Clinical trial NCT03166124
Conditions: Diabetes Mellitus, Type 1
Sponsor: Eli Lilly and Company
Start date: 2017-05-24; Completion date: 2017-11-18
Enrollment: 80 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to compare LY900014 with insulin lispro (Humalog) in elderly and younger adults with type 1 diabetes mellitus.

Screening is required within 28 days prior to the start of the study. For each participant, the total duration of the clinical trial will be between 3 to 8 weeks.

Detailed description:

Arms: arm 1: Single, subcutaneous (SC) 15-U dose of LY900014 in the elderly adult group. arm 2: Single, SC 15-U dose of insulin lispro (Humalog) in in the elderly adult group. arm 3: Single, SC 15-U dose of LY900014 in the younger adult group. arm 4: Single, SC 15-U dose of insulin lispro (Humalog) in the younger adult group.
Interventions: intervention 1: LY900014 intervention 2: Insulin Lispro
Intervention descriptions: intervention 1: Administered SC intervention 2: Administered SC

Protocol documents:
Prot_000.pdf: 
 
 
Protocol/Statistical Analysis Plan: I8B-MC-ITRR  
 
 
Pharmacokinetics and Glucodynamics of LY900014 Compared to Insulin Lispro Following 
Single Dose Administration in Elderly and Younger Adults With Type 1 Diabetes Mellitus   
 
 
NCT03166124 
 
 
Approval Date: 


I8B-MC-ITRR(c)Clinical Pharmacology Protocol
Page 1
LY900014
Protocol I8B-MC-ITRR(c)
Pharmacokinetics and Glucodynamics of LY900014 
Compared to Insulin Lispro Following Single Dose 
Administration in Elderly and Younger Adults with Type 1 
DiabetesMellitus
EudraCT Number:  2016-004308-67
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 
LY900014, 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.
Approval Date: 04-Aug-2017 GMT
LY900014
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly: 08 December 2016
Amendment (a) Electronically Signed and Approved by Lilly:09 March 2017
Amendment (b) Electronically Signed and Approved by Lilly: 24 May 2017
Amendment (c) Electronically Signed and Approved by Lillyon approval date provided below.


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LY900014
Table of Contents
Pharmacokinetics and Glucodynamics of LY900014 
Compared to Insulin Lispro Following Single Dose 
Administration in Elderly and Younger Adults with Type 1 
Diabetes Mellitus
Section
Page
Protocol I8B-MC-ITRR(c) Pharmacokinetics and Glucodynamics of 
LY900014 Compared to Insulin Lispro Following Single Dose 
Administration in Elderly and Younger Adults with Type 1 Diabetes 
Mellitus...............................................................................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................8
2.
Schedule of Activities .......................................................................................................11
3.
Introduction ......................................................................................................................15
3.1.
Study Rationale............................................................................................................15
3.2.
Background..................................................................................................................15
3.3.
Benefit/Risk Assessment..............................................................................................16
4.
Objectives and Endpoints..................................................................................................18
5.
Study Design.....................................................................................................................19
5.1.
Overall Design .............................................................................................................19
5.1.1.
Inpatient Dosing Visits.........................................................................................20
5.1.2.
Outpatient Procedure............................................................................................20
5.2.
Number of Participants.................................................................................................21
5.3.
End of Study Definition ...............................................................................................21
5.4.
Scientific Rationale for Study Design...........................................................................21
5.5.
Justification for Dose ...................................................................................................22
6.
Study Population...............................................................................................................23
6.1.
Inclusion Criteria..........................................................................................................23
6.2.
Exclusion Criteria ........................................................................................................24
6.3.
Lifestyle and/or Dietary Requirements .........................................................................26
6.3.1.
Meals and Dietary Restrictions.............................................................................26
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................27
6.3.3.
Activity................................................................................................................27
6.4.
Screen Failures.............................................................................................................27
7.
Treatment..........................................................................................................................28
7.1.
Treatment Administered...............................................................................................28


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7.1.1.
Packaging and Labeling .......................................................................................28
7.2.
Method of Treatment Assignment ................................................................................28
7.2.1.
Selection and Timing of Doses.............................................................................28
7.3.
Blinding .......................................................................................................................29
7.4.
Dose Modification........................................................................................................29
7.5.
Preparation/Handling/Storage/Accountability...............................................................29
7.6.
Treatment Compliance .................................................................................................29
7.7.
Concomitant Therapy...................................................................................................30
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...........................................................................................31
9.
Study Assessments and Procedures ...................................................................................32
9.1.
Efficacy Assessments...................................................................................................32
9.2.
Adverse Events ............................................................................................................32
9.2.1.
Serious Adverse Events........................................................................................33
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................34
9.2.2.
Complaint Handling.............................................................................................34
9.3.
Treatment of Overdose.................................................................................................34
9.4.
Safety...........................................................................................................................34
9.4.1.
Physical Examinations .........................................................................................34
9.4.2.
Body Weight........................................................................................................34
9.4.3.
Hip and Waist Circumference ..............................................................................35
9.4.4.
Laboratory Tests ..................................................................................................35
9.4.5.
Vital Signs ...........................................................................................................35
9.4.6.
Electrocardiograms ..............................................................................................35
9.4.7.
Safety Monitoring ................................................................................................35
9.4.7.1.
Glucose Monitoring........................................................................................36
9.4.7.1.1.
Severe Hypoglycaemia .............................................................................37
9.4.8.
Injection-Site Assessments (Local Tolerability)....................................................37
9.4.8.1.
Pain Measurements Using the Visual Analog Scale ........................................37
9.4.9.
Immunogenicity Assessments ..............................................................................38
9.5.
Pharmacokinetics .........................................................................................................38
9.5.1.
Bioanalysis...........................................................................................................38
9.6.
Glucodynamics (Euglycaemic Glucose Clamp)............................................................38
9.7.
Genetics .......................................................................................................................39


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9.8.
Biomarkers...................................................................................................................40
9.9.
Health Economics ........................................................................................................40
10.
Statistical Considerations and Data Analysis.....................................................................41
10.1. Sample Size Determination ..........................................................................................41
10.2. Populations for Analyses..............................................................................................41
10.2.1.
Study Participant Disposition ...............................................................................41
10.2.2.
Study Participant Characteristics ..........................................................................41
10.3. Statistical Analyses ......................................................................................................41
10.3.1.
Safety Analyses....................................................................................................42
10.3.1.1.
Clinical Evaluation of Safety..........................................................................42
10.3.1.2.
Statistical Evaluation of Safety.......................................................................42
10.3.1.2.1.
Statistical Evaluation of the Intensity of Injection-
Site Pain ...................................................................................................42
10.3.2.
Pharmacokinetic Analyses....................................................................................43
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................43
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................44
10.3.3.
Glucodynamic Analyses.......................................................................................44
10.3.3.1.
Pharmacodynamic Parameter Estimation ........................................................44
10.3.3.2.
Glucodynamic Statistical Inference.................................................................44
10.3.4.
Evaluation of Immunogenicity .............................................................................45
10.3.5.
Interim Analyses..................................................................................................45
11.
References ........................................................................................................................46


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List of Tables
Table
Page
Table ITRR.1.
Objectives and Endpoints .......................................................................18
Table ITRR.2.
Treatments Administered........................................................................28


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List of Figures
Figure
Page
Figure ITRR.1.
Illustration of study design for Protocol I8B-MC-ITRR..........................21


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................47
Appendix 2.
Clinical Laboratory Tests........................................................................51
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................52
Appendix 4.
Blood Sampling Summary......................................................................55
Appendix 5.
Protocol Amendment I8B-MC-ITRR(c) Summary
Pharmacokinetics and Glucodynamics of LY900014 Compared to 
Insulin Lispro Following Single Dose Administration in Elderly 
and Younger Adults with Type 1 Diabetes Mellitus................................56


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1. Protocol Synopsis
Title of Study: 
Pharmacokinetics and Glucodynamics of LY900014 Compared to Insulin Lispro Following Single Dose 
Administration in Elderly and Younger Adults with Type 1 Diabetes Mellitus
Rationale: 
LY900014 is an ultra-rapid-acting insulin lispro formulation with increased initial absorption compared to 
commercially available insulin lispro formulation (Humalog®; Eli Lilly and Company).  LY900014 aims at 
mimicking the physiological prandial insulin secretion pattern better than the currently available treatments, which 
may more effectively control postprandial glucose excursions and allow increased flexibility in the time of dosing 
relative to a meal.
The aim of this study is to compare the insulin lispro pharmacokinetic (PK) and glucodynamic (GD) profiles of 
LY900014 with those of insulin lispro (Humalog) during a euglycaemic glucose clamp in elderly and younger adults 
with type 1 diabetes mellitus (T1DM).
Objective(s)/Endpoints:
Objectives
Endpoints
Primary

To evaluate the PK of insulin lispro following 
administration of a single 15-U SC dose of 
LY900014 compared to insulin lispro (Humalog)
within each T1DM population (elderly and younger 
adults).

Early 50% tmax and AUC(0-30min)
Secondary

To compare the GD during a euglycaemic clamp of 
LY900014 and insulin lispro (Humalog) following 
administration of a single 15-U SC dose in elderly 
and younger adults with T1DM.

To evaluate the safety and tolerability of the novel 
LY900014 formulation.

Early 50% TRmax, Gtot(0-30min), Gtot(0-1hour), and Tonset

AEs
Abbreviations:  AE = adverse event; AUC(0-30min) = area under the concentration versus time curve from time zero to 
30 minutes; early 50% tmax = time to early half-maximal plasma concentration; early 50% TRmax = time to early 
half-maximal glucose infusion rate; GD = glucodynamics; Gtot(0-30min) = total amount of glucose infused over 30 
minutes; Gtot(0-1hour) = total amount of glucose infused over 1 hour; PK = pharmacokinetics; SC = subcutaneous; 
T1DM = type 1 diabetes mellitus; Tonset = time to onset of insulin action.
Summary of Study Design:
Study I8B-MC-ITRR is a randomized, subject- and investigator-blind, 2-treatment, 2-period, crossover study in 
elderly and younger adults with T1DM.


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LY900014
Treatment Arms and Duration:  
LY900014 (test): Single 15-U dose
Insulin lispro (Humalog) (reference): Single 15-U dose
Number of Subjects: Up to 42 younger adult (aged 18 to 45 years inclusive) and 42 elderly (aged ≥65 years) 
subjects may be enrolled to ensure that at least 34 subjects in each age group complete the study.
Statistical Analysis: The primary statistical analyses for PK will be conducted on subjects who receive at least 1 
dose of study drug and have measurable insulin lispro concentrations.  The primary statistical analysis for GD will 
be conducted on those subjects who complete at least 1 clamp procedure.  Supportive analyses will be done on the 
key parameters for the subjects who complete all treatment periods with evaluable data. Safety analyses will be 
conducted for all enrolled subjects who received at least 1 dose of study drug, whether or not they completed all 
protocol requirements.
Unless otherwise noted, all tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, and 
confidence intervals (CIs) will be calculated at 95%, 2-sided.
Safety: All investigational and protocol procedure adverse events (AEs) will be listed, and if the frequency of 
events allows, safety data will be summarized using descriptive methodology. Safety parameters that will be 
assessed include safety laboratory parameters, vital signs, and electrocardiogram parameters as well as injection-site 
reactions. The parameters will be listed and summarized using standard descriptive statistics.
Pharmacokinetics: Subjects who receive at least 1 dose of study drug and have measurable insulin lispro 
concentrations will be included in the PK analysis dataset.  PK parameter estimates for insulin lispro will be 
calculated using standard noncompartmental methods of analysis.
Log-transformed maximum observed concentration (Cmax), clearance, and area under the plasma concentration-time 
curve estimates for insulin lispro will be evaluated to estimate least-squares geometric means, ratios of geometric 
means between LY900014 and Humalog (reference), and their corresponding 95% CIs for each age group using the 
statistical model that includes treatment, sequence, and period as fixed effects and subject within sequence as a
random effect.  The same model without log transformation will be used for time to early half-maximal plasma 
concentration (early 50% tmax), time to late half-maximal plasma concentration (late 50% tmax), and time to 
maximum concentration (tmax) to estimate least-squares means, treatment differences in least-squares means, and the 
corresponding 95% CIs for each age group. The treatment ratios and the corresponding 95% CIs for these time 
parameters will be calculated using Fieller’s theorem.
As treprostinil plasma concentrations after administration of LY900014 are expected to be very low, a descriptive 
statistical analysis may be conducted if sufficient data are available for this analysis. The primary analysis of the 
treprostinil concentrations will be focused on assessing tmax and Cmax.
Glucodynamics:  GD assessments will be determined from the glucose clamp procedure, where the glucose infusion 
rate (GIR) over time will be used as a measure of insulin effect. GD analyses will be conducted on those subjects 
who complete at least 1 clamp procedure.
A locally weighted scatterplot smoothing (LOESS) function will be applied to all individual GIR versus time 
profiles in each treatment group and/or period. The fitted data for each subject will be used to calculate the GD 


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LY900014
parameters. The values of these GD parameters will be summarized by treatment and/or period through descriptive 
statistics.  Mean LOESS fits of GIR versus time profiles will be generated.
The GD statistical model will be similar to the model used for the analysis of the PK parameters. The variables of
maximum GIR (Rmax), total amount of glucose infused (Gtot), total amount of glucose infused over 30 minutes 
(Gtot[0-30min]), total amount of glucose infused over 1 hour (Gtot[0-1h]), and total amount of glucose infused over 10 
hours (Gtot[0-10h]) will be log-transformed prior to analysis. The time variables including time to onset of insulin 
action (Tonset), time to Rmax (TRmax), time to half-maximal GIR before TRmax (early 50% TRmax), and time to half-
maximal GIR after TRmax (late 50% TRmax) will be analyzed using the same model without log transformation to 
estimate least-squares means, treatment differences in least-squares means, and the corresponding 95% CIs. The 
treatment ratios and the corresponding 95% CIs for these time parameters will be calculated using Fieller’s theorem.
Immunogenicity:
The immunogenicity data will be listed.  The relationship between treatment-emergent antidrug antibodies and AEs 
will be evaluated. The relationship between the presence of antibodies and the PK parameters and GD response to 
insulin lispro may also be evaluated.


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2. Schedule of Activities


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Study Schedule: Protocol I8B-MC-ITRR
Procedures
Screening
Euglycaemic Clamp Procedure Periods 1 and 2
FU/ED
a
Instructions/Comments
Up to 
Day -28
Day -
1
Day 1
Informed consentb
X
Subject admission to 
CRU
X
Standardized dinner
X
All subjects will receive short-acting insulin either 
via an injection or via a bolus dose from the 
insulin pump before the start of a standardized 
dinner and 6 hours prior to dosing.
Fasting
X
X
X
Subjects are expected to fast for at least 8 hours 
before screening and FU, and at least 8 hours 
before each dose until after the glucose clamp 
procedure is completed. (Up to 20 g of 
carbohydrates will be allowed to prevent 
hypoglycaemia.)
Height
X
Weight
X
Predose for Period 1 and Period 2
X
Waist and hip 
circumferenced
X
Alcohol breath test
X
X
X
Run-in and stabilization 
of glucose
X
To start approximately 1-6 hours prior to study 
drug dosing.
Medical assessment and 
physical examination
X
X
Before discharge from CRU for each period
X
Physical examination and medical history at 
screening.  Thereafter, medical review and 
targeted examination, as appropriate.
Vital signs:  body 
temperature, blood 
pressure, and pulse rate
X
X
Predose, 0.5 and 2 hours after dose and at 
the end of the clamp procedure
X
Vital signs can be collected after the subject is 
supine for at least 5 minutes.  Body temperature at 
screening only.  Predose vital signs may be 
collected up to 2 hours before the start of the 
clamp procedure.  
Randomization
X
Only at Period 1


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Procedures
Screening
Euglycaemic Clamp Procedure Periods 1 and 2
FU/ED
a
Instructions/Comments
Up to 
Day -28
Day -
1
Day 1
12-Lead ECG
X
Predose and at the end of the clamp 
procedure
X
Predose ECGs can be collected up to 2 hours
before the start of the clamp procedure. Subjects
must be supine for at least 10 minutes before ECG 
collection and remain supine but awake during 
ECG collection.
Clinical laboratory tests
X
Predose for Period 1 only
X
Fasting laboratory test for screening, Period 1, and 
FU.  To monitor patient safety, additional tests 
may be performed at the discretion of the 
investigator, as needed throughout the study.
Pregnancy test/urine drug 
screenc
X
X
X
Pregnancy test for all female subjects.  Urine drug 
screen for all subjects at CRU admission.
Study drug administration
X
Time = 0 minutes
Injection-site local 
tolerability assessments
0, 60, and 240 minutes postdose and at the 
end of clamp procedure
Time 0:  assessments of injection-site reaction will 
occur immediately following the injection.
VAS assessment of 
injection site pain
0, 20, and 60 minutes postdose
Time 0:  assessments of injection-site pain will 
occur immediately following the injection.
Insulin lispro PK 
sampling
0, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 
60, 70, 90, 120, 150,180, 240, 300, 360, 
420, 480, 540, and 600 minutes
Sampling times are relative to study drug 
administration time (0 minutes).
Treprostinil PK sampling 
15, 30, 60, and 120 minutes
Sampling times are relative to study drug 
administration time (0 minutes).
Blood glucose sampling
for euglycaemic clamp
Blood glucose monitoring every minute 
starting from the run-in and throughout the 
duration of the clamp until 10 hours after 
dosing
Pharmacogenetic sample
Predose for Period 1 only
Refer to sample collection instructions provided by 
the sponsor.
Immunogenicity sample
Predose for Period 1 and Period 2
X
Discharge from CRU
X
After completion of all study procedures and 
medical assessment on Day 1. Investigator’s 
discretion to discharge on Day 2. 


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Abbreviations:  CRU = clinical research unit; ECG = electrocardiogram; ED = early discontinuation; FU = follow-up; ICF = informed consent form; 
PK = pharmacokinetic; VAS = visual analog scale.
a
Procedures should be performed at least 14 days after the last dose of study drug.
b
Screening shall be completed within 28 days of dose of study drug.  The ICF will be signed at least 1 day prior to screening.
c
A FSH test will be performed for women who are menopausal
d
The average of triplicate measurements.
NOTE:  The site should schedule activities as appropriate. In cases where several study procedures are scheduled at the same time, the order of priority will be 
as follows:  PK samples including blood sampling for blood glucose and laboratory samples per protocol nominal times. ECGs and vital sign measurement 
should be scheduled before but as close as possible to the PK sampling times. VAS and injection-site assessments can be done after PK sampling If the 
investigator decides based on clinical judgment not to dose a subject on a given day (eg, because of low blood glucose), the subject’s visit may be 
rescheduled; any procedures performed in that period may be repeated.


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LY900014
3. Introduction
3.1.
Study Rationale
The use of LY900014 in elderly subjects (≥65 years of age) is anticipated. Study I8B-MC-ITRR
(ITRR) is being conducted in accordance with regulatory guidance to conduct clinical trials of 
medicines that are likely to have significant use in the elderly.
LY900014 is an ultra-rapid-acting insulin lispro formulation, which has shown an increased 
initial absorption compared to commercially available insulin lispro formulation (Humalog®, Eli 
Lilly and Company).  LY900014 aims at mimicking the physiological prandial insulin secretion 
pattern, which may more effectively control postprandial glucose excursions and allow increased 
flexibility of the time of dosing relative to a meal.
A population of elderly subjects is selected as changes in the body composition due to aging 
(such as increased body fat, reduced lean body mass, decreased total body water) may alter the 
pharmacokinetic (PK) profile of insulin lispro in LY900014.
Minimal data are available for the evaluation of the PK and glucodynamics (GD) of insulin 
lispro after LY900014 administration in subjects ≥65 years of age. Therefore, the aim of this 
study is to compare the PK and GD profiles of insulin lispro from LY900014 with those of 
insulin lispro (Humalog) during a euglycaemic glucose clamp in elderly subjects and younger 
adults with type 1 diabetes mellitus (T1DM) and also in a population of younger adults to 
support prescribing information and gain further data in this population.
3.2.
Background
The insulin analog insulin lispro (Humalog) has been shown to be absorbed more quickly than 
regular human insulin (Humalog package insert, 2015). In healthy volunteers given 
subcutaneous (SC) doses of insulin lispro ranging from 0.1 to 0.4 units/kg, peak serum levels 
were seen 30 to 90 minutes after dosing (Humalog package insert, 2015). However, the general 
consensus is that rapid-acting insulin, administered either through pumps or syringes/pen 
injectors, is still not rapid enough to match carbohydrate absorption profiles, which limits
efficacy and dosing flexibility. An ultra-rapid-acting prandial insulin would shift the PK/GD of 
insulin analogs so that they have an even faster onset to better match carbohydrate absorption
and also may allow important flexibility in the time of dosing relative to meals.
LY900014 represents a new formulation that contains insulin lispro, treprostinil, citrate, and 
other excipients. This formulation involves the novel use of a small amount of treprostinil
(Remodulin®) as an excipient to enhance the absorption of insulin lispro by local vasodilatation 
rather than as an active pharmaceutical ingredient to elicit a systemic effect. Treprostinil is a 
prostacyclin analog, administered either through inhalation (Tyvaso®), as an intravenous (IV)
infusion, or as a continuous SC administration for the treatment of symptomatic pulmonary 
arterial hypertension and has been approved in the United States (US) since 2002 and in 
Germany since 2007 (Remodulin package insert, 2014). Each of the other excipients (such as 
sodium citrate and magnesium chloride) in the LY900014 formulation is listed in the US Food 
and Drug Administration’s (FDA’s) Generally Recognized as Safe Food Additives database and 


I8B-MC-ITRR(c)Clinical Pharmacology Protocol
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LY900014
in the FDA’sInactive Ingredients in Approved Drugs database.Furthermore, the excipient 
concentration in LY900014 is within the limits identified for approved drug products in the FDA 
Inactive Ingredients in Approved Drugs database.
Safety and tolerability of LY900014 has been demonstrated in healthy subjects in 2previous 
clinical studies,
. Both were Phase 1, 
randomized, subject-blind studies in which the PK and GD of LY900014 and Humalog insulin 
lispro were evaluated during a euglycaemic glucose clamp following SC administration. The 
total insulin lispro exposure and GD effect were similar for LY900014 and Humalog insulin 
lispro; however, LY900014 demonstrated a faster and earlier insulin lispro absorption and faster 
elimination compared to Humalog insulin lispro.
Preliminary data from 3 ongoing Phase 1b studies 
 showed LY900014 was well tolerated in 
subjects with T1DM using eithermultiple daily injections(MDI)or insulin pump treatment.  
There were no serious adverse events (SAEs)related to study treatment ordiscontinuationsfrom 
the studies because ofa drug-related adverse event(AE).  Small numbersof treatment-emergent 
adverse eventswere reported, andthere wereno notableincreasesin these events in relation to 
any of the LY900014 formulations compared to those in relation to Humalog.
More information can be found in the Investigator’sBrochure (IB) ofLY900014.
3.3. Benefit/Risk Assessment
CCI
Study I8B-MC-ITRR will not offer any direct benefits to the subjects participating in the study.
The data from previous studies 
 andpreliminary data from ongoing 
studies 
 
have shownthat LY900014 was welltoleratedand the adverse drug reactions are in keeping with 
those reported for Humalog.
Potential risks associated with LY900014, derived from the known risks of insulin lispro 
(Humalog)-the active pharmaceutical ingredient in LY900014, are hypoglycaemia, 
hypersensitivity reactions (localized allergy and/or systemic allergy), undesirable effects at the 
injection site (injection-site reactions and lipodystrophy), and peripheral edema (Humalog 
package insert,2015).
Notably, across alldoses in the Lilly clinical studies that have evaluated treprostinil as a local 
vasodilator with or without insulin lispro, there was no clinically significant increase in those 
AEs associated with systemic absorption of treprostinil, as described in the Remodulin package 
insert(2014) (that is, headache, diarrhea, nausea, jaw pain, vasodilatation, rash, edema, anorexia, 
vomiting, asthenia, abdominal pain,and hypotension).  Theexposures of treprostinil in 
LY900014for participants in this study are expected to be undetectablecompared tothose 
observed in the dose ranges previously explored with SC bolus administration of treprostinil and 
are expected to be substantially lower than those observed in the treatment of pulmonary arterial 
hypertension.
CCI
CCI
CCI
CCI


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LY900014
No additional potential risks of LY900014 or treprostinil alone were identified in preclinical 
safety pharmacology and toxicity studies or clinical pharmacology studies.  No known potential 
risks are associated with the use of small amounts of treprostinil (Remodulin) in the LY900014 
formulation.
Additionally, local and systemic toxicity profiles of Humalog and Remodulin do not suggest the 
potential for additive or synergistic toxicity.
Following administration of the study insulins, subjects will receive IV glucose infusion at a 
variable rate to maintain euglycaemia up to 10 hours after insulin lispro administration. The aim 
of the clamp procedure is to maintain blood glucose within the normal glycaemic range. In 
addition, the clamp is performed while the subject is inpatient and under the investigator’s 
supervision. These considerations should minimize the risk of hypoglycaemia in subjects 
participating in Study ITRR. 
More information about the known and expected benefits, risks, SAEs, and reasonably 
anticipated AEs of LY900014 is to be found in the IB.  
More detailed information about the known and expected benefits and risks of Humalog insulin 
lispro may be found in the Humalog package insert (2015).


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LY900014
4. Objectives and Endpoints
Table ITRR.1 shows the objectives and endpoints of the study.
Table ITRR.1.
Objectives and Endpoints
Objectives
Endpoints
Primary

To evaluate the PK of insulin lispro following 
administration of a single 15-U SC dose of 
LY900014 compared to insulin lispro (Humalog) 
within each T1DM population (elderly and younger 
adults).

Early 50% tmax and AUC(0-30min)
Secondary

To compare the GD during a euglycaemic clamp of 
LY900014 and insulin lispro (Humalog) following 
administration of a single 15-U SC dose in elderly 
and younger adults with T1DM.

To evaluate the safety and tolerability of the novel 
LY900014 formulation.

Early 50% TRmax, Gtot(0-30min), Gtot(0-1hour), and Tonset

AEs
Exploratory

To evaluate whether the difference between 
LY900014 and insulin lispro in PK and PD 
parameters is similar between elderly and younger 
adults.

Early 50% tmax and Gtot(0-30min)
Abbreviations: AE = adverse event; AUC(0-30min) = area under the concentration versus time curve from time zero to 
30 minutes; early 50% tmax = time to early half-maximal plasma concentration; early 50% TRmax = time to early 
half-maximal glucose infusion rate; GD = glucodynamics; Gtot(0-30min) = total amount of glucose infused over 30 
minutes; Gtot(0-1h) = total amount of glucose infused over 1 hour; PD = pharmacodynamics; PK = 
pharmacokinetics; SC = subcutaneous; T1DM = type 1 diabetes mellitus; Tonset = time to onset of insulin action.


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LY900014
5. Study Design
5.1.
Overall Design
This is a Phase 1, randomized, subject- and investigator-blind, 2-treatment, 2-period, crossover 
study that compares the PK and GD of insulin lispro from LY900014 and insulin lispro 
(Humalog) following administration of a single 15-U SC dose in elderly and younger adults with 
T1DM who are either on multiple daily insulin injections or on CSII via a sponsor-approved 
insulin pump. Study ITRR will be conducted at 1 or more sites.
Figure ITRR.1 illustrates the study design.
Subjects will be randomized to 1 of 2 treatment sequences according to the actual randomization 
table provided to the site.  Each subject will participate in a screening visit, 2 clinical research 
unit (CRU) inpatient dosing visits, and a follow-up visit.  Before each dose, a run-in period of 1 
to 6 hours to stabilize blood glucose will occur.  Dosing visits will be separated by a wash-out 
period of 3 to 15 days, during which subjects will resume their normal insulin treatment with the 
exemption of the insulin switch 48 to 72 hours prior to dosing as mentioned below.  At each 
visit, subjects will receive either LY900014 or insulin lispro and undergo a euglycaemic clamp 
procedure where the time-concentration and time-action profiles of the study treatment will be 
evaluated simultaneously for up to 10 hours using an automated clamp device. Briefly, the aim 
of the euglycaemic clamp is to maintain euglycaemia after the administration of a dose of insulin 
by means of variable glucose infusion. The variable glucose infusion maintains or “clamps” 
glucose at a constant euglycaemic target; therefore, the glucose infusion rate (GIR) reflects the
GD effect of the insulin.
Prior to each dosing visit, subjects with T1DM on multiple daily insulin injections have to 
discontinue their basal insulin, according to the following guidance:

For subjects using insulin degludec or insulin glargine U300, the last injection of insulin 
degludec should occur no later than 72 hours prior to dosing.

For subjects using insulin detemir or glargine, the last injection of insulin detemir or 
glargine should occur no later than 48 hours prior to dosing.

For subjects using neutral protamine Hagedorn (NPH) insulin or other intermediate-
acting insulin, the last injection of NPH insulin or other intermediate-acting insulin 
should occur no later than 24 hours prior to dosing.

Subjects requiring any infusion via CSII of insulin lispro (Humalog) will switch to 
insulin glulisine (Apidra®) at least 8 hours prior to dosing. Basal infusion rate via CSII 
should not occur later than 3 hours prior to dosing.

Any injection or bolus infusion via CSII of more than 6 U of short-acting insulin should 
not occur between 11 and 6 hours prior to dosing. Any bolus injection or bolus infusion 
via CSII should occur no later than 6 hours prior to dosing. 


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All subjects will be instructed to perform at least 4-point daily self-monitoring plasma glucose
(SMPG), as well as continue their short-acting insulin during lead-in. The SMPG and prandial 
insulin doses should be recorded in the patient’s diary, which will serve as a source document.
5.1.1. Inpatient Dosing Visits
The patient will check into the CRU on Day -1 of each period in the early evening (at 
approximately 1700 hours).  Subjects on multiple daily insulin injections would have 
discontinued their basal insulin but subjects using pump therapy (CSII) should arrive at the CRU
with their basal rate running.  All subjects will receive short-acting insulin either via an injection 
or via a bolus dose from the insulin pump before the start of a standardized dinner within the 
CRU. This prandial dose should be administered no later than 6 hours prior to the planned study 
drug dosing the next day. After dinner (at approximately 2200 hours), the subject is required to 
fast until the completion of the clamp procedure the following day.  Consumption of food or 
beverages other than water later than approximately 2200 hours on the evening before dosing is 
not allowed, with the exception of minor intake of rapidly absorbable carbohydrates (not more 
than 20 g) if necessary to prevent hypoglycaemia (if carbohydrates have been ingested, subjects’
blood glucose measurement will have to confirm that they are not hypoglycaemic).   If 
hypoglycaemia (blood glucose level ≤3.5 mmol/L [≤ 63 mg/dL] or plasma glucose ≤3.9 mmol/L 
[≤70 mg/dL]) or more than 20 g of carbohydrates are needed to prevent hypoglycaemia less than 
24 hours prior to dosing, the dosing visit can be rescheduled 1 to 7 days later. Each of the dosing 
visits can only be rescheduled once.
Prior to study treatment dosing, the patient will be connected to the clamp device for continuous 
glucose monitoring and the start of the baseline run-in period.  Variable IV infusion of either 
glucose (20% dextrose solution) or insulin (insulin glulisine [Apidra]) will be started to reach a 
target blood glucose level. Once the target blood glucose level is attained and remains stable, 
with the predose activities as specified in the Schedule of Activities completed, the patient will 
receive a dose and undergo the clamp procedure proper. More information on the clamp 
methodology can be found in Section 9.6.
5.1.2. Outpatient Procedure
After completing each period, subjects will resume their previous insulin regimen. The 
investigator will provide instructions for transition back to a normal insulin regimen. Subjects 
will return for the second dosing period within a 3- to 15-day interval, during which they will 
have to perform at least 4-point daily SMPG.  The basal insulin will have to be discontinued as 
described previously.
After completing all study treatment dosing and clamp procedures, subjects will resume their
former insulin regimen and SMPG routine.  A CRU visit for follow-up or early discontinuation 
should occur at least 14 days after the last dose of study drug.


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Abbreviations:  CRU = clinical research unit; ED = early discontinuation; SC = 
subcutaneous; T1DM = type 1 diabetes mellitus.
Figure ITRR.1.
Illustration of study design for Protocol I8B-MC-ITRR.
5.2.
Number of Participants
Up to 42 younger adult and 42 elderly subjects may be enrolled to ensure that at least 34 subjects
in each age group complete the study.
If subjects drop out of the study before completion of both clamp periods, replacement subjects
may be enrolled; the replacement subjects will assume the same treatment sequence as the 
subjects who dropped out and will complete that treatment sequence in its entirety.
5.3.
End of Study Definition
End of study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last patient in Period 2.
5.4.
Scientific Rationale for Study Design
The use of a crossover design allows each patient to serve as his or her own control, thereby 
reducing variability. The study is subject- and investigator-blind to minimize potential bias.


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A euglycaemic clamp technique, the gold standard methodology for assessing insulin action, will 
be used in this study to provide data onthe GD activity of each study insulin lispro formulation 
(see Section9.6fora detailed description of the clamp methodology).
A population of elderly subjectsis selected as changes in the body composition due to aging 
(such as increased body fat, reduced lean body mass, decreased total body water) may alter the 
PK profile of insulin lispro in LY900014.
Based on the PK properties of treprostinil (t
1/2=approximately1 hour)and Humalog 
(t
1/2=0.79hours), the durationof the washout period between clamp visits (a minimum of 
3days) and the durationbetween the last dose of study drug and the follow-up visit (at least
14days) are considered appropriate.
5.5. Justification for Dose
CCI
Based on previous studies of both insulin lispro (Humalog) and LY900014,the 15-U dose is 
within the clinical dose range and should provide measurable PK and GD profiles for both study 
insulins. The safety, PK, and pharmacology of LY900014 at similar doses and with similar 
formulation compositionhave been assessed in 2 clinical studies in healthy subjects 
 
and in ongoing studies in patients with T1DM using MDI 
 or insulin pump 
treatment 
 and type 2 diabetes mellitususing MDI 
  In patients with 
T1DM, the weight-based total daily insulin dose for a large majority of patients is 
0.4to0.8U/kg/dayof whichapproximately 50% is delivered as the basal insulin dose and the 
other 50% isdivided among preprandial insulin doses (Herbst and Hirsch 2002; Heller et al. 
2009).  Therefore, a reasonably high estimate fortotal daily preprandial insulin dose in T1DM is 
0.4U/kg/day.  It is estimated that the lowest body weight for either population would be around 
56kg.  Thus, the 15-U dose of LY900014 within this studywould delivery approximatelya 
0.26-U/kg dose and would not exceed this high estimate for the total daily preprandialinsulin 
dose.
A 15-U dose of LY900014 contains 
 of treprostinil in a single SC dose, which is within 
therange evaluated as safe and tolerated in all previous studies 
 
. The PK of treprostinil in LY900014 following SC administration of 15 U of 
LY900014 was assessed previously in 
, treprostinil exposure was 
not detectable for the 15-U dose of LY900014 
Based on the 
treprostinil exposures observed in 
, treprostinil blood concentrations in this study are 
expected to be 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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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 electrocardiogram (ECG). 
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented.
Screening may occur up to 28 days prior to enrollment. 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, is 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 male or female subjects with T1DM for at least 1 year.  A diagnosis of 
T1DM is based on medical history with a fasting C-peptide ≤0.30 nmol/L.
[1a] Male subjects:
agree to use an effective method of contraception for the duration of the 
study and for 1 month following the last dose of the investigational product.
[1b] Female subjects:
women of childbearing potential may participate and include those who test 
negative for pregnancy before initiation of treatment based on a serum
pregnancy test and agree to use 1 highly effective method of contraception 
or a combination of 2 effective methods of contraception during the study 
and for 1 month following the last dose of the investigational product.
women of nonchildbearing potential may participate in the study without using 
adequate contraceptive methods, and include those who are:
o
infertile due to surgical sterilization (hysterectomy, bilateral 
oophorectomy, or tubal ligation), congenital anomaly such as 
mullerian agenesis; 
o
or postmenopausal, defined as women aged <52 years and being 
amenorrhoeic for more than 1 year with a serum follicle-stimulating 
hormone (FSH) level compatible with postmenopausal status or aged 
≥52 years and being amenorrhoeic for less than 1 year and with a 
serum FSH level compatible with postmenopausal status or aged ≥52 
years being amenorrhoeic for more than 1 year


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LY900014
[2]
are aged 18 to 45 years (both inclusive) (younger adult group) or at least 65
years (elderly group) at the time of screening.
[3]
have a body mass index (BMI) of 18.5 to 30.0 kg/m
2, 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 glucose infusion and blood 
sampling procedures as per 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 approved by Lilly and 
the ethical review board (ERB) governing the site.
[8]
have a glycated hemoglobin (HbA1c) <9.0% at screening.
[9]
have had no episodes of severe hypoglycaemia in the last 6 months (see 
Section 9.4.7.1).
6.2.
Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or enrollment:
[10]
are investigative site personnel directly affiliated with this study and their 
immediate families.  Immediate family is defined as a spouse, biological or 
legal guardian, child, or sibling.
[11]
are Lilly employees or employees of the investigational site/CRU.
[12]
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.  
[13]
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.
[14]
have previously completed or withdrawn from this study.
[15]
have known allergies to treprostinil (Remodulin), insulin lispro, insulin 
glulisine (Apidra), related compounds, or any components of the formulation, 
or a history of significant atopy.
[16]
have an abnormality in the 12-lead ECG that, in the opinion of the 
investigator, increases the risks associated with participating in the study. 
Elderly patients with clinically significant bradycardia will be excluded. 


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LY900014
[17]
have a supine blood pressure at screening outside the range of 90 to
140mmHg for systolic or 50 to 95 mmHg for diastolic (1 repeat is allowed) as 
determined by the investigator, or results with unacceptable deviations that are 
judged by the investigator to be clinically significant for the population, or 
have a heart rate outside the range of 50 to 90 beats/minute.
[18]
have a history or current cardiovascular, respiratory, hepatic, renal, 
gastrointestinal, endocrine (apart from T1DM), hematological, or neurological 
disorders capable of significantly altering the absorption, metabolism, or 
elimination of drugs; of constituting a risk when taking the investigational 
product; or of interfering with the interpretation of data.
[19]
have known or ongoing psychiatric disorders.
[20]
regularly use known drugs of abuse and/or show positive findings on urinary 
drug screening.
[21]
show evidence of an acute infection with fever or infectious disease at the 
time of study entry.
[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 (the 
presence of hepatitis C antibodies in the setting of normal liver function tests 
and a negative hepatitis C polymerase chain reaction are not an exclusion).
[24]
show evidence of hepatitis B and/or positive hepatitis B surface antigen (the 
presence of antibodies to the hepatitis B surface antigen is not an exclusion).
[25]
are women who are pregnant or lactating.
[26]
have significant lipohypertrophy in the target abdominal injection area as 
judged by the investigator.
[27]
have, except for current regimen of insulin therapy and concomitant 
medication(s) (for example, antihypertensive medication, lipid-lowering 
agent, thyroid hormone replacement medication, hormonal contraception, 
hormonal replacement therapy), regular use of or intended use of any over-
the-counter or prescription medications or nutritional supplements that treat 
hyperglycaemia or insulin resistance or that promote weight loss within 14 
days before dosing.
[28]
are currently a smoker, used tobacco products on a regular basis in the 
6 months before screening, or are intending to smoke during the study period.
[29]
are receiving chronic (lasting longer than 14 consecutive days) systemic or 
inhaled glucocorticoid therapy (excluding topical, intra-articular, and 
intraocular preparations), or have received such therapy within the 4 weeks 
before screening.


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[30]
have donated blood of more than 450 mL or more in the last 3 months or 
provided any blood donation within the last month before screening.
[31]
have a significant history of alcoholism or drug abuse as judged by the 
investigator or consuming more than 24 g of alcohol per day for men, or more 
than 12 g of alcohol per day for women (1 unit of alcohol is defined as 10 mL 
[8 g] of pure alcohol).
[32]
are unwilling to comply with the dietary requirements/restrictions during the 
study:  (i) comply with the fasting requirements of the study, (ii) consume 
only the meals/snacks provided during the inpatient visits.
[33]
in the opinion of the investigator or sponsor, are unsuitable for inclusion in the 
study.
[34]
have a history of renal impairment (exclusion only if glomerular filtration rate 
[estimated GFR] <60 mL/minute/1.73 m2 [GFR is estimated according to the 
Chronic Kidney Disease Epidemiology Collaboration creatinine equation], or 
have a serum creatinine level ≥126 µmol/L [male] or ≥111 µmol/L [female]).
[35]
have a history of deep vein thrombosis of the leg or repeated episodes of deep 
leg vein thrombosis in first-degree relatives (parents, siblings, or children) as 
judged by the investigator.
[36]
have proliferative retinopathy or maculopathy and/or severe neuropathy; in 
particular, autonomic neuropathy as judged by the investigator based on a 
recent (<1.5 years) ophthalmologic examination.
[37]
any significant changes in insulin regimen and/or unstable blood glucose 
control within the past 3 months prior to screening as assessed by the 
investigator.
[38]
require daily insulin treatment >1.5 U/kg/body weight.
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
In both treatment periods, subjects will fast for at least 8 hours prior to dosing until after the 
glucose clamp procedure is completed, after which subjects will receive a meal. Water can be 
consumed freely during this time.  If the clamp procedure is completed in less than 10 hours, 
then the meal should be delayed until the last PK sample has been taken, unless the investigator 
deems it necessary to administer the meal for safety reasons.
While resident in the CRU, subjects may not consume any food or caloric drinks other than that
provided by the CRU.  When not resident in the CRU, subjects will be encouraged to follow 
their normal diets.


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6.3.2. Caffeine, Alcohol, and Tobacco
Subjects should refrain from caffeine-containing food/beverages (for example, cola, chocolate 
drinks, tea, coffee, energy drinks containing methylxanthine [caffeine, theophylline, or 
theobromine]) for at least 12 hours before each dose and throughout the duration of each CRU 
visit.
No alcohol will be allowed at least 24 hours before each CRU admission (Day –1) and 
throughout the duration of each CRU visit (see Additional Exclusion Criterion [31]). Between 
dosing visits, daily alcohol should not exceed 3 units for males and 1.5 units for females (a unit 
is defined in Exclusion Criterion [31], Section 6.2).
Smoking (cigars, cigarettes, or pipes) and the use of smokeless tobacco will not be permitted
during the study (see Exclusion Criterion [28]).
6.3.3. Activity
Subjects are encouraged to maintain their regular exercise habits; however, subjects engaging in 
strenuous physical exercise (for example, weightlifting, football, cycling/swimming/running at a 
level higher than normal) within 48 hours prior to (planned) dosing will be excluded from this 
study, as judged by the investigator to interfere with study results. After dosing, subjects should 
remain recumbent or sitting in the CRU until the end of the glucose clamp. Movement will be 
restricted to retain the integrity of connections to the infusion(s) and the study procedures.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study may be rescreened 1 time.  
Any further rescreening must be done in consultation with the sponsor.  Individuals who still do 
not meet participation criteria after rescreening (screen failure) may not be rescreened.


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7.Treatment
7.1. TreatmentAdministered
This study involves a comparison ofLY900014 administered once by SC injectionwith insulin 
lispro administered once by SC injection.TableITRR.2shows the treatment regimens.
TableITRR.2.
TreatmentsAdministered
Treatment Name
LY900014
Insulin lispro(Humalog)
Dosage Formulation
100 U/mL
100 U/mL
Dosage Level
15 U
15 U
Treprostinil concentration and 
approximate treprostinil dose 
administered
 
NA
Route of Administration
SC injection
SC injection
Abbreviation: SC = subcutaneous.
Sites may destroythe material if, during the investigativesite selection, the evaluator has verified 
and documented that the site has appropriate facilities and written procedures to dispose of 
clinical trial materials.
7.1.1. Packaging and Labeling
Clinical trial materials will be labeled according to the country’s regulatory requirements.  
LY900014 will be supplied by Lilly or its representative, in accordance with current good 
manufacturing practicesand will be supplied with lot numbers.  Reference drug will be 
commercially available insulin lispro (Humalog) supplied by Lilly.
The study insulinswill be provided to the site unblinded. 
 
.An 
unblinded pharmacist at the site or other site personnel who are unblinded will use the insulin 
vials provided to prepare the blinded syringes.
7.2. Method of Treatment Assignment
The study insulinto be injected ina given treatment periodwill be determined according to a 
randomization schedule.
7.2.1. Selection and Timing of Doses
CCI
The actual date and time of all dose preparationswill be documented, and the actual time of all 
dose administrationswill be recorded in the patient’s case report form (CRF).For each patient, 
the doses will be administered at approximately the same timeon Day 1 of each study period.
All study treatments will be given in the CRUby qualified blinded site personnel as designated 
by the investigator. Study injections should be given by a limited number of individuals for 
consistency.
The site of administration of each injection will be recorded. The insulin used in this study will 
be injected using syringes and vials. Injection sites selected should be about 5 cm from the 
CCI
CCI


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LY900014
umbilicus and the treatment is administered SC. An appropriate size of needle shall be used to 
ensure all injections are delivered to a consistent target depth into the SC space; if an 8-mm (or 
greater) needle is used to administer the injection, the skinfold should be pinched. Injection sites
will be rotated between the left lower quadrant and right lower quadrant on the anterior 
abdominal wall during the 2 study periods.
7.3.
Blinding
This is a subject- and investigator-blind study. The Lilly clinical pharmacologist/Lilly study 
team is unblinded.
Emergency codes will be available to the investigator. An unblinded pharmacist or other site 
personnel is required to prepare the insulin doses for administration. A code, which reveals the 
treatment group for a specific study subject, may be opened during the study only if the patient’s 
well-being requires knowledge of the patient’s treatment assignment.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
a patient’s treatment assignment is warranted for medical management of the event. Patient’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 clinical research physician (CRP) prior to unblinding a study 
patient’s treatment assignment unless this could delay emergency treatment of the patient. If a 
study patient’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
Dose adjustments are not allowed in this study.
7.5.
Preparation/Handling/Storage/Accountability
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.
All insulin products must be stored at the investigative site under refrigerated conditions
(between 2°C and 8°C) in a locked and secure place. Insulin must not be frozen.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (such as
receipt, reconciliation, and final disposition records).
7.6.
Treatment Compliance
The study drugs will be administered at the clinical site, and documentation of treatment 
administration will occur at the site.


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7.7.
Concomitant Therapy
Subjects on stable concomitant medication(s) at the time of study entry should continue their 
regular, unchanged dose throughout the study. Subjects receiving multiple daily insulin 
injections will discontinue their basal and prandial insulin regimens as described in the Study 
Design, prior to receiving study treatment (Section 5.1).  Similarly, the patient’s insulin regimen 
should resume in between dosing periods and discontinued prior to the next period following the 
guidance in Section 5.1.
Subjects should not use over-the-counter or prescription medications (other than their current 
regimen of insulin therapy and concomitant medication(s) [for example, anti-hypertensive
medication, lipid-lowering agent, thyroid hormone replacement medication]) or nutritional 
supplements that affect blood glucose or the body’s sensitivity to insulin or that promote weight 
loss 14 days before dosing (apart from vitamin/mineral supplements, occasional acetaminophen 
[paracetamol], ibuprofen, or hormonal replacement therapy) or throughout the study (refer to 
Section 6.2).
Subjects should not be receiving chronic (lasting longer than 14 consecutive days), systemic, or 
inhaled glucocorticoid therapy (excluding topical, intra-articular, and intraocular preparations), 
or have received such therapy within the 4 weeks before screening.
Subjects should not apply any creams or lotions to the abdominal skin on the morning of the 
study treatment dosing or during the inpatient study procedure.
If the need for concomitant medication arises, inclusion or continuation of the patient may be at 
the discretion of the investigator, and when possible, after consultation with a Lilly clinical 
pharmacologist. Any additional medication used during the course of the study must be 
documented.
Any changes in concomitant medications from screening will be recorded upon admission to the 
CRU.
7.8.
Treatment After the End of the Study
Insulin lispro (Humalog) and LY900014 will not be made available from the sponsor to subjects
after conclusion of the study. Subjects will resume their previous insulin regimen after the study 
procedure has been completed.


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8. Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
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
The criteria for enrollment must be followed explicitly. If the investigator site identifies a 
subject who did not meet enrollment criteria and who was inadvertently enrolled, the sponsor 
will be notified. If the sponsor identifies a subject who did not meet enrollment criteria and who 
was inadvertently enrolled, the investigator site will be notified.
If the subject was enrolled but did not receive study drug, the subject will be discharged from the 
study without receiving study drug; if the subject received the single dose of the study drug prior 
to realizing the subject did not meet enrollment criteria, they will continue to be monitored per 
protocol.
8.2.
Discontinuation from the Study
Subjects will be discontinued under 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)

Investigator Decision
o
the investigator decides that the patient should be discontinued from the study

Subject Decision
o
the patient requests to be withdrawn from the study

Participation in the study needs to be stopped for safety reasons in the case of a severe 
hypoglycaemic episode
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 4 provides a summary of the maximum number and volume of invasive samples, for
all sampling, during the study.
The specifications in this protocol for the timings of safety and sample collection are given as 
targets to be achieved within reasonable limits. Modifications may be made to the time points 
based upon merging clinical information. The scheduled time points may be subject to minor 
alterations; however, the actual time must be correctly recorded in the electronic CRF (eCRF). 
Late collection outside the stipulated time allowances or failure to obtain samples due to clinical 
issues (such as venous access), technical issues (such as equipment problems), or subject 
defaulting on a scheduled procedure will not be considered as protocol deviations but the site 
will still be required to notify the sponsor in writing via a file note.
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 patient.
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 patient to discontinue the investigational product before 
completing the study. The patient should be followed until the event resolves, stabilizes with 
appropriate diagnostic evaluation, or is reasonably explained. The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator.
After the informed consent form (ICF) is signed, study site personnel will record, via eCRF, the 
occurrence and nature of each patient’s preexisting conditions, including clinically significant 
signs and symptoms of the disease under treatment in the study. Additionally, site personnel will 
record any change in the condition(s) and the occurrence and nature of any AEs.


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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, study device, and/or study procedure and the AE.
Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study.
If a patient’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via eCRF.
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in 1 of the following:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

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 eCRF after signing informed consent, SAE reporting begins 
after the patient has signed informed consent and has received the investigational product.
However, if an SAE occurs after signing informed consent, but prior to receiving investigational 
product, AND is considered reasonably possibly related to a study procedure then it MUST be 
reported.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued from and/or completed the study (the patient summary CRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly.


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Pregnancy (maternal or paternal exposure to the investigational product) does not meet the 
definition of an AE.  However, to fulfill regulatory requirements any pregnancy should be 
reported following the SAE process to collect data on the outcome for both mother and fetus.
9.2.1.1.
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 the investigational product or procedure.  
US 21 Code of Federal Regulations 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.
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 (or drug delivery system) so that the 
situation can be assessed.
9.3.
Treatment of Overdose
For the purposes of this study, an overdose of LY900014 or Humalog is considered any dose 
higher than the dose assigned through randomization.
Excess insulin administration may cause hypoglycaemia and hypokalemia. Mild episodes of
hypoglycaemia usually can be treated with oral glucose. More severe episodes with coma, 
seizure, or neurologic impairment may be treated with intramuscular/SC glucagon or 
concentrated IV glucose. Sustained carbohydrate intake and observation may be necessary 
because hypoglycaemia may recur after apparent clinical recovery. Hypokalemia must be 
corrected appropriately.
9.4.
Safety
9.4.1. Physical Examinations
Physical examinations and routine medical assessments will be conducted as specified in the 
Schedule of Activities (Section 2) and as clinically indicated.
9.4.2. Body Weight
Body weight will be recorded as specified in the Schedule of Activities (Section 2) and as 
clinically indicated.


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9.4.3. Hip and Waist Circumference
Hip and waist circumference will be recorded as specified in the Schedule of Activities (Section 
2). The average of triplicate measurements of waist (narrowest circumference between lowest 
aspect of the ribs and anterior superior iliac crests) and the hip (widest circumference between 
the anterior superior iliac crests and the greater trochanters) circumference will be measured.
9.4.4. Laboratory Tests
Laboratory tests detailed in Appendix 2 should be conducted according to the Schedule of 
Activities (Section 2).
9.4.5. Vital Signs
For each patient, vital sign measurements should be conducted according to the Schedule of 
Activities (Section 2) and as clinically indicated.
9.4.6. Electrocardiograms
For each patient, ECGs should be collected according to the Schedule of Activities (Section 2).
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
patient receives the first dose of the investigational product should be reported to Lilly, or its 
designee, as an AE via eCRF.
For each patient, a single 12-lead digital ECG will be collected according to the Schedule of 
Activities. ECGs must be recorded and reviewed before receiving study treatment. Subjects
must be supine for at least 10 minutes before ECG collection and remain supine but awake 
during ECG collection. ECGs may be obtained at additional times, when deemed clinically 
necessary. All ECGs recorded should be stored at the investigational site.
ECGs will be interpreted by a qualified physician (the investigator or a qualified designee) at the 
site as soon after the time of ECG collection as possible, and ideally while the patient is still 
present, to determine whether the patient meets entry criteria at the relevant visit(s) and for 
immediate patient management, should any clinically relevant findings be identified.
If a clinically significant finding is identified (including, but not limited to, changes in QT/QTc 
interval from baseline) after enrollment, the investigator will determine if the patient can 
continue in the study. The investigator, or a qualified designee, is responsible for determining if 
any change in patient management is needed, and must document his/her review of the ECG 
printed at the time of collection. Any new clinically relevant finding should be reported as an 
AE.
9.4.7. Safety Monitoring
The Lilly clinical pharmacologist or CRP/scientist will monitor safety data throughout the course 
of the study.
Lilly will review SAEs within time frames mandated by company procedures. The Lilly clinical 
pharmacologist or research physician will consult with the functionally independent Global 


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Patient Safety therapeutic area physician or clinical research scientist when appropriate, and 
periodically review:

trends in safety data

laboratory analytes 

AEs
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the group level, additional analyses of the safety data will be conducted by the personnel 
included in the Unblinding/Blinding Plan.
9.4.7.1.
Glucose Monitoring
Hypoglycaemia will be described using the following definitions:

Documented hypoglycaemia:
o
Symptomatic hypoglycaemia: an event during which typical symptoms of 
hypoglycaemia are accompanied by plasma glucose ≤70 mg/dL (3.9 mM)
o
Asymptomatic hypoglycaemia: an event not accompanied by typical 
symptoms of hypoglycaemia but with plasma glucose ≤70 mg/dL (3.9 mM)

Unspecified hypoglycaemia: an event during which plasma glucose is ≤70 mg/dL 
(3.9 mM) but no information relative to symptoms of hypoglycaemia was recorded

Probable symptomatic hypoglycaemia: an event during which symptoms 
indicative of hypoglycaemia are not accompanied by a plasma glucose determination 
(but that was presumably caused by plasma glucose ≤70 mg/dL [3.9 mM])

Severe hypoglycaemia: an event requiring assistance of another person to actively 
administer carbohydrate, glucagon, or other resuscitative actions. During these 
episodes, the subject has an altered mental status, and cannot assist in their care, is 
semiconscious or unconscious, or experiences coma with or without seizures, and 
may require parenteral therapy. Plasma glucose measurements may not be available 
during such an event, but neurological recovery attributable to the restoration of 
blood glucose concentration to normal level is considered sufficient evidence that the 
event is induced by a low plasma glucose concentration (≤70 mg/dL [3.9 mM])

Nocturnal hypoglycaemia: any hypoglycaemic event (documented symptomatic, 
asymptomatic, probable symptomatic, or severe hypoglycaemia) that occurs between 
bedtime and waking

Relative hypoglycaemia: an event during which typical symptoms of 
hypoglycaemia, that do not require the assistance of another person, are accompanied 
by plasma glucose >70 mg/dL (3.9 mM), but these levels may be quickly approaching 
the 70 mg/dL (3.9 mM) threshold

Overall (or total) hypoglycaemia: This optional category combines all cases of 
hypoglycaemia. If an event of hypoglycaemia falls into multiple subcategories, the 
event is only counted once in this category
The goal of the euglycaemic clamp is to maintain blood glucose concentrations at 
normoglycaemic levels close to a pre-defined target. Therefore, plasma glucose concentrations 


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below 70 mg/dL (equivalent to blood glucose 63 mg/dL) will not routinely be recorded as 
hypoglycaemic events during the glucose clamp procedure. However, at the discretion of the 
investigator, decrease in glucose concentrations may be recorded as a hypoglycaemic event 
based on clinical concern, or related to technical issues resulting in hypoglycaemia.
9.4.7.1.1. Severe Hypoglycaemia
The determination of a hypoglycaemic event as an episode of severe hypoglycaemia, as defined 
above, is made by the investigator based upon the medical need of the subject to have required 
assistance and is not predicated on the report of a subject simply having received assistance.
Only severe hypoglycaemic episodes will be reported as AEs. All episodes of severe 
hypoglycaemia will be reported as SAEs.
9.4.8. Injection-Site Assessments (Local Tolerability)
Injection-site assessments for local tolerability will be conducted as specified in the Schedule of 
Activities and more frequently if deemed necessary by the investigator (Section 2).
Local tolerability at the injection site will be evaluated by means of assessments within the 
following categories: pain (including burning), itching, erythema, edema, and 
induration/infiltration.
Additional assessments will be performed until resolution, as judged necessary by the 
investigator.
Digital pictures may be taken of the injection site at the time of identification of local 
intolerability and thereafter as judged as necessary by the investigator. The pictures should 
include subject number, visit number, time after injection, and a ruler for scaling.
An injection-site reaction should be recorded as either an AE or an SAE according to respective 
definitions/criteria.
9.4.8.1.
Pain Measurements Using the Visual Analog Scale
Pain measurements will be assessed using the electronic version of the 100-mm validated visual 
analog scale (VAS) (or electronic VAS [eVAS]) for pain.  The VAS is a well validated tool 
(Williamson and Hoggart 2005) to assess injection-site pain.
The eVAS (van Duinen et al. 2008) is presented as a 10-cm (100-mm) line, anchored by verbal 
descriptors, usually “no pain” and “worst imaginable pain.” The patient will be asked to mark 
the 100-mm line electronically to indicate pain intensity associated with each injection on a scale 
of 0 (no pain) to 100 mm (worst imaginable pain) according to the Study Schedule and as 
clinically indicated.  
As injection-site pain is an expected AE injection-site pain (especially transient episodes of pain) 
will generally not be considered a clinically significant event unless the duration or intensity of 
the pain interferes with normal activities of daily living or constitutes a risk to the wellbeing of 
the subject.  Analgesia can be prescribed in response to pain and must be documented in the 
concomitant medication section of the CRF.


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9.4.9. Immunogenicity Assessments 
Blood samples for immunogenicity testing will be collected to determine antibody production 
against insulin lispro as described in the Schedule of Activities (Section 2).  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 antidrug antibodies in 
the presenceofinsulin lispro.
Serum from the blood sample will be divided into 3 aliquots;the first aliquot is used for initial 
testing and the remaining aliquots will be stored at -70°C,and retained for a maximum of 15 
years after the lastsubject visit, or for a shorter period if local regulations and ERBs allow,at a 
facility selected by the sponsor.  The duration allows the sponsor to respond to future regulatory 
requests related to the study insulins.  Any samples remaining after 15 years will be destroyed.
9.5. Pharmacokinetics
At the visits and times specified in the Schedule of Activities, venous bloodsamples of 
approximately2.5mL each will be collected to determine serum concentrations of insulin lispro, 
and samples of approximately 2.0mL each will be collected to determine plasma concentrations 
of treprostinil. 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
Serum concentrations of insulin lispro will be measured using a 
 
specific for insulin lispro at a laboratory approved by thesponsor. Plasma 
concentrations of treprostinilwill be measured using a validated 
 
at a laboratory approved by the sponsor. Samples will be 
retained for a maximum of 1 yearafter the last subject visit. During this time, plasma and serum 
remaining may be used for other exploratory analyses on insulin lispro or treprostinil.
9.6. Glucodynamics(Euglycaemic Glucose Clamp)
CCI
The aim of the euglycaemic glucose clamp is to maintain target glucose levels through infusion 
of a 20% D-glucose (dextrose) solution after the administration of a dose of insulin.During the 
glucose clamp, the GIR will be adjusted to maintain a predetermined target blood glucose 
concentration for the individual subject. Thus, blood glucose concentrations are keptconstant 
while theGIR varies. The varying GIR will then reflect the GD activity of insulin.
Subjectswith T1DM will participate in euglycaemic glucose clamps on 2separate visits.  All 
glucose clamp procedures will be performed after an overnight fast of at least8hours.
Approximately 1-6hours before the plannedadministration of study drug, subjectswill be 
connected to the clamp devicefor continuous blood glucosemonitoring and receive a variable IV 
infusion of either insulin glulisine or glucose to obtain a steady blood glucose clamp target of 
100mg/dL(±20%) (5.5[±1.1] mmol/L).The target blood glucose level of 5.5 mmol/L (100 
mg/dL)±20% (upper and lower limits included) must be kept at -60to -30 minutesbefore trial 
productadministration, followed by a target blood glucose level of 5.5 mmol/L (100 
CCI


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mg/dL)±10% (upper and lower limits included) the last 30 minutesprior to trial product 
administration without any glucose infusion.The intravenous insulin infusion (if any) is lowered 
as much as possible to keep theBG concentrations at the target without having to infuse 
glucose.The insulin infusion is tapered off and should be stopped 10 minutesprior to dosing.
Baseline is defined as the mean of blood glucose concentrations at–6, –4, and –2 minutes before 
trial product administration as measured using 
, and the onset of action occurs when 
blood glucose drops to 0.3 mmol/L (5 mg/dL) from baseline.  If there are no stable BG 
measurements using  
 in the last minutes before intended dosing, dosing should be 
postponed and the run-in period will be prolonged.If the target blood glucose level cannot be 
established before 1400 hours, the visit will be terminated and the subject may be rescheduled 
for a new dosing visit1to7 days later. Aftertheonsetof action hasbeen reached, a variable IV
glucose infusion will be initiated in order to keep BG constant at the target level (5.5 mmol/L; 
100 mg/dL).  The GIRnecessary to keep the BG concentration at the target level will be 
recorded every minute throughout the glucose clamp. Frequently or at least every 30 minutes
throughout the glucose clamp, BG measurements for safety will be performed using 
 
.
The clamp procedure will continue for up to 10 hours after dose or until after blood glucose 
concentrations increased to >200 mg/dL (11.1 mmol/L) without any glucose being administered 
for at least 30 minutes, whichever is earlier.
At the end of the clampprocedure,the patient will receive a medical assessment, and be given a 
meal along with their prandial insulin treatment. Their basal insulin regimen may be restarted 
accordingly, albeit subjected to the stopping guidance as described in Section 5.1, prior to the 
next dosing visit, if applicable.
The sample(s) will be stored for upto a maximum of 1 year after the lastpatient visit for the 
study at a facility selected by the sponsor.
9.7. Genetics
CCI
A blood sample will be collected for pharmacogenetic analysis as specified in the Schedule of 
Activities, where local regulations allow.
Samples willnotbeused toconduct unspecified disease or population genetic research either 
now or in the future. Samples will be used to investigate variable response to LY900014and to 
investigate genetic variants thought to play a role in diabetes mellitus.Assessment of variable 
response may include evaluation of AEsor differences in efficacy.
All samples will be coded with the patient number. These samples and any data generated can 
be linked back to the patient only by the investigativesite personnel.
Samples will be retained for a maximum of 15 years after the lastpatient visit, or for a shorter 
period iflocal regulationsand/or ERBs/institutional review boardsimpose shorter time limits, 
for the study at a facility selected byLilly or its designee. This retention period enables use of 
new technologies, response to regulatory questions, and investigation of variable response that 
CCI
CCI


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may not be observed until later in the development of LY900014 or after LY900014 is 
commercially available.  
Molecular technologies are expected to improve during the 15-year storage period and therefore
cannot be specifically named. However, existing approaches include whole genome or exome 
sequencing, genome-wide association studies, multiplex assays, and candidate gene studies.  
Regardless of technology utilized, data generated will be used only for the specific research 
scope described in this section.
9.8.
Biomarkers
Not applicable for this study.
9.9.
Health Economics
Not applicable for this study.


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10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
Up to 42 younger adult and 42 elderly subjects may be enrolled to ensure that at least 34 subjects
in each age group complete the study. Thirty-four completing subjects in each age group will 
provide approximately 95%% power to demonstrate a 40% increase in the insulin lispro area 
under the plasma concentration-time curve from time zero to 30 minutes (AUC[0-30min]) between 
LY900014 and Humalog within each age group. Testing will be done at an alpha level of 0.05 
with a 2-sided confidence interval (CI).  The variability was estimated by analyzing a Lilly 
internal study that showed a log-scale standard deviation of within-subject difference in 
AUC(0-30min) of 0.5.  Analysis of internal data showed a log-scale standard deviation of within-
subject difference in time to early half-maximal plasma concentration (early 50% tmax) of 0.5, 
which provides approximately 95% power to show a 30% reduction in early 50% tmax, testing 
with an alpha level of 0.05 and a 2-sided CI.
In addition, the study is adequately powered to evaluate the GD parameters within each age 
group. There is approximately 80% power to detect a 20% decrease in both time to onset of 
insulin action (Tonset) and time to half-maximal GIR before TRmax (early 50% TRmax), and 
approximately 85% power to detect at least a 40% increase in total amount of glucose infused 
over 30 minutes (Gtot[0-30min]) and total amount of glucose infused over 1 hour (Gtot[0-1h]).
10.2. Populations for Analyses
10.2.1. Study Participant Disposition
A detailed description of patient disposition will be provided at the end of the study. 
10.2.2. Study Participant Characteristics
The patient’s age, sex, height, weight, BMI, race/subrace, or other demographic characteristics 
will be recorded.
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Lilly.
The primary statistical analyses for PK will be conducted on those subjects who receive at least 1 
dose of study drug and have measurable insulin lispro concentrations.  The primary statistical 
analysis for GD will be conducted on those subjects who complete at least 1 clamp procedure.  
Supportive analyses will be done on the key parameters for the subjects who complete all 
treatment periods with evaluable data. Safety analyses will be conducted for all enrolled subjects
who receive at least 1 dose of study drug, whether or not they complete all protocol 
requirements.
Any change in the data analysis methods described in the protocol will require an amendment 
only if it changes a principal feature of the protocol.  Any other change to the data analysis 


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methods described in the protocol and the justification for making the change will be described 
in the study results.
Summary statistics (including number of subjects, mean, standard deviation or standard error, 
minimum, and maximum) will be presented for continuous variables.  A linear mixed-effect 
model will be used for continuous variables unless otherwise stated in the below subsections. 
The primary comparison between LY900014 and insulin lispro for each age group will be 
performed using the model that includes treatment, sequence, and period as fixed effects, and 
subject within sequence as a random effect. Unless otherwise noted, all tests of treatment effects 
will be conducted at a 2-sided alpha level of 0.05, and CIs will be calculated at 95%, 2-sided.
An exploratory analysis on the interaction between treatment and age group will be assessed 
using data from both age groups by a model similar to that for each age group, with the addition 
of age group and the interaction of treatment by age group as fixed effects.  This test will be used 
to compare whether the LY900014 versus insulin lispro treatment effect is similar between the 
elderly and younger adult groups.
Additional exploratory analyses of the data will be conducted as deemed appropriate.  Study 
results may be pooled with the results of other studies for population PK analysis purposes to 
avoid issues with post-hoc analyses and incomplete disclosures of analyses.
10.3.1. Safety Analyses
10.3.1.1. Clinical Evaluation of Safety
All investigational and protocol procedure AEs will be listed, and if the frequency of events 
allows, safety data will be summarized using descriptive methodology.
The incidence of symptoms for each treatment will be presented by severity and by association 
with investigational product as perceived by the investigator. Symptoms reported to occur prior 
to enrollment will be distinguished from those reported as new or increased in severity during the 
study. Each symptom will be classified by the most suitable term from the Medical Dictionary 
for Regulatory Activities.
The number of investigational product-related SAEs will be reported.
10.3.1.2. Statistical Evaluation of Safety
Safety parameters that will be assessed include safety laboratory parameters and vital signs, as 
well as evaluation of injection-site reactions. The parameters will be listed, and may be 
summarized using standard descriptive statistics. Additional analysis will be performed if 
warranted upon review of the data.
10.3.1.2.1.Statistical Evaluation of the Intensity of Injection-Site Pain
The primary study assessment will be the intensity of pain at each injection site immediately 
after the injection (time 0) as reported by the subject and measured according to the 0- to 100-
mm VAS.


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A mixed-effect model will be used to analyze the time 0 (immediately after dosing) data 
separately by age group, using thestatistical model that includes treatment, sequence,and period 
as fixed effects and subjectwithin sequenceas a randomeffect. It is possible that VAS scores 
will be zero;henceif thedistribution of the data implies that a logtransformation is required 
then the score may beupdated to log(VAS+1) to allow for the inclusion of the 0 values in the 
analysis.
A descriptive summarywill be providedforthe following categories of scores:  0, 1-10, 11-20,
21-30, 31-40, etc.up to the maximum category by treatment for eachtimepoint.
10.3.2.Pharmacokinetic Analyses
10.3.2.1.Pharmacokinetic Parameter Estimation
Subjects who receive at least 1 dose of study drugand havemeasurable insulin lispro 
concentrations will be included in the PK analysis dataset.
PKanalyses will be conducted using standard noncompartmental methods of analysis using 
on a computer that meets or exceeds the 
minimum system requirements for these programs. The version of any software used for the 
analysis will be documented and the program will meet the Lilly requirements of software 
validation.  It is possible that other validated equivalent PK software programs may be utilized if 
appropriate, warranted, and approved by global PK management.
Free serum insulin lispro concentrations will be used to calculate several PK parameters, 
including early50% tmax,time to late half-maximal plasma concentration(late 50% t
max), 
maximum observed concentration(C
max), t
max, t
1/2, and area under the plasma concentration-time 
curvefrom time zero to the last recorded time, AUC(0-30min), area under the plasma concentration-
time curvefrom time zero to 1 hour, area under the plasma concentration-time curvefrom time 
zero to 10 hours, and area under the plasma concentration-time curvefrom time zero to infinity.  
Other parameters may be calculated as deemed appropriate. Additional partial area under the 
plasma concentration-time curves(AUCs)may be computed as necessary. The primary insulin 
lispro PK parameters for faster insulin lispro absorption analysis are early 50% t
maxand 
AUC(0-30min).
Given the predicted low systemic concentrationsof treprostinil, the PK analysis of treprostinil 
from the LY900014 dosing will be conducted using the available data. The primary analysis of 
the treprostinil concentrations will be focused on assessing time to maximum concentration (tmax)
and C
max.
Although attempts will be made to adhere to the scheduled collection times (Section 2)
CCI
, it is 
recognized that situations arise that may compromise the scheduled times. Parameters will be 
individually calculated for each subject based on actual collection times and presented using
summary statistics.


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10.3.2.2. Pharmacokinetic Statistical Inference
Log-transformed Cmax and AUC estimates for insulin lispro will be evaluated to estimate least-
squares geometric means, ratios of geometric means between LY900014 and Humalog 
(reference), and their corresponding 95% CIs for each age group using the statistical model that 
includes treatment, sequence, and period as fixed effects and subject within sequence as a 
random effect. 
The same model without log transformation will be used for the analysis of the PK time 
parameters (early 50% tmax, late 50% tmax, tmax, and t1/2). Least-squares means, treatment 
differences in least-squares means, and the corresponding 95% CIs for the treatment differences 
will be estimated from the model. The treatment ratios and 95% CIs for the ratios will be 
calculated using Fieller’s theorem (Chow and Liu 2009). 
As treprostinil plasma concentrations after administration of LY900014 are expected to be very 
low, a descriptive statistical analysis may be conducted if sufficient data are available for this 
analysis.
10.3.3. Glucodynamic Analyses
10.3.3.1. Pharmacodynamic Parameter Estimation
GD assessments will be determined from the glucose clamp procedure, where the GIR over time 
will be used as a measure of insulin effect. GD analyses will be conducted on those subjects
who complete at least 1 clamp procedure.
A locally weighted scatterplot smoothing (LOESS) function will be applied to all individual GIR 
versus time profiles in each treatment group and age group using S-PLUS software (version 8.2).  
The fitted data for each subject will be used to calculate the following GD parameters:  Tonset, 
maximum GIR (Rmax), time to Rmax (TRmax), early 50% TRmax, time to half-maximal GIR after 
TRmax (late 50% TRmax), total amount of glucose infused (Gtot), Gtot(0-30min), Gtot(0-1h), and total 
amount of glucose infused over 10 hours (Gtot[0-10h]).  Additional partial glucose AUCs, such as 
total amount of glucose infused over 2 hours, may be computed as necessary.  The values of 
these GD parameters will be summarized by treatment group and age group through descriptive 
statistics. Mean LOESS fits of GIR versus time profiles will be generated.  The primary GD 
parameters for analysis are early 50% TRmax, Gtot(0-30min), Gtot(0-1h), and Tonset.
10.3.3.2. Glucodynamic Statistical Inference
The statistical model will be the same as the model used for the analysis of the PK parameters.  
The variables will be log-transformed prior to analysis and will include Rmax, Gtot, Gtot(0-30min), 
Gtot(0-1h), and Gtot(0-10h).  For GD parameters that have at least 1 subject with a value equal to 
zero, a value equal to the smallest non-zero observed GD value for that parameter divided by 2 
will be added to all values, and the analysis of the log-transformed data will be performed.


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Similarly to the PK time parameters, the GD time parameters (Tonset, TRmax, early 50% TRmax,
and late 50% TRmax) will be evaluated without log transformation. Least-squares means, 
treatment differences in least-squares means, and the corresponding 95% CIs for the treatment 
differences will be estimated from the model. The treatment ratios and 95% CIs for the ratios 
will be calculated using Fieller’s theorem.
10.3.4. Evaluation of Immunogenicity 
The immunogenicity data will be listed.  The relationship between treatment-emergent antidrug 
antibodies and AEs will be evaluated. The relationship between the presence of antibodies and 
the PK parameters and GD response to insulin lispro may also be evaluated.
10.3.5. Interim Analyses
An interim analysis may be conducted after all subjects in the younger adult group have
completed the study to analyze the safety, PK and GD data in order to support regulatory 
submission.  The Lilly clinical pharmacologist/Lilly study team is unblinded.  The individuals 
and unblinded data are as specified in the unblinding plan.  Information that may unblind the 
study during the analyses will not be reported to study sites or blinded study team until the study 
has been unblinded.
Data may be analyzed while the trial is ongoing, but no changes to the study design are planned.  
The results may help Lilly expedite final delivery and to enable planning of future studies. An 
assessment committee will not be formed.


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11.
References
Chow SC, Liu JP. Design and analysis of bioavailability and bioequivalence studies. 3rd ed. 
Florida: Taylor and Francis Group, LLC; 2009:p88-90.
Heller S, Koenen C, Bode B. Comparison of insulin detemir and insulin glargine in a basal-bolus 
regimen, with insulin apart as the mealtime insulin, in patients with type 1 diabetes: a 52-
week, multinational, randomized, open-label, parallel-group, treat-to-target noninferiority trial. 
Clin Therapeutics. 2009;31:2086-2097.
Herbst KL and Hirsch IB. Insulin strategies for primary care providers. Clin Diabetes.
2002;2011-17.
Humalog [package insert]. Indianapolis, IN: Eli Lilly and Company; 2015.
Remodulin [package insert]. Research Triangle Park, NC: United Therapeutics Corp; 2014.
Williamson A, Hoggart B. Pain: a review of three commonly used pain rating scales. 
J Clin Nurs. 2005;14(7):798-804.
van Duinen M, Rickelt J, Griez E. Validation of the electronic visual analogue scale of anxiety. 
Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(4):1045-1047.


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Appendix 1.
Abbreviations and Definitions


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Term
Definition
AE
adverse event:  any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.
AUC
area under the plasma concentration-time curve
AUC(0-30min)
AUC from time zero to 30 minutes
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.
BMI
body mass index 
CI
confidence interval
Cmax
maximum observed 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 (GCP) requirements, 
and the applicable regulatory requirements.
confirmation
A process used to confirm that laboratory test results meet the quality requirements defined 
by the laboratory generating the data and that Lilly is confident that results are accurate.  
Confirmation will either occur immediately after initial testing or will require that samples 
be held to be retested at some defined time point, depending on the steps required to obtain 
confirmed results.
CRF
case report form
CRP
clinical research physician:  Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research scientist, 
global safety physician, or other medical officer.
CRU
clinical research unit
CSII
continuous subcutaneous insulin infusion
early 50% tmax
time to early half-maximal plasma concentration
early 50% TRmax
time to half-maximal GIR before TRmax


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ECG
Electrocardiogram
eCRF
electronic case report form
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
eVAS
electronic visual analog scale
FDA
Food and Drug Administration
GCP
good clinical practice
GD
glucodynamic(s)
GFR
glomerular filtration rate
GIR
glucose infusion rate
Gtot
total amount of glucose infused
Gtot(0-30min)
total amount of glucose infused over 30 minutes
Gtot(0-1h)
total amount of glucose infused over 1 hour
Gtot(0-10h)
total amount of glucose infused over 10 hours
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.


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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.
IV
Intravenous
late 50% tmax
time to late half-maximal plasma concentration
late 50% TRmax
time to half-maximal GIR after TRmax
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.
LOESS
locally weighted scatterplot smoothing
NPH
neutral protamine Hagedorn 
PK
pharmacokinetic(s)
Rmax
maximum GIR
SAE
serious adverse event
SC
subcutaneous/subcutaneously
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.  
SMPG
self-monitoring plasma glucose
SUSAR
suspected unexpected serious adverse reaction 
T1DM
type 1 diabetes mellitus
treatment-
emergent adverse 
event
Any untoward medical occurrence that emerges during a defined treatment period, having 
been absent pretreatment, or worsens relative to the pretreatment state, and does not 
necessarily have to have a causal relationship with this treatment 
tmax
time to maximum concentration
Tonset
time to onset of insulin action
TRmax
time to Rmax
US
United States
VAS
visual analog scale


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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)
C-peptide, fastingb
Absolute counts of
Glucose, fasting
Neutrophils
Blood urea nitrogen (BUN)
Lymphocytes
Uric acid
Monocytes
Total cholesterol
Eosinophils
Total protein
Basophils
Albumin
Platelets
Total bilirubin
HbA1cb
Alkaline phosphatase (ALP)
Urinalysisa
Aspartate aminotransferase (AST)
Specific gravity
Alanine aminotransferase (ALT)
pH
Creatinine
Protein
Gamma-glutamyl transferase (GGT)
Glucose
Ketones
Ethanol breath test
b,c
Bilirubin
Urine drug screen
b,c
Urobilinogen
Hepatitis B surface antigen
b
Erythrocytes/hemoglobin
Hepatitis C antibody
b
Nitrite
HIV
b
Leucocytes
Pregnancy teste
Microscopy
d
FSH
b
Coagulationb
Prothrombin time (PT)
Partial thromboplastin time (PTT)
Abbreviations:  FSH = follicle-stimulating hormone; HbA1c = glycated hemoglobin; 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
Performed at screening only. Hepatitis B and HIV tests may be waived if they have been performed within the
6 months before screening (with reports available for review). FSH test only applicable at screening in
menopausal women, if necessary.
c
Urine drug screen and ethanol breath test may be repeated prior to admission to the clinical research unit. Urine 
drug screen: amphetamine, cannabis, cocaine, barbiturates, methadone, benzodiazepines, tricyclic 
antidepressants, methamphetamine, opiates, and phencyclidine.
d
If clinically indicated, at investigator’s discretion.
e
All females:  serum pregnancy test at screening; urine pregnancy test for all other visits.


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Appendix 3.
Study Governance, Regulatory and Ethical 
Considerations
Informed Consent
The investigator is responsible for

ensuring that the patient understands the potential risks and benefits of participating in 
the study.

ensuring that informed consent is given by each patient or legal representative. This 
includes obtaining the appropriate signatures and dates on the ICF prior to the 
performance of any protocol procedures and prior to the administration of investigational 
product.

answering any questions the patient may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the patient’s willingness to 
continue his or her participation in the trial.
Ethical Review
The investigator or appropriate local representative must give assurance that the 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 GCP.
The study site’s ERB(s) should be provided with the following:

the current IB and updates during the course of the study

ICF

relevant curricula vitae
Regulatory Considerations
This study will be conducted in accordance with
1) consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International
Organizations of Medical Sciences International Ethical Guidelines
2) applicable ICH GCP Guidelines 
3) applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third-party organization.


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Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Final Report Signature
The investigator or designee will sign the clinical study report for this study, indicating 
agreement with the analyses, results, and conclusions of the report.
The sponsor’s responsible medical officer and statistician will sign/approve the final clinical 
study report for this study, confirming that, to the best of his or her knowledge, the report 
accurately describes the conduct and results of the study.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate.

provide training to instruct the investigators and study coordinators.  This training will 
give instruction on the protocol, the completion of the CRFs, and study procedures.

make periodic visits to the study site.

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax.

review and evaluate CRF data and/or use standard computer edits to detect errors in data
collection.

conduct a quality review of the database.
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site. The study may be audited by Lilly and/or 
regulatory agencies at any time. Investigators will be given notice before an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes. If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to the original source 
documents.
Data Collection Tools/Source Data
An electronic data capture system will be used in this study.  The site must define and retain all 
source records and must maintain a record of any data where source data are directly entered into 
the data capture system.


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Study and Site Closure
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, 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 judges it necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP.


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Appendix 4.
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 I8B-MC-ITRR Sampling Summary
Purpose
Maximum Blood Volume 
Per Sample (mL)
Maximum Number 
of Blood Samples
Maximum Total 
Volume (mL)
Screening testsa
11
1
11
Clinical laboratory testsa
9
2
18
Pharmacokinetics – insulin lispro
2.5
50
125
Pharmacokinetics - treprostinil
2.0
8
16
Clamp device sampling for 
glucoseb
N/A
N/A
64
Immunogenicity
5
3
15
Pharmacogenetics
10
1
10
Blood glucose during clamp period 
(Super GL)c
0.3
128
38.4
Total
-
-
297.4
Total for clinical purposes [rounded up to nearest 10 mL] 
300
a
Additional samples may be drawn if needed for safety purposes.
b
Clamp device sampling: 6 hour run-in plus 10 hour clamp = 16 hours x 2 periods = 32 hours x 2 mL/hour = 64
mL. 
c
Blood glucose during clamp period (Super GL): 6 hour run-in plus 10 hour clamp = 16 hours x 2 periods = 32
hours x up to 4 samples/hour = 128 blood samples x 0.3 mL/blood sample = 38.4 mL


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Appendix 5.
Protocol Amendment I8B-MC-ITRR(c) 
Summary
Pharmacokinetics and Glucodynamics of LY900014 
Compared to Insulin Lispro Following Single Dose 
Administration in Elderly and Younger Adults with Type 
1 Diabetes Mellitus
Overview
Protocol I8B-MC-ITRR(b), Pharmacokinetics and Glucodynamics of LY900014 Compared to 
Insulin Lispro Following Single Dose Administration in Elderly and Younger Adults with Type 
1 Diabetes Mellitus, has been amended.  The new protocol is indicated by Amendment (c) 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:

Text in Sections 1, 5.2, and 10.3 has been amended to indicate an increase in sample size 
in each group such that up to 6 additional young adults and 6 additional elderly subjects 
may be enrolled. This change is intended to ensure there is sufficient statistical power to 
make robust comparisons between the study groups.  As such, estimations of statistical 
power have been adjusted throughout and confidence intervals have been increased to 
95% two-sided, with an alpha level of 0.05.

Text in Sections 1 and 10.3 has been amended to indicate that all enrolled subjects who 
received at least 1 dose of the study drug will be included in safety analysis, whether or 
not they completed all protocol requirements. 

In Sections 1 and 10, descriptions of the statistical PK and PD analyses have been 
updated to be consistent with the latest approved Statistical Analysis Plan, as well as
analyses conducted for other studies in this programme.  In particular, PK and GD time 
parameters such as tmax will be evaluated without log transformation, and there will be 
no sensitivity analysis for GD parameters. 

Text in Sections 1 and 10.3.4 has been updated to clarify that immunogenicity data in 
addition to TEADA will be evaluated.

The Schedule of Activities (Section 2) has been amended to indicate that 2 of the 
procedures (clinical laboratory tests and the collection of immunogenicity samples) will 
be performed prior to dosing but, for practical reasons, not necessarily within the 
previously indicated 2-hour time window.  

Text in Section 7.2.1 has been amended to instruct that subjects’ skinfold should be 
pinched if needles sized 8 mm or greater are used.


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
In Section 9.4.7.1, the term “total hypoglycaemia” has been replaced with “overall (or 
total) hypoglycaemia” to keep consistency with the terminology used in external 
publications.

Text in Section 10.3.1.2.1 has been adjusted to clarify that injection-site pain scores will 
be analyzed for each age group separately.


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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.
1.    Protocol Synopsis
Number of Subjects: Up to 4236 younger adult (aged 18 to 45 years inclusive) and 42 36 elderly (aged ≥65 years) 
subjects may be enrolled to ensure that at least 34 28 subjects in each age group complete the study.
Statistical Analysis:  The primary statistical analyses for PK will be conducted on subjects who receive at least 1 
dose of study drug and have measurable insulin lispro concentrations.  The primary statistical analysis for GD will 
be conducted on those subjects who complete at least 1 clamp procedure.  Supportive analyses will be done on the 
key parameters for the subjects who complete all treatment periods with evaluable data.  Safety analyses will be 
conducted for all enrolled subjects who received at least 1 dose of study drug, whether or not they completed all 
protocol requirements.
Unless otherwise noted, all tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, and 
confidence intervals (CIs) will be calculated at 95%, 2-sided.
Pharmacokinetics:  
Log-transformed time to early half-maximal plasma concentration (early 50% tmax), time to late half-maximal 
plasma concentration (late 50% tmax), time to maximum concentration (tmax), maximum observed concentration 
(Cmaxmax), clearance, and area under the plasma concentration-time curve estimates for insulin lispro will be 
evaluated to estimate least-squares geometric means, ratios of geometric means between LY900014 and Humalog 
(reference), and their corresponding 95% 90% confidence intervals (CIs) for each age group using the statistical 
model that includes treatment, sequence, and period as fixed effects and subject within sequence as a random effect.  
The same model without log transformation will be used for time to early half-maximal plasma concentration (early 
50% tmaxmax), time to late half-maximal plasma concentration (late 50% tmaxmax), and time to maximum 
concentration (tmaxmax) to estimate least-squares means, treatment differences in least-squares means, and the 
corresponding 95% CIs for each age group. The treatment ratios and the corresponding 95% CIs for these time 
parameters will be calculated using Fieller’s theorem.  For the primary inference, LY900014 will be concluded to 
have a significantly faster PK action compared to Humalog (reference) if the upper confidence bound of the 2-sided 
90% CI of the ratio of geometric means of early 50% tmax is less than 1, or if the lower confidence bound of the 2-
sided 90% CI of the ratio of geometric means of area under the plasma concentration-time curve from time zero to 
30 minutes is greater than 1.
Glucodynamics:  
The GD statistical model will be similar to the model used for the analysis of the PK parameters.  The variables of
will be log-transformed prior to analysis and will include time to onset of insulin action (Tonset), maximum GIR 
(Rmax), time to Rmax (TRmax), time to half-maximal GIR before TRmax (early 50% TRmax), time to half-maximal GIR 
after TRmax (late 50% TRmax), total amount of glucose infused (Gtot), total amount of glucose infused over 30 


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minutes (Gtot (0-30min)), total amount of glucose infused over 1 hour (Gtot(0-1h)), and total amount of glucose infused 
over 10 hours (Gtot[0-10h]) will be log transformed log transformed prior to analysis. The time variables including 
time to onset of insulin action (Tonsetonset), time to Rmax (TRmax), time to half-maximal GIR before TRmax (early 50% 
TRmaxTRmax), and time to half-maximal GIR after TRmax (late 50% TRmaxTRmax) will be analyzed using the same 
model without log transformation to estimate least-squares means, treatment differences in least-squares means, and 
the corresponding 95% CIs. The treatment ratios and the corresponding 95% CIs for these time parameters will be 
calculated using Fieller’s tTheorem. If subjects have a GD parameter with a value equal to zero, then a 
nonparametric analysis will be used instead.
Immunogenicity:
Treatment-emergent antidrug antibodies (TEADAs) The immunogenicity data will be listed.  The relationship 
between treatment-emergent antidrug antibodies and AEs will be evaluated.  The relationship between the presence 
of antibodies and the PK parameters and GD response to insulin lispro may also be evaluated.
2. Schedule of Activities
Procedures
Screening
Euglycaemic Clamp Procedure
Periods 1 and 2
FU/ED
a
Instructions/Comments
Up to 
Day -28
Day -
1
Day 1
Clinical 
laboratory tests
X
Predose for Period 1 only
(up to 2 hours before 
dosing)
X
Fasting laboratory test for screening, 
Period 1, and FU.  To monitor patient 
safety, additional tests may be performed 
at the discretion of the investigator, as 
needed throughout the study.
Immunogenicity 
sample
Predose for Period 1 and 
Period 2
X
Predose up to 2 hours before dosing
5.2
Number of Participants
Up to 4236 younger adult and 42 36 elderly subjects may be enrolled to ensure that at least 34 28
subjects in each age group complete the study.
7.2.1 Selection and Timing of Doses
The site of administration of each injection will be recorded.  The insulin used in this study will 
be injected using syringes and vials. Injection sites selected should be about 5 cm from the 
umbilicus and the treatment is administered SC with the needle applied at about 90°.  An 
appropriate size of needle shall be used to ensure all injections are delivered to a consistent target 
depth into the SC space; without pinching the skinfold. If if an 8-mm (or greater) insulin syringes 
are needle is used to administer the injection, the skinfold needs to be pinched.  An appropriate 
size of needle shall be used to ensure all injections are delivered to a consistent target depth into 
the SC space.  Injections sites will be rotated between the left lower quadrant and right lower 
quadrant on the anterior abdominal wall during the 2 study periods.
9.4.7.1 Glucose Monitoring


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
Overall (or Total total) hypoglycaemia: This optional category combines all cases 
of hypoglycaemia. If an event of hypoglycaemia falls into multiple subcategories, the 
event is only counted once in this category
10.1 Sample Size Determination
Up to 4236 younger adult and 4236 elderly subjects may be enrolled to ensure that at least 34 28
subjects in each age group complete the study. Thirty-four Twenty-eightcompleting subjects in 
each age group will provide approximately 95% power to demonstrate a 40% increase in the 
insulin lispro area under the plasma concentration-time curve from time zero to 30 minutes 
(AUC[0-30min]) between LY900014 and Humalog within each age group.  Testing will be done at 
an alpha level of 0.050.1 with a 2-sided confidence interval (CI).  The variability was estimated 
by analyzing a Lilly internal study that showed a log-scale standard deviation of within-subject 
difference in AUC(0-30min) of 0.5.  Analysis of internal data showed a log-scale standard deviation 
of within-subject difference in time to early half-maximal plasma concentration (early 50% tmax)
of 0.5, which provides approximately 95% power to show a 30% reduction in early 50% tmax, 
testing with an alpha level of 0.050.1 and a 2-sided CI.
In addition, the study is adequately powered to evaluate the GD parameters within each age 
group.  There is approximately 80% power to detect a 20% decrease in both time to onset of 
insulin action (Tonset) and time to half-maximal GIR before TRmax (early 50% TRmax), and
approximately 9085% power to detect at least a 40% increase in total amount of glucose infused 
over 30 minutes (Gtot[0-30min]) and total amount of glucose infused over 1 hour (Gtot[0-1h]).
10.3 Statistical Analyses
The primary statistical analyses for PK will be conducted on those subjects who receive at least 1 
dose of study drug and have measurable insulin lispro concentrations.  The primary statistical 
analysis for GD will be conducted on those subjects who complete at least 1 clamp procedure.  
Supportive analyses will be done on the key parameters for the subjects who complete all 
treatment periods with evaluable data.  Safety analyses will be conducted for all enrolled subjects
who receive at least 1 dose of study drug, whether or not they complete all protocol 
requirements.
Summary statistics (including number of subjects, mean, standard deviation or standard error, 
minimum, and maximum) will be presented for continuous variables.  A linear mixed-effect 
model will be used for continuous variables unless otherwise stated in the below subsections.  
The primary comparison between LY900014 and insulin lispro for each age group will be 
performed using the model that includes treatment, sequence, and period as fixed effects, and 
subject within sequence as a random effect.  Unless otherwise noted, all tests of treatment effects 
will be conducted at a 2-sided alpha level of 0.05, and CIs will be calculated at 95%, 2-sided.  
10.3.1.2.1 Statistical Evaluation of the Intensity of Injection-Site Pain
A mixed-effect model will be used to analyze the time 0 (immediately after dosing) data 
separately by age group, using the statistical model that includes treatment, sequence, age group 


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(if applicable), the 2-way interaction between treatment and age group (will be included only 
when age group is included in the model), and period as fixed effects and subject within 
sequence as a random effect.  The distribution of the score data will be explored prior to analysis 
to determine whether data transformation is required.  It is possible that VAS scores will be zero; 
hence if the distribution of the data implies that a log transformation is required then the score 
may be updated to log (VAS+1) to allow for the inclusion of the 0 values in the analysis.
10.3.2.2 Pharmacokinetic Statistical Inference
Log-transformed early 50% tmax, late 50% tmax, tmax, Cmax, t1/2 and AUC estimates for insulin 
lispro will be evaluated to estimate least-squares geometric means, ratios of geometric means 
between LY900014 and Humalog (reference), and their corresponding 95%90% CIs for each age 
group using the statistical model that includes treatment, sequence, and period as fixed effects 
and subject within sequence as a random effect.  
The same model without log transformation will be used for the analysis of the PK time 
parameters (early 50% tmax, late 50% tmax, tmax, and t1/2). Least-squares means, treatment 
differences in least-squares means, and the corresponding 95% CIs for the treatment differences 
will be estimated from the model. The treatment ratios and 95% CIs for the ratios will be 
calculated using Fieller’s theorem (Chow and Liu 2009).
For the primary inference, LY900014 will be concluded to have a significantly faster PK action 
compared to insulin lispro (Humalog) if the upper confidence bound of the 2-sided 90% CI of the 
ratio of geometric means of early 50% tmax is less than 1, or if the lower confidence bound of the 
2-sided 90% CI of the ratio of geometric means of AUC(0-30min) is greater than 1.If model 
assumptions are severely violated for the time parameters, early 50% tmax, late 50% tmax, and tmax
will be analyzed using the Wilcoxon signed-rank test.  The difference in medians between 
LY900014 and insulin lispro and the 90% CIs for the difference will be presented.
10.3.3.2 Glucodynamic Statistical Inference
The statistical model will be the same as the model used for the analysis of the PK parameters.  
The variables will be log-transformed prior to analysis and will include Rmax, Gtot, Gtot(0-30min), 
Gtot(0-1h), and Gtot(0-10h).  For GD parameters that have at least 1 subject with a value equal to 
zero, a value equal to the smallest non-zero observed GD value for that parameter divided by 2 
will be added to all values, and the analysis of the log-transformed data will be performed.  In 
addition, as a sensitivity analysis, a nonparametric analysis will be performed for that parameter.
Similarly to the PK time parameters, The the GD time parameters (Tonset, TRmax, early 50% 
TRmax, and late 50% TRmax) will be evaluated without log transformation using a linear mixed-
effects model assuming that model assumptions are satisfied with treatment, sequence, and 
period as fixed effects, and subject within sequence as a random effect. Least-squares means, 
treatment differences in least-squares means, and the corresponding 95% CIs for the treatment 
differences will be estimated from the model. The treatment ratios and 95% CIs for the ratios 
will be calculated using Fieller’s theorem. Fieller’s Theorem may be applied to calculate the CI 
of treatment comparison ratio.


I8B-MC-ITRR(c) Clinical Pharmacology Protocol
Page 62
LY900014
10.3.4 Evaluation of Immunogenicity
Treatment-emergent antidrug antibodies (TEADAs)The immunogenicity data will be listed.  The 
relationship between treatment-emergent antidrug antibodies and AEs will be evaluated.  The
relationship between the presence of antibodies and the PK parameters and GD response to 
insulin lispro may also be evaluated.
11. References
Chow SC, Liu JP. Design and analysis of bioavailability and bioequivalence studies. 3rd ed.  
Florida: Taylor and Francis Group, LLC; 2009:p88-90.


PPD
Leo Document ID = 8ffb4a91-42f3-4f9f-baa0-59026151d2ed
Approver: 
Approval Date & Time: 02-Aug-2017 12:38:42 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 04-Aug-2017 13:16:04 GMT
Signature meaning: Approved
PPD

SAP_001.pdf: 
 
 
Protocol/Statistical Analysis Plan: I8B-MC-ITRR  
 
 
Pharmacokinetics and Glucodynamics of LY900014 Compared to Insulin Lispro Following 
Single Dose Administration in Elderly and Younger Adults With Type 1 Diabetes Mellitus   
 
 
NCT03166124 
 
 
Approval Date: 


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STATISTICAL ANALYSIS PLAN
Pharmacokinetics andGlucodynamicsof LY900014Compared to Insulin Lispro Following 
Single DoseAdministration in Elderly and Younger Adults with Type 1Diabetes Mellitus
Approval Date: 11-Sep-2017 GMT
Statistical Analysis Plan Status:  FinalVersion 2
Statistical Analysis Plan Date:  01-September-2017
Study Drug:LY900014
Sponsor Reference:  I8B-MC-ITRR
Clinical Phase I
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1.TABLE OF CONTENTS
1. TABLE OF CONTENTS...............................................................................................2
2. ABBREVIATIONS........................................................................................................4
3. INTRODUCTION.........................................................................................................6
4. STUDY OBJECTIVES..................................................................................................6
4.1 Primary...................................................................................................................6
4.2 Secondary................................................................................................................6
4.3 Exploratory.............................................................................................................7
5. STUDY DESIGN...........................................................................................................7
6. TREATMENTS.............................................................................................................8
7. SAMPLE SIZE JUSTIFICATION.................................................................................8
8. DEFINITION OF ANALYSIS POPULATIONS............................................................9
9.
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STATISTICAL METHODOLOGY...............................................................................9
9.1 General....................................................................................................................9
9.2 Demographics and Patient Disposition...................................................................10
9.3 Pharmacokinetic Assessment.................................................................................10
9.3.1
Pharmacokinetic Parameter Estimation.........................................................10
9.3.2
Pharmacokinetic Statistical Inference...........................................................11
9.4 Glucodynamic Assessment....................................................................................12
9.4.1
Glucodynamic Parameter Estimation............................................................12
9.4.2
Glucodynamic Statistical Inference...............................................................12
9.5 Safety and Tolerability Assessments......................................................................13
9.5.1
Adverse events.............................................................................................13
9.5.2
Concomitant medication...............................................................................13
9.5.3
Clinical laboratory parameters......................................................................13
9.5.4
Vital signs....................................................................................................13
9.5.5
Electrocardiogram (ECG).............................................................................13
9.5.6
Blood Glucose Monitoring and Hypoglycemia.............................................14
9.5.7
Injection Site Local Tolerability Assessment Data........................................14
9.5.8
Pain measurements Using the Visual Analog Scale (VAS)...........................14
9.5.9
Immunogenicity...........................................................................................15
9.5.10 Other assessments.........................................................................................15


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10.INTERIM ANALYSES...............................................................................................15
11.CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES......15
12.REFERENCES............................................................................................................15
13.
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DATA PRESENTATION............................................................................................16
13.1Derived Parameters...............................................................................................16
13.2Missing Data.........................................................................................................16
13.3Insufficient Data for Presentation..........................................................................16


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2.ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP)only (not thetables, figures and 
listings[TFLs]).
AE
Adverse event
AUC
Area under the concentration versus time curve
AUC(0-30min)
AUC from time zero to 30 minutes
Cmax
Maximum observed drug concentration
CI
Confidence interval
CRF
Case Report Form
CSR
Clinical Study Report
CSII
Continuous subcutaneous insulin infusion
CRU
Clinical Research Unit
CV
Coefficient of variation
Early 50% tmax
Time to early half-maximal drug concentration
Early 50%TRmax Time to half-maximal glucose infusion ratebefore TRmax
EC
Early Clinical 
ECG
Electrocardiogram
e.g.
For example (Latin: exempli gratia)
GD
glucodynamic
GIR
Glucose infusion rate
Gtot
Total amount of glucose infused 
Gtot(0-30min)
Total amount of glucose infused over 30 minutes
Gtot(0-1h)
Total amount of glucose infused over 1 hour
ICH
International Council on Harmonisation
Late 50% tmax
Time to late half-maximal drug concentration
Late 50% TRmax
CCI
Time to half-maximal glucose infusion rateafterTRmax
LS
Least square
LOESS 
Locally weighted scatterplot smoothing 
MedDRA
Medical Dictionary for Regulatory Activities
NA
Not applicable


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NPH
Neutral protamine Hagedorn 
PK
Pharmacokinetic
Rmax
Maximum GIR
SAP
Statistical Analysis Plan
SC
Subcutaneous 
SD
Standard deviation 
SMPG
Self monitoring plasma glucose
SOP
Standard Operating Procedure
T1DM
Type 1 diabetes mellitus
TFLs
Tables, Figures, and Listings
Tonset
Time to onset of insulin action
t
1/2
Half-life associated with the terminal rate constant (λ
z) in non-
compartmentalanalysis
t
max
Time ofmaximum observed drugconcentration
TRmax
Time to Rmax
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VAS
Visual analogue scale
WHO
World Health Organization


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3.INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 08 
December 2016), amendment (a) (dated 09March 2017),amendment (b) (dated 24 May 2017) 
and amendment (c) (dated 04 August 2017).
This SAP describes the planned analysis of the safety, tolerability, pharmacokinetic(PK)and 
glucodynamic (GD) data from this study. A detailed description of the planned TFLs to be 
presented in the clinical study report (CSR) is provided in the accompanying TFL shell 
document.
The intent of this document is to provide guidance for the statistical and PK analyses of data. In 
general, the analyses are based on information from the protocol, unless they have been modified 
by agreement between Eli Lilly and Company and 
.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 patient 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 supersedesthe 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 
and identified in the CSR.Any 
minor deviations from the TFLs may not be documented in the CSR.
This SAP is written with consideration of the recommendations outlined in the International 
Council on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials1and the ICH E3 Guideline entitled Guidance for Industry: Structure 
and Content of Clinical Study Reports
2.
4.STUDY OBJECTIVES
4.1
Primary
To evaluate the PK of insulin lispro following administration of a single 15-U subcutaneous (SC)
dose of LY900014 compared to insulin lispro (Humalog) within each type 1 diabetes mellitus 
(T1DM)population (elderly and younger adults).
4.2
Secondary
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To compare the GD during a euglycaemic clamp of LY900014 and insulin lispro (Humalog) 
following administration of a single 15-U SC dose in elderly and younger adults with T1DM.
To evaluate the safety andtolerability of the novel LY900014 formulation.
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4.3
Exploratory
To evaluate whether the difference between LY900014 and insulin lispro in PK and PD 
parameters is similar between elderly and younger adults.
5.STUDY DESIGN
This is a Phase 1, randomized, patient-and investigator-blind, 2-treatment, 2-period, crossover
study that compares the PK and GD of insulin lispro from LY900014 and insulin lispro
(Humalog) following administration of a single 15-U SC dose in elderly and younger adults with
T1DM who are either on multiple daily insulin injections or on continuous subcutaneous insulin 
infusion (CSII)via a sponsor-approvedinsulin pump. Study ITRR will be conducted at 1 or more 
sites.
Figure 1 illustrates the study design.
Abbreviations: CRU = clinical research unit; ED = early discontinuation; SC = subcutaneous; 
T1DM = type 1 diabetes mellitus
Figure 1. Illustration of study design 
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Patients will be randomized to 1 of 2 treatment sequences according to the actual randomization
table provided to the site. Each patientwill participate in a screening visit, 2 clinical researchunit 
(CRU) inpatient dosing visits, and a follow-up visit. Before each dose, a run-in period of 1to 6 
hours to stabilize blood glucose will occur. Dosing visits will be separated by a wash-outperiod 
of 3 to 15 days, during which patients will resume their normal insulin treatment with the
exemption of the insulin switch 48 to 72 hours prior to dosing as describedin the protocol. At 
eachvisit, patients will receive either LY900014 or insulin lispro and undergo a euglycaemic 
clampprocedure where the time-concentration and time-action profiles of the study treatment 
will beevaluated simultaneously for up to 10 hours using an automated clamp device. Briefly,
the aimof the euglycaemic clamp is to maintain euglycaemia after the administration of a dose 
of insulinby means of variable glucose infusion. The variable glucose infusion maintains or “
clamps” glucose at a constant euglycaemic target; therefore, the glucose infusion rate (GIR) 
reflects theGD effect of the insulin.
All patients will be instructed to perform at least 4-point daily self-monitoring plasma glucose
(SMPG), as well as continue their short-acting insulin during lead-in. The SMPG and prandial
insulin doses should be recorded in the patient’s diary, which will serve as a source document.
6.TREATMENTS
The following is a list of the study treatmentand age group names that will be used in the TFLs.
Study Treatment Name
Treatment order in TFL
LY900014
1
Humalog
2
Age GroupName
Age Grouporder in TFL
Elderly adults
1
Younger adults
2
7.SAMPLE SIZE JUSTIFICATION
Up to 42 younger adult and 42 elderly patients may be enrolled to ensure that at least 34 patients 
in each age group complete the study. Thirty-fourcompleting patients in each age group will 
provide approximately 95% power to demonstrate a 40% increase in the insulin lispro area under 
the plasma concentration-time curve from time zero to 30 minutes (AUC[0-30min]) between 
LY900014 and Humalog within each age group. Testing will be done at an alpha level of 0.05
with a 2-sided confidence interval (CI). The variability was estimated by analyzing a Lilly
internal study that showed a log-scale standard deviation of within-patientdifference in
AUC(0-30min) of 0.5. Analysis of internal data showed a log-scale standard deviation of within
patientdifference in time to early half-maximal plasma concentration (early 50% tmax
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which provides approximately 95% power to show a 30% reduction in early 50% t
max, testing
with an alpha level of 0.05and a 2-sided CI.
In addition, the study is adequately powered to evaluate the GD parameters within each age
group. There is approximately 80% power to detect a 20% decrease in both time to onset of
insulin action (Tonset) and time to half-maximal GIR before TRmax(early 50% TR
max), and
approximately 85% power to detect at least a 40% increase in total amount of glucose infused
over 30 minutes (Gtot[0-30min]) and total amount of glucose infused over 1hour (Gtot[0-1h]).
8.DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all patients who received at least one dose of study drug.
The primary statistical analyses for PK will be conducted on those patients who receive at least 1 
dose of study drug and have measurable insulin lispro concentrations.
The primary statisticalanalysis for GD will be conducted on those patients who complete at least 
1 clamp procedure.
Supportive analyses will be done on the key PK and GD parameters for the patients who 
complete alltreatment periods with evaluable data.
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when patients are assigned to analysis populations.
9.STATISTICAL METHODOLOGY
9.1
General
Data listings will be provided for all datathat isdatabased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include thearithmetic mean, arithmetic standard deviation (SD), median, 
min, max and N; for log-normal data (e.g. the PK parameters: AUCs and Cmax
CCI
) 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 patients 
up to the point of withdrawal, with any patients excluded from the relevant population 
highlighted. Summary statistics and statistical analyses will generally only be performed for 
patients included in the relevant analysis population.For the calculation of summary statistics 
and statistical analysis, unrounded data will be used. 
Mean change from baseline is the mean of all individual patients’ change from baseline values. 
Each individual change from baseline will be calculated by subtracting the individual patient’s 
baseline value from the value at the timepoint. The individual patient’s change from baseline 
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 
or greater.
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9.2
Demographics and PatientDisposition
Patientdisposition will be listed. The demographic variables age, sex, race, ethnicity,country of 
enrolment, site ID,hip and waist circumference,body weight, height and body mass index will 
be summarized by age groupand listed.In addition, screening HbA1c, fasting blood glucose, 
fasting C-peptide, previous insulin therapy(basal and prandial)and duration of T1DM will be 
summarized and listed.
Alcohol consumption will be reported in the SDTMs in units of alcohol and will be converted to
grams for the TFLs, where 1 unit is equal to 8 grams of pure alcohol.
9.3 Pharmacokinetic Assessment
9.3.1 Pharmacokinetic Parameter Estimation
Patients who receive at least 1 dose of study drug and have measurable insulin lispro
concentrations will be included in the PK analysis dataset.
PK analyses will be conducted using standard noncompartmental methods ofanalysis using
 on a computer that meets or 
exceeds theminimum system requirements for these programs. The version of any software used 
for theanalysis will be documented and the program will meetthe Lilly requirements of software
validation. It is possible that other validated equivalent PK software programs may be utilized if
appropriate, warranted, and approved by global PK management.
Free serum insulin lispro concentrations will be used to calculate several PK parameters,
including early 50% t
max, time to late half-maximal plasma concentration (late 50% tmax),
maximum observed concentration (Cmax), t
max, t
1/2, and areaunder the plasma concentration-time
curve from time zero to the last recorded time, AUC(0-30min),area under the plasma 
concentration-timecurve from time zero to 1 hour, area under the plasma concentration-time 
curve from timezero to 10 hours, and area under the plasma concentration-time curve from time 
zero to infinity.Other parameters may be calculated as deemed appropriate. Additional partial 
area under theplasma concentration-time curves (AUCs) may be computed as necessary. The 
primary insulinlispro PK parameters for faster insulin lispro absorption analysis are early 
50%tmax andAUC(0-30min).
Given the predicted low systemic concentrations of treprostinil, the PK analysis of treprostinil
from the LY900014 dosing will be conducted using the available data. The primary analysis of
the treprostinil concentrations will be focused on assessing time to maximum concentration (t
max)
and C
max
CCI
.
Although attempts will be made to adhere to the scheduled collection times (Section 2of the 
protocol), it isrecognized that situations arise that may compromise the scheduled times. 
Parameters will beindividually calculated for each patientbased on actual collection times and 
presented usingsummary statistics.
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9.3.2Pharmacokinetic Statistical Inference
Log-transformedCmax,AUC(0-30min) , AUC(0-1h), AUC(0-10h), AUC(2-10h), AUC(0-t
last), 
AUC(0-inf),  CL/F and V
z/F for insulinlispro will be evaluated to estimate least-squares 
geometric means, ratios of geometric meansbetween LY900014 and Humalog (reference), and 
their corresponding 95% CIs for each agegroupseparately using the statistical model that 
includes treatment, sequence, and period as fixed effectsand patientwithin sequence as a 
random effect.
Example SAS code:
proc mixed data=pk;
class patient period treatment sequence ;
model logpk = treatment period sequence / ddfm=kr;
random patient(sequence);
lsmeans treatment;
run;
The same model without log-transformation will be used for the analysis of the PK time 
parameters (early 50% t
max, late 50% t
max, t
max, and t
1/2).  Least-squares means, treatment 
differences in least-squares means, and the corresponding 95% CIs for the treatment differences 
will be estimated from the model.  The treatment ratios and 95% CIs for the ratios will be 
calculated using Fieller’s Theorem (Chow and Liu 2009
3).
All analyses will be repeated for the population of patients who complete the study.
An exploratory analysis on the interaction betweentreatment and age group will be assessed 
using data from both age groups by a model similar tothat for each age group, with the addition 
of age group and the interaction of treatment by agegroup as fixed effects. This test will be used 
to compare whether the LY900014 versus insulinlispro treatment effect is similar between the 
elderly and younger adult groups.The analysis will include all PK parameters analysed 
previously(both untransformed and log-transformed PK parameters).
Example SAS code:
proc mixed data=pk;
class patient period treatment sequence agegrp;
model logpk = treatment period sequence agegrp agegrp*treatment / 
ddfm=kr;
random patient(sequence);
lsmeans agegrp*treatment;
run;
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As treprostinil plasma concentrations after administration of LY900014 are expected to be very
low, a descriptive statistical analysis may be conducted if sufficient data are available for this
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9.4 Glucodynamic Assessment
9.4.1Glucodynamic Parameter Estimation
GD assessments will be determined from the glucose clamp procedure, where the GIR over time
will be used as a measure of insulin effect. GD analyses will be conducted on those patientswho 
complete at least 1 clamp procedure.A locally weighted scatterplot smoothing (LOESS) function 
will be applied to all individual GIRversus time profiles in each treatment group and age group 
using 
The fitted data for each patientwill be used to calculate the following GD parameters: T
onset,
maximum GIR (Rmax), time to R
max(TR
max), early 50% TR
max, time to half-maximal GIR after
TRmax(late 50% TR
max), total amount of glucose infused (Gtot), G
tot(0-30min),andGtot(0-1h), 
Additionalpartial glucose AUCs, such astotal amount of glucose infused over 2 hours, may be 
computed as necessary. The values ofthese GD parameters will be summarized by treatment 
group and age group through descriptivestatistics. Mean LOESS fits of GIR versus time profiles 
will be generated. The primary GDparameters for analysis are early 50% TR
max, G
tot(0-30min), 
Gtot(0-1h), and Tonset.
9.4.2Glucodynamic Statistical Inference
The GD parameters will be listed and summarized by treatment and age group.
The statistical model will be the same as the model used for the analysis of the PK parameters.
Thenon-timevariables will be log-transformed prior to analysis and will include R
max, G
tot, 
Gtot(0-30min),Gtot(0-1h), and Gtot(0-10h). For GD parameters that have at least 1 patientwith a 
value equal tozero, a value equal to the smallest non-zero observed GD value for that parameter 
divided by 2will be added to all values, and the analysis of the log-transformed data will be 
performed. 
The same model without log-transformation will be used for the analysis of the GDtime 
parameters (Tonset, TR
max, early 50% TR
max, and late 50% TR
max
CCI
).  Least-squares means, 
treatment differences in least-squares means, and the corresponding 95% CIs for the treatment 
differences will be estimated from the model.  The treatment ratios and 95% CIs for the ratios 
will be calculated using Fieller’s Theorem
All analyses will be repeated for the population of patients who complete the study.
An exploratory analysis on the interaction betweentreatment and age group will be assessed 
using data from both age groups by a model similar tothat for each age group, with the addition 
of age group and the interaction of treatment by
 agegroup as fixed effects. This test will be used 
to comparewhether the LY900014 versus insulinlispro treatment effect is similar between the 
elderly and younger adult groups.The analysis will include all GD parameters analysed 
previously (both untransformed and log-transformed GD parameters).
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9.5 Safety and Tolerability Assessments
9.5.1Adverse events
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the adverse event(AE)will be reported in the listings, only the most severe will be used in the 
summary tables. A pre-existing condition is defined as an AE that starts before the patienthas 
provided written informed consentand is ongoing at consent. A non-treatment emergent AE is 
defined as an AE which startsafter informed consent but prior to dosing. A treatment-emergent 
AE is defined as an AE which occurs postdose or which is present prior to dosing and becomes 
more severe postdose.
All AEs will be listed.  Treatment-emergentAEs will be summarized by treatment, age group, 
severity and relationship to the study drug. The frequency (the number of adverse events, the 
number of patients experiencing an adverse event and the percentage of patients experiencing an 
adverse event) of treatment-emergent adverse events will be summarized by treatment, age 
group, MedicalDictionary for Regulatory Activities (MedDRA)version 19.1system organ class 
and preferred term. The summary and frequency adverse event tables will be presented for all 
causalities and those considered related to the study drug.Any serious adverse events will be 
tabulated.
9.5.2Concomitant medication
Concomitant medication will be coded using the WHO drug dictionary (Version September 
2016).Concomitant medication will be listed.
9.5.3Clinical laboratory parameters
All clinical chemistry, hematologyand urinalysisdatawill 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 patientdata listings.
9.5.4Vital signs
Vital signs data will be summarized by treatment and age group, together withchanges from 
baseline, where baseline is defined as predose of Day 1. 
Furthermore, values for individual patients will belisted. 
9.5.5Electrocardiogram (ECG)
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ECG data will be listed for individual patients.


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9.5.6Blood Glucose Monitoring and Hypoglycemia
Hypoglycemic events will be appropriately recorded in the CRF. In the case of a hypoglycemic 
event, the actual blood glucose value, if measured, will be recorded in the CRF, together with 
any treatments administered. Each category of hypoglycemic events (defined below) will be 
listed and summarized by treatment and age group.
Hypoglycemia is defined as follows:
•Documented Hypoglycemia:
o Documented symptomatic hypoglycemia: An event during which typical symptoms of 
hypoglycemia are accompanied by plasma glucose (PG) ≤70 mg/dL (≤3.9 mmol/L).
o Asymptomatic hypoglycemia: An event not accompanied by typical symptomsof
hypoglycemia but with PG ≤70 mg/dL (≤3.9 mmol/L).
• Unspecifiedhypoglycemia:An event during which PG ≤70 mg/dL (≤3.9 mmol/L) but no
information relative to symptoms of hypoglycemia was recorded
• Probable symptomatic hypoglycemia:An event during which symptoms indicative of
hypoglycemia are not accompanied by a PG determination (but that was presumably caused by 
PG ≤70 mg/dL [≤3.9 mmol/L]).
• Severe hypoglycemia:An event requiring assistance of another person to actively administer 
carbohydrate, glucagon, or other resuscitative actions.
• Nocturnal hypoglycemia:Any hypoglycemic event (documented symptomatic, asymptomatic, 
probable symptomatic or severe hypoglycemia) that occurs between bedtime and waking.
• Overall hypoglycemia:This optional category combines all cases of hypoglycemia. If an event 
of hypoglycemia falls into multiple subcategories, the event is only counted once in this 
category.
9.5.7Injection Site Local Tolerability Assessment Data
Injection-site assessment data will be listed and summarized in frequency tables by treatment, 
age groupand timepoint.
9.5.8Pain measurements Using the Visual Analog Scale(VAS)
CCI
Intensity of pain data at the injection site as soon as practicably possible after the injection, and
at multiple postdose timepoints, as reported by the patientand measured according to the 0-to
100-mm visual analog scale will be listed and summarized by treatmentand age group.
The time 0 (immediately after dosing) data will be analyzedseparately by age group ,using the 
Wilcoxon signed-rank test. The difference in medians between LY900014 and Humalog and the 
95% CIs for the difference will be presented. 


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VAS data will also be summarized based on the following categories of score: 0, 1-10, 11-20, 
21-30, 31-40,etcupto the maximum category by treatment, age groupand timepointand also
the categories <=10 mm, <=20 mm and <=45 mm.The table will shownumber and percent of 
patients with observations in each category.
9.5.9Immunogenicity
Immunogenicity data will be listed. The number of patients who have not-detected anti-insulin 
lispro antibody at pre-dose (for period 1) and detected anti-insulin lispro antibody at post-dose 
(measured in period 2 or follow-up) will be summarized by age group for combined treatments. 
The number of patients who have detected anti-insulin lispro antibody at pre-dose for period 1 
and 57% increase from the pre-dose (for period 1) to post-dose (measured in period 2 orfollow-
up) will also be summarizedin a similar way.
9.5.10Other assessments
All other safety assessments not detailed in this sectionwill be listed but not summarized or 
statistically analyzed. 
10.
INTERIM ANALYSES
An interim analysis may be conducted after all patients in the younger adult group have 
completed the study to analyze the safety, PK and GD data in order to support regulatory
submission. The Lilly clinical pharmacologist/Lilly study team is unblinded. The individuals and 
unblinded data are as specified in the unblinding plan. Information that may unblind the study 
during the analyses will not be reported to study sites or blinded study team until the study has 
been unblinded.
Data may be analyzed while the trial is ongoing, but no changes to the study design are planned. 
The results may help Lilly expedite final delivery and to enable planning of future studies. An 
assessment committee will not be formed.
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
The protocol originally planned to analyse PK time parameters using a log-normal model. This 
was updated to a linear model with Fieller methodology added.Non-parametric analysis of the 
PK and GD data was originally planned in the protocol but this was removed for consistency 
with other studies. The VAS statistical analysis was updated to a non-parametric analysis due to 
issues observed in ITSC.
12.
REFERENCES
CCI
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.


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Statistical Analysis Plan 
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Sponsor Reference I8B-MC-ITRR
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.
3. Chow SC, Liu JP. Design and analysis of bioavailability and bioequivalence studies. 3 rd ed. 
Florida: Taylor and Francis Group, LLC; 2009:88-90.
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. C
max, should be reported 
as received. Observedtime data, e.g. t
max, should be reported as received. N and percentage 
valuesshould 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
CCI
Some of the TFLs maynot have sufficient numbers of patients or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the centre of the table, 
such as, “No serious adverse events occurred for this study.”


PPD
Leo Document ID = e5b3ab59-c94d-4bf1-9b50-fce862e61160
Approver: 
Approval Date & Time: 07-Sep-2017 18:38:14 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 11-Sep-2017 14:35:38 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 11-Sep-2017 15:08:51 GMT
Signature meaning: Approved
PPD
PPD