Clinical trial NCT03334448
Conditions: Healthy
Sponsor: Eli Lilly and Company
Start date: 2017-12-04; Completion date: 2018-03-15
Enrollment: 49 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The study involves a comparison of a LY900014 U-200 formulation with a LY900014 U-100 formulation. LY900014 is a type of fast acting insulin. Study participants will be administered LY900014 U-100 two times and LY900014 U-200 two times, over 4 study periods, by injection under the skin. Blood samples will be taken to compare how the body handles the study drugs and how they affect the blood sugar levels. Side effects and tolerability will be documented. The study will last about 4 weeks, not including screening and follow up. Screening is required within 28 days prior to the start of the study and follow up is required at least 2 weeks after the last dose of study drug.

Detailed description:

Arms: arm 1: Single subcutaneous (SC) dose of 15 units (U) LY900014 U-200 in two of four study periods arm 2: Single SC dose of 15 U LY900014 U-100 in two of four study periods
Interventions: intervention 1: LY900014-U200 intervention 2: LY900014-U100
Intervention descriptions: intervention 1: Administered SC intervention 2: Administered SC

Protocol documents:
Prot_001.pdf: 
Protocol: I8B-MC-ITRQ(a) 
 
Bioequivalence Study Comparing the Pharmacokinetics and Glucodynamics of LY900014  
U-200 Formulation with LY900014 U-100 Formulation in Healthy Subjects 
 
NCT03334448 
 
Approval Date: 19-Oct-2017 


I8B-MC-ITRQ(a)Clinical Pharmacology Protocol
Page 1
LY900014
Protocol I8B-MC-ITRQ(a)
Bioequivalence Study Comparing the Pharmacokinetics 
and Glucodynamicsof LY900014 U-200 Formulation with 
LY900014 U-100Formulation 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/orcommercially 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: 19-Oct-2017 GMT
LY900014
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly: 
21August2017.
Amendment (a) Electronically Signed and Approved by Lilly
on approval date provided below.


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 2
LY900014
Table of Contents
Bioequivalence Study Comparing the Pharmacokinetics and 
Glucodynamics of LY900014 U-200 Formulation with 
LY900014 U-100 Formulation in Healthy Subjects
Section
Page
Protocol I8B-MC-ITRQ (a) Bioequivalence Study Comparing the 
Pharmacokinetics and Glucodynamics of LY900014 U-200 
Formulation with LY900014 U-100 Formulation in Healthy Subjects .................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................8
2.
Schedule of Activities .......................................................................................................11
3.
Introduction ......................................................................................................................14
3.1.
Study Rationale............................................................................................................14
3.2.
Background..................................................................................................................14
3.3.
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...........................................................................19
5.5.
Justification for Dose ...................................................................................................20
6.
Study Population...............................................................................................................21
6.1.
Inclusion Criteria..........................................................................................................21
6.2.
Exclusion Criteria ........................................................................................................22
6.3.
Lifestyle and/or Dietary Requirements .........................................................................24
6.3.1.
Meals and Dietary Restrictions.............................................................................24
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................24
6.3.3.
Activity................................................................................................................24
6.4.
Screen Failures.............................................................................................................24
7.
Treatment..........................................................................................................................25
7.1.
Treatment Administered...............................................................................................25
7.1.1.
Packaging and Labeling .......................................................................................26
7.2.
Method of Treatment Assignment ................................................................................26
7.2.1.
Selection and Timing of Doses.............................................................................26
7.3.
Blinding .......................................................................................................................26


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 3
LY900014
7.4.
Dose Modification........................................................................................................26
7.5.
Preparation/Handling/Storage/Accountability...............................................................27
7.6.
Treatment Compliance .................................................................................................27
7.7.
Concomitant Therapy...................................................................................................27
7.8.
Treatment after the End of the Study............................................................................27
8.
Discontinuation Criteria ....................................................................................................28
8.1.
Discontinuation from Study Treatment.........................................................................28
8.1.1.
Discontinuation of Inadvertently Enrolled Subjects..............................................28
8.2.
Discontinuation from the Study....................................................................................28
8.3.
Subjects Lost to Follow-up...........................................................................................29
9.
Study Assessments and Procedures ...................................................................................30
9.1.
Efficacy Assessments...................................................................................................30
9.2.
Adverse Events ............................................................................................................30
9.2.1.
Serious Adverse Events........................................................................................31
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................31
9.2.2.
Complaint Handling.............................................................................................31
9.3.
Treatment of Overdose.................................................................................................32
9.4.
Safety...........................................................................................................................32
9.4.1.
Laboratory Tests ..................................................................................................32
9.4.2.
Vital Signs ...........................................................................................................32
9.4.3.
Electrocardiograms ..............................................................................................32
9.4.4.
Other Tests...........................................................................................................33
9.4.4.1.
Physical Examinations....................................................................................33
9.4.4.2.
Body Weight and Height ................................................................................33
9.4.4.3.
Hip and Waist Circumference.........................................................................33
9.4.5.
Safety Monitoring ................................................................................................33
9.4.5.1.
Glucose Monitoring........................................................................................34
9.4.5.1.1.
Severe Hypoglycemia ...............................................................................35
9.4.5.2.
Hepatic Safety................................................................................................35
9.4.6.
Injection-Site Assessments (Local Tolerability)....................................................35
9.4.6.1.
Pain Measurements Using the Visual Analog Scale ........................................36
9.5.
Pharmacokinetics .........................................................................................................36
9.5.1.
Bioanalysis...........................................................................................................36
9.6.
Glucodynamics (Euglycemic Glucose Clamp)..............................................................36
9.6.1.
Immunogenicity Assessments ..............................................................................37
9.7.
Genetics .......................................................................................................................38
9.8.
Exploratory Biomarkers ...............................................................................................38
9.8.1.
C-Peptide .............................................................................................................38


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 4
LY900014
9.9.
Health Economics ........................................................................................................38
10.
Statistical Considerations and Data Analysis.....................................................................39
10.1. Sample Size Determination ..........................................................................................39
10.2. Populations for Analyses..............................................................................................39
10.2.1.
Study Participant Disposition ...............................................................................39
10.2.2.
Study Participant Characteristics ..........................................................................39
10.3. Statistical Analyses ......................................................................................................39
10.3.1.
Safety Analyses....................................................................................................40
10.3.1.1.
Clinical Evaluation of Safety..........................................................................40
10.3.1.2.
Statistical Evaluation of Safety.......................................................................40
10.3.1.3.
Statistical Evaluation of the Intensity of Injection-Site 
Pain................................................................................................................40
10.3.2.
Pharmacokinetic Analyses....................................................................................41
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................41
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................41
10.3.3.
Pharmacodynamic Analyses.................................................................................42
10.3.3.1.
Pharmacodynamic Parameter Estimation ........................................................42
10.3.3.2.
Pharmacodynamic Statistical Inference...........................................................42
10.3.4.
Evaluation of Immunogenicity .............................................................................42
10.3.5.
C-Peptide .............................................................................................................43
10.3.6.
Data Review During the Study.............................................................................43
10.3.7.
Interim Analyses..................................................................................................43
11.
References ........................................................................................................................44


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 5
LY900014
List of Tables
Table
Page
Table ITRQ.1.
Objectives and Endpoints .......................................................................17
Table ITRQ.2.
Treatment Sequence Example for I8B-MC-ITRQ...................................18
Table ITRQ.3.
Treatments Administered........................................................................25


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 6
LY900014
List of Figures
Figure
Page
Figure ITRQ.1.
Illustration of study design for Protocol I8B-MC-ITRQ..........................18


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 7
LY900014
List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................45
Appendix 2.
Clinical Laboratory Tests........................................................................48
Appendix 3.
Study Governance, Regulatory, and Ethical Considerations....................49
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............52
Appendix 5.
Blood Sampling Summary......................................................................53
Appendix 6.
Protocol Amendment I8B-MC-ITRQ(a) Summary 
Bioequivalence Study Comparing the Pharmacokinetics and 
Glucodynamics of LY900014 U-200 Formulation with LY900014 
U-100 Formulation in Healthy Subjects..................................................54


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 8
LY900014
1. Protocol Synopsis
Title of Study:
Bioequivalence study comparing the pharmacokinetics and glucodynamics of LY900014 U-200 formulation with 
LY900014 U-100 formulation in healthy subjects
Rationale: 
The aim of the current study is to demonstrate the bioequivalence of a new concentrated form (U-200) of LY900014 
relative to LY900014 U-100 after subcutaneous (SC) administration of a 15 U insulin lispro dose to healthy 
subjects; in addition, the study will evaluate the glucodynamics (GD) of these formulations.  The concentrated form 
of LY900014 (U-200) is being developed as an option for patients with diabetes who require a higher daily 
mealtime insulin dose.  An increased strength formulation would allow for a greater number of units to be included 
in each injection device.
Objectives/Endpoints:  
Objectives
Endpoints
Primary
To demonstrate the bioequivalence of 
pharmacokinetic (PK) parameters for the LY900014
U-200 versus LY900014 U-100 formulations after SC 
administration to healthy subjects.
Area under the concentration versus time curve (AUC)
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 infinity (AUC[0-∞]), and maximum 
observed drug concentration (Cmax)
Secondary
To compare the GD responses to LY900014 U-200 
versus LY900014 U-100 formulations after SC 
administration.
To assess the safety and tolerability of the LY900014 
U-200 and LY900014 U-100 formulations.
Total amount of glucose infused (Gtot) and maximum 
glucose infusion rate (Rmax)
Adverse events
Summary of Study Design:  
Study I8B-MC-ITRQ is a Phase 1, single-center, subject- and investigator-blind, 4-sequence, 4-period, randomized, 
replicated-crossover, 10-hour euglycemic clamp study in healthy subjects to compare the PK and GD of insulin 
lispro in LY900014 U-200 formulation versus insulin lispro in LY900014 U-100 formulation after SC 
administration of a 15 U insulin lispro dose.
Treatment Arms and Planned Duration for an Individual Subject:  
Subjects will be randomly assigned to 1 of 4 dosing sequences; each sequence will have 4 periods.  Subjects will be 
administered single doses of LY900014 U-200 formulation (on 2 occasions) and LY900014 U-100 formulation (on 
2 occasions).
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.


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 9
LY900014
Number of Subjects:
Up to 60 healthy men and women may be enrolled so that approximately 44 subjects complete the study.
Statistical Analysis:  
Safety:  Safety analyses will be conducted for all enrolled subjects who receive at least 1 dose of the study drug, 
whether or not they completed all protocol requirements.  Safety assessments including, but not limited to vital 
signs, safety laboratory parameters, and adverse events will be captured and summarized using descriptive statistical 
methodologies.
Pharmacokinetics:  Pharmacokinetic analyses will be conducted on data from all subjects receiving at least 1 dose 
of study drug and have evaluable PK data.  Pharmacokinetic analyses will be conducted using standard 
noncompartmental method of analysis.  Pharmacokinetic parameters will be assessed using free serum insulin lispro.
To compare PK parameters between LY900014 U-200 relative to LY900014 U-100, log-transformed AUC(0-tlast), 
AUC(0-∞), and Cmax will be analyzed using the mixed-effects model that includes treatment, sequence, and period 
as fixed effects and subject within sequence as a random effect.  From the model, the difference in least-squares 
means (LSmeans) and the corresponding 2-sided 90% confidence intervals (CIs) for the difference will be estimated 
and back-transformed from the log scale to provide estimates of the ratio of geometric LSmeans and 90% CI for the 
ratio of the LSmeans.  Bioequivalence will be concluded if the 2-sided 90% CI is completely contained within the 
interval (0.80, 1.25).  
The same model without log transformation will be used for the analysis of the PK time parameters (time to early 
half-maximal drug concentration [early 50% tmax] and time to Cmax [tmax]).  LSmeans, treatment differences in 
LSmeans, and the corresponding 90% CIs for the treatment differences will be estimated from the model.  The 
treatment ratios and 90% CIs for the ratios will be calculated using Fieller’s theorem.  Other PK time parameters 
may be analyzed in a similar manner.  
In addition, the analyses described above will also be performed on the population of subjects who completed and 
had evaluable PK data in all study periods.
Glucodynamics: Glucodynamic assessments will be determined from the glucose clamp procedure, where the 
glucose infusion rate (GIR) over time will be used as a measure of insulin effect. Glucodynamic analyses will be 
conducted on those subjects who complete at least 1 clamp procedure.  A locally weighted scatterplot smoothing 
function will be applied to all individual GIR versus time profiles in each treatment group and/or period. 
To address the secondary objective of comparing GD parameters (Gtot and Rmax) between the LY900014 U-200 
and LY900014 U-100 formulations, log-transformed Gtot and Rmax estimates will be analyzed using the 
mixed-effects model that includes treatment, sequence, and period as fixed effects and subject within sequence as a 
random effect.  From the model, the difference in LSmean estimates and the corresponding 90% for the difference 
will be estimated and back-transformed from the log scale to provide estimates of the ratios of geometric LSmeans 
and 90% for the ratio of the LSmeans.  Other GD parameters may be analyzed in a similar manner.  
The same model without log transformation will be used for the analysis of the GD time parameters (time to 
half-maximal GIR before tRmax [early 50% tRmax], and time to maximal GIR [tRmax]).  Least-squares means, 
treatment differences in LSmeans, and the corresponding 90% CIs for the treatment differences will be estimated 
from the model.  The p-value for the difference between LSmeans will be used to determine statistical significance.  


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 10
LY900014
The treatment ratios and 90% CIs for the ratios will be calculated using Fieller’s theorem. Other GD time
parameters may be analyzed in a similar manner.  
In addition, the analyses described above will also be performed on the population of subjects who completed and 
had evaluable GD data in all study periods.


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 11
LY900014
2. Schedule of Activities
Study Schedule Protocol I8B-MC-ITRQ
Screening
Periods 1, 2, 3, 4
FU/EDa
Comments
Procedure
Up to 
Day -28
Day -1
Day 1
Day 
2
Informed consent
X
Subject admission to CRU
X
Enrollment
X
Applicable to Period 1 only.
Fasting
X
X
Subjects are expected to fast for 
approximately 8 hours before screening 
and at least 8 hours before each study 
drug dose (starting from the night of Day
-1) until the end of the glucose clamp 
procedure (Day 1).
Physical examination
X
X
Physical examination at screening.  
Thereafter, targeted examination, as 
appropriate.
Medical assessment
X
Predose 
X
X
Medical history at screening.  Thereafter, 
medical assessments per Section 9.4.4.1.
Height
X
Weight
X
X*
X
*Applicable to Period 1 only
Waist and hip circumference 
X*
*Applicable to Period 1 only
Vital signs (supine)
X
Predose and 10 hours postdose (at the 
end of clamp procedure)
X
Vital signs:  Body temperature, blood 
pressure, and pulse rate.  Body 
temperature will be measured only at 
screening.  
12-lead ECG
X
X
X
Single ECGs will be collected for safety.
Clinical laboratory tests
X
Predose of Period 1
X
See Appendix 2, Clinical Laboratory 
Tests, for details.


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 12
LY900014
Screening
Periods 1, 2, 3, 4
FU/EDa
Comments
Procedure
Up to 
Day -28
Day -1
Day 1
Day 
2
Pregnancy test 
X
X
X
For females of childbearing potential 
only.  A serum pregnancy test will be 
performed at screening.  Urine 
pregnancy tests at all other time points.
Study drug administration
0 hour
Time of study drug administration = 0 
hour.
Study drug will be administered at 
approximately the same times on Day 1 
of each study period.
Injection-site assessments
0, 1, 4, and 10 hours postdose (at the 
end of clamp procedures)
Assessments of injection-site reaction at 
time ‘0’ will occur immediately 
following injection of study drug.
Visual Analog Scale (VAS)
0, 20, and 60 min postdose
VAS assessment at time ‘0’ will occur 
immediately following injection of study 
drug.
Insulin lispro PK sampling
0, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 
55, 60, 70, 90, 120, 150, 180, 240, 
300, 360, 420, 480, 540, and 600 
minutes
Sampling times are relative to the time 
of study treatment administration (time 
0). Time 0 sample is to be collected 
immediately prior to injection.
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).
Time 0 sample is to be collected 
immediately prior to injection.
Blood glucose sampling for 
euglycemic clamp
Approximately every 10 min for 
approximately 30 min 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).  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.


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 13
LY900014
Screening
Periods 1, 2, 3, 4
FU/EDa
Comments
Procedure
Up to 
Day -28
Day -1
Day 1
Day 
2
Pharmacogenetics sample
Predose for Period 1 only
Refer to sample collection instructions 
provided by the sponsor.
Immunogenicity sample
Predose Period 1, Period 2, and Period 
3 only
X
Discharge from CRU
X
Abbreviations:  CRU = clinical research unit; ECG = electrocardiogram; ED = early discontinuation; FU = follow-up; min = minutes; PK = pharmacokinetics. 
Note:  In cases when several study procedures have the same scheduled time point, the collection of PK samples should be scheduled to occur at the exact time, 
whilst other procedures may be scheduled to occur earlier or later, as deemed appropriate by the investigator.  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.
a
At least 14 days after last dose or early discontinuation.


I8B-MC-ITRQ(a)Clinical Pharmacology Protocol
Page 14
LY900014
3.Introduction
3.1. Study Rationale
LY900014 is an ultra-rapid-acting insulin lispro formulation that has shown an increased early 
absorption compared to commercially available insulin lispro (Humalog®; Eli Lillyand 
Company).  LY900014 U-200 represents a new formulationstrengthof LY900014.The insulin 
lispro pharmacokinetics(PK) and glucodynamics(GD)ofa 19 unit (U)subcutaneous (SC) dose 
administration of LY900014 U-193 and LY900014 U-95havebeen comparedin a previously 
completed pilot study(
).
The aim of the current study is to demonstrate the bioequivalence of a new concentrated form 
(U-200) of LY900014 relativeto LY900014U-100after SC administration of a 15 Uinsulin 
lispro dose to healthy subjects; in addition, the study willevaluate the GDof these formulations.  
The concentrated form of LY900014 (U-200) is being developed as an option for patients with 
diabetes who require a higher daily mealtime insulin dose.An increased strength formulation 
would allow for a greater number of units to be included in each injection device. 
3.2. Background
CCI
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 (
 
) and other ingredients.  LY900014 has an increased early absorption of insulin 
lispro compared to commercially available insulin lispro(Humalog). 
 
 
 
Treprostinil is a prostacyclin analog, administered either through inhalation (
), as an 
intravenous (IV)infusion, or as a continuous SC administrationfor the treatment of symptomatic 
pulmonary arterial hypertension (PAH) and has been approved in the US since 2002 (
 
.  Sodium citrate, an excipient that speeds insulin absorption (likely in part 
by enhancing vascular permeability), is also included in the formulation to further enhance the 
absorption of insulin lispro. Each of the other excipients (such as 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 
CCI
CCI
CCI
CCI
CCI


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 15
LY900014
identified for approved drug products in the FDA Inactive Ingredients in Approved Drugs 
database.
Safety and tolerability of LY900014 at approximately U-100 concentration have been 
demonstrated in healthy subjects in 4 previous clinical studies, in approximately 103 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; however, LY900014 demonstrated a faster 
and earlier insulin lispro absorption and insulin action compared to Humalog.  
In addition, data from two Phase 1b studies showed LY900014 U-95 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.
A recent pilot study compared the insulin lispro PK and GD of a concentrated formulation of 
LY900014 (U-193 LY900014) with U-95 LY900014 administered as single 19 U doses to 
healthy subjects. Both formulations were well tolerated with no clinically relevant differences 
between formulations.  No deaths or SAEs occurred during this study, and no subjects 
discontinued the study due to an AE. The most common AEs were events related to the glucose 
clamp procedure.  The PK of the 2 formulations was found to be bioequivalent with 90% 
confidence intervals (CIs) for the ratios of area under the concentration versus time curve (AUC)
from time zero to 8 hours, AUC 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 infinity (AUC[0-∞]), and 
maximum observed drug concentration (Cmax) falling within (0.80, 1.25).  The GD profiles 
were largely consistent across the 2 formulations.
More information can be found in the Investigator’s Brochure (IB) of LY900014.
3.3.
Benefit/Risk Assessment
Study I8B-MC-ITRQ (ITRQ) will not offer any direct benefits to the healthy 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).  Consistent with the risks stated above, in 
previous Phase 1 studies with LY900014, there were no events of severe hypoglycemia reported
and most events of injection-site reactions were of mild severity.


I8B-MC-ITRQ(a)Clinical Pharmacology Protocol
Page 16
LY900014
CCI
Notably, across alldoses in the Lilly clinical studies with healthy subjects and patients with 
diabetesthat 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 
.  Moreover, data from Lilly 
Phase 1b patient studies showed that 1 out of 472 plasma samples had detectable treprostinil 
levels taken from a total of 30 patients with T1DM (doses up to  
 per SC bolus injection) and 
30 patients with T2DM (doses up to 
 per SC bolus injection) following MDI administration 
of LY900014.  The exposure levels of treprostinil fromthe doses of LY900014 planned in this 
study are expected to be undetectable and substantially lower(at least 
)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 
 no additional risks were identified.  No known 
potential risks are associated with the use of small amounts of treprostinil ( 
) in the 
LY900014 formulation.  Additionally, local and systemic toxicity profiles of Humalog and 
 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 isto maintain blood glucose within the normal glycemicrange.  In 
addition, the clamp is performed while the subject is inpatient and under the investigator’s 
supervision.  These considerations should minimize the risk of hypoglycemiain subjects 
participating in Study ITRQ.
More information about the known and expected benefits, risks, SAEs, and reasonably 
anticipated AEs of LY900014 is to be found in the IB.
CCI
CCI
CCI
CCI
CCI
CCI


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 17
LY900014
4. Objectives and Endpoints
Table ITRQ.1 shows the objectives and endpoints of the study.
Table ITRQ.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To demonstrate the bioequivalence of PK parameters 
for the LY900014 U-200 versus LY900014 U-100 
formulations after SC administration to healthy 
subjects.
AUC(0-tlast), AUC(0-∞), and Cmax
Secondary
1.
To compare the GD responses to LY900014 
U-200 versus LY900014 U-100 formulations 
after SC administration.
2.
To assess the safety and tolerability of the 
LY900014 U-200 and LY900014 U-100 
formulations.
1.
Gtot and Rmax
2.
Adverse events
Tertiary/Exploratory Objectives
1.
To compare other PK and GD parameters for 
LY900014 U-200 versus LY900014 U-100
after SC administration.
2.
Explore the formation of anti-drug antibodies 
to insulin lispro.
3.
To assess C-peptide levels following 
administration of LY900014.
1.
tmax, early 50% tmax
tRmax and early 50% tRmax
2.
Anti-insulin lispro antibodies
3.
C-peptide concentration
Abbreviations:  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; Cmax = maximum observed drug concentration; early 50% tmax = time to early half-
maximal drug concentration; early 50% tRmax = time to half-maximal glucose infusion rate before tRmax; GD = 
glucodynamic(s); Gtot = total amount of glucose infused; PK = pharmacokinetic(s); Rmax = maximum glucose 
infusion rate; SC = subcutaneous; tmax = time of maximum observed drug concentration; tRmax = time to 
Rmax.


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 18
LY900014
5. Study Design
5.1.
Overall Design
This is a Phase 1, single-center, investigator- and subject-blind, 4-sequence, 4-period, 
randomized, replicated-crossover, 10-hour euglycemic clamp study in healthy subjects to 
compare the PK and GD of insulin lispro in LY900014 U-200 formulation versus insulin lispro 
in LY900014 U-100 after SC administration of 15 U insulin lispro dose.  The treatments will be 
replicated such that each formulation is administered twice on different occasions to healthy 
subjects over 4 study periods.  
Figure ITRQ.1 illustrates the study design.
Abbreviation: CRU = clinical research unit.
*Single dose of LY900014 U-200 or LY900014 U-100 administered subcutaneously to 
the abdomen.
Figure ITRQ.1.
Illustration of study design for Protocol I8B-MC-ITRQ.
Each subject will be administered LY900014 U-200 formulation (on 2 occasions) and LY900014 
U-100 formulation (on 2 occasions).  Subjects will be randomly assigned to 1 of the 4 dosing 
sequences (Table ITRQ.2). 
Table ITRQ.2.
Treatment Sequence Example for I8B-MC-ITRQ
Treatment 
Sequence
Period 1
Period 2
Period 3
Period 4
1
LY900014 U-200
LY900014 U-100
LY900014 U-200
LY900014 U-100
2
LY900014 U-100
LY900014 U-200
LY900014 U-100
LY900014 U-200
3
LY900014 U-200
LY900014 U-100
LY900014 U-100
LY900014 U-200
4
LY900014 U-100
LY900014 U-200
LY900014 U-200
LY900014 U-100
Note:  This is only an example table for illustration purpose; subjects will be assigned a treatment sequence 
according to the actual treatment randomization schedule provided to the unblinded site pharmacist.
Subjects will be required to attend the clinical research unit (CRU) on at least 6 occasions: 

1 screening visit (may occur up to 28 days prior to randomization)

4 inpatient treatment visits for the clamp procedure (Periods 1 to 4) with a 
wash-out period of ≥3 days between discharge and the next admission to the 
CRU
LY900014 U-200/ 
LY900014 U-100*
Screening
Follow-up
Period 1
Period 2
Period 3
Period 4
Wash-out
Wash-out
Wash-out
Healthy Subjects
Up to 28 days
CRU Inpatient
(1 day)
CRU Inpatient
(1 day)
CRU Inpatient
(1 day)
CRU Inpatient
(1 day)
At least 14 days
≥ 3 
days
≥ 3 
days
≥ 3 
days
Euglycemic
Glucose Clamp 
(~10 hours)
Euglycemic
Glucose Clamp 
(~10 hours)
Euglycemic
Glucose Clamp 
(~10 hours)
Euglycemic
Glucose Clamp 
(~10 hours)
LY900014 U-200/ 
LY900014 U-100*
LY900014 U-200/ 
LY900014 U-100*
LY900014 U-200/ 
LY900014 U-100*


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 19
LY900014

1 follow-up visit (at least 14 days after the last dose).
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.  Subjects may remain in the 
CRU if deemed necessary for safety monitoring, as determined by the investigator.
Safety will be assessed throughout the study by monitoring AEs, clinical laboratory tests, 
electrocardiograms (ECGs), vital signs measurement and through medical assessments.
Study governance considerations are described in detail in Appendix 3.
5.2.
Number of Participants
Up to 60 subjects may be enrolled so that at least 44 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 a subject discontinues from the study before completion of all 4 dosing periods, replacement 
subjects may be enrolled up to 60 subjects following agreement between the investigator and the 
sponsor.
The replacement subject will be assigned the treatment sequence of the discontinued subject and 
complete that 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.
5.4.
Scientific Rationale for Study Design
A population of healthy subjects is selected 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 of a crossover design allows each subject to serve as his or her own control, thereby 
reducing variability.  The replicate crossover design, which was also the design in the pilot study,
allows for a decreased sample size and is a commonly used design in bioequivalence studies.  
The study is subject- and investigator-blind to minimize potential bias related to the clamp 
procedure.  
A euglycemic clamp technique, the gold standard methodology for assessing insulin action, will 
be used in this study to provide data on the GD activity of each study insulin lispro formulation 
(see Section 9.6 for a detailed description of the clamp methodology).


I8B-MC-ITRQ(a)Clinical Pharmacology Protocol
Page 20
LY900014
Based on the PK properties of treprostinil (half-life associated with the terminal rate constant in 
noncompartmental analysis [t
1/2]=
) and Humalog (t1/2=approximately 
), a minimum duration of 3days for the washout period between clamp visits and 
atleast 14-day duration between the last dose of study drug and the follow-up visit are 
considered appropriate.
5.5. Justification for Dose
CCI
Based on previous studies of both insulin lispro (Humalog) and LY900014(approximately 
U-100concentration), the 15U 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 adequate 
glucose infusion rate (GIR) for assessment of GD.
The safety, PK, and pharmacology of LY900014(approximately U-100 concentration) at similar 
doses and with the similar formulation composition have been assessed in clinical studies in 
healthy subjects, in patients with T1DM using MDI or insulin pump treatment and T2DM using 
MDI.  Inaddition, 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 
(
).
All tested doses of treprostinil (up to  
), insulin lispro(upto  
), and LY900014 (up to 
) 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 studies.  No subject discontinued 
from the studies because of drug-related AEs.  There were small numbers of TEAEs and 
injection-site AEs, but there was no clinically significant increase in these or other events 
compared to placebo or to Humalog and no 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 
 (ie, headache, diarrhea, nausea, jaw pain, vasodilatation, rash, 
edema, and hypotension).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 (VAS) pain scores 
showed that the SC injections of insulin lispro plus treprostinil co-formulations and treprostinil 
alone were well tolerated.
The PK of treprostinil in LY900014 following SC administration of 15U of LY900014
(approximatelyU-100)in healthy subjectswas assessed in previous studies.  In these studies, 
treprostinil exposure was not detectable (
ng/mL) for the 15U dose of LY900014. In 
addition, theconcentration of treprostinil in LY900014 U-200 
 than in 
LY900014 U-100 
;therefore the exposure to treprostinil in the U-200 formulation is 
expected to benegligible.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 21
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 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] No male contraception required except in compliance with specific local 
government requirements.
[1b] females:
For females 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
Females 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


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 22
LY900014
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, 
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 70 years of age, inclusive, at the time of screening.
[3]
have a body weight of ≥45 kg, and body mass index (BMI) of 18 to 30 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 glucose 
administration, and clamp procedure as per the protocol.
[6]
are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures.
[7]
are able and willing to give signed informed consent.
[8]
have a hemoglobin level of ≥12.5 g/dL at screening.
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 
or any other type of medical research judged not to be scientifically or 
medically compatible with this study.
[12] have participated, within the past 30 days, in a clinical study involving an 
investigational product.  If the previous investigational product has a long 
half-life, 5 half-lives or 30 days (whichever is longer) should have passed.
[13] have previously completed or withdrawn from this study.
[14] have known allergies to insulin lispro or treprostinil-related compounds or any 
components of the formulation, or a history of significant atopy.


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 23
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 a clinically relevant abnormal blood pressure and/or pulse rate as 
determined by the investigator.
[17] have a history or current cardiovascular, respiratory, hepatic, renal, 
gastrointestinal, endocrine, hematological, or neurological disorders capable 
of significantly altering the absorption, metabolism, or elimination of drugs; 
of constituting a risk when taking the investigational product; or of interfering 
with the interpretation of data.
[18] have known or ongoing 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 C and/or positive hepatitis C antibody.
[22] show evidence of hepatitis B and/or positive hepatitis B surface antigen.
[23] use over-the-counter or prescription medication within 7 or 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 used nicotine-containing products (eg, cigarettes, cigars, pipes, 
smokeless tobacco or nicotine replacement therapy) within 2 months of study 
entry or intend to use for the duration of the study
[25] have donated blood of more than 450 mL or have participated in a clinical 
study that required similar blood volume drawn for the past 3 months.
[26] 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 each 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).
[27] are unwilling to comply with the dietary requirements/restrictions during the 
study: (i) comply with the fasting requirements of the study, (ii) consume only 
the meals/snacks provided during the inpatient visits.
[28] in the opinion of the investigator or sponsor, are unsuitable for inclusion in the 
study.


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 24
LY900014
6.3.
Lifestyle and/or Dietary Requirements
Throughout the study, subjects may undergo medical assessments and review of compliance with 
requirements before continuing in the study.
6.3.1. Meals and Dietary Restrictions
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.  There is no 
restriction on water during the fasting periods of the study.
When not resident at the CRU, subjects will be encouraged to follow their normal diets.
6.3.2. Caffeine, Alcohol, and Tobacco
No alcohol will be allowed at least 24 hours before each dose and for the duration of each CRU 
visit.  Between the study periods, subjects’ alcohol consumption should not exceed 2 units per 
day.
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), nicotine replacements, and the use of smokeless tobacco 
will not be permitted during the study.
6.3.3. Activity
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-ITRQ(a)Clinical Pharmacology Protocol
Page 25
LY900014
7.Treatment
7.1. Treatment Administered
The study will compare formulationsofLY900014containing 200U/mL of insulin lispro 
(LY900014 U-200) and100U/mL of insulin lispro (LY900014 U-100). TableITRQ.3shows 
the treatments to be administered.
TableITRQ.3.
TreatmentsAdministered
Treatment Name
LY900014 U-200
LY900014 U-100
Insulin lispro dosage formulation
200U/mL
100U/mL
Insulin lispro dosage level
15U
15U
Treprostinil concentration (treprostinil dose)
Route of administration
SC injection
SC injection
Injection volume administered
Abbreviation:  SC= subcutaneous.
The investigator or designee is responsible for
explaining the correct use of the investigational product(s) to the CRU personnel
verifying that instructions are followed properly
maintaining accurate records of investigational product dispensationand collection

CCI
returning all unused medicationsto Lilly or its designee at the end of the study(if 
required) or destroying the materials (if the site has appropriate facilities/service provider
and written procedures to dispose of clinical materials) following authorization by the 
study sponsor.
Qualified CRUpersonnel will be instructed on proper preparation andadministration techniques 
for all study drugsused in this study. To maintain the blind, all insulininjections will be given 
by only a few appropriately qualified members of the CRU staff who areindependent of the 
clamp team and who will not provide assessment of AEs. In addition, where possible, the same 
personnel should give the injectionsto reduce variability of the injection technique.
Injection sites selected should be about 5 cm from the umbilicus and the treatment administered 
SCwith the needle applied at about 90°without pinching the skinfold.  Injections will be rotated 
among different injection sites on the anterior abdominal wall duringthe 4 study periods (ie, left 
and right lower quadrants). All subjects will receive study drugsas a single SC injection in each 
period.
CCI
C
C
I
CCI
CCI


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 26
LY900014
7.1.1. Packaging and Labeling
Clinical study materials will be labeled according to the country’s regulatory requirements.  The 
study insulins will be supplied by Lilly or its representative in accordance with current good 
manufacturing practices and will be supplied with lot numbers.
The study insulins (LY900014 U-200 and LY900014 U-100) will be provided to the CRU 
unblinded.  Each formulation will be supplied in 3 mL glass cartridges for use with disposable 
pens.
7.2.
Method of Treatment Assignment
The study insulin to be injected in a given treatment period will be determined according to a 
randomization schedule.
7.2.1. Selection and Timing of Doses
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.
7.3.
Blinding
Blinding will be maintained throughout the conduct of the study as described in the separate 
Blinding Plan.
The study is subject- and investigator-blind with reference to the identity of the study drug 
administered.  The CRU pharmacy staff (involved in preparation of study drug for 
administration) and dosing nurses will be unblinded to the identity of the study drug 
administered due to the difference in the appearance of the pens. Appropriate measures at the 
CRU are to be taken to maintain the blind to subjects and blind the CRU staff.
The Lilly clinical pharmacologist (CP)/Lilly study team will be unblinded.
Emergency codes will be available to the investigator.  A code that reveals the treatment group 
for a specific study subject may be opened during the study only if the subject’s well-being 
requires knowledge of the subject’s treatment assignment.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a subject’s treatment assignment is warranted for medical management of the event.  The 
subject’s safety must always be the first consideration in making such a determination.  If the 
investigator decides that unblinding is warranted, it is the responsibility of the investigator to 
promptly document the decision and rationale and notify Lilly as soon as possible.
Upon completion of the study, all codes must be returned to Lilly or its designee.
7.4.
Dose Modification
Dose adjustments are not allowed in this study.


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 27
LY900014
7.5.
Preparation/Handling/Storage/Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained, as communicated by the sponsor, during transit for all study drugs received and any 
discrepancies are reported and resolved before use of the study treatment.
Only participants enrolled in the study may receive the study drugs, and only authorized CRU
personnel may supply or administer the investigational product. All investigational products
should be stored in an environmentally controlled and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized CRU personnel.
The study drugs must be stored at the CRU under refrigerated conditions (between 2°C and 8°C) 
in a locked and secure place.  Insulin must not be frozen.
The investigator is responsible for study treatment accountability, reconciliation, and record 
maintenance (such as receipt, reconciliation, and final disposition records).
7.6.
Treatment Compliance
The study drug will be administered at the CRU, and documentation of treatment administration 
will occur at the CRU.
7.7.
Concomitant Therapy
Subjects should not use over-the-counter or prescription medications as described in exclusion 
criterion 23 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 after consultation with a Lilly CP or clinical research physician 
(CRP).  Any medication used during the course of the study must be documented.
7.8.
Treatment after the End of the Study
Not applicable.


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 28
LY900014
8. Discontinuation Criteria
Subjects discontinuing the study drug and/or study prematurely for any reason should complete 
follow-up procedures per Section 2 of this protocol.
8.1.
Discontinuation from Study Treatment
Discontinuation of the investigational product due to abnormal liver tests should be considered
by the investigator when a subject meets 1 of the following conditions after consultation with the 
Lilly-designated medical monitor:

alanine aminotransferase (ALT), aspartate aminotransferase (AST) >5X upper limit of 
normal (ULN) for healthy subjects

ALT or AST >3X ULN for healthy subjects sustained for more than 2 weeks or

ALT or AST >3X ULN and total bilirubin level (TBL) >2X ULN or international 
normalized ratio (INR) >1.5 or

ALT or AST >3X ULN with the appearance of fatigue, nausea, vomiting, right 
upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

alkaline phosphatase (ALP) >3X ULN

ALP >2.5X ULN and TBL >2X ULN

ALP >2.5X ULN with the appearance of fatigue, nausea, vomiting, right quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%).
8.1.1. Discontinuation of Inadvertently Enrolled Subjects
If the sponsor or investigator identifies a subject who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Lilly 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 
investigational product.  
8.2.
Discontinuation from the Study
Subjects will be discontinued under the following circumstances:

Enrollment in any other clinical study involving an investigational product or enrollment 
in any other type of medical research judged not to be scientifically or medically 
compatible with this study

Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP)

Investigator Decision
o
the investigator decides that the subject should be discontinued from the study

Subject Decision
o
the subject, or legal representative, requests to be withdrawn from the study.


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 29
LY900014
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 personnel.  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 personnel.


I8B-MC-ITRQ (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.
Appendix 2 lists the laboratory tests that will be performed for this study.
Appendix 5 provides a summary of the maximum number and volume of invasive samples, for 
all sampling, during the study.
Unless otherwise stated in subsections below, all samples collected for specified laboratory tests 
will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may be 
retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1.
Efficacy Assessments
This section is not applicable for this study.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of subjects who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the subject.
The investigator is responsible for the appropriate medical care of subjects during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the subject to discontinue the investigational product before 
completing the study.  The subject should be followed until the event resolves, stabilizes with 
appropriate diagnostic evaluation, or is reasonably explained.  The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator.
After the informed consent form (ICF) is signed, the 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 investigational product, and/or study procedure and the AE.
Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study.


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 31
LY900014
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in 1 of the following:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (ie, 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 subject 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 
investigational product.  However, if an SAE occurs after signing informed consent, but prior to 
receiving study drug, AND is considered Reasonably Possibly Related to a study procedure then 
it MUST be reported.
Pregnancy (maternal or paternal exposure to study drug) 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 investigational product or procedure.  Lilly 
has procedures that will be followed for the recording and expedited reporting of SUSARs that 
are consistent with global regulations and the associated detailed guidances.
9.2.2. Complaint Handling
Lilly collects product complaints on study drugs and drug delivery systems used in clinical trials 
in order to ensure the safety of study participants, monitor quality, and to facilitate process and 
product improvements.


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 32
LY900014
Subjects should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
9.3.
Treatment of Overdose
For the purposes of this study, an overdose of the study drugs is considered any dose higher than 
the dose assigned through randomization.
Excess insulin administration, including LY900014, may cause hypoglycemia.  Mild episodes of 
hypoglycemia usually can be treated with oral glucose.  Adjustments in drug dosage, meal 
patterns, or exercise may be needed.  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.
Refer to the IB for further information.
9.4.
Safety
9.4.1. Laboratory Tests
For each subject, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2). 
With the exception of safety laboratory test results that may unblind the study, Lilly or its 
designee will provide the investigator with the results of laboratory tests analyzed by a central 
vendor, if a central vendor is used for the study.
9.4.2. Vital Signs
For each subject, vital signs measurement 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.
9.4.3. Electrocardiograms
For each subject, ECGs should be collected according to the Schedule of Activities (Section 2).  
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
subject receives the first dose of the investigational product should be reported to Lilly, or its 
designee, as an AE via electronic data entry. 
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 


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 33
LY900014
obtained at additional times, when deemed clinically necessary.  All ECGs recorded should be 
stored at the investigational site.
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.
9.4.4. Other Tests
9.4.4.1.
Physical Examinations
Physical examinations and routine medical assessments (including review of AEs, concomitant 
medications, inquiry of subjects’ health status and performing targeted examinations, as deemed 
appropriate by the investigator) will be conducted as specified in the Schedule of Activities 
(Section 2) and as clinically indicated.
9.4.4.2.
Body Weight and Height
Body weight and height 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.
9.4.5. Safety Monitoring
The Lilly CP or CRP/scientist will monitor safety data throughout the course of the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly CP or 
CRP will periodically review 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.
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the group level, additional analyses of the safety data will be conducted by the personnel 
included in the Unblinding/Blinding Plan.


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 34
LY900014
9.4.5.1.
Glucose Monitoring
Hypoglycemia will be described using the following definitions:

Documented Glucose Alert Level (Level 1), Plasma Glucose (PG) ≤70mg/dL 
(3.9 mmol/L):
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)
o
Unspecified hypoglycemia:  an event during which plasma glucose 
≤70 mg/dL (3.9 mmol/L) but with no available information related to 
symptoms of hypoglycemia

Probable symptomatic hypoglycemia:  an event during which symptoms indicative 
of hypoglycemia are observed but not accompanied by a plasma glucose 
determination (but that was presumably caused by plasma glucose ≤70 mg/dL 
[3.9 mmol/L])

Documented Clinically significant hypoglycemia (Level 2) PG <54 mg/dL 
(3.0 mmol/L):
o
Symptomatic hypoglycemia: an event during which typical symptoms of 
hypoglycemia are accompanied by PG ≤54 mg/dL (3.0 mmol/L)
o
Asymptomatic hypoglycemia: an event not accompanied by typical 
symptoms of hypoglycemia but with PG ≤54 mg/dL (3.0 mmol/L)
o
Unspecified hypoglycemia:  an event during which PG ≤54 mg/dL 
(3.0 mmol/L) but no information relative to symptoms of hypoglycemia was 
recorded.

Severe hypoglycemia (Level 3):  an event during which patients had altered mental
status, and could not assist in their own care, or were semiconscious or unconscious, 
or experienced coma with or without seizures, and the assistance of another person 
was to actively administer carbohydrate, glucagon, or other resuscitative actions.
Plasma glucose measurements may not be available during such an event, but 
neurological recovery attributable to the restoration of plasma glucose to normal is
considered sufficient evidence that the event was induced by a low plasma glucose 
concentration (≤70 mg/dL [3.9 mmol/L]). 
o
Severe hypoglycemia requiring medical attention:  a severe hypoglycemic 
event when patients require therapy by HCPs (EMTs, emergency room 
personnel, etc.).

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

Overall (or total) hypoglycemia:  This optional category combines most cases of 
hypoglycemia except relative hypoglycemia.  Nocturnal and severe hypoglycemia are 


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 35
LY900014
special cases of documented or probable hypoglycemia. If an event of hypoglycemia
falls into multiple subcategories, that event should be counted only once in this
category of overall (or total) hypoglycemia.  
The goal of the euglycemic clamp is to maintain glucose concentrations at normoglycemic levels 
close to a predefined target.  Therefore, the equivalence of 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.
Episodes of severe hypoglycemia as determined by the investigator must be reported as SAEs.
9.4.5.2.
Hepatic Safety
If a study subject experiences elevated ALT ≥3X ULN, ALP ≥2X ULN, or elevated TBL ≥2X 
ULN, liver tests (Appendix 4) should be repeated within 3 to 5 days including ALT, AST, ALP, 
TBL, direct bilirubin, gamma-glutamyl transferase, and creatinine kinase to confirm the 
abnormality and to determine if it is increasing or decreasing.  If the abnormality persists or 
worsens, clinical and laboratory monitoring should be initiated by the investigator based on 
consultation with the Lilly CP or CRP.  Monitoring should continue until levels normalize and/or 
are returning to approximate baseline levels. 
Additional safety data should be collected if 1 or more of the following conditions occur: 

elevation of serum ALT to ≥5X ULN on 2 or more consecutive blood tests

elevation of serum TBL to ≥2X ULN (except for cases of known Gilbert’s 
syndrome)

elevation of serum ALP to ≥2X ULN on 2 or more consecutive blood tests

patient/subject discontinued from treatment due to a hepatic event or abnormality 
of liver tests

hepatic event considered to be an SAE.
9.4.6. Injection-Site Assessments (Local Tolerability)
Injection-site assessments for local tolerability will be conducted as specified in the Schedule of 
Activities and more frequently if deemed necessary by the investigator (Section 2).
Digital pictures of the injection site will be taken, if possible, 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.


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 36
LY900014
Local tolerability at the injection site will be evaluated by means of assessments within the 
following categories:  pain on palpation, itching, erythema, edema, and induration/infiltration.
9.4.6.1.
Pain Measurements Using the Visual Analog Scale
Pain measurements will be assessed using a 100-mm validated VAS for pain.  The VAS is a 
well-validated tool (Williamson and Hoggart 2005) to assess injection-site pain.  The VAS is 
presented as a 10-cm (100-mm) line, anchored by verbal descriptors, usually “no pain” and 
“worst imaginable pain.”  The subject will be asked to mark the 100-mm line to indicate pain 
intensity at time points according to the Schedule of Activities (Section 2) and as clinically 
indicated.  A staff member will use a caliper to measure the distance from 0 to the mark that the 
subject placed on the VAS and record the measurement in the source document.
As injection-site pain is an expected AE, injection-site pain (especially transient episodes of 
pain) will generally not be considered a clinically significant event unless the duration or 
intensity of the pain interferes with normal activities of daily living or constitutes a risk to the 
well-being of the subject.  Analgesia can be prescribed in response to pain and must be 
documented in the concomitant medication section of the eCRF.
9.5.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
of approximately 1 mL each will be collected to determine serum concentrations of insulin 
lispro.  Instructions for the collection and handling of blood samples will be provided by the 
sponsor.  The actual date and time (24-hour clock time) of each sampling will be recorded.
Failure to obtain blood samples due to clinical reasons, such as problems with venous access, 
will not be considered protocol violations.  However, the CRU personnel will still be required to 
notify the sponsor in writing to account for missing samples for data reconciliation purpose.
9.5.1. Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.
Concentrations of insulin lispro in serum following LY900014 U-200 and LY900014 U-100
administration will be assayed using a validated enzyme-linked immunosorbent assay. 
Bioanalytical samples collected to measure investigational product concentrations will be 
retained for a maximum of 1 year following last subject visit for the study.
9.6.
Glucodynamics (Euglycemic Glucose Clamp)
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 GIR will be adjusted to maintain a predetermined target blood glucose 
concentration for the individual subject.  Thus, blood glucose concentrations are kept constant 
while the GIR varies.  The varying GIR will then reflect the GD activity of insulin.


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 37
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 concentration.
The target value for blood glucose concentrations is defined as 5 mg/dL below the mean of 
predose fasting blood glucose 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 fasting blood glucose 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]).
9.6.1. Immunogenicity Assessments
Blood samples for immunogenicity testing will be collected to determine antibody production 
against insulin lispro as described in the Schedule of Activities (Section 2).  Additional samples 
may be collected if there is a possibility that an AE is immunologically mediated.
Immunogenicity will be assessed using 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-ITRQ (a) Clinical Pharmacology Protocol
Page 38
LY900014
sponsor.  The duration allows the sponsor to respond to future regulatory requests related to the 
study drugs.  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 study 
drugs and to investigate genetic variants thought to play a role in diabetes mellitus.  Assessment 
of variable response may include evaluation of AEs or differences in efficacy.
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 investigative site 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
9.8.1. C-Peptide
Blood samples (2.5 mL) will be collected to determine serum concentrations of C-peptide as 
described in the Schedule of Activities (Section 2) using a validated method at a central 
laboratory.  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-ITRQ(a)Clinical Pharmacology Protocol
Page 39
LY900014
10. Statistical Considerations and Data Analysis
10.1.Sample SizeDetermination
Up to 60subjects may be enrolled so that approximately 44subjects complete the study. 
Forty-fourcompleting subjects in a replicated design will provide at least 95% power to show 
the 2-sided 90% CIs of the ratios of geometric least-squares means (LSmeans) for AUC(0-∞), 
AUC(0-tlast)between LY900014 U-200 and LY900014 U-100 to be within limits of 0.80 to 
1.25. This calculation assumes a log-scale standard deviationfor within-subject difference of   
and up to a 5% difference in geometric LSmean ratio. There is also at least 95% power to show 
the 2-sided 90% CI of the ratio of the geometric means for Cmax between the 2formulations 
also within 0.80 to 1.25. This calculation assumes a log-scale standard deviationfor 
within-subject differenceof 
and a 10% difference in geometric LSmean ratio for Cmax with 
LY900014 U-200 compared to LY900014 U-100.
In addition, the study is adequately powered to evaluate the GD parameters. There isat least
85% power to show the 2-sided 90% CI of the ratio of the geometric means between the 2 
formulations for total amount of glucose infused (Gtot)and maximumGIR (Rmax)are within 
0.80 to 1.25.  This calculation assumes a log-scale standard deviation for within-subject 
difference of  
for Gtot and 
 for Rmax and up to a 10% difference in the LSmean ratios.
Subjects who are randomized but not administeredtreatment may be replaced to ensure that 
approximately 44subjects complete the study. The replacement subjects will assume the same 
treatment sequence as the subjects who dropped out and will complete that treatment sequence in 
its entirety.
10.2.Populations for Analyses
10.2.1.Study Participant Disposition
A detailed description of subjectdisposition will be provided at the end of the study. 
10.2.2.Study Participant Characteristics
The subject’s age, sex, weight, BMI, height, race/subrace, smoking habits, or other demographic 
characteristics will be recorded.
10.3.Statistical Analyses
CC
I
Statistical analysis of this study will be the responsibility of Eli Lilly and Companyor its 
designee.
Pharmacokinetic/pharmacodynamic analyses will be conducted on data from all subjectswho 
receive at least 1dose of the study drugand have evaluable PK.
Primary statistical analyses will be conducted on the set of subjectswho complete at least the
first period of treatment.  Supportive analyses may be done on the key parameters for the
subjectswho complete all treatment periods.  Safety analyses will be conducted for all enrolled
CCI
CCI
C
C
I
CCI


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 40
LY900014
subjects who receive at least 1 dose of the study drug 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. Safety Analyses
10.3.1.1. Clinical Evaluation of Safety
All study drugs and protocol-procedure AEs will be listed; if the frequency of events allows, 
safety data will be summarized using descriptive methodology.
The incidence of symptoms for each treatment will be presented by severity and by association 
with study drug as perceived by the investigator.  Symptoms reported to occur prior to study 
entry/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 study drug-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.  The 
parameters will be listed, and summarized using standard descriptive statistics.  Additional 
analysis will be performed if warranted upon review of the data.
10.3.1.3. Statistical Evaluation of the Intensity of Injection-Site Pain
Pain intensity will be assessed at each injection site immediately after the injection as reported 
by the subject and measured according to the 0- to 100-mm VAS.
A mixed-effect model will be used to analyze the time 0 (immediately after dosing) data using 
the statistical model that includes treatment, sequence, and period as fixed effects; and subject
within sequence as a random effect.  The distribution of the score data will be explored prior to 
analysis to determine whether data transformation is required.  It is possible that VAS scores will 
be 0; hence if the distribution of the data implies that a log transformation is required, then the 
score may be updated to log (VAS+1) to allow for the inclusion of the 0 values in the analysis.
Visual analog scale data will also be summarized based on the following categories of score:  0, 
1 to 10, 11 to 20, 21 to 30, 31 to 40, etc., up to the maximum category by treatment and time
point.  


I8B-MC-ITRQ(a)Clinical Pharmacology Protocol
Page 41
LY900014
10.3.2.Pharmacokinetic Analyses
10.3.2.1.Pharmacokinetic Parameter Estimation
Subjects who completed at least 1 period and had evaluableinsulin lispro concentrations willbe 
included in the PK analysis dataset.  Pharmacokineticanalyses will be conducted using standard 
noncompartmental methods of analysis using
on a computer that meets or exceeds 
the minimum system requirements for theseprograms. The version of any software used for the 
analysis will be documented and theprogram will meet the Lilly requirements of software 
validation. It is possible that othervalidated equivalent PK software programs may be utilized if 
appropriate, warranted, andapproved by global PK management.
Free serum insulin lispro concentrations will be used to calculate several PK parameters, 
including Cmax, time of maximum observed drug concentration (tmax), half-life (t
1/2),time to 
early half-maximal drug 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 t
lastwhere tlastis the last time point with a measurable concentration(AUC[0-tlast]), area 
under the concentration versus time curvefrom time zero to 10 hours(AUC[0-10h]), area under 
the concentrationversustime 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.Other parameters may be calculated as deemedappropriate, such as partial AUCs.
Although attempts will be made to adhere to the scheduled collection times, 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 by summary statistics.
10.3.2.2.Pharmacokinetic Statistical Inference
CCI
To compare PK parametersbetween LY900014 U-200relative to LY900014 U-100, 
log-transformed AUCparameter estimates (AUC[0-tlast],AUC[0-∞], and Cmax)will be 
analyzed using themixed-effectsmodel that includes treatment, sequence,and period as fixed 
effects and subjectwithin sequenceas a randomeffect.  From the model, the difference in 
LSmeansand the corresponding 2-sided 90% CIsfor the difference will be estimated and 
back-transformed from the log scale to provide estimates of the ratio of geometric LSmeans and 
90% CI for the ratio of the LSmeans.  Bioequivalence will be concluded if the 2-sided 90% CI is 
completely contained within the interval (0.80, 1.25).  
In addition, the same model without log transformation will be used for the analysis of the PK
time parameters (early 50% tmax,and tmax).  Least-squares means, treatment differences in 
LSmeans,and the corresponding 90% CIs for the treatment differences will be estimated from 
the model.  The treatment ratios and 90% CIs for the ratios will be calculated using Fieller’s 
theorem.  As a sensitivity analysis, the PK time parameters will beanalyzed nonparametrically 
using Wilcoxon signed rank test.  OtherPK time parameters may be analyzed in a similar 
manner.  
In addition, the analyses described above will also be performed on the population of subjects
who completed and had evaluable PK data in allstudy periods.


I8B-MC-ITRQ(a)Clinical Pharmacology Protocol
Page 42
LY900014
10.3.3.Pharmacodynamic Analyses 
10.3.3.1.Pharmacodynamic Parameter Estimation
Glucodynamic assessments will be determined from the glucose clamp procedure, where the 
GIRover time will be used as a measure of insulin effect.  Glucodynamic analyses will be 
conducted on those subjectswho complete at least 1 clamp procedure.
A locally weighted scatterplot smoothing (LOESS) function will be applied to all individual GIR 
versus time profiles in each treatment group and/or period using 
.  
The fitted data for each subject will be used to calculate the following GD parameters: time to 
onset of insulin action (tonset), time to maximal GIR (Rmax), time to Rmax(tRmax), time to 
half-maximal GIR beforetRmax(early 50% tRmax),time to half-maximal GIR after tRmax(late 
50% tRmax), total amount of glucose infused (Gtot), Gtotover 30 minutes(Gtot
0-30min),and
Gtotover 1 hour(Gtot
0-1h).  Additional partial glucose AUCs, such as Gtotover 2hours, and 
Gtotfrom 3 hoursto 10hours may be computed as necessary.  The values of these GD 
parameters will be summarized by treatment and/or period through descriptive statistics.  Mean 
LOESS fits of GIR versus time profiles will be generated. 
10.3.3.2.Pharmacodynamic Statistical Inference
To address the secondary objective of comparing GD parameters (Gtotand Rmax) between the 
LY900014 U-200 and LY900014 U-100formulations,log-transformed Gtotand Rmaxestimates 
will be analyzed using themixed-effectsmodel that includes treatment, sequence,and period as 
fixed effects and subjectwithin sequenceas a randomeffect.  From the model, the difference in 
LSmean estimates and the corresponding 90% for the difference will be estimated and 
back-transformed from the logscale to provide estimates of the ratios of geometric LSmeans and 
90% for the ratio of the LSmeans.  
In addition, the same model without log transformation will beused for the analysis of the GD 
time parameters (tRmaxand early 50% tRmax).  Least-squares means, treatment differences in 
LSmeans,and the corresponding 90% CIs for the treatment differences will be estimated from 
the model.  The p-value forthe difference between LSmeans will be used to determine statistical 
significance.  The treatment ratios and 90% CIs for the ratios will be calculated using Fieller’s 
theorem.  Other GD time parameters may be analyzed in a similar manner.  
In addition, the analyses described above will also be performed on the population of subjects
who completed and had evaluable GD data in allstudy periods.
10.3.4.Evaluation of Immunogenicity
CCI
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-ITRQ (a) Clinical Pharmacology Protocol
Page 43
LY900014
10.3.5. C-Peptide
Mean and individual C-peptide concentration versus time plots with both treatments will be 
presented.  In addition, individual plots overlaying the C-peptide concentration versus time with 
the insulin lispro serum concentration versus time will be presented.  Other plots that may be 
explored include the C-peptide concentrations relative to the GIR, and/or blood glucose 
concentrations during the euglycemic clamp.
10.3.6. Data Review During the Study
This section is not applicable for this study.
10.3.7. Interim Analyses
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-ITRQ(a)Clinical Pharmacology Protocol
Page 44
LY900014
11. References
Humalog [package insert]. Indianapolis, IN 46285: Lilly USA, LLC; 2015.
 
Williamson A, Hoggart B. Pain: a review of three commonly used pain rating scales. 
JClinNurs.
CCI
2005;14(7):798-804.


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 45
LY900014
Appendix 1.
Abbreviations and Definitions
Term
Definition
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
AUC(0-tlast)
AUC from time zero to time t, where t is the last time point with a measurable concentration
AUC(0-∞)
AUC from time zero to infinity
blinding
A procedure in which 1 or more parties to the study are kept unaware of the treatment 
assignment(s).  Unless otherwise specified, blinding will remain in effect until final 
database lock.
BMI
body mass index
CI
confidence interval
Cmax
maximum observed drug concentration
compliance
Adherence to all the study-related requirements, good clinical practice (GCP) requirements, 
and the applicable regulatory requirements.
CP
clinical pharmacologist
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
early 50% tmax
time to early half-maximal drug concentration
early 50% tRmax
time to half-maximal glucose infusion rate before tRmax
ECG
electrocardiogram
eCRF
electronic case report form
ERB
ethical review board
FDA
Food and Drug Administration
GCP
good clinical practice
GD
glucodynamic(s)
GIR
glucose infusion rate
Gtot
total amount of glucose infused


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 46
LY900014
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.  
INR
international normalized ratio
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical study, including products already on the market when used or assembled 
(formulated or packaged) in a way different from the authorized form, or marketed products 
used for an unauthorized indication, or marketed products used to gain further information 
about the authorized form.
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
LSmeans
least-squares means
MDI
multiple daily injection
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
SC
subcutaneous(ly)
screen
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical 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
TBL
total bilirubin level
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 


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 47
LY900014
tmax
time of maximum observed drug concentration
tRmax
time to Rmax
U
units
ULN
upper limit of normal
VAS
visual analog scale


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 48
LY900014
Appendix 2.
Clinical Laboratory Tests
Safety Laboratory Testsa
Hematology
Clinical Chemistry
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume 
Chloride
Mean cell hemoglobin 
Calcium
Mean cell hemoglobin concentration 
Phosphate
Leukocytes (WBC)
Glucose
Absolute counts of:
Blood urea
Neutrophils
Uric acid
Lymphocytes
Total cholesterol
Monocytes
Triglycerides
Eosinophils
Total protein
Basophils
Albumin
Platelets
Total bilirubin
Urinalysis
Alkaline phosphatase (ALP)
Specific gravity
Aspartate aminotransferase (AST)
pH
Alanine aminotransferase (ALT)
Protein
Creatinine
Glucose
Serologyb
Ketones
Hepatitis B surface antigen
Bilirubin
Hepatitis C antibody
Urobilinogen
HIV
Blood
Pregnancy testc
Nitrite
Beta human chorionic gonadotropin (HCG)
Leukocytes
FSHd
Microscopye
Abbreviations:  ED = early discontinuation; FSH = follicle-stimulating hormone; HCG = human chorionic 
gonadotropin; HIV = human immunodeficiency virus; RBC = red blood cell; WBC = white blood cell.
a
Fasting at screening and at predose of Day 1 in Period 1.
b
Only at screening.
c
Pregnancy test is applicable to women only. A blood test for pregnancy will be done at screening (HCG, rapid), 
and a urine pregnancy test (HCG, urine) will be done during the study and at follow-up/ED as 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-ITRQ (a) Clinical Pharmacology Protocol
Page 49
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 investigational 
product.

answering any questions the subject may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the subject’s willingness to 
continue his or her participation in the study.

providing a copy of the ICF to the participant or the participant’s legal representative and 
retaining a copy on file.
Recruitment
Lilly is responsible for the central recruitment strategy for subjects.  Individual investigators may 
have additional local requirements or processes.  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 guideline 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


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 50
LY900014
Regulatory Considerations
This study will be conducted in accordance with the protocol and with
1) consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines 
2) applicable ICH GCP Guidelines
3) applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third-party organization.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Final Report Signature
The 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 eCRFs, 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 eCRF data and/or use standard computer edits to detect errors in data 
collection.

conduct a quality review of the database.


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 51
LY900014
In addition, Lilly or its representatives will periodically check a sample of the subject data 
recorded against source documents at the study site.  The study may be audited by Lilly and/or 
regulatory agencies at any time.  Investigators will be given notice before an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to the original source 
documents.
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/patient personal information collected will be provided in a 
written document to the subject/patient 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-ITRQ (a) Clinical Pharmacology Protocol
Page 52
LY900014
Appendix 4.
Hepatic Monitoring Tests for Treatment-
Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with subjects in consultation with Lilly or its designee CRP.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin time
WBC
Prothrombin time, INR
Neutrophils
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Conjugated bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear Antibody
AST
Alkaline Phosphatase Isoenzymesa
GGT
CPK 
Anti-smooth Muscle Antibody (or Anti-actin 
Antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized
ratio; RBC = red blood cell; WBC = white blood cell.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 53
LY900014
Appendix 5.
Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.  
Protocol I8B-MC-ITRQ 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
11 (fasting)
1
11
9 (non-fasting)
1
9
Pharmacokinetic samples serum 
insulin lispro
1
25 samples ×4
periods = 100
100
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
C-peptide samples
2.5
12 samples × 4 
periods = 48
120
Immunogenicity
5
4
20
Pharmacogenetics
10
1
10
Total
423.8
Total for clinical purposes (rounded up to nearest 10 mL)
430
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-ITRQ (a) Clinical Pharmacology Protocol
Page 54
LY900014
Appendix 6.
Protocol Amendment I8B-MC-ITRQ(a) 
Summary 
Bioequivalence Study Comparing the Pharmacokinetics 
and Glucodynamics of LY900014 U-200 Formulation with 
LY900014 U-100 Formulation in Healthy Subjects
Overview
Protocol I8B-MC-ITRQ [Bioequivalence Study Comparing the Pharmacokinetics and 
Glucodynamics of LY900014 U-200 Formulation with LY900014 U-100 Formulation 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:

Subjects who had participated in a study requiring similar blood sampling as the current 
study within 3 months of screening will be excluded as per the ethics committee’s 
suggestion 

The hypoglycemia criteria was clarified further

The number of blood samples to be obtained for immunogenicity testing was corrected in 
the blood sampling summary

Other minor edits, such as typographical corrections that do not affect the content of this 
protocol, were made.  These changes may not be reflected in the Revised Protocol 
Sections.


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 55
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.
6.2.
Exclusion Criteria
[25] have donated blood of more than 450 mL or have participated in a clinical 
study that required similar blood volume drawn for the past 3 months within 
the previous 3 months of study screening.
9.4.5.1
Glucose Monitoring

Documented Glucose Alert Level (Level 1), Plasma Glucose (PG) ≤70mg/dL 
(3.9 mmol/L)hypoglycemia:

Documented Clinically significant hypoglycemia (Level 2) PG <54 mg/dL 
(3.0 mmol/L):  
o
Symptomatic hypoglycemia: an event during which typical symptoms of 
hypoglycemia are accompanied by PG ≤54 mg/dL (3.0 mmol/L)
o
Asymptomatic hypoglycemia: an event not accompanied by typical 
symptoms of hypoglycemia but with PG ≤54 mg/dL (3.0 mmol/L)
o
Unspecified hypoglycemia:  an event during which PG ≤54 mg/dL 
(3.0 mmol/L) but no information relative to symptoms of hypoglycemia was 
recorded.
o
an event during which plasma glucose is <54 mg/dL (3.0 mmol/L), where it is 
considered sufficiently low to indicate serious, clinically important hypoglycemia.

Severe hypoglycemia (Level 3):
o
Severe hypoglycaemia requiring medical attention:  a severe hypoglycemic 
event when patients require therapy by HCPs (EMTs, emergency room 
personnel, etc.).


I8B-MC-ITRQ (a) Clinical Pharmacology Protocol
Page 56
LY900014
Appendix 5
Blood 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
11 (fasting)
1
11
9 (non-fasting)
1
9
Pharmacokinetic samples serum 
insulin lispro
1
25 samples ×4
periods = 100
100
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
C-peptide samples
2.5
12 samples × 4 
periods = 48
120
Immunogenicity
5
34
1520
Pharmacogenetics
10
1
10
Total
418423.8
Total for clinical purposes (rounded up to nearest 10 mL)
420430

SAP_000.pdf: