from the central ECG laboratory back to 
the sites for any ECGs.


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Section 9.4.4.2.
Telemetry
The ECG waveform and cardiac rhythm will be monitored continuously using an ECG telemetry 
monitor during the inpatient stay at the CRU, from the night of Day -1 to 4 hours after the last 
dose on Day 1, morning of Day 2 for all 3 periods.  Telemetry data from Day -1 up to 
approximately 1 hour before dosing will be reviewed by the investigator before administration of 
the first dose on Day 1.  Subjects will not be dosed if any exclusion criteria are observed (for 
example, Exclusion Criterion [14]).  Any other observations, such as changes in the ECG 
waveform and rhythm, should be evaluated by the investigator and the decision to dose will be at 
the investigator’s discretion.  Any confirmed abnormalities/events assessed to be clinically 
significant by the investigator during monitoring should be recorded in the medical record and 
reported as a preexisting condition or AE on the AE CRF page.


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Appendix 2.
Clinical Laboratory Tests
Laboratory Tests
Hematologya
Clinical Chemistrya
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume 
Chloride
Mean cell hemoglobin
Calcium
Mean cell hemoglobin concentration
Phosphorus
Leukocytes (WBC)
Magnesium
Absolute counts of:
Glucose (fasting)
Neutrophils
Blood urea nitrogen
Lymphocytes
Total cholesterol
Monocytes
Total protein
Eosinophils
Albumin
Basophils
Total bilirubin
Platelets
Alkaline phosphatase
Aspartate aminotransferase
Urinalysisa
Alanine aminotransferase
Specific gravity
Creatinine
pH
Gammaglutamyl transferase
Protein
Glucose
Hepatitis B surface antigenc
Ketones
Hepatitis C antibodyc
Bilirubin
HIVc
Urobilinogen
Pregnancy testd
Blood
FSHe
Nitrite
Thyroid-stimulating hormonef
Leukocytes
LY3185643 antibodies as indicated in Section 2
Microscopyb
Abbreviations:  FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cells; 
WBC = white blood cells.
a
Results will be validated by the local laboratory at the time of initial testing.
b
If clinically indicated, per investigator’s discretion.
c
Performed at screening only.  Tests may be waived if they have been performed within 6 months before 
screening and the corresponding reports are available for review.
d
Only for females.  Test will be performed at screening, at every admission to the clinical research unit, and at the 
follow-up or early termination visit.
e
For women only when needed to confirm postmenopausal status.
f
Only for subjects who are being treated with thyroxine or have a history of thyroid disease.


Leo Document ID = e01fc640-8cb9-44bc-a72d-82993d510454
Approver: 
Approval Date & Time: 08-Dec-2016 16:13:22 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 08-Dec-2016 19:30:23 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
Statistical Analysis Plan I8Z-MC-APCA 
 
A Randomized, 9-Way, Single-Dose, Crossover Study to Evaluate the Pharmacokinetics, 
Pharmacodynamics, Safety, and Tolerability of LY3185643 and rGlucagon in Healthy Subjects 
NCT02951780 
Approval Date: 19-Oct-2016 
 
 
 


Final, 18 October 2016
             Page 1 of 14
STATISTICAL ANALYSIS PLAN
A Randomized, 9-Way, Single-Dose, Crossover Study to Evaluate the Pharmacokinetics, 
Pharmacodynamics, Safety, and Tolerability of LY3185643 and rGlucagon in Healthy 
Subjects
Statistical Analysis Plan Status:  Final
Statistical Analysis Plan Date:  18-October-2016
Study Drug: LY3185643
Sponsor Reference:  I8Z-MC-APCA
Covance CRU Study: 1000071-8340902
Clinical Phase I
Approval Date: 19-Oct-2016 GMT


Final, 18 October 2016
             Page 2 of 14
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8340902
Sponsor Reference I8Z-MC-APCA
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS ............................................................................................... 2
2.
ABBREVIATIONS........................................................................................................ 4
3.
INTRODUCTION ......................................................................................................... 5
4.
STUDY OBJECTIVES.................................................................................................. 5
Primary Objective ............................................................................................................ 5
Secondary Objective ........................................................................................................ 5
Exploratory Objective ...................................................................................................... 5
5.
STUDY DESIGN........................................................................................................... 6
6.
TREATMENTS ............................................................................................................. 8
7.
SAMPLE SIZE JUSTIFICATION ................................................................................. 9
8.
DEFINITION OF ANALYSIS POPULATIONS............................................................ 9
9.
STATISTICAL METHODOLOGY ............................................................................... 9
9.1
General.................................................................................................................... 9
9.2
Demographics and Subject Disposition.................................................................. 10
9.3
Pharmacokinetic Assessment................................................................................. 10
9.3.1
Pharmacokinetic Analysis............................................................................. 10
9.3.2
Pharmacokinetic Statistical Methodology ..................................................... 10
9.4
Pharmacodynamic Assessment .............................................................................. 11
9.4.1
Pharmacodynamic Analysis.......................................................................... 11
9.4.2
Pharmacodynamic Statistical Methodology .................................................. 11
9.4.3
Glucose and C-peptide samples .................................................................... 12
9.4.4
Immunogenicity ........................................................................................... 12
9.5
Safety and Tolerability Assessments ...................................................................... 12
9.5.1
Adverse events ............................................................................................. 12
9.5.2
Concomitant medication............................................................................... 13
9.5.3
Clinical laboratory parameters ...................................................................... 13
9.5.4
Vital signs .................................................................................................... 13
9.5.5
Holter monitoring ......................................................................................... 13
9.5.6
Glucose ........................................................................................................ 13
9.5.7
Other assessments......................................................................................... 14
9.5.8
Safety and Tolerability Statistical Methodology ............................................ 14


Final, 18 October 2016
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8340902
Sponsor Reference I8Z-MC-APCA
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 ......................................................................................................... 14
13.3 Insufficient Data for Presentation .......................................................................... 14


Final, 18 October 2016
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8340902
Sponsor Reference I8Z-MC-APCA
2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
AE
Adverse event
AUC
Area under the concentration versus time curve
Cmax
Maximum observed drug concentration
CI
Confidence interval
CRF
Case Report Form
CSR
Clinical Study Report
CRU
Clinical Research Unit
CV
Coefficient of variation
EC
Early Clinical 
ECG
Electrocardiogram
e.g.
For example (Latin: exempli gratia)
ICH
International Council on Harmonisation
MedDRA
Medical Dictionary for Regulatory Activities
PD
Pharmacodynamic
PK
Pharmacokinetic
SAP
Statistical Analysis Plan
SC
Subcutaneous
SD
Standard deviation 
TFLs
Tables, Figures, and Listings
t1/2
Half-life associated with the terminal rate constant (λz) in non-
compartmental analysis
tmax
Time of maximum observed drug concentration


Final, 18 October 2016
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8340902
Sponsor Reference I8Z-MC-APCA
3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
17 August 2016).
This SAP describes the planned analys is of the safety, tolerability, pharmacokinetic (PK) and 
pharmacodynamic (PD) data from this study. A detailed description of the planned TFLs to be 
presented in the clinical study report (CSR) is provided in the accompanying TFL shell 
document.
The intent of this document is to provide guidance for the statistical, PD and PK analyses of data. 
In general, the analyses are based on information from the protocol, unless they have been 
modified by agreement between Eli Lilly and Company and Covance Early Clinical (EC)
Biometrics.
A limited amount of information concerning this study (e.g., objectives, study 
design) is given to help the reader’s interpretation. This SAP must be signed off prior to first 
subject administration for this study.
When the SAP and TFL shells are agreed upon and 
finalized, they will serve as the template for this study’s CSR.
This SAP supersedes
the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified.
If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon 
between Eli Lilly and Company and Covance EC Biometrics and identified in the CSR.
Any 
minor deviations from the TFLs may not be documented in the CSR.
This SAP is written with consideration of the recommendations outlined in the Inte rnational 
Council on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: 
Statistical 
Principles for Clinical Trials1 and the ICH E3 Guideline entitled Guidance for Industry: 
Structure and Content of Clinical Study Reports2.
4. STUDY OBJECTIVES
Primary Objective
The primary objective of this study is to evaluate the PK and PD profiles of LY3185643 and 
rGlucagon after single doses of study treatment.
Secondary Objective
To evaluate the safety and tolerability of LY3185643 after single doses of study treatment.
Exploratory Objective
To evaluate immunogenicity of LY3185643 after multiple single doses of study treatment.


Final, 18 October 2016
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8340902
Sponsor Reference I8Z-MC-APCA
5. STUDY DESIGN
This study is a Phase 1, single-center, subject- and investigator-blind, randomized, 9-way,
3-period crossover study in healthy subjects to evaluate the PK and PD of LY3185643 and
rGlucagon after subcutaneous (SC) administration.
Up to 27 healthy men and women may be enrolled to target approximately 18 subjects to
complete the study. Each subject will receive 3 doses on each of 3 dosing days (total of 9 doses:  
5 doses of LY3185643 and 4 doses of rGlucagon) administered SC. Doses will be administered
in a 9-way complete crossover design in 3 periods, and subjects will be randomized to predefined
treatment sequences. Completers are defined as subjects who have received all 9 doses.
Subjects will be required to attend the Clinical Research Unit (CRU) on at least 5 occasions:

1 screening visit (may occur up to 28 days before randomization)

3 treatment periods

1 follow-up visit (at least 30 days after completing the last dose of study treatment)
Each treatment period will consist of 3 days (Days -1 to 2). Subjects should return for the next
period with a minimum of 3 days between treatment periods.
On Day -1, subjects will be 
admitted to the CRU. Subjects will be provided a carbohydrate-rich meal in the evening at 
approximately 10:00 PM and will remain fasted until completion of the study procedures on 
Day 1. On Day 1, study drug will be administered SC as follows:

Dose 1: morning of Day 1

Dose 2: approximately 4 hours after administration of the first dose

Dose 3: approximately 4 hours after administration of the second dose
Blood samples will be collected for the determination of concentrations of LY3185643,
glucagon, glucose, C-peptide, and for immunogenicity as shown in the Schedule of Activities.   
Blood samples for measurement of g lucose concentrations using YSI glucose analyzer will also 
be collected.
Safety data will include clinical examinations, vital signs, elec trocardiograms (ECGs; including 
telemetry, holter monitoring), clinical laboratory tests, concomitant medications and a record of 
adverse events (AEs).
All study procedures will end approximately 4 hours after the third dose. 
Subjects will be
provided dinner and stay overnight in the CRU for observation. Subjects will be discharged the
following day (Day 2) after completion of all assessments as shown in the Schedule of Activities.
Figure 1 illustrates the study design:


Final, 18 October 2016
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8340902
Sponsor Reference I8Z-MC-APCA
Figure 1.
Approximately 18 subjects are expected to complete the study. Each subject will be randomized 
to 1 of 9 treatment sequences comprising single SC doses of LY3185643 or rGlucagon (Table 1).  
Subjects who discontinue may be replaced to target at least 18 com pleters; the replacement 
subject will be assigned the treatment sequence of the discontinued subject and complete all 3 
treatment periods (total of 9 doses).


Final, 18 October 2016
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8340902
Sponsor Reference I8Z-MC-APCA
Table 1.
6. TREATMENTS
The following is a list of the study treatment names that will be used in the TFLs.
Study Treatment Name
Treatment order in TFL
{Insertbrief description of 
indication}3185643
1
{Insertbrief description of 
indication}3185643
2
{Insertbrief description of 
indication}3185643
3
{Insertbrief description of 
indication}3185643
4
{Insertbrief description of 
indication}3185643
5
10 g rGlucagon
6
25 g rGlucagon
7
50 g rGlucagon
8
200 g rGlucagon
9


Final, 18 October 2016
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8340902
Sponsor Reference I8Z-MC-APCA
7. SAMPLE SIZE JUSTIFICATION
The sample size is customary for Phase 1 studies evaluating safety, PK, and/or PD parameters 
and is considered sufficient to evaluate the primary objective of this study.
Subjects who discontinue the study may be replaced so that at least 18 subjects complete the 
study.  Replacement subjects will be assigned the treatment sequence of the subject that
discontinued the study.
8. DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all subjects who received at least one dose of study drug, 
and have at least one postdose safety assessment.
The “Pharmacokinetic” population will consist of a ll subjects who received at least one dose of 
study drug and have evaluable PK data.  
The “Pharmacodynamic” population will consist of all subjects who received at least one dose of 
study drug and have evaluable PD data.
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when subjects are assigned to analysis populations.
9. STATISTICAL METHODOLOGY
9.1
General
Data listings will be provided for all data that is databased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. 
For continuous data, 
summary statistics will include the arithmetic mean, arithmetic standard deviation (SD), median, 
min, max and N; for log-normal data (e.g. the PK parameters: area under the concentration 
versus time curve [AUCs] and maximum observed drug concentration [Cmax]) the geometric 
mean and geometric coefficient of variation (CV%) will also be presented. For categorical data, 
frequency count and percentages will be presented. Data listings will be provided for all subjects 
up to the point of withdrawal, with any subjects excluded fro m the relevant population 
highlighted. Summary statistics and statistical analyses will generally only be performed for 
subjects included in the relevant analysis population.
For the calculation of summary statistics 
and statistical analysis, unrounded data will be used. 
Mean change from baseline is the mean of all individual subjects’ change from baseline values. 
Each individual change from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoin t. The individual subject’s change from baseline 
values will be used to calculate the mean change from baseline using a SAS procedure such as 
Proc Univariate.
Data analysis will be performed using SAS® Version 9.3 or greater.


Final, 18 October 2016
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8340902
Sponsor Reference I8Z-MC-APCA
9.2
Demographics and Subject Disposition
Subject disposition will be listed. The demographic variables age, sex, race, ethnicity, country of 
enrolment, site ID, body weight, height and body mass index will be summarized and listed.
9.3
Pharmacokinetic Assessment
9.3.1 Pharmacokinetic Analysis
PK parameter estimates for LY3185643 and rGlucagon will be calculated by standard 
noncompartmental methods of analysis.
The primary parameters for analysis will be C max and AUC.  Other noncompartmental 
parameters, such as t 1/2, apparent clearance, and apparent volume of distribution, may be 
reported.  Population PK and exposure -response analyses may be performed using PK, PD and 
safety data.
PK parameters for LY3185643 and rGlucagon will be summarized for each dose group. 
Concentration-time profiles (mean and individual) will be generated.  All PK data analyses will 
be the responsibility of the Lilly team.
9.3.2 Pharmacokinetic Statistical Methodology
PK parameter estimates (Cmax and AUC) will be provided to Covance to delineate effects of dose 
proportionality for LY3185643 and rGlucagon separately using a power model as follows:
                                                  
i
i
i
dose
PK






)
log(
.
)
log(
Where i represents the ith subject, PK represents a PK parameter (AUC or C max), and εi is a 
residual error term.  The estimated ratios of dose-normalized means
                                                                 
1
ˆ
ˆ







l
h
Rdnm
and the corresponding 90% confidence intervals will be reported, where h and l denote the 
highest and lowest doses, respectively.
An example of the SAS code that will be used is as follows:
/* Lack of fit test */
proc mixed data=<indata>;
  class trtmnt vol;
  model l_pk = logdose trtmnt / htype=1 ddfm=kr;
   random intercept / subject=vol;
  ods output tests1=tests;
run; 
/* Power model */


 
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proc mixed data=<indata>; 
   class vol; 
   model l_pk = logdose / solution cl alpha=0.1 oupred=resids ddfm=kr; 
   estimate ‘ x mg’ intercept 1 logdose a / alpha=0.1 cl; /* a=Log value of x*/  
   estimate ‘ y mg’ intercept 1 logdose b / alpha=0.1 cl; /* b=Log value of y*/ 
   estimate ‘ z mg’ intercept 1 logdose c / alpha=0.1 cl; /* c=Log value of z*/ 
   estimate ‘z mg – x mg’ logdose d / alpha=0.1 cl; /* d = Difference in log values of highest       
   and lowest dose*/  
   random intercept / subject=vol; 
   ods output solutionf=estimate; 
   ods output estimates=estims; 
run; 
Where l_pk is the log-transformed (base e) PK parameter. 
Additional analyses may be conducted as appropriate.  
9.4 
Pharmacodynamic Assessment 
9.4.1 Pharmacodynamic Analysis 
The PD time-action and response of LY3185643 and rGlucagon will be compared to establish 
the relative potency between LY3185643 and rGlucagon. 
The primary PD response variables of interest include tmax, Cmax, change from baseline in Cmax 
and change from baseline to each time point, and incremental AUCs for glucose measured by 
YSI glucose analyzer and C-peptide.  Similar PD response variables using laboratory measured 
glucose will also be estimated.   
9.4.2 Pharmacodynamic Statistical Methodology 
All PD parameters including the baseline-corrected parameters will be summarized by dose 
group and tabulated.  The individual observed and mean (by dose group) time profile of the PD 
measurements after dosing will be plotted. 
For these parameters, a linear model will be fitted to account for the PD difference between 
LY3185643 and rGlucagon.  The model is detailed below.  In addition, partial AUC for glucose 
over appropriate time intervals will be calculated using the trapezoidal rule.  The AUC for each 
subject after each dose will also be baseline-adjusted.  Baseline for each dose will be defined as 
the average of predose values for that dose. 
For each PD parameter, the linear model that is proposed to account for differences between 
LY3185643 and rGlucagon is: 
 
 
 
 
 
 
ࢅ࢑࢒ൌࢼ૙൅ࢼ૚ࢊ࢑࢒൅ࢼ૛ࢊ࢑࢒∗ࢆ࢑࢒൅࢛࢑൅ࢋ࢑࢒  
 
 
 
( 1 ) 
where ݇ denotes the subject index, ݈ denotes the period index, ݀௞௟ is the dose in mg during each 
period, ܼ௞௟ is the treatment indicator (0 for rGlucagon and 1 for LY3185643), ݑ௞∼NIሺ0, ߪ௨మሻ 
denotes the between subject error, and ݁௞௟∼NIሺ0, ߪ௘మሻ denotes the within-subject error.  The 


 
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notation “NI” means “Normally Independent.”  There is no term for the treatment group 
indicator ܼ௞௟ because at dose = 0 the response should be the same for both treatment groups.  
Setting the mean responses for each treatment equal to each other, it follows that: 
ߚ଴൅ߚଵܦଵ൅ߚଶܦଵൌߚ଴൅ߚଵܦ଴ 
where ܦ଴ denotes the rGlucagon dose and ܦଵ denotes the LY3185643 dose.  It follows that 
ܦଵൌߣܦ଴ where ߣൌߚଵ/ሺߚଵ൅ߚଶሻ is the conversion factor that determines how many mg of 
LY3185643 are equivalent to one mg of rGlucagon.  The model (1) can be reparameterized as a 
nonlinear mixed model: 
ܻ௞௟ൌߚ଴൅ߚଵ݀௞௟൅ሺ1 െߣሻ/ߣ ߚଵ݀௞௟∗ܼ௞௟൅ݑ௞൅݁௞௟. 
Then, the conversion factor ߣ (the point estimate and the 90% confidence interval) will be 
directly estimated from this nonlinear model.  This model may be extended to allow for multiple 
parameter values, if deemed appropriate. 
9.4.3 Glucose and C-peptide samples 
Glucose concentrations from the PD sample and the YSI glucose analyzer samples, along with 
C-peptide data will be summarized by treatment together with changes from baseline, where 
baseline is defined as Day 1 predose of each dose within each period.  The glucose and C-peptide 
data will be listed for individual subjects.  In addition, partial AUC for the lab measured glucose 
and C-peptide over appropriate time intervals will be calculated using the trapezoidal rule.  The 
AUC for each subject after each dose will also be baseline-adjusted.  Baseline for each dose will 
be defined as the average of predose values for that dose. 
9.4.4 Immunogenicity 
The frequency of antibody formation to LY3185643 will be determined.  If a neutralization assay 
is performed, the frequency of neutralizing antibodies will be determined.  The relationship 
between the presence (or absence) of antibodies and AEs will be assessed.  Likewise, the 
relationship between the presence of antibodies and the PK parameters and PD response to 
LY3185643 will be assessed.  Any inferential analyses to explore the relationship between the 
presence (or absence) of antibodies and AEs will be the responsibility of the Lilly team.   
9.5 
Safety and Tolerability Assessments 
9.5.1 Adverse events 
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the AE will be reported in the listings, only the most severe will be used in the summary 
tables.  A pre-existing condition is defined as an AE that starts before the subject has provided 
written informed consent and is ongoing at consent.  A non-treatment emergent AE is defined as 
an AE which starts after informed consent but prior to dosing.  A treatment-emergent AE is 
defined as an AE which occurs postdose or which is present prior to dosing and becomes more 
severe postdose.   


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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 19.0 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 tabulated.
9.5.2 Concomitant medication
Concomitant medication will be coded using the World Health Organization drug dictionary 
(Version March 2016).  Concomitant medication will be listed.
9.5.3 Clinical laboratory parameters
All clinical chemistry, hematology and urinalysis data will be listed.
Additionally clinical 
chemistry, hematology and urinalysis data outside the reference ranges will be listed.
Values for any clinical chemistry, hematology and urinalysis values outside the reference ranges 
will be flagged on the individual subject data listings.
9.5.4 Vital signs
Vital signs data will be summarized by treatment together with changes from baseline, where 
baseline is defined as Day 1 predose of each dose within each period. Figures of mean vital 
signs and mean changes from baseline profiles will be presented by treatment. 
Furthermore, 
values for individual subjects will be listed.
Vital signs data will be listed for individual subjects.
9.5.5 Holter monitoring 
Continous 12-lead Holter recordings will be measured on Day 1 to extract 15 ECGs at -5, 30, 60, 
120 and 180 minutes postdose for each Day 1 dose administration.
All Holter ECG parameters (PR, RR, QT, QTcF, QRS, Heart rate) will be summarized by 
treatment together with changes from baseline, where baseline is defined as Day 1 predose of 
each dose within each period.  All Holter ECG data will be listed for individual subjects. 
All Holter ECG interpretations will be from the central lab will be listed for individual subjects.
Exposure-response analysis of the change from baseline QTcF versus the drug concentration will 
be performed.
9.5.6 Glucose 
Glucose will also be available for safety evaluation as well as glucose collected as part of the PD 
objective.  Glucose will be summarized by treatment together with changes from baseline, where 


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baseline is defined as Day 1 predose of each dose within each period.  The glucose data will be 
listed for individual subjects.
9.5.7 Other assessments
All other safety assessments not detailed in this section will be listed but not sum marized or 
statistically analyzed. 
9.5.8 Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.
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.
13.
DATA PRESENTATION
13.1
Derived Parameters
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be 
reported to three significant figures. Observed concentration data, e.g. Cmax, should be reported 
as received. Observed time data, e.g. t max, should be reported as received. N and percentage 
values should be reported as whole numbers.
Median values should be treated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values.
13.2
Missing Data
Missing data will not be displayed in listings.
13.3
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of subjects or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the centre of the table, 
such as, “No serious adverse events occurred for this study.”


Leo Document ID = 3887a8d9-7221-4e8c-84b4-4b1be7f57c99
Approver: 
Approval Date & Time: 19-Oct-2016 15:55:06 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 19-Oct-2016 16:01:55 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 19-Oct-2016 17:35:53 GMT
Signature meaning: Approved
PPD
PPD
PPD