Conditions: Diabetes Mellitus, Type 2
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 28
Healthy volunteers: yes

Brief summary:
This study evaluates a new formulation of insulin lispro, LY900014, a drug that lowers blood sugar. It is administered by injection into the vein and under the skin of the abdomen, thigh and arm.

The study will be conducted in healthy people to investigate the effect of different injection sites on the amount of insulin lispro in the bloodstream.

Side effects and tolerability will be documented. The study will last for about 10 weeks for each participant, including screening and follow up. Screening is required within 28 days prior to entering the study.

Detailed description:

Arms:
arm 1: Single dose of 15-U of LY900014 administered subcutaneously (SC) into the abdomen in one period arm 2: Single dose of 15-U of LY900014 administered SC into the thigh in one period arm 3: Single dose of 15-U of LY900014 administered SC into the arm (deltoid) in one period arm 4: Single dose of 15-U of LY900014 administered intravenously (IV) in one period

Interventions: intervention 1: LY900014 (SC) intervention 2: LY900014 (IV)
Intervention descriptions: intervention 1: Administered SC intervention 2: Administered IV

Protocol document:
Prot_000.pdf: 
 
 
Protocol/Statistical Analysis Plan: I8B-MC-ITRT  
 
Effect of Injection Site on the Relative and Absolute Bioavailability of Single Dose of 
LY900014 in Healthy Subjects 
 
 
NCT03233983 
 
 
Approval Date: 


I8B-MC-ITRT(a)Clinical Pharmacology Protocol
Page 1
LY900014
Protocol I8B-MC-ITRT(a) 
Effect of Injection Site on the Relative and Absolute 
Bioavailability of Single Dose of LY900014 in Healthy 
Subjects
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
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: 14-Jul-2017 GMT
LY900014
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Clinical Pharmacology Protocol Electronically Signed and Approved by 
Lilly:24May2017
Amendment (a) Electronically Signed and Approved by Lillyon approval date provided 
below.


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 2
LY900014
Table of Contents
Effect of Injection Site on the Relative and Absolute 
Bioavailability of Single Dose of LY900014 in Healthy 
Subjects
Section
Page
Protocol I8B-MC-ITRT(a)  Effect of Injection Site on the Relative and 
Absolute Bioavailability of Single Dose of LY900014 in Healthy 
Subjects ..............................................................................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................8
2.
Schedule of Activities .......................................................................................................10
3.
Introduction ......................................................................................................................14
3.1.
Study Rationale............................................................................................................14
3.2.
Background..................................................................................................................14
3.3.
Benefit–Risk Assessment .............................................................................................15
4.
Objectives and Endpoints..................................................................................................17
5.
Study Design.....................................................................................................................18
5.1.
Overall Design .............................................................................................................18
5.2.
Number of Participants.................................................................................................19
5.3.
End of Study Definition ...............................................................................................19
5.4.
Scientific Rationale for Study Design...........................................................................20
5.5.
Justification for Dose ...................................................................................................20
6.
Study Population...............................................................................................................22
6.1.
Inclusion Criteria..........................................................................................................22
6.2.
Exclusion Criteria ........................................................................................................23
6.3.
Lifestyle and/or Dietary Requirements .........................................................................24
Meals and Dietary Restrictions.............................................................................25
6.3.1.
Caffeine, Alcohol, and Tobacco ...........................................................................25
6.3.2.
Activity................................................................................................................25
6.3.3.
6.4.
Screen Failures.............................................................................................................25
7.
Treatment..........................................................................................................................26
7.1.
Treatment Administered...............................................................................................26
Packaging and Labeling .......................................................................................26
7.1.1.
7.2.
Method of Treatment Assignment ................................................................................26
Selection and Timing of Doses.............................................................................27
7.2.1.
7.3.
Blinding .......................................................................................................................27


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 3
LY900014
7.4.
Dose Modification........................................................................................................27
7.5.
Preparation/Handling/Storage/Accountability...............................................................27
7.6.
Treatment Compliance .................................................................................................27
7.7.
Concomitant Therapy...................................................................................................28
7.8.
Treatment after the End of the Study............................................................................28
8.
Discontinuation Criteria ....................................................................................................29
8.1.
Discontinuation from Study Treatment.........................................................................29
Discontinuation of Inadvertently Enrolled Subjects ..............................................29
8.1.1.
8.2.
Discontinuation from the Study....................................................................................29
8.3.
Subjects Lost to Follow-up...........................................................................................29
9.
Study Assessments and Procedures ...................................................................................30
9.1.
Efficacy Assessments...................................................................................................30
9.2.
Adverse Events ............................................................................................................30
Serious Adverse Events........................................................................................31
9.2.1.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................31
Complaint Handling.............................................................................................32
9.2.2.
9.3.
Treatment of Overdose.................................................................................................32
9.4.
Safety...........................................................................................................................32
Laboratory Tests ..................................................................................................32
9.4.1.
Vital Signs ...........................................................................................................32
9.4.2.
Electrocardiograms ..............................................................................................32
9.4.3.
Other Tests...........................................................................................................33
9.4.4.
9.4.4.1.
Physical Examinations....................................................................................33
9.4.4.2.
Body Weight ..................................................................................................33
9.4.4.3.
Hip and Waist Circumference.........................................................................33
Safety Monitoring ................................................................................................33
9.4.5.
9.4.5.1.
Glucose Monitoring........................................................................................34
9.4.5.1.1.
Severe Hypoglycemia ...............................................................................34
Injection-Site Assessments (Local Tolerability)....................................................35
9.4.6.
9.5.
Pharmacokinetics .........................................................................................................35
Bioanalysis...........................................................................................................35
9.5.1.
9.6.
Glucodynamics (Euglycemic Glucose Clamp)..............................................................35
Immunogenicity Assessments ..............................................................................36
9.6.1.
9.7.
Genetics .......................................................................................................................37
9.8.
Exploratory Biomarkers ...............................................................................................37
9.9.
Health Economics ........................................................................................................37
10.
Statistical Considerations and Data Analysis .....................................................................38
10.1. Sample Size Determination ..........................................................................................38


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 4
LY900014
10.2. Populations for Analyses..............................................................................................38
Study Participant Disposition ...............................................................................38
10.2.1.
Study Participant Characteristics ..........................................................................38
10.2.2.
10.3. Statistical Analyses ......................................................................................................38
Safety Analyses....................................................................................................38
10.3.1.
10.3.1.1.
Clinical Evaluation of Safety ..........................................................................38
10.3.1.2.
Statistical Evaluation of Safety .......................................................................39
Pharmacokinetic Analyses....................................................................................39
10.3.2.
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................39
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................40
Glucodynamic Analyses.......................................................................................40
10.3.3.
10.3.3.1.
Glucodynamic Parameter Estimation ..............................................................40
10.3.3.2.
Glucodynamic Statistical Inference.................................................................40
Pharmacokinetic/Pharmacodynamic Analyses......................................................40
10.3.4.
Evaluation of Immunogenicity .............................................................................41
10.3.5.
Data Review during the Study..............................................................................41
10.3.6.
Interim Analyses ..................................................................................................41
10.3.7.
11.
References ........................................................................................................................42


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 5
LY900014
List of Tables
Table
Page
Table ITRT.1.
Objectives and Endpoints .......................................................................17
Table ITRT.2.
LY900014 Treatment Sequences ............................................................19
Table ITRT.3.
Treatments Administered........................................................................26


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 6
LY900014
List of Figures
Figure
Page
Figure ITRT.1.
Illustration of study design of Protocol I8B-MC-ITRT............................19


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 7
LY900014
List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................43
Appendix 2.
Clinical Laboratory Tests........................................................................47
Appendix 3.
Study Governance, Regulatory, and Ethical Considerations....................48
Appendix 4.
Blood Sampling Summary......................................................................51
Appendix 5.
Protocol Amendment I8B-MC-ITRT(a) Summary
Effect of Injection Site on the Relative and Absolute 
Bioavailability of Single Dose of LY900014 in Healthy Subjects ...........52


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 8
LY900014
1. Protocol Synopsis
Title of Study:
Effect of injection site on the relative and absolute bioavailability of single dose of LY900014 in healthy subjects.
Rationale: 
In clinical practice, it is recommended that patients rotate insulin injections and may inject insulin at different tissue 
sites.  The actual site of subcutaneous (SC) injection may influence the absorption pharmacokinetics (PK), as well 
as, the glucodynamic (GD) effect.  The primary objective of this study is therefore to compare the bioavailability of 
insulin lispro following administration of the commercial formulation of LY900014 at 3 different injection sites SC 
in the abdominal wall, thigh, and deltoid.  In addition, the intravenous (IV) administration will serve as the reference 
to determine the absolute bioavailability of SC injections into the deltoid, thigh or abdomen and GD activity.
Objectives/Endpoints:
Objectives
Endpoints
Primary
To determine the relative bioavailability of insulin 
lispro from LY900014 after SC injection into the thigh
and deltoid compared to the abdomen in healthy 
subjects.
Area under the concentration versus time curve from 
time zero to infinity (AUC[0-∞])
To determine absolute bioavailability of insulin lispro 
following SC administrations of LY900014 into the 
thigh, deltoid and abdomen compared to IV 
administration of LY900014 in healthy subjects.
Percent of the ratio of AUC(0-∞)
Secondary
To evaluate the tolerability of LY900014 in healthy 
subjects.
Adverse events (AEs) and injection-site reactions
To evaluate the GD during euglycemic clamp 
procedure of LY900014 after SC injection into the 
abdomen, thigh and deltoid and IV in healthy subjects.
Total amount of glucose infused (Gtot) and maximum 
glucose infusion rate (Rmax).
Summary of Study Design:  
Study I8B-MC-ITRT is a single-center, open-label, 4-period, randomized, crossover, up to 10-hour euglycemic 
clamp study in healthy subjects to compare the insulin lispro PK and GD of LY900014 after SC administration of a 
15-U injection at 3 different injection sites and a single IV bolus injection of 15 U.  The SC injection sites are the 
abdomen, thigh, and deltoid.  An IV injection into the forearm will be used to assess absolute bioavailability.
Treatment Arms and Planned Duration for an Individual Subject:  
Subjects will be randomly assigned to 1 of 4 treatment sequences; each sequence will have 4 periods.  In 3 of the 
4 periods, subjects will be administered single SC doses of 15 U of LY900014 at 3 different injection sites, which 
include the thigh, abdomen and deltoid.  One study period will include a single IV dose of 15 U of LY900014.


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 9
LY900014
The study will include a 28-day screening period, followed by 4 study periods.  There will be a wash-out period of at 
least 3 days between each study period. The follow-up visit will take place at least 14 days after the last dose.  
Number of Subjects:
Up to 28 healthy men and women may be enrolled to target at least 22 subjects complete the study.
Statistical Analysis:
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, whether or not they complete all protocol requirements.  
All investigational product and protocol-procedure AEs will be listed, and if the frequency of events allows, safety 
data will be summarized using descriptive methodology. 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.
Log-transformed AUC(0-∞) and maximum observed serum concentration (Cmax) for insulin lispro will be evaluated 
to estimate geometric least-squares means (LSmeans), ratios of geometric LSmeans between injection sites (deltoid 
and thigh compared with the abdomen), and their corresponding 90% confidence interval (CI) using the statistical 
model that includes injection site, period, and sequence as fixed effects, and subject within sequence as a random 
effect.  The primary parameter for the statistical analysis of the relative bioavailability between injection sites will 
be the AUC(0-∞).
Log-transformed Rmax and Gtot will be evaluated to estimate geometric LSmeans, ratios of geometric LSmeans 
between injection sites (deltoid and thigh compared with the abdomen), and their corresponding 90% CIs using the 
statistical model that includes injection site, period, and sequence as fixed effects, and subject within sequence as a 
random effect.  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.
The PK and GD analyses will also be performed using the subset of the subjects who complete all treatment periods 
with evaluable data.
The frequency of antibody formation to insulin lispro will be determined.  The relationship between the presence (or 
absence) of antibodies and AEs will be assessed.  Likewise, the relationship between the presence of antibodies and 
the PK parameters and GD response to insulin lispro may be assessed.


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 10
LY900014
2. Schedule of Activities


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 11
LY900014
Study Schedule of Protocol I8B-MC-ITRT
Procedures
Screening
Periods 1, 2, 3, 4
FU/
EDa
Comments
Up to 
Day -28
Day -1
Day 1
Day 2
Informed consent
X
Admission to CRU
X
Enrollment
X
Enrollment prior to taking first predose blood 
sample for the study.
Overnight fast
X
X
Subjects are expected to fast for approximately 
8 hours before screening, and at least 8 hours 
before each dose until the end of the glucose 
clamp procedure.
Height
X
Weight
X
X#
X
# Period 1 only
Hip and waist 
circumference
X#
# Period 1 only
Medical history and 
physical examination
X
Medical assessment
X
Predose 
X*
X
Medical assessment includes medical review and 
physical examination, as appropriate.  *Prior to
discharge from CRU for each period
Vital signs (supine): blood 
pressure and pulse rate 
X
Predose, 1 hour postdose (IV period 
only), and 10 hours postdose (at the 
end of clamp procedure)
X
Predose vital signs may be collected up to 
3 hours before dosing.  
12-Lead ECG
X
Predose and 10 hours postdose (at 
the end of clamp procedure)
X
Single ECGs will be collected for safety.  
Predose ECGs may be collected up to 3 hours
before dosing.  
Clinical laboratory tests
X
Predose of Period 1. For IV period: 
1 hour postdose 
X
One hour postdose blood samples will be drawn 
only for the study period when LY900014 is 
administered intravenously.  
Pregnancy test 
X
X
X
For females of childbearing potential only.  A 
serum pregnancy test will be performed at 
screening and urine pregnancy tests will be 
performed at all other time points.


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 12
LY900014
Procedures
Screening
Periods 1, 2, 3, 4
FU/
EDa
Comments
Up to 
Day -28
Day -1
Day 1
Day 2
Study drug administration
0 hour
Time of study drug administration = 0 hour.  
Study drug will be administered at approximately 
the same time on Day 1 of each study period. 
The site of administration will be determined by 
the randomization schedule.
Injection-site assessments
0, 1, 4, and 10 hours postdose
Time 0:  assessments will occur immediately 
following the injection.
Insulin lispro PK sampling
2.5, 5, 10, 15, 20, 25, 30, 40, 60, 70, 
90, 120, 150, 180, 210, 240, 300, 
360, 420, 480, 540, and 600 minutes
Sampling times are relative to the time of study 
drug administration (time 0).
Treprostinil PK sampling
(IV period only)
2.5, 5, 10, and 30 minutes
Only for the study period when LY900014 is 
administered intravenously.  
Sampling times are relative to the time of study 
drug administration (time 0).
C-peptide samples
0, 30, 60, 120, 180, 240, 300, 360, 
420, 480, 540, and 600 minutes
Sampling times are relative to the time of study 
drug administration (time 0).
Blood glucose sampling for 
euglycemic clamp
Approximately every 10 minutes for 
approximately 30 minutes before the 
start of dosing (for baseline 
measurement).  
During clamp, sampling occurs 
every 2.5 minutes for the first 30 
minutes; every 5 minutes for 30 to 
120 minutes; every 10 minutes for 
120 to 480 minutes and every 
20 minutes for 480 to 600 minutes.
Sampling times are relative to study drug 
administration (time 0).  Glucose samples should 
be taken before PK samples.  Failure to obtain 
samples due to clinical issues, such as problems 
with venous access, will not be considered a 
protocol violation.  Repeat samples for counter-
checking of apparent spurious results may be 
taken where indicated.
Pharmacogenetic sample
X
Period 1 only.
Immunogenicity sample
Predose of Periods 1 and 3
X
Additional samples may be collected if the 
investigator considers there is a possibility that 
an adverse event is immunologically indicated.  
Discharge from CRU
X
Subjects will be discharged on Day 2.  


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 13
LY900014
Abbreviations: CRU = clinical research unit; ECG = electrocardiogram; ED = early discontinuation; FU = follow-up; IV = intravenous; PK = pharmacokinetics.
a
Procedures should be performed at least 14 days after the last dose of study drug.
Note:  The site should schedule activities as appropriate.  In cases when several study procedures are scheduled at the same time, the order of priority will be as 
follows:  glucose samples, PK samples, injection-site assessments, vital signs, ECG, clinical laboratory samples.  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.


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 14
LY900014
3. Introduction
3.1.
Study Rationale
In clinical practice, it is recommended that patients rotate insulin injections and may inject 
insulin at different tissue sites.  The actual site of subcutaneous (SC) injection may influence the 
absorption pharmacokinetics (PK), as well as, the glucodynamic (GD) effect. The primary 
objective of this study is therefore to compare the bioavailability of insulin lispro following 
administration of the commercial formulation of LY900014 at 3 different injection sites SC in 
the abdominal wall, thigh, and deltoid. In addition, the intravenous (IV) administration will 
serve as the reference to determine the absolute bioavailability of SC injections into the deltoid,
thigh, or abdomen and GD activity.
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 SC doses of 
insulin lispro ranging from 0.1 to 0.4 U/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 and GD profiles so that they have an even faster 
onset to better match carbohydrate absorption.
LY900014 is an ultra-rapid-acting insulin lispro formulation with treprostinil (active ingredient 
in Remodulin) and other ingredients.  LY900014 has an increased early absorption of insulin 
lispro compared to commercially available insulin lispro (Humalog; Eli Lilly and Company).  
This formulation involves the novel use of a microdose of treprostinil as an excipient to enhance 
the absorption of insulin lispro through 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 IV 
infusion, or as a continuous SC administration for the treatment of symptomatic pulmonary 
arterial hypertension (PAH) and has been approved in the US since 2002 (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 (FDA)’s Generally 
Recognized as Safe Food Additives database and in the FDA’s Inactive 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 have been demonstrated in healthy subjects in 3 previous 
clinical studies, in approximately 71 healthy subjects across a dose range of 7.5 to 30 U.  All 
4 studies were Phase 1, randomized, subject-blind studies in which the PK and GD of LY900014 
and Humalog were evaluated during a euglycemic glucose clamp following SC administration.  
The total insulin lispro exposure and GD effect were similar for LY900014 and Humalog; 


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 15
LY900014
however, LY900014 demonstrated a faster and earlier insulin lispro absorption compared to 
Humalog.  
In addition, data from two Phase 1b studies showed LY900014 was well tolerated in patients 
with type 1 diabetes mellitus (T1DM; 30 patients) and type 2 diabetes mellitus (T2DM; 
30 patients) using multiple daily injections (MDIs).  There were no serious adverse events 
(SAEs) related to study treatment or discontinuations from the studies because of a drug-related 
adverse event (AE).  Small numbers of treatment-emergent adverse events (TEAEs) were 
reported, and there were no notable increases in 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’s Brochure (IB) of LY900014.
3.3.
Benefit–Risk Assessment
Study I8B-MC-ITRT (ITRT) will not offer any direct benefits to the subjects participating in the 
study. The data from previous studies in healthy subjects and data from studies in patients with 
T1DM and T2DM have shown that LY900014 was well tolerated and 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), are hypoglycemia, 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 all doses 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).  The exposures of treprostinil in LY900014 in this study are expected to be 
undetectable compared to those 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 PAH.  
In preclinical safety pharmacology and toxicity studies, or clinical pharmacology studies 
involving LY900014 or treprostinil alone, other than known risks associated with Humalog and 
Remodulin, no additional risks were identified.  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 insulin, subjects will receive IV glucose infusion at a 
variable rate to maintain euglycemia up to 10 hours after insulin lispro administration.  The aim 
of the clamp procedure is to maintain blood glucose within the normal glycemic 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 hypoglycemia in subjects 
participating in Study ITRT.


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 16
LY900014
More information about the known and expected benefits, risks, SAEs, and reasonably 
anticipated AEs of LY900014 are to be found in the IB.  


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 17
LY900014
4. Objectives and Endpoints
Table ITRT.1 shows the objectives and endpoints of the study.
Table ITRT.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To determine the relative bioavailability of insulin 
lispro from LY900014 after SC injection into the thigh 
and deltoid compared to the abdomen in healthy 
subjects.
AUC(0-∞)
To determine absolute bioavailability of insulin lispro 
following SC administrations of LY900014 into the 
thigh, deltoid, and abdomen compared to IV 
administration of LY900014 in healthy subjects.
Percent of the ratio of AUC(0-∞)
Secondary
To evaluate the tolerability of LY900014 in healthy 
subjects.
Adverse events and injection-site reactions
To evaluate the GD during euglycemic clamp procedure
of LY900014 after SC injection into the abdomen, 
thigh, and deltoid and IV in healthy subjects.
Gtot and Rmax
Exploratory Objectives
To evaluate C-peptide levels after administration of 
LY900014.
C-peptide concentrations
To determine plasma concentrations of the excipient, 
treprostinil, following administration of a single, IV 15-
U dose of LY900014 in healthy subjects.
Plasma concentrations–over-time profile
Abbreviations: AUC(0-∞) = area under the concentration versus time curve from time zero to infinity; GD = 
glucodynamics; Gtot = total amount of glucose infused; IV = intravenous; Rmax = maximum glucose infusion 
rate; SC = subcutaneous.


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 18
LY900014
5. Study Design
5.1.
Overall Design
This is a Phase 1, single-center, open-label, 4-period, randomized, crossover, up to 10-hour 
euglycemic clamp study in approximately 28 healthy subjects to compare the insulin lispro PK
and GD of LY900014 after SC administration of a 15-U dose at 3 different injection sites and a 
single IV bolus injection of 15 U. The SC injection sites are the abdomen, thigh, and deltoid.
Subjects will be required to attend the clinical research unit (CRU) on at least 6 occasions: 

screening visit (may occur up to 28 days before randomization)

four treatment visits for the clamp procedure (study Periods 1 to 4) with a 
wash-out period of ≥3 days between discharge and the next admission to the CRU

follow-up visit (at least 14 days after last dose), or early discontinuation.
Each subject will be randomly assigned to a treatment sequence and will be administered single 
doses of 15 U of LY900014 (on 4 occasions).
Subjects will be admitted to the CRU on the evening before each dosing day and will remain in 
the CRU for the duration of the clamp period and until discharge by the investigator.  Subjects 
are expected to fast for at least 8 hours before each dose.  Following dose administration, each 
subject will undergo an euglycemic clamp procedure of up to 10 hours. Upon completion of the 
clamp procedures, the subjects will be provided a meal and observed overnight.  Subjects will be
discharged from the CRU the next day after medical assessments.
Study governance considerations are described in detail in Appendix 3.
Figure ITRT.1 illustrates the study design and Table ITRT.2 presents the treatment sequences.


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 19
LY900014
Abbreviations: CRU = clinical research unit; IV = intravenous; SC = subcutaneous.
*Single dose of LY900014 administered either SC in the abdomen, thigh, deltoid or IV.
Up to 10-hour euglycemic clamp procedure after each dose.
Figure ITRT.1.
Illustration of study design of Protocol I8B-MC-ITRT.
Table ITRT.2.
LY900014 Treatment Sequences
Treatment 
Sequence
Period 1
Period 2
Period 3
Period 4
1
LY900014 Abdomen
LY900014 Thigh
LY900014 Deltoid
LY900014 IV
2
LY900014 Deltoid
LY900014 Abdomen
LY900014 IV
LY900014 Thigh
3
LY900014 IV
LY900014 Deltoid
LY900014 Thigh
LY900014 Abdomen
4
LY900014 Thigh
LY900014 IV
LY900014 Abdomen
LY900014 Deltoid
Abbreviation:  IV = intravenous.
Note: Subcutaneous injection sites are the abdomen, deltoid and thigh.
5.2.
Number of Participants
A total of 28 subjects may be enrolled so that at least 22 subjects complete the study. For 
purposes of this study, a subject completes the study when all scheduled procedures shown in the 
Schedule of Activities (Section 2) have been completed.
If subjects discontinue from the study before completion of all 4 study periods, replacement 
subjects may be enrolled up to 28 subjects following agreement between the investigator and the 
sponsor.
A replacement subject will be assigned the treatment sequence of the discontinued subject and 
complete that treatment sequence in its entirety.
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last subject.
LY900014*
LY900014*
LY900014*
LY900014*
Screening
Period 1
Period 2
Period 3
Period 4
Follow-up
Wash-out
Wash-out
Wash-out
Healthy 
Subjects
≤28 days
CRU Inpatient
CRU Inpatient
CRU Inpatient
CRU Inpatient
≥3 
days
≥3 
days
≥3 
days
≥14 days


I8B-MC-ITRT(a)Clinical Pharmacology Protocol
Page 20
LY900014
5.4. ScientificRationale for Study Design
A population of healthy subjectsisselected based on the likelihood of less physiologic 
variability in the absence of disease states that may affect multiple organ systems and absence of 
other confounding factors such as concomitant medications.  
The use ofa crossover design allows each subject to serve as his or her own control, thereby 
reducing variability.
A euglycemic clamp technique, the gold standard methodology for assessing insulin action, will 
be used in this study to provide data onthe GD activity of LY900014(see Section9.6for a 
detailed description of the clamp methodology).Based on previous studies,the 10-hourduration 
of the euglycemic glucose clamp will allow for a complete assessment of GD activity of 
LY900014.
Based on the PK properties of treprostinil (half-life associated with the terminal rate constant in 
noncompartmental analysis[t
1/2]=approximately1 hour)and Humalog (t1/2=0.79hours), the 
durationof the washout period between clamp visits (a minimum of 3days) and the duration
between 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 insulin 
lispro.  The insulin lispro concentrations in the body resulting from administration of this dose to 
healthy subjects are anticipated to be measurable over the sampling period. Additionally, it is 
anticipated that this dose will provide an adequateglucose infusion rate (GIR)for assessment of 
GD.
The safety, PK, and pharmacology of LY900014 at similar doses and with the similar 
formulation composition have been assessed inclinical studies in healthy subjects,in patients 
with T1DMusing MDI or insulin pump treatment andT2DMusing MDI.In addition, the
components of LY900014 have been tested in 3 clinical studies that included the evaluation of 
the safety, PK, and pharmacology of SC bolus doses of treprostinil (see LY900014 IB).
All tested doses of treprostinil (
), insulin lispro, and LY900014 were well tolerated
in healthy subjects,patients with T1DM,and patients with T2DM. There were no SAEs related 
to study treatment in any of the 8studies.No subject discontinued from the studies because of
drug-related AEs. Trial participants in these studies were monitored for changes in vital signs;
there were no significant systemic hemodynamic effects of treprostinil at the doses administered
based on blood pressure and heart rate. Visual analog scale pain scores showed that theSC 
injections of insulin lispro plus treprostinil co-formulations and treprostinil alone were well 
tolerated.
In summary, there were smallnumbers of TEAEsand injection-site AEs, but there was no 
clinically significant increase in these or other events compared to placebo or toHumalog and no 


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 21
LY900014
clinically significant increase in frequency with higher doses of treprostinil. Notably, at the 
higher doses of treprostinil, there was no clinically significant increase in those AEs associated 
with systemic absorption as described in the Remodulin package insert (2014) (that is, headache, 
diarrhea, nausea, jaw pain, vasodilatation, rash, edema, and hypotension). This is likely 
attributable to the relatively lower exposures of treprostinil demonstrated in these clinical 
studies.
It is expected that the treprostinil concentration in the plasma following the 15-U IV bolus 
administration of LY900014 containing 
 of treprostinil to be below the lower limit of 
quantitation (LLOQ).  As published, the SC infusion of Remodulin has a 100% absolute 
bioavailability (Remodulin package insert, 2014); thus, it is expected that plasma exposures of 
treprostinil between IV and SC administrations of LY900014 will be similar.  The PK of 
treprostinil in LY900014 following SC administration of 15 U of LY900014 was assessed in 
previous studies.  In these studies, treprostinil exposure was not detectable for the 15-U dose of 
LY900014.
CCI
e be


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 22
LY900014
6. Study Population
Eligibility of subjects for the study 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:
[1]
are overtly healthy males or females, as determined by medical history and 
physical examination  
[1a] female subjects:
For female subjects of childbearing potential (defined as not surgically sterilized 
and between menarche and 1-year postmenopause):
o
test negative for pregnancy at the time of screening
o
are not lactating
o
intend not to become pregnant during the study
o
are sexually inactive or have practiced a reliable method of birth control 
(eg, use of oral contraceptives or levonorgestrel, diaphragms with 
contraceptive jelly, cervical caps with contraceptive jelly, condoms with 
contraceptive foam, intrauterine devices, partner with vasectomy, or 
abstinence) for at least 6 weeks prior to screening
o
agree to continue to use a reliable method of birth control (as determined 
by the investigator) until the end of the study
Female subjects not of childbearing potential due to surgical sterilization (at least 
6 weeks after surgical bilateral oophorectomy with or without hysterectomy or at least 
6 weeks after tubal ligation) confirmed by medical history or due to menopause.
o
Menopausal women include women with either
1) spontaneous amenorrhea for at least 12 months, not induced by a medical 
condition such as anorexia nervosa and not taking medications during the 
amenorrhea that induced the amenorrhea (eg, oral contraceptives, hormones, 


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 23
LY900014
gonadotropin-releasing hormone, antiestrogens, selective estrogen receptor 
modulators, or chemotherapy)
or
2) spontaneous amenorrhea for 6 to 12 months and a follicle-stimulating 
hormone level consistent with menopausal state
[2]
are between 21 and 65 years of age at the time of screening, inclusive.
[3]
have a body weight of ≥45 kg, and body mass index (BMI) of 18.0 to 
30.0 kg/m2, inclusive
[4]
have clinical laboratory test results within normal reference range for the 
population or CRU, or results with acceptable deviations that are judged to be 
not clinically significant by the investigator.
[5]
have venous access sufficient to allow for blood sampling, IV administration,
and clamp procedure as per the protocol.
[6]
are nonsmokers, have not smoked for at least 6 months before entering the 
study, and agree not to smoke (cigars, cigarettes, or pipes) or use smokeless 
tobacco or nicotine products for the duration of the study.
[7]
are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures.
[8]
are able and willing to give signed informed consent.
6.2.
Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or enrollment:
[9] are CRU personnel directly affiliated with this study and their immediate 
families.  Immediate family is defined as a spouse, biological or legal
guardian, child, or sibling.
[10] are Lilly employees.
[11] are currently enrolled in a clinical study involving an investigational product 
(IP) or any other type of medical research judged not to be scientifically or 
medically compatible with this study.
[12]
have participated, within the last 30 days, in a clinical study involving an IP.  
If the previous IP has a long half-life, 5 half-lives, or 3 months (whichever is 
longer) should have passed.
[13]
have previously completed or withdrawn from this study.  
[14]
have known allergies to treprostinil or insulin lispro, related compounds, or 
any components of the formulation, or history of significant atopy.


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 24
LY900014
[15]
have an abnormality in the 12-lead ECG that, in the opinion of the 
investigator, increases the risks associated with participating in the study.  
[16]
have an abnormal blood pressure and/or pulse rate as deemed to be clinically 
significant by the investigator.
[17]
have a history or presence of cardiovascular, respiratory, hepatic, renal, 
gastrointestinal, endocrine, hematological, or neurological disorders capable 
of significantly altering the absorption, metabolism, or elimination of drugs; 
of constituting a risk when taking the IP; or of interfering with the 
interpretation of data.
[18]
have a history or presence of psychiatric disorders as deemed clinically 
significant by the investigator.
[19]
regularly use known drugs of abuse.
[20]
show evidence of human immunodeficiency virus (HIV) infection, and/or 
positive human HIV antibodies.
[21]
show evidence of hepatitis B and/or positive hepatitis B surface antigen.
[22]
show evidence of hepatitis C and/or positive hepatitis C antibody.
[23]
use over-the-counter or prescription medication within 7 to 14 days, 
respectively, prior to dosing (apart from vitamin/mineral supplements, 
occasional paracetamol, thyroid replacement medication, or birth control 
methods) and throughout the study period.  If this situation arises, inclusion of 
an otherwise suitable subject may be at the discretion of the investigator and 
sponsor.
[24]
have donated blood or have blood loss of more than 450 mL within the 
previous 3 months of study screening.
[25]
have an average weekly alcohol intake that exceeds 21 units per week (males) 
and 14 units per week (females), or are unwilling to stop alcohol consumption 
from 24 hours prior to dosing and until discharge from the CRU
(1 unit = 12 oz or 360 mL of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of 
distilled spirits).
[26]
in the opinion of the investigator or sponsor, are unsuitable for inclusion in the 
study.
Additional inclusion criterion:
[27]
have a hemoglobin level of ≥12.5 g/dL at screening.
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.  


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 25
LY900014
Meals and Dietary Restrictions
6.3.1.
For all treatment periods subjects will fast for at least 8 hours prior to dosing and until the 
glucose clamp procedure is completed, after which subjects will receive a meal.  Water can be 
consumed freely during this time.
When not a resident at the CRU, subjects will be encouraged to follow their normal diets.
Caffeine, Alcohol, and Tobacco
6.3.2.
No alcohol will be allowed at least 24 hours before each dose and for the duration of each CRU 
visit.
Subjects should refrain from caffeine-containing food/beverages (eg, cola, chocolate, Milo, tea, 
and coffee) for at least 12 hours before each dose and throughout the duration of each CRU visit.  
Smoking (cigars, cigarettes, or pipes) and the use of smokeless tobacco will not be permitted 
during the study.
Activity
6.3.3.
Subjects are encouraged to maintain their regular exercise habits; however, they should not 
undertake vigorous or prolonged exercise within 48 hours prior to dosing.  These subjects will be 
excluded from this study, as judged by the investigator to prevent interference 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 (screen failure) may not be 
re-screened.


I8B-MC-ITRT(a)Clinical Pharmacology Protocol
Page 26
LY900014
7.Treatment
7.1. TreatmentAdministered
Thestudy involves a comparison of LY900014administered once throughSC at different 
injection sites which include, the abdomen, thigh, and deltoid and administered once throughIV
in the forearm.  TableITRT.3showsthetreatment regimens.
The CRUmust have resuscitation equipment, emergency drugs, and appropriately trained staff 
available during theIP administration.
TableITRT.3.
TreatmentsAdministered
Treatment Name
LY900014
Insulin lispro dosage formulation
100 U/mL
Insulin lispro dosage level
15 U
Treprostinil concentration (treprostinil dose)
Route of administration
SC injection or IVbolus
Abbreviations:  IV = intravenous; SC = subcutaneous.
The investigator or designee is responsible for
explaining the correct use of the IPto the CRUpersonnel 
verifying that instructions are followed properly
maintaining accurate records of IPdispensationand collection
and returning all unused medicationsto Lilly or its designee at the end of the study
Note: In some cases, the CRUmay destroy the material if, during the investigativesite 
selection, the evaluator has verified and documented that the CRUhas appropriate facilities and 
written procedures to dispose of clinical materials.
Packaging and Labeling
7.1.1.
Clinical studymaterials 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.  
Eachvial will contain 
.A pharmacist at the 
CRU or other CRU personnel will use the insulin vials provided to prepare the syringesfor dose 
administrations.  
7.2. Method of Treatment Assignment
CCI
The injection site where LY900014 isto be injected on a given treatment day will be determined 
according to a randomization schedule.
CCI


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 27
LY900014
Selection and Timing of Doses
7.2.1.
The actual date and time of all dose preparations will be documented, and the actual time of all 
dose administrations will be recorded in the subject’s electronic case report form (eCRF).  For 
each subject, the doses will be administered at approximately the same time on Day 1 of each 
study period.
Subjects will receive LY900014 at the injection site specified in the treatment sequence to which 
they have been randomized.  The SC injection site shall be either a lower quadrant of the 
abdominal wall, nondominant upper lateral arm, or the anterior midline of the thigh or subjects 
will receive one IV dose of LY900014.  An appropriate size of needle shall be used to ensure all 
injections are delivered to a consistent depth target into the SC space.
The IV administration of LY900014 will be a bolus push through a cannula into a vein in the 
forearm, followed immediately by flushing with normal saline.
All study treatments will be given in the CRU by qualified CRU 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.
7.3.
Blinding
This is an open-label study.
7.4.
Dose Modification
Dose adjustments are not allowed in this study.
7.5.
Preparation/Handling/Storage/Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained, as communicated by the sponsor, during transit for all IPs received and any 
discrepancies are reported and resolved before use of the study treatment.
Only participants enrolled in the study may receive IP, and only authorized CRU staff may 
supply or administer IP. All IPs 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 CRU staff.
The IP must be stored at the CRU under refrigerated conditions (between 2°C to 8°C) in a locked 
and secure place.  Insulin must not be frozen.
The investigator is responsible for the IP accountability, reconciliation, and record maintenance 
(such as receipt, reconciliation, and final disposition records).
7.6.
Treatment Compliance
The IP will be administered at the CRU, and documentation of treatment administration will 
occur at the CRU.


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 28
LY900014
7.7.
Concomitant Therapy
Subjects should not use over-the-counter or prescription medications within 7 and 14 days, 
respectively, before each dosing (apart from vitamin and mineral supplements, occasional 
paracetamol, thyroid replacement therapy, or birth control medication) and throughout the study 
period.  If a subject does use these medications, inclusion of the subject may be at the discretion 
of the investigator and sponsor.
If the need for concomitant medication arises, inclusion or continuation of the subject may be at 
the discretion of the investigator, and when possible, after consultation with a Lilly clinical 
pharmacologist (CP)/clinical research physician (CRP).  Any additional medication used during 
the course of the study must be documented.  
7.8.
Treatment after the End of the Study
Not applicable.


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 29
LY900014
8. Discontinuation Criteria
Subjects discontinuing the IP and/or study prematurely for any reason should complete 
procedures per Section 2 of this protocol.
8.1.
Discontinuation from Study Treatment
Discontinuation of Inadvertently Enrolled Subjects
8.1.1.
If the sponsor or investigator identifies a subject who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Lilly CP/CRP and the investigator to 
determine if the subject may continue in the study.  If both agree it is medically appropriate to 
continue, the investigator must obtain documented approval from the Lilly CP/CRP to allow the 
inadvertently enrolled subject to continue in the study with or without continued treatment with 
IP.  
8.2.
Discontinuation from the Study
Subjects will be discontinued under the following circumstances:

Enrollment in any other clinical study involving an IP 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 subject should be discontinued from the study

Subject Decision
o
the subject, or legal representative, requests to be withdrawn from the study.
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 CRU.  The CRU 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 CRU.


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 30
LY900014
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.
Unless otherwise stated in the subsections below, all samples collected for specified laboratory 
tests will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may 
be retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1.
Efficacy Assessments
Not applicable for this study.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of subjects who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the subject.
The investigator is responsible for the appropriate medical care of subjects during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for the following, through an appropriate health care 
option, AEs that are serious or otherwise medically important, considered related to the IP or the 
study, or that caused the subject to discontinue the IP before completing the study.  The subject
should be followed until the event resolves, stabilizes with appropriate diagnostic evaluation, or 
is reasonably explained.  The frequency of follow-up evaluations of the AE is left to the 
discretion of the investigator.
After the informed consent form (ICF) is signed, CRU personnel will record, via electronic data 
entry, the occurrence and nature of each subject’s preexisting conditions, including clinically 
significant signs and symptoms of the disease under treatment in the study.  Additionally, CRU
personnel will record any change in the condition(s) and the occurrence and nature of any AEs.  
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, or a study procedure, taking into account the disease, 
concomitant treatment, or pathologies.
A “reasonable possibility” means that there is a potential cause and effect relationship between 
the IP, 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.


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 31
LY900014
If a subject’s IP is discontinued as a result of an AE, CRU personnel must report this to Lilly or 
its designee via electronic data entry.
Serious Adverse Events
9.2.1.
An SAE is any AE from this study that results in 1 of the following:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the patient or may require intervention to prevent 1 
of the other outcomes listed in the definition above.
The CRU personnel must alert the Lilly CRP/CP, or its designee, of any SAE as soon as 
practically possible.
Additionally, CRU personnel must alert Lilly Global Patient Safety, or its designee, of any SAE 
within 24 hours of investigator awareness of the event via a sponsor-approved method.  If alerts 
are issued via telephone, they are to be immediately followed with official notification on 
study-specific SAE forms.  This 24-hour notification requirement refers to the initial SAE 
information and all follow-up SAE information.
Although all AEs are recorded in the electronic data entry after signing informed consent, SAE 
reporting to the sponsor begins after the subject has signed informed consent and has received IP.  
However, if an SAE occurs after signing ICF, but prior to receiving IP, AND is considered 
Reasonably Possibly Related to a study procedure then it MUST be reported.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued from and/or completed the study (the subject summary eCRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly.
Pregnancy (maternal or paternal exposure to IP) 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 reports as related to IP or procedure.  Lilly has procedures that 


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 32
LY900014
will be followed for the recording and expedited reporting of SUSARs that are consistent with 
global regulations and the associated detailed guidances.
Complaint Handling
9.2.2.
Lilly collects product complaints on IPs and drug delivery systems used in clinical studies 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 IP so that the situation can be assessed.
9.3.
Treatment of Overdose
For the purposes of this study, an overdose of LY900014 is considered any dose higher than the 
dose assigned through randomization.
Excess insulin administration may cause hypoglycemia and hypokalemia. Mild episodes of 
hypoglycemia 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 hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be 
corrected appropriately.
9.4.
Safety
Laboratory Tests
9.4.1.
For each subject, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2).  
Vital Signs
9.4.2.
For each subject, vital sign measurements should be conducted according to the Schedule of 
Activities (Section 2) and as clinically indicated.
Blood pressure and pulse rate should be measured after at least 5 minutes supine.
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms.  Additional vital signs may be measured during each study period if 
warranted.
Electrocardiograms
9.4.3.
For each subject, ECGs should be collected according to the Schedule of Activities (Section 2).  
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
subject receives the first dose of the IP, should be reported to Lilly, or its designee, as an AE via 
electronic data entry methods.  


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 33
LY900014
For each subject, a single 12-lead digital ECG will be collected according to the Schedule of 
Activities (Section 2).  Subjects must be supine for approximately 5 to 10 minutes before ECG 
collection and remain supine but awake during ECG collection.  Electrocardiograms may be 
obtained at additional times, when deemed clinically necessary.  All ECGs recorded should be 
stored at the CRU.
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the CRU as soon after the time of ECG collection as possible, and ideally while the 
subject is still present, to determine whether the subject meets entry criteria at the relevant 
visit(s) and for immediate subject management, should any clinically relevant findings be 
identified.
If a clinically significant finding is identified (including, but not limited to, changes in 
QT/corrected QT interval from baseline) after enrollment, the investigator will determine if the 
subject can continue in the study.  The investigator, or qualified designee, is responsible for 
determining if any change in subject 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.
Other Tests
9.4.4.
9.4.4.1.
Physical Examinations
Physical examinations and routine medical assessments will be conducted as specified in the 
Schedule of Activities (Section 2) and as clinically indicated.
9.4.4.2.
Body Weight
Body weight will be recorded as specified in the Schedule of Activities (Section 2) and as 
clinically indicated.
9.4.4.3.
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.
Safety Monitoring
9.4.5.
The Lilly CP or CRP/scientist will monitor safety data throughout the course of the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly CP or 
CRP will periodically review all safety data including laboratory analytes and AEs.
When appropriate, the Lilly CP or CRP will consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical research scientist.


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 34
LY900014
9.4.5.1.
Glucose Monitoring
Hypoglycemia will be described using the following definitions:

Documented hypoglycemia:
o
Symptomatic hypoglycemia: an event during which typical symptoms of 
hypoglycemia are accompanied by plasma glucose ≤70 mg/dL (3.9 mmol/L)
o
Asymptomatic hypoglycemia: an event not accompanied by typical 
symptoms of hypoglycemia but with plasma glucose ≤70 mg/dL (3.9 mmol/L)

Unspecified hypoglycemia:  an event during which plasma glucose ≤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 plasma glucose determination (but that 
was presumably caused by plasma glucose ≤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.  During these 
episodes, the subject has an altered mental status and cannot assist in their care, is 
semiconscious or unconscious, or experienced 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 is considered sufficient evidence that the event 
was induced by a low plasma glucose concentration (≤70 mg/dL [3.9 mmol/L])

Nocturnal hypoglycemia: any hypoglycemic event (documented symptomatic, 
asymptomatic, probable symptomatic, or severe hypoglycemia) that occurs between 
bedtime and waking

Relative hypoglycemia: an event during which typical symptoms of hypoglycemia, 
that do not require the assistance of another person, are accompanied by plasma 
glucose >70 mg/dL (3.9 mmol/L), but these levels may be quickly approaching the 
70-mg/dL (3.9-mmol/L) threshold

Total hypoglycemia:  This optional category combines all cases of hypoglycemia.  If 
an event of hypoglycemia falls into multiple subcategories, the event is counted only 
once in this category
The goal of the euglycemic clamp is to maintain glucose concentrations at normoglycemic levels 
close to a predefined target.  Therefore, plasma glucose concentrations below 70 mg/dL will not 
routinely be recorded as hypoglycemic events during the glucose clamp procedure.  However, at 
the discretion of the investigator, decrease in glucose concentrations may be recorded as a 
hypoglycemic event based on clinical concern or related to technical issues resulting in 
hypoglycemia.
9.4.5.1.1. Severe Hypoglycemia
The determination of a hypoglycemic event as an episode of severe hypoglycemia as defined 
above will be made by the investigator based on the medical need of the subject to have required 
assistance and is not predicated on the report of a subject simply having received assistance.


I8B-MC-ITRT(a)Clinical Pharmacology Protocol
Page 35
LY900014
Only severe hypoglycemia episodeswill be reported as AEs.  All episodes of severe 
hypoglycemia will be reported as SAEs.
Injection-Site Assessments (Local Tolerability)
9.4.6.
Injection-site assessments for local tolerability will be conducted as specified in the Schedule of 
Activities (Section 2) and more frequently if deemed necessary by the investigator.
Digital pictures will be taken, if possible,of the injection site at the time of identification of local 
intolerability and thereafter as often as judged necessary by the investigator.  The pictures should 
include subject number, visit number, time after dosing, and a ruler for scaling.
Local tolerability at the injection site will be evaluated by means of assessments within the 
following categories:  painon palpation, itching, erythema, edema, and induration/infiltration.
9.5. Pharmacokinetics
At the visits and times specified in the Scheduleof Activities(Section 2), venous blood samples 
of approximately
 1mL each will be collected to determine the serum concentrations of insulin 
lisproand samples of approximately 2 mL 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) of each sampling will be recorded.  Failure to obtain 
blood samples due to clinical reasons, such as problems with venous access, will not be 
considered protocol violations.  However, the CRU will still be required to notify the sponsor in 
writing to account for missing samples for data reconciliation purpose.
Bioanalysis
9.5.1.
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.
Concentrations of insulin lisproin serum following LY900014 administration will be assayed 
using a 
.  Concentrations of treprostinil in plasma
following LY900014 IV administrationwill be assayed using a validated 
 
.
Bioanalytical samplescollected to measureinsulin lispro and treprostinil concentrationswill be 
retained for a maximum of 1 year following the last subject visit for the study.
9.6. Glucodynamics(Euglycemic Glucose Clamp)
CCI
The aim of the euglycemic 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 GIRwill be adjusted to maintain a predetermined target blood glucose 
concentration for the individual subject.  Thus, blood glucose concentrations are kept constant 
whilethe GIR varies.  The varying GIR will then reflect the GD activity of insulin.
CCI
CCI


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 36
LY900014
All glucose clamp procedures will be performed after an overnight fast of at least 8 hours.  On 
the morning of each study period, a small catheter will be placed into a forearm vein, ideally at 
the elbow, for infusion of glucose.  Another catheter will be placed at the wrist or hand or, in the 
case of difficult venous access, in the forearm as close to the wrist as possible for blood 
sampling.  This area will be heated with a warming device to approximately 55°C to 60°C for 
sampling arterialized venous blood.  Blood samples will be obtained at the bedside for 
immediate determination of whole blood glucose concentrations using an automated glucose 
oxidase technique or other appropriate analytical method.  These glucose measurements shall be 
used for subject safety management as well as for GD evaluations.
The time of administration of LY900014 will be defined as time zero.  Following completion of 
dosing, in conjunction with frequent blood sampling for measurement of blood glucose, 20% 
dextrose will be infused IV at a variable rate in order to maintain euglycemia up to 10 hours after 
LY900014 administration.
The clamp procedure will continue for up to 10 hours after dose or until after blood glucose 
concentrations return to baseline without any glucose being administered for at least 30 minutes, 
whichever is earlier.
Sampling for blood glucose should occur as described in the Schedule of Activities (Section 2).  
Repeat samples for counter-checking of apparent spurious results may be taken where indicated.  
Three or 4 predose glucose values will be used for calculation of mean predose fasting blood 
glucose (FBG) concentration.
The target value for blood glucose concentrations is defined as 5 mg/dL below the mean of 
predose FBG concentration measured on the day of the glucose clamp.  Subjects will not be 
clamped to a glucose target of lower than 63 mg/dL (whole blood).  Therefore, subjects with a 
mean predose FBG less than 68 mg/dL (equivalent to a fasting plasma glucose of 76 mg/dL 
[4.21 mmol/L]) will not undergo the clamp procedure but may be deferred to a later period.  In 
addition, any study procedures conducted up to that time may be repeated in that later period.
The GIRs required to maintain target glucose levels and blood glucose concentrations will be 
documented throughout the procedure.  Subjects will be medically assessed before discharge 
from the CRU (see Schedule of Activities [Section 2]).
Immunogenicity Assessments 
9.6.1.
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 presence of insulin lispro.
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and ethical review boards (ERBs) allow, at a facility selected by the 


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 37
LY900014
sponsor.  The duration allows the sponsor to respond to future regulatory requests related to the 
IP.  Any samples remaining after 15 years will be destroyed.  
9.7.
Genetics
A blood sample will be collected for pharmacogenetic analysis as specified in the Schedule of 
Activities (Section 2), where local regulations allow.
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable exposure or response to the 
study drug and to investigate genetic variants thought to play a role in diabetes mellitus.  
Assessment of variable response may include evaluation of AEs.  
All samples will be coded with the subject number.  These samples and any data generated can 
be linked back to the subject only by the CRU personnel.
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and/or ERBs impose shorter time limits, for the study at a facility 
selected by Lilly.  This retention period enables use of new technologies, response to regulatory 
questions, and investigation of variable response that may not be observed until later in the 
development of 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.
Exploratory Biomarkers
Blood samples will be obtained for determination of C-peptide concentrations as specified in the 
Schedule of Activities (Section 2).  These samples and any remaining serum after C-peptide 
analyses will be discarded. Instructions for the collection and handling of these samples will be 
provided by the sponsor. 
9.9.
Health Economics
This section is not applicable for this study.


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 38
LY900014
10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
Up to 28 subjects may be enrolled to ensure that at least 22 subjects complete the study.  
Twenty-two completing subjects will provide estimated 2-sided 90% confidence intervals (CIs) 
of the ratios of geometric means for AUC[0-∞] after SC injection into the thigh and deltoid, 
compared to the abdomen, to be within approximately 0.8 to 1.25 when the observed ratio is 1.  
This calculation is based on the assumption of a log-normal distribution and an estimate of 
intrasubject log-scale standard deviation of 0.2. 
10.2. Populations for Analyses
Study Participant Disposition
10.2.1.
A detailed description of subject disposition will be provided at the end of the study.  
Study Participant Characteristics
10.2.2.
Standard baseline characteristics of age, sex, ethnicity, race, height, weight, and BMI will be
summarized for all randomized subjects.  
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.
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
10.3.1.
Safety analyses will be conducted for all enrolled subjects, whether or not they completed all 
protocol requirements.
Any change to the data analysis methods described in the protocol will require an amendment
only if it changes a principal feature of the protocol.  Any other change to the data analysis
methods described in the protocol and the justification for making the change will be described
in the study results.
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.  
10.3.1.1. Clinical Evaluation of Safety
All IP and protocol procedure AEs will be listed, and if the frequency of events allows, safety 
data will be summarized using descriptive methodology.


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 39
LY900014
The incidence of symptoms for each treatment will be presented by severity and by association 
with IP 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 IP-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.
Pharmacokinetic Analyses
10.3.2.
10.3.2.1. Pharmacokinetic Parameter Estimation
Insulin lispro PK parameter estimates for LY900014 will be calculated using standard 
noncompartmental methods of analysis.
Free serum insulin lispro concentrations will be used to calculate several PK parameters, 
including maximum observed drug concentration (Cmax), time of maximum observed drug 
concentration (tmax), t1/2, area under the concentration versus time curve from time zero to time 
t, where t is the last time point with a measurable concentration (AUC[0-tlast]), AUC from time 
zero to 10 hours (AUC[0-10h]), area under the concentration versus time curve from time zero to 
infinity (AUC[0-∞]), apparent total body clearance of drug calculated after extra-vascular 
administration (CL/F), and apparent volume of distribution during the terminal phase after extra-
vascular administration (Vz/F) will be determined. In addition, the total body clearance of drug 
calculated (CL), and volume of distribution (V) after IV administration also will be determined.
Other parameters may be calculated as deemed appropriate.  Additional partial AUCs may be 
computed as necessary.
Additional model-based analysis will be conducted as deemed appropriate to describe the 
elimination and absorption profiles.
Given the predicted low systemic concentrations of treprostinil, the PK analysis of treprostinil 
from the IV LY900014 dosing will be conducted using the available data.  The primary analysis 
of the treprostinil concentrations will be focused on assessing tmax and Cmax.
Although attempts will be made to adhere to the scheduled collection times (Section 2), 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.
The absolute bioavailability will be calculated using the ratio of the insulin lispro AUC(0-∞) 
following injection into the thigh, abdomen, and deltoid to the insulin lispro AUC(0-∞)


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 40
LY900014
following IV administration.  A table of these percent absolute bioavailabilities will be 
presented.
10.3.2.2. Pharmacokinetic Statistical Inference
Log-transformed AUC(0-∞) and Cmax for insulin lispro will be evaluated to estimate geometric 
least-squares means (LSmeans), ratios of geometric LSmeans between injection sites (deltoid 
and thigh compared with the abdomen), and their corresponding 90% CIs using the statistical 
model that includes injection site, period, and sequence as fixed effects, and subject within 
sequence as a random effect. The primary parameter for the statistical analysis of the relative 
bioavailability between injection sites will be the AUC(0-∞).
The analyses will also be performed using the subset of the subjects who complete all treatment 
periods with evaluable data.
Glucodynamic Analyses
10.3.3.
10.3.3.1. Glucodynamic Parameter Estimation
Glucodynamic assessments will be determined from the glucose clamp procedure, where the 
GIR over time will be used as a measure of insulin effect.  Glucodynamic 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:
maximum GIR (Rmax), time to Rmax (tRmax), and total amount of glucose infused (Gtot).  
Additional GD parameters, may be computed as necessary.  The values of these GD parameters 
will be summarized by treatment group through descriptive statistics.  Mean LOESS fits of GIR 
versus time profiles will be generated.
10.3.3.2. Glucodynamic Statistical Inference
Log-transformed Rmax and Gtot will be evaluated to estimate geometric LSmeans, ratios of 
geometric LSmeans between injection sites (deltoid and thigh compared with the abdomen), and 
their corresponding 90% CIs using the statistical model that includes injection site, period, and 
sequence as fixed effects, and subject within sequence as a random effect. 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.
The analyses will also be performed using the subset of the subjects who complete all treatment 
periods with evaluable data.
Pharmacokinetic/Pharmacodynamic Analyses
10.3.4.
Not applicable.


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 41
LY900014
Evaluation of Immunogenicity
10.3.5.
The frequency of antibody formation to insulin lispro will be determined.  The relationship 
between the presence (or absence) of antibodies and AEs will be assessed.  Likewise, the 
relationship between the presence of antibodies and the PK parameters and GD response to 
insulin lispro may be assessed.
Data Review during the Study
10.3.6.
This section is not applicable for this study.
Interim Analyses
10.3.7.
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the Lilly CP, CRP/investigator, or designee will consult with the appropriate medical 
director or designee to determine if it is necessary to amend the protocol.


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 42
LY900014
11.
References
Humalog [package insert]. Indianapolis, IN 46285: Lilly USA, LLC; 2015.
Remodulin [package insert]. Research Triangle Park, NC 27709: United Therapeutics Corp.;
2014.


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 43
LY900014
Appendix 1.
Abbreviations and Definitions


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 44
LY900014
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 concentration versus time curve
AUC(0-10h)
area under the concentration versus time curve from time zero to 10 hours
AUC(0-tlast)
area under the concentration versus time curve from time zero to tlast where tlast is the 
last time point with a measurable concentration
AUC(0-∞)
area under the concentration versus time curve from time zero to infinity
BMI
body mass index
CI
confidence interval
CL
total body clearance of drug calculated after intravenous administration
CL/F
apparent total body clearance of drug calculated after extra-vascular administration
Cmax
maximum observed serum concentration
compliance
Adherence to all the study-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements.
CP
clinical pharmacologist
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
ECG
electrocardiogram
eCRF
electronic case report form
ERB
ethical review board
FBG
fasting blood glucose
FDA
Food and Drug Administration
GCP
good clinical practice
GD
glucodynamic(s)


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 45
LY900014
GIR
glucose infusion rate
Gtot
total amount of glucose infused
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
informed consent
A process by which a subject voluntarily confirms his or her willingness to participate in 
a particular study, after having been informed of all aspects of the study that are relevant 
to the subject’s decision to participate.  Informed consent is documented by means of a 
written, signed, and dated informed consent form.  
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigational 
product (IP)
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical study, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible 
leader of the team and may be called the principal investigator.
IV
Intravenous
LOESS
locally weighted scatterplot smoothing
LLOQ
lower limit of quantitation
LSmeans
least-squares means
MDI
multiple daily injection
open-label
A study in which there are no restrictions on knowledge of treatment allocation, 
therefore the investigator and the study participant are aware of the drug therapy 
received during the study.
PAH
pulmonary arterial hypertension
PK
pharmacokinetic(s)
randomize
The process of assigning subjects to an experimental group on a random basis.
Rmax
maximum glucose infusion rate
SAE
serious adverse event


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 46
LY900014
SC
Subcutaneous
screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study.
SUSAR
suspected unexpected serious adverse reaction
t1/2
half-life associated with the terminal rate constant in noncompartmental analysis
T1DM
type 1 diabetes mellitus
T2DM
type 2 diabetes mellitus
TEAE
treatment-emergent adverse event:  Any untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment 
tmax
time to maximum concentration
tRmax
time to Rmax
V
volume of distribution
V/F
apparent volume of distribution after extravascular administration


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 47
LY900014
Appendix 2.
Clinical Laboratory Tests
Safety Laboratory Tests
Hematologya
Clinical Chemistrya
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume 
Chloride
Mean cell hemoglobin 
Calcium (total)
Calcium (ionized)
Mean cell hemoglobin concentration 
Magnesium
Leukocytes (WBC) 
Phosphate
Absolute counts of
Glucose
Neutrophils
Blood urea 
Lymphocytes
Total protein
Monocytes
Albumin
Eosinophils
Total bilirubin
Basophils
Alkaline phosphatase (ALP)
Platelets
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Creatinine
Urinalysisa
Serologyb
Specific gravity
Hepatitis B surface antigen
Ph
Hepatitis C antibody
Protein
HIV
Glucose
Pregnancy Tests
Ketones
Pregnancy testc
Bilirubin
FSHd
Urobilinogen
Blood
Nitrite
Leukocytes
Microscopye
Abbreviations:  FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cell; 
WBC = white blood cell.
a
Performed at screening, Predose Day 1 Period 1, 1 hour postdose (IV period) and follow-up.  Fasting clinical 
laboratory tests at screening and Predose Day 1 Period 1. 
b
Only at screening.  This test will not be performed if results of the same test have been obtained from the subject 
within the past 6 months.
c
A blood test for pregnancy will be done at screening, and a urine pregnancy test will be done at times indicated in 
the Schedule of Activities (Section 2).
d
Only at screening in women for assessment of menopause status if necessary.
e
If clinically indicated, per investigator’s discretion.
Note:  Results of these assays will be validated by the local laboratory at the time of testing.  Additional tests may be 
performed or auto-calculated by the laboratory as part of its standard panel that cannot be removed.  Some of the 
above parameters are calculated from measured values.  Omission of calculated values will not be considered as 
a protocol violation.


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 48
LY900014
Appendix 3.
Study Governance, Regulatory, and 
Ethical Considerations
Informed Consent
The investigator is responsible for

ensuring that the subject understands the nature of the study, the potential risks and 
benefits of participating in the study, and that their participation is voluntary.

ensuring that informed consent is given by each subject 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 IP.

answering any questions the subject may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the subject’s willingness to 
continue his or her participation in the study.

providing a copy of the ICF to the participant or the participant’s legal representative and 
retaining a copy on file.
Recruitment
Study-specific recruitment material should be approved by Lilly.
Ethical Review
The investigator or appropriate local representative must give assurance that the ERB was 
properly constituted and convened as required by International Council for Harmonisation (ICH)
guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the CRU.  Lilly or its representatives must approve the ICF before it is used 
at the CRU.  All ICFs must be compliant with the ICH guidelines on GCP.
The CRU’s ERB(s) should be provided with the following:

the current IB and updates during the course of the study

ICF

relevant curricula vitae
Regulatory Considerations
This study will be conducted in accordance with the protocol and with
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 


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 49
LY900014
3) applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third-party organization.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, the 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 subject data 
recorded against source documents at the CRU.  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.


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 50
LY900014
Data Collection Tools/Source Data
An electronic data capture system will be used in this study.  The CRU must define and retain all 
source records and must maintain a record of any data where source data are directly entered into 
the data capture system.
Data Protection
Data systems used for the study will have controls and requirements in accordance with local 
data protection law.
The purpose and use of subject personal information collected will be provided in a written 
document to the subject by the sponsor.
Study and Site Closure
Discontinuation of Study Sites
Clinical research unit participation may be discontinued if Lilly, the investigator, or the ERB of 
the CRU 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.


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 51
LY900014
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.
Protocol I8B-MC-ITRT Sampling Summary
Purpose
Blood Volume per 
Sample (mL)
Number of Blood Samples
Total Volume 
(mL)
Screening testsa,b
17
1
17
Clinical laboratory testsa,b
1×11 (fasting)
1
29
1×9 (nonfasting)
2
Pharmacokinetic samples serum 
insulin lispro
1
22 samples × 4 periods = 88
88
Pharmacokinetic samples plasma
treprostinil 
2
4 samples × 1 period = 4
8
C-peptide samples
2
12 samples × 4 periods = 48 
96
Blood for glucose
0.2
76 samples × 4 periods = 
304
60.8
Blood discard for cannula patency
0.25
76 samples × 4 periods = 
304
76
Immunogenicity
5
3
15
Pharmacogenetics
10
1
10
Total for clinical purposes 
399.8
Total for clinical purposes rounded up to the nearest 10 mL
400
a
Additional samples may be drawn if needed for safety purposes.
b
Fasting clinical laboratory tests at screening, and Predose Day 1 Period 1.


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 52
LY900014
Appendix 5.
Protocol Amendment I8B-MC-ITRT(a) 
Summary
Effect of Injection Site on the Relative and Absolute 
Bioavailability of Single Dose of LY900014 in Healthy 
Subjects
Overview
Protocol I8B-MC-ITRT [Effect of Injection Site on the Relative and Absolute Bioavailability of 
Single Dose of LY900014 in Healthy Subjects] has been amended.  The new protocol is 
indicated by Amendment (a) and will be used to conduct the study in place of any preceding 
version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:

The sample size was adjusted to ensure adequate precision to estimate the 90% CI for the 
ratio for SC injection into the thigh and deltoid, compared to the abdomen.

The arm injection site was changed to deltoid to ensure consistency in protocol language. 

PK and GD parameters (time to early half-maximal plasma concentration [early 50% 
tmax], time to late half-maximal drug concentration [late 50% tmax], time to half-maximal 
GIR before tRmax [early 50% tRmax], time to half-maximal GIR after tRmax [late 50% 
tRmax], time to onset of insulin action [Tonset], and Gtot over 10 hours [Gtot[0-10h]], partial 
glucose AUCs, such as total amount of glucose infused over 30 minutes, 1 or 2 hours)
were removed as they were not required for the statistical analysis to support the 
objectives of the study.  There is no change to primary and secondary endpoints.

The criterion to include subjects with body weight ≥45 kg and hemoglobin level of 
≥12.5 g/dL at screening was included based on recommendation of Domain Specific 
Review Board (DSRB), Singapore.  The rationale given was that a blood volume of 
approximately 400 mL or more would be withdrawn per subject throughout the study.


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 53
LY900014
Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
The numbering system used for inclusion and exclusion criteria provides a unique number for 
each criterion and allows for efficiency in data collection.
In case an amendment to the protocol adds a criterion, that criterion will receive the next 
available number, regardless of whether it is an inclusion or exclusion criterion.
1
Protocol Synopsis
Rationale:
The primary objective of this study is therefore to compare the bioavailability of insulin lispro 
following administration of the commercial formulation of LY900014 at 3 different injection 
sites SC in the abdominal wall, thigh, and arm deltoid.  In addition, the intravenous (IV) 
administration will serve as the reference to determine the absolute bioavailability of SC 
injections into the arm deltoid, thigh or abdomen and GD activity.
Number of Subjects:
Up to 24 28 healthy men and women may be enrolled to target at least 16 22 subjects complete 
the study.
3.1
Study Rationale
The primary objective of this study is therefore to compare the bioavailability of insulin lispro 
following administration of the commercial formulation of LY900014 at 3 different injection 
sites SC in the abdominal wall, thigh, and arm deltoid. In addition, the intravenous (IV) 
administration will serve as the reference to determine the absolute bioavailability of SC 
injections into the arm deltoid, thigh, or abdomen and GD activity.
5.1
Overall Design
This is a Phase 1, single-center, open-label, 4-period, randomized, crossover, up to 10-hour 
euglycemic clamp study in approximately 2428 healthy subjects to compare the insulin lispro PK
and GD of LY900014 after SC administration of a 15-U dose at 3 different injection sites and a 
single IV bolus injection of 15 U.
5.2
Number of Participants
A total of 24 28 subjects may be enrolled so that at least 16 22 subjects complete the study.  
If subjects discontinue from the study before completion of all 4 study periods, replacement 
subjects may be enrolled up to 24 28 subjects following agreement between the investigator and 
the sponsor.


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 54
LY900014
6.1
Inclusion Criteria
[3]
have a body weight of ≥45 kg, and body mass index (BMI) of 18.0 to 
30.0 kg/m2, inclusive
6.2
Exclusion Criteria
Additional inclusion criterion:
[27] have a hemoglobin level of ≥12.5 g/dL at screening
10.1.
Sample Size Determination
Up to 24 28 subjects may be enrolled to ensure that at least 16 22 subjects complete the study.  
Sixteen Twenty-two completing subjects will provide at least 90% power to show the estimated 
2-sided 90% confidence intervals (CIs) of the ratios of geometric means for area under the 
concentration versus time curve (AUC) from time zero to infinity (AUC[0-∞]) after SC injection 
into the thigh and deltoid, compared to the abdomen, to be within approximately 20% of the 
geometric mean ratio estimate 0.8 to 1.25 when the observed ratio is 1. This calculation is based 
on the assumption of a log-normal distribution and an estimate of intrasubject log-scale standard 
deviation of 0.2. There is also approximately 86% power for the comparisons between injection 
sites for maximum observed serum concentration (Cmax), assuming an intrasubject log-scale 
standard deviation of 0.35.
10.3.2.1
Pharmacokinetic Parameter Estimation
Free serum insulin lispro concentrations will be used to calculate several PK parameters, 
including maximum observed drug concentration (Cmax), time of maximum observed drug 
concentration (tmax), t1/2,  time to early half-maximal plasma concentration (early 50% tmax), 
time to late half-maximal drug concentration (late 50% tmax), and area under the concentration 
versus time curve from time zero to time t, where t is the last time point with a measurable 
concentration (AUC[0-tlast]), AUC from time zero to 10 hours (AUC[0-10h]), area under the 
concentration versus time curve from time zero to infinity (AUC[0-∞]), apparent total body 
clearance of drug calculated after extra-vascular administration (CL/F), and apparent volume of 
distribution during the terminal phase after extra-vascular administration (Vz/F) will be 
determined.
10.3.3.1
Glucodynamic Parameter Estimation
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:  
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), time to onset of insulin action 
(Tonset), and total amount of glucose infused (Gtot), and Gtot over 10 hours (Gtot[0-10h]).  
Additional GD parameters partial glucose AUCs, such as total amount of glucose infused over 
30 minutes, 1 or 2 hours may be computed as necessary.  The values of these GD parameters will 


I8B-MC-ITRT(a) Clinical Pharmacology Protocol
Page 55
LY900014
be summarized by treatment group through descriptive statistics.  Mean LOESS fits of GIR 
versus time profiles will be generated.


PPD
Leo Document ID = 3d691570-b5ac-4e8d-ac55-5ebcfe66512e
Approver: 
Approval Date & Time: 14-Jul-2017 12:38:59 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 14-Jul-2017 13:11:04 GMT
Signature meaning: Approved
PPD

SAP_001.pdf: 
 
 
Protocol/Statistical Analysis Plan: I8B-MC-ITRT  
 
Effect of Injection Site on the Relative and Absolute Bioavailability of Single Dose of 
LY900014 in Healthy Subjects 
 
 
NCT03233983 
 
 
Approval Date: 


Final, 03 Aug 2017
       Page 1of 13
STATISTICAL ANALYSIS PLAN
Effect of Injection Site on the Relative and Absolute Bioavailability of Single Dose of 
LY900014 in Healthy Subjects
Approval Date: 04-Aug-2017 GMT
Statistical Analysis Plan Status:Final
Statistical Analysis Plan Date:03-Aug-2017
Study Drug:LY900014
Sponsor Reference:I8B-MC-ITRT
Clinical Phase I
CCI


Final, 03 Aug 2017
       Page 2of 13
Statistical Analysis Plan 
CONFIDENTIAL
Sponsor Reference I8B-MC-ITRT
1.TABLE OF CONTENTS
1. TABLE OF CONTENTS...............................................................................................2
2. ABBREVIATIONS........................................................................................................4
3. INTRODUCTION.........................................................................................................6
4. STUDY OBJECTIVES..................................................................................................6
4.1 Primary Objectives..................................................................................................6
4.2 Secondary Objectives..............................................................................................6
4.3 Exploratory Objectives............................................................................................7
5. STUDY DESIGN...........................................................................................................7
6. TREATMENTS.............................................................................................................8
7. SAMPLE SIZE JUSTIFICATION.................................................................................8
8. DEFINITION OF ANALYSIS POPULATIONS............................................................8
9.
CCI
STATISTICAL METHODOLOGY...............................................................................9
9.1 General....................................................................................................................9
9.2 Demographics and Subject Disposition....................................................................9
9.3 Pharmacokinetic Assessment...................................................................................9
9.3.1
Pharmacokinetic Analysis...............................................................................9
9.3.2
Pharmacokinetic Statistical Methodology.....................................................10
9.4 Glucodynamic Assessment....................................................................................11
9.4.1
Glucodynamic Analysis................................................................................11
9.4.2
Glucodynamic Statistical Methodology........................................................11
9.5 Safety and Tolerability Assessments......................................................................11
9.5.1
Adverse events.............................................................................................11
9.5.2
Concomitant medication...............................................................................12
9.5.3
Clinical laboratory parameters......................................................................12
9.5.4
Vital signs....................................................................................................12
9.5.5
Electrocardiogram (ECG).............................................................................12
9.5.6
Injection Site Assessment.............................................................................12
9.5.7
Immunogenicity...........................................................................................12
9.5.8
Other assessments.........................................................................................12
9.5.9
Safety and Tolerability Statistical Methodology............................................12


Final, 03 Aug 2017
       Page 3of 13
Statistical Analysis Plan 
CONFIDENTIAL
Sponsor Reference I8B-MC-ITRT
10.INTERIM ANALYSES...............................................................................................13
11.CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES......13
12.REFERENCES............................................................................................................13
13.
CCI
DATA PRESENTATION............................................................................................13
13.1Derived Parameters...............................................................................................13
13.2Missing Data.........................................................................................................13
13.3Insufficient Data for Presentation..........................................................................13


Final, 03 Aug 2017
       Page 4of 13
Statistical Analysis Plan 
CONFIDENTIAL
Sponsor Reference I8B-MC-ITRT
2.ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
AE
Adverse event
AUC
Area under the concentration versus time curve
AUC(0-10h)
Area under the concentration versus time curve from time zero to 10 
hours
AUC(0-t
last)
Area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable concentration
AUC(0-∞)
Area under the concentration versus time curve from time zero to 
infinity
Cmax
Maximum observed drug concentration
CI
Confidence interval
CL
Total body clearance of drug calculated after intravenous 
administration
CRF
Case Report Form
CSR
Clinical Study Report
CRU
Clinical Research Unit
CV
Coefficient of variation
EC
Early Clinical 
ECG
Electrocardiogram
e.g.
For example (Latin: exempli gratia)
Gtot
Total amount of glucose infused
GD
Glucodynamic
GIR
Glucose infusion rate
ICH
International Council on Harmonisation
IV
Intravenous
LOESS
Locally weighted scatterplot smoothing
LS
Least square
MedDRA
Medical Dictionary for Regulatory Activities
PK
Pharmacokinetic
Rmax
CCI
Maximum glucose infusion rate


Final, 03 Aug 2017
       Page 5of 13
Statistical Analysis Plan 
CONFIDENTIAL
Sponsor Reference I8B-MC-ITRT
SAP
Statistical Analysis Plan
SC
Subcutaneous
SD
Standard deviation 
TFLs
Tables, Figures, and Listings
t
1/2
Half-life associatedwith the terminal rate constant (λ
z) in non-
compartmental analysis
t
max
Time of maximum observed drugconcentration
tR
max
Time to Rmax
V
Volume of distribution
Vz
CCI
/F
Apparent volume of distribution during the terminal phase after 
extra-vascular administration
WHO
World Health Organization


Final, 03 Aug 2017
       Page 6of 13
Statistical Analysis Plan 
CONFIDENTIAL
Sponsor Reference I8B-MC-ITRT
3.INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
24 May 2017and amendment (a) dated 14 July 2017).
This SAP describes the planned analysisof 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 subjectadministration
for this study.When the SAP and TFL shells are agreed upon and finalized, they will serve as the 
template for this study’s CSR.
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified.If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR.Any substantial deviations from this SAP will be agreed upon 
between Eli Lilly and Company and 
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 Objectives
To determine the relative bioavailability of insulin lisprofrom LY900014 after SC 
injection into the thigh and deltoid compared to the abdomen in healthy subjects.
To determine absolute bioavailability of insulin lispro following SC administrations of 
LY900014 into the thigh, deltoid, and abdomen compared to IV administration of 
LY900014 in healthy subjects.
4.2
Secondary Objectives
To evaluate the tolerability of LY900014 in healthy subjects.

CCI
To evaluate the GD during euglycemic clamp procedure of LY900014 after SC injection 
into the abdomen, thigh, and deltoid and IV in healthy subjects.
CCI
CCI


Final, 03 Aug 2017
       Page 7of 13
Statistical Analysis Plan 
CONFIDENTIAL
Sponsor Reference I8B-MC-ITRT
4.3
Exploratory Objectives
To evaluate C-peptide levels after administration of LY900014.
To determine plasma concentrations of the excipient, treprostinil, following 
administration of a single, IV 15-U dose of LY900014 in healthy subjects.
5.STUDY DESIGN
This is a Phase 1, single-center, open-label, 4-period, randomized, crossover, up to 10-hour 
euglycemic clamp study in approximately 28healthy subjects to compare the insulin lispro PK 
and GD of LY900014 after SC administration of a 15-U dose at 3 different injection sites and a 
single IV bolus injection of 15 U.The SC injection sites are the abdomen, thigh, and deltoid.
Subjects will be required to attend the clinical research unit (CRU) on at least 6 occasions:
screening visit (may occur up to 28 days before randomization)
four treatment visits for the clamp procedure (study Periods 1 to 4) with a wash-out 
period of ≥3 days between discharge and the next admission to the CRU
follow-up visit (at least 14 days after last dose), or early discontinuation.
Each subject will be randomly assigned to a treatment sequence and will be administered single
doses of 15 U of LY900014 (on 4 occasions).
Subjects will be admitted to the CRU on the evening before each dosing day and will remain in 
theCRU for the duration of the clamp period and until discharge by the investigator.Subjects are 
expected to fast for at least 8 hours before each dose.Following dose administration, each 
subject will undergo aeuglycemic clamp procedure of up to 10 hours.Upon completion of the 
clamp procedures, the subjects will be provided a meal and observed overnight.Subjects will be 
discharged from the CRU the next day after medical assessments.
Study governance considerations are described in detail in Appendix 3 of the protocol.
Figure ITRT.1
CCI
illustrates the study design.


Final, 03 Aug 2017
       Page 8of 13
Statistical Analysis Plan 
CONFIDENTIAL
Sponsor Reference I8B-MC-ITRT
Figure ITRT.2illustrates the treatment sequences.
6.TREATMENTS
The following is a list of the study treatment namesthat will be used in the TFLs.
7.SAMPLE SIZE JUSTIFICATION
Up to 28 subjects may be enrolled to ensure that at least 22 subjects complete the study.
Twenty-two completing subjects will provide estimated 2-sided 90% confidence intervals (CIs)
of the ratios of geometric means for AUC[0-∞] after SC injection into the thigh and deltoid,
compared to the abdomen, to be within approximately 0.8 to 1.25 when the observedratio is 1.
This calculation is based on the assumption of a log-normal distribution and an estimate of
intrasubject log-scale standard deviation of 0.2.
If subjects discontinue from the study before completion of all 4 study periods, replacement
subjects may be enrolled up to 24 subjects following agreement between the investigator and the
sponsor.
A replacement subject will be assigned the treatment sequence of the discontinued subject and
complete that treatment sequence in its entirety.
8.DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all subjectswho received at least one dose of study drug.
The “Pharmacokinetic” population will consist of those subjects who receive at least 1 dose of 
study drug and have measurable insulin lispro concentrationsand had evaluable PK data.
Study Treatment Name
Treatment order in TFL
15 U LY900014 Abdomen 
1
15 U LY900014 Thigh 
2
15 U LY900014 Deltoid
3
15 U LY900014 IV
4
CCI


Final, 03 Aug 2017
       Page 9of 13
Statistical Analysis Plan 
CONFIDENTIAL
Sponsor Reference I8B-MC-ITRT
The “Glucodynamic” population will consist of those subjects who complete at least 1 clamp 
procedure.
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when subjects are assigned to analysis populations.
9.STATISTICAL METHODOLOGY
9.1
General
Data listings will be provided for all 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) the geometric 
mean and geometric coefficient of variation (CV) will also be presented.For categorical data, 
frequency count and percentages will be presented.Data listings will be provided for all subjects 
up to the point of withdrawal, with any subjects excluded from the relevant population 
highlighted.Summary statistics and statistical analyses will generally only be performed for 
subjects included in the relevant analysis population.For the calculation of summary statistics 
and statistical analysis, unrounded data will be used. 
Mean change from baseline is the mean of all individual subjects’ change from baseline values.
Each individual change from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint.The individual subject’s change from baseline 
values will be used to calculate the mean change from baseline using a SAS procedure such as 
Proc Univariate.
Data analysis will be performed using 
or greater.
9.2
Demographics and Subject Disposition
Subject disposition will be listed.The demographic variables age, sex,ethnicity,race, height, 
weight and body mass index (BMI) will be summarized and listed.
9.3
Pharmacokinetic Assessment
9.3.1Pharmacokinetic Analysis
Insulin lispro PK parameter estimates for LY900014 will be calculated using standard 
noncompartmental methods of analysis.
Free serum insulin lispro concentrations will be used to calculate several PK parameters, 
including maximum observed drug concentration (C
max), time of maximum observed drug 
concentration (t
max), t
1/2, , and area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable concentration (AUC[0-t
last]), AUC from 
time zero to 10 hours (AUC[0-10h]), area under the concentration versus time curve from time 
zero to infinity (AUC[0-∞]), apparent total body clearance of drug calculated after extra-vascular 
administration (CL/F), and apparent volume of distribution during the terminal phase after extra-
CCI
CCI


Final, 03 Aug 2017
       Page 10of 13
Statistical Analysis Plan 
CONFIDENTIAL
Sponsor Reference I8B-MC-ITRT
vascular administration (Vz/F) will be determined. In addition, the total body clearance of drug 
calculated (CL), and volume of distribution (V) after IV administration also will be determined.
Other parameters may be calculated as deemed appropriate.Additional partial AUCs may be 
computed as necessary.
Additional model-based analysis will be conducted as deemed appropriate to describe the
elimination and absorption profiles.
Given the predicted low systemic concentrations of treprostinil, the PK analysis of treprostinil
from the IV LY900014 dosing will be conducted using the available data.The primary analysis
of the treprostinil concentrations will be focused on assessing t
maxand C
max.
Although attempts will be made to adhere to the scheduled collection times (Section 2), 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.
The absolute bioavailability will be calculated using the ratio of the insulin lispro AUC(0-∞)
following injection into the thigh, abdomen, and deltoid to the insulin lispro AUC(0-∞)
following IV administration.A table of these percent absolute bioavailabilities will bepresented.
9.3.2Pharmacokinetic Statistical Methodology
Log-transformed AUC(0-∞) and Cmax for insulin lispro will be evaluated to estimate geometric 
least-squares means (LSmeans), ratios of geometric LSmeans between injection sites (deltoid
and thigh compared with the abdomen), and theircorresponding 90% CIs using the statistical
model that includes injection site, period, and sequence as fixed effects, and subject within
sequence as a random effect.Data from the deltoid, thigh and abdomen injection sites will be 
included in the same model. The primary parameter for the statistical analysis of the relative
bioavailability between injection sites will be the AUC(0-∞).
Example SAS Code:
proc mixed data=pk;
class subject site period sequence ;
model logpk = site period sequence / ddfm=kr;
lsmeans site / pdiff=control('abdomen') alpha=0.1;
random subject(sequence);
run;
CCI
The analyses will also be performed usingall available data and repeated usingthe subset of the 
subjects who complete all treatmentperiods with evaluable data.


Final, 03 Aug 2017
       Page 11of 13
Statistical Analysis Plan 
CONFIDENTIAL
Sponsor Reference I8B-MC-ITRT
9.4
Glucodynamic Assessment
9.4.1Glucodynamic Analysis
Glucodynamicassessments will be determined from the glucose clamp procedure, where the 
GIR over time will be used as a measure of insulin effect.Glucodynamic 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 
.
The fitted data for each subject will be used to calculate the following GD parameters:maximum 
GIR (Rmax), time to R
max(tR
max), and total amount of glucose infused (Gtot)AdditionalGD 
parameters,may be computed as necessary.The values of these GD parameters will be 
summarized bytreatment group through descriptive statistics.Mean LOESS fits of GIR versus 
time profiles willbe generated.
9.4.2Glucodynamic Statistical Methodology
Log-transformed R
maxand G
totwill be evaluated to estimate geometric LSmeans, ratios of 
geometric LSmeansbetween injection sites (deltoid and thigh compared with the abdomen), and 
their corresponding 90% CIs using the statistical model that includes injection site, period, and 
sequence as fixed effects, and subject within sequence as a random effect.Data from the deltoid, 
thigh and abdomen injection sites will be included in the same model.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 parameterbased on the original parametersusing a Wilcoxon 
Signed Rank test.SimilarSAS code to that used to analyze the PK parameters will be used to 
analyze the GD parameters.
The analyses will also be performed usingall available data and repeated usingthe subset of the 
subjects who complete all treatment periods with evaluable data.
9.5
Safety and Tolerability Assessments
9.5.1Adverse events
CCI
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the adverse event (AE) will be reported in the listings, only the most severe will be used in the
summary tables.A pre-existing condition is defined as an AE that starts before the subject has 
provided written informed 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-emergent AEs will be summarized by injection site, severity 
and relationship to the study drug.The frequency (the number of AEs, the number of subjects 
experiencing an AEand the percentage of subjects experiencing an AE) of treatment-emergent 
CCI


Final, 03 Aug 2017
       Page 12of 13
Statistical Analysis Plan 
CONFIDENTIAL
Sponsor Reference I8B-MC-ITRT
AEswill be summarized by treatment,Medical Dictionary for Regulatory Activities (MedDRA) 
version 19.1system organ class and preferred term.The summary and frequency AEtables will 
be presented for all causalities and those considered related to the study drug.Any serious AEs 
will be tabulated.
9.5.2Concomitant medication
Concomitant medication will be coded using the World Health Organisation (WHO)drug 
dictionary (Version September 2016).Concomitant medication will be listed.
9.5.3Clinical laboratory parameters
Allclinical chemistry,hematologyand urinalysis datawill be listed.Additionally clinical 
chemistry, hematology and urinalysis data outside the reference ranges will be listed.
Values for any clinical chemistry, hematology and urinalysis values outside the reference ranges 
will be flagged on the individual subject data listings.
9.5.4Vital signs
Vital signs data will belisted for individual subjects.Vital signs data willbe summarized by 
treatment.
9.5.5Electrocardiogram (ECG)
ECG data is not databased for this study so will not be reported.
9.5.6Injection Site Assessment
Injection site assessment data will belisted for individual subjects and willbe summarizedin 
frequency tablesby treatment.This is collected during the non-IV treatment periods.
9.5.7Immunogenicity
The frequency of antibody formation to insulin lispro will be determined.The relationship
between the presence (or absence) of antibodies and AEs will be assessed.Likewise, the
relationship between the presence of antibodies and the PK parameters and GD response to
insulin lispro may be assessed.The data will be listed and also presented in a frequency table.
9.5.8Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed. 
9.5.9Safety and Tolerability Statistical Methodology
CCI
No inferential statistical analyses are planned.


Final, 03 Aug 2017
       Page 13of 13
Statistical Analysis Plan 
CONFIDENTIAL
Sponsor Reference I8B-MC-ITRT
10.
INTERIM ANALYSES
No interim statistical analyses are planned.
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
There were no changes from the protocol specified statistical analyses.
12.
REFERENCES
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998.
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.
13.
DATA PRESENTATION
13.1
Derived Parameters
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be 
reported to three significant figures.Observed concentration data, e.g. Cmax, should be reported 
as received.Observed time data, e.g. tmax, should be reported as received.N and percentage 
values should be reported as whole numbers.Median values should be treated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values.
13.2
Missing Data
Missing data will not be displayed in listings.
13.3
Insufficient Data for Presentation
CCI
Some of the TFLs may not have sufficient numbers of subjects or data for presentation.If this 
occurs, the blank TFL shell will be presented with a message printed in the centerof the table, 
such as, “No serious AEsoccurred for this study.”


PPD
Leo Document ID = 49b9e09e-70d8-4737-bcd6-70dea591bb20
Approver: 
Approval Date & Time: 04-Aug-2017 07:31:52 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 04-Aug-2017 11:25:56 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 04-Aug-2017 13:44:17 GMT
Signature meaning: Approved
PPD
PPD