Clinical trial NCT03616977
Conditions: Healthy
Sponsor: Eli Lilly and Company
Start date: 2018-08-03; Completion date: 2018-10-19
Enrollment: 69 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The study involves a comparison of 2 formulations of LY900014, which 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 LY900014 U-200 in two of four study periods. arm 2: Single SC dose of LY900014 U-100 in two of four study periods.
Interventions: intervention 1: LY900014 U-200 intervention 2: LY900014 U-100
Intervention descriptions: intervention 1: Administered SC intervention 2: Administered SC

Protocol documents:
Prot_000.pdf: 
Protocol I8B-MC-ITSS (a) 
 
Bioequivalence Study Comparing 2 Formulations of LY900014 in Healthy Subjects 
 
NCT03616977 
 
Approval Date: 20-Jul-2018 
 
 


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Protocol I8B-MC-ITSS(a)
Bioequivalence Study Comparing 2 Formulations of 
LY900014 in Healthy Subjects
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
LY900014, unless such persons are bound by a confidentiality agreement with Eli Lilly and 
Company or its subsidiaries.
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
Approval Date: 20-Jul-2018 GMT
LY900014
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly: 
14June2018
Amendment (a) Electronically Signed and Approved by Lilly
on approval date provided below.


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Table of Contents
Bioequivalence Study Comparing 2 Formulations of 
LY900014 in Healthy Subjects
Section
Page
Protocol I8B-MC-ITSS(a) Bioequivalence Study Comparing 2 
Formulations of LY900014 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 .......................................................................................25
7.2.
Method of Treatment Assignment ................................................................................26
7.2.1.
Selection and Timing of Doses.............................................................................26
7.3.
Blinding .......................................................................................................................26
7.4.
Dose Modification........................................................................................................26


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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..........................................32
9.2.2.
Complaint Handling.............................................................................................32
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 ..............................................................................................33
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 ................................................................................................34
9.4.5.1.
Glucose Monitoring........................................................................................34
9.4.5.2.
Severe Hypoglycemia.....................................................................................35
9.4.5.3.
Hepatic Safety................................................................................................35
9.4.6.
Injection-Site Assessments (Local Tolerability)....................................................36
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)..............................................................37
9.6.1.
Immunogenicity Assessments ..............................................................................38
9.7.
Genetics .......................................................................................................................38
9.8.
Exploratory Biomarkers ...............................................................................................38
9.8.1.
C-Peptide .............................................................................................................38
9.9.
Health Economics ........................................................................................................39


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10.
Statistical Considerations and Data Analysis.....................................................................40
10.1. Sample Size Determination ..........................................................................................40
10.2. Populations for Analyses..............................................................................................40
10.2.1.
Study Participant Disposition ...............................................................................40
10.2.2.
Study Participant Characteristics ..........................................................................40
10.3. Statistical Analyses ......................................................................................................40
10.3.1.
Safety Analyses....................................................................................................41
10.3.1.1.
Clinical Evaluation of Safety..........................................................................41
10.3.1.2.
Statistical Evaluation of Safety.......................................................................41
10.3.1.3.
Statistical Evaluation of the Intensity of Injection Site 
Pain................................................................................................................41
10.3.2.
Pharmacokinetic Analyses....................................................................................42
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................42
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................42
10.3.3.
Pharmacodynamic Analyses.................................................................................43
10.3.3.1.
Pharmacodynamic Parameter Estimation ........................................................43
10.3.3.2.
Pharmacodynamic Statistical Inference...........................................................43
10.3.4.
Evaluation of Immunogenicity .............................................................................43
10.3.5.
C-Peptide .............................................................................................................44
10.3.6.
Data Review during the Study..............................................................................44
10.3.7.
Interim Analyses..................................................................................................44
11.
References ........................................................................................................................45


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List of Tables
Table
Page
Table ITSS.1.
Objectives and Endpoints .......................................................................17
Table ITSS.2.
Treatment Sequence Example for I8B-MC-ITSS....................................18
Table ITSS.3.
Treatments Administered........................................................................25


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List of Figures
Figure
Page
Figure ITSS.1.
Illustration of study design for Protocol I8B-MC-ITSS...........................18


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................46
Appendix 2.
Clinical Laboratory Tests........................................................................49
Appendix 3.
Study Governance, Regulatory, and Ethical Considerations....................50
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............53
Appendix 5.
Blood Sampling Summary......................................................................54
Appendix 6.
Protocol Amendment I8B-MC-ITSS(a) Summary 
Bioequivalence Study Comparing 2 Formulations of LY900014 in 
Healthy Subjects.....................................................................................55


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1. Protocol Synopsis
Title of Study:
Bioequivalence Study Comparing 2 Formulations of LY900014 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-ITSS is a Phase 1, single-center, subject- and investigator-blind, 2-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 2 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). 


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The study will include a 28-day screening period, followed by 4 study periods.  There will be a wash-out period of at 
least 3 days between each study period.  The follow-up visit will take place at least 14 days after the last dose.
Number of Subjects:
Up to 72 healthy men and women may be enrolled so that approximately 58 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 
parameter estimates (AUC[0-tlast], AUC[0-∞], and Cmax) will be analyzed using a repeated measures, linear 
mixed-effects model where treatment, sequence, and period will be considered as fixed effects and subject as a 
random effect.  From the model, the difference in least-square means (LSmeans) and the corresponding 2-sided 90% 
CIs for the treatment 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).   
AUC(0-tlast) and AUC(0-∞) will also be analyzed using a linear fixed-effects model. The parameter estimates will be 
log-transformed before analysis. The model will include fixed effects for sequence, period, treatment, and subject 
nested within sequence. The LSmeans for each formulation, the difference in means between treatments, and the 
90% CIs will be estimated from the model and back transformed from the log scale to provide estimates of the 
geometric LSmeans, the ratio of the geometric LSmeans, and the 90% CIs. This analysis will only include 
completers.
A model with fixed effects for sequence, period, treatment, and subject nested within sequence 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.  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 a repeated measures, 


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linear mixed-effects model where treatment, sequence, and period will be considered as fixed effects and subject as 
a random effect.  From the model, the difference in LSmeans and the corresponding 2-sided 90% CIs for the 
treatment 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.
A model with fixed effects for sequence, period, treatment, and subject nested within sequence without log 
transformation will be used for the analysis of the GD time parameters (tRmax and 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 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.


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2. Schedule of Activities


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Study Schedule Protocol I8B-MC-ITSS
Procedure
Screening
Periods 1, 2, 3, 4
FU/EDa
Comments
Up to 
Day -28
Day 
-1
Day 1b
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:  Blood pressure, and pulse rate.   
12-lead ECG
X
Predose
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.
Pregnancy test 
X
X
X
Serum and urine pregnancy tests for all 
females at screening; urine pregnancy test 
only for females of childbearing potential at 
other visits.  
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.
Insulin lispro PK sampling
0, 5, 10, 15, 20, 25, 30, 35, 40, 45, 
Sampling times are relative to the time of 


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Procedure
Screening
Periods 1, 2, 3, 4
FU/EDa
Comments
Up to 
Day -28
Day 
-1
Day 1b
Day 
2
50, 55, 60, 70, 90, 120, 150, 180, 
240, 300, 360, 420, 480, 540, and 
600 min
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 min
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 
~30 min before the start of dosing 
(for baseline measurement).  
During clamp, sampling occurs 
every 2.5 min for the first 30 min; 
every 5 min for 30 to 120 min; 
every 10 min for 120 to 480 min
and every 20 min for 480 to 600 
min.
Sampling times are relative to study drug 
administration (time 0).  Repeat samples for 
counter-checking of apparent spurious results 
may be taken where indicated.
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, 
while 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 ED.
b
Predose assessments or sample collections can be performed up to 3 hours prior to dosing .


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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 Lilly and 
Company).  LY900014 U-200 represents a new formulation strength of LY900014.  The insulin 
lispro pharmacokinetics (PK) and glucodynamics (GD) of a 19 unit (U) subcutaneous (SC) dose 
administration of LY900014 U-193 and LY900014 U-95 have been compared in a previously 
completed pilot study (
; see Section 3.2of current protocol).
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 SC administration of a 15 U insulin 
lispro dose to healthy subjects; in addition, the study will evaluate the 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.
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, 2017).  In healthy volunteers given SC doses of 
insulin lispro ranging from 0.1 to 0.4 U/kg, peak serum levelswere seen 30 to 90 minutes after 
dosing (Humalog package insert, 2017).  However, the general consensus is that rapid-acting 
insulin 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/pharmacodynamicsand GD profiles of insulin analogs so that they have an even faster onset 
to better match carbohydrate absorption and also allow greater flexibility in the time of dosing 
relative to meals.
LY900014 represents a new formulation that contains insulin lispro, treprostinil, citrate, and 
other excipients.  This formulation involves the novel use of a microdose of treprostinil 
(
) as an excipient to enhance the absorption of insulin lispro by local vasodilatation 
rather than as an active pharmaceutical ingredient to elicit a systemic effect.  Treprostinil is a 
prostacyclin analog, administered either through inhalation (
), as an intravenous (IV) 
infusion or as a continuous SC administration for the treatment of symptomatic pulmonary 
arterial hypertension (PAH) and has been approved in the US since 2002 and in Germany since 
2006 (AMIS database [WWW]).  Sodium citrate is also included in the formulation to further 
enhance the absorption of insulin lispro, at least in part by enhancing vascular permeability.  
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 identified for approved drug products in 
the FDA Inactive Ingredients in Approved Drugs database.
C
C
I
C
C
I


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Safety and tolerability of LY900014 at approximately U-100 concentration have been 
demonstrated in healthy subjects in 5 previous clinical studies, in approximately 130 healthy 
subjects across a dose range of 7.5 to 30U.  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; 
30patients) 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).  Smallnumbers 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
CCI
This study will not offer any direct benefits to the healthy subjects participating in the study.  
The data from previous studies in healthy subjects and 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, 2017).
Notably, across all doses in the studies that have evaluated treprostinil ( 
) as a local 
vasodilator with or without insulin lispro, there was no clinically significant increase in those 
AEs associated with systemic absorption of treprostinil, as described in the 
 
.  Theexposures of treprostinil in LY900014 for participants in ongoing and future 
clinical studies are expected to be much lower than those observed in the dose ranges previously 
explored with SC bolus administration of treprostinil.Accordingly, treprostinilexposure in 
CCI


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LY900014
CCI
diabetic patients is generally below the detection limit (
) and is substantially lower 
(at least ~200-fold lower) than those observed in adults for the treatment of PAH.  No known 
potential risks are associated with the microdoses of treprostinil in the LY900014 formulation.
In preclinical safety pharmacology and toxicity studies, or clinical pharmacology studies 
involving LY900014 or treprostinil alone, other than known risks associated with Humalog and 
Remodulin, no additional risks were identified.  Additionally, local and systemic toxicity profiles 
of Humalog and Remodulin do not suggest the potential for additive or synergistic toxicity.
Following administration of the study insulin, subjects will receive IV glucose infusion at a 
variable rate to maintain euglycemia up to 10 hours after insulin lispro administration.  The aim 
of the clamp procedure is to maintain blood glucose level within the normal glycemic range.  In 
addition, the clamp is performed while the subject is inpatient and under the investigator’s 
supervision.  These considerations should minimize the risk of hypoglycemia in subjects 
participating in Study I8B-MC-ITSS.
More information about the known and expected benefits, risks, SAEs,and reasonably 
anticipated AEs of LY900014 is to be found in the IB.


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4. Objectives and Endpoints
Table ITSS.1 shows the objectives and endpoints of the study.
Table ITSS.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
1.
To compare other PK and GD parameters for 
LY900014 U-200 versus LY900014 U-100 after 
SC administration.
2.
Explore the formation of antidrug 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.


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LY900014
5. Study Design
5.1.
Overall Design
This is a Phase 1, single-center, investigator- and subject-blind, 2-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 ITSS.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 ITSS.1.
Illustration of study design for Protocol I8B-MC-ITSS.
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 2 dosing 
sequences (Table ITSS.2). 
Table ITSS.2.
Treatment Sequence Example for I8B-MC-ITSS
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
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

1 follow-up visit (at least 14 days after the last dose).
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*


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LY900014
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 a 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 sign measurement, and through medical assessments.
Study governance considerations are described in detail in Appendix 3.
5.2.
Number of Participants
Up to 72 subjects may be enrolled so that at least 58 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 72 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).
Based on the PK properties of treprostinil (half-life associated with the terminal rate constant in 
noncompartmental analysis [t1/2] = approximately 1 hour) and Humalog (t1/2 = approximately 


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LY900014
0.79hours), 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-100 concentration), 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.  In addition, the components of LY900014 have been tested in 3 clinical studies that 
included the evaluation of the safety, PK, and pharmacology of SC bolus doses of treprostinil 
(see LY900014 IB).
All tested doses of treprostinil (
), insulin lispro (up to 50 U), and LY900014 (up to 
50U) were welltolerated 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 
Remodulin package insert (2014) (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 
(approximately U-100) in healthy subjects was assessed in previous studies.  In these studies, 
treprostinil exposure was not detectable 
) for the 15U dose of LY900014.  In 
addition, the concentration of treprostinil in LY900014 U-200 is lower ( 
) than in 
LY900014 U-100 ( 
); therefore the exposure to treprostinil in the U-200 formulation is 
expected to be negligible.
CCI
CCI
CCI


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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:
i.
Women of child-bearing potential are abstinent (if this is complete 
abstinence, as their preferred and usual lifestyle) or in a same sex 
relationship (as part of their preferred and usual lifestyle) must agree 
to either remain abstinent or stay in a same sex relationship without 
sexual relationships with males.
ii.
Otherwise, women of child-bearing potential participating in the 
study should not be lactating and must agree to use 1 highly effective 
method of contraception until discharge from final treatment period.
1. Women of child-bearing potential must test negative for 
pregnancy prior to initiation of treatment as indicated by a 
negative serum pregnancy test at the screening visit followed by a 
negative urine pregnancy test within 24 hours prior to exposure in 
Period 1.
2. A highly effective method of contraception includes a combined 
(estrogen and progestogen containing) or progestogen-only 
hormonal contraception administered orally, intravaginally or 
transdermally and is associated with inhibition of ovulation.  
Alternatively, patients may use either an intrauterine device, 
intrauterine hormone-releasing system, bilateral tubal occlusion, 
or the partner should have been vasectomized. 


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iii.
Women not of child-bearing potential may participate and include 
those who are
1. infertile due to surgical sterilization (hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy), congenital anomaly 
such as Mullerian agenesis; or
2. post-menopausal – defined as a woman being amenorrhoeic for 
more than 1 year without an alternative medical cause and a serum 
follicle-stimulating hormone (FSH) level compatible with 
post-menopausal status.  An FSH level in the post-menopausal 
range may be used to confirm a post-menopausal state in women 
not using hormonal contraception or hormonal replacement 
therapy.
[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 (males) or ≥11.4 g/dL (females) 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 last 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.


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[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.
[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 draw within the last 3 calendar 
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.


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[28] in the opinion of the investigator or sponsor, are unsuitable for inclusion in 
the study.
6.3.
Lifestyle and/or Dietary Requirements
Throughout the study, subjects may undergo medical assessments and review of compliance with 
requirements before continuing in the study.  
6.3.1. Meals and Dietary Restrictions
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. 


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LY900014
7.Treatment
7.1. Treatment Administered
The study will compare formulations of LY900014 containing 200U/mL of insulin lispro 
(LY900014 U-200) and 100U/mL of insulin lispro (LY900014 U-100).  TableITSS.3shows the 
treatment to be administered.
TableITSS.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
Approximately 0.075 mL
Approximately0.150 mL
Abbreviation:  SC = subcutaneous.
The investigator or designee is responsible for
explaining the correct use of the investigational products to the CRU personnel
verifying that instructions are followed properly
maintaining accurate records of investigational product dispensation and collection
returning all unused medications to Lilly or its designee at the end of the study (if 
required) or destroying the materials (if the CRUhas appropriate facilities/service 
provider and written procedures to dispose of clinical materials) following authorization 
by the study sponsor.
Qualified CRU personnel will be instructed on proper preparation and administration techniques 
for all study drugs used in this study.  To maintain the blind, all insulin injections will be given 
by only a few appropriately qualified members of the CRU staff who are independent of the 
clamp team and who will not provide assessment of AEs.  In addition, where possible, the same 
personnel should give the injections to reduce variability of the injection technique. 
Injection sites selected should be about 5 cm from the umbilicus and the treatment administered 
SC with the needle applied at about 90° without pinching the skinfold.  Injections will be rotated 
among different injection sites on the anterior abdominal wall during the 4 study periods (ie, left 
and right lower quadrants).  All subjects will receive study drugs as a single SC injection in each 
period.
7.1.1. Packaging and Labeling
CCI
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.


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LY900014
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. 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 with 
specific instructions 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, which reveals the treatment 
group for a specific study subject, may be opened during the study only if the subject’s 
well-being requires knowledge of the subject’s treatment assignment.
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.


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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 investigational products
received and any discrepancies are reported and resolved before use of the study treatment.
Only participants enrolled in the study may receive study drugs, and only authorized CRU 
personnel may supply or administer 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).  Specific instructions 
and training for preparation, and administration of the 2 formulations of the study drug will be 
provided separately.
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.


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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 for 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 >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 >2.5 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


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o
the investigator decides that the subject should be discontinued from the study

Subject Decision
o
the subject requests to be withdrawn from the study.
8.3.
Subjects Lost to Follow-up
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the CRU 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.


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9. Study Assessments and Procedures
Section 2 lists the Schedule of Activities, detailing the study procedures and their timing 
(including tolerance limits for timing).  Failure to obtain samples within the permitted sampling 
window as defined by the sponsor, will be considered a protocol deviation.
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.  All AEs will be documented.
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, the 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, study device, and/or study procedure and the AE.


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Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study.
If a subject’s study drug is discontinued as a result of an AE, the CRU personnel must report this 
to Lilly or its designee via eCRF.
Hypoglycemic events will be collected and reported throughout the trial as described in 
Section 9.4.5.2.  All hypoglycemic events will be recorded in the hypoglycemia module of the 
eCRF; this allows for the collection of comprehensive safety information relating to these events.
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, the 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 eCRF 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 the 
study drug, AND is considered Reasonably Possibly Related to a study procedure then it MUST 
be reported.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued from and/or completed the study (the subject summary eCRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly. 


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Pregnancy (maternal or paternal exposure to the 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 investigational products and drug delivery systems used in 
clinical trials in order to ensure the safety of study participants, monitor quality, and to facilitate 
process and product improvements.
Subjects should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
9.3.
Treatment of Overdose
For the purposes of this study, an overdose of 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.  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 sign measurements should be conducted according to the Schedule of 
Activities (Section 2) and as clinically indicated.
Blood pressure and pulse rate should be measured after at least 5 minutes supine.


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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 12-lead digital ECG will be collected according to the Schedule of Activities
(Section 2).  Electrocardiograms must be recorded before collecting any blood samples.  Subjects 
must be supine for at least 5 minutes before ECG collection and remain supine but awake during 
ECG collection.  Electrocardiograms may be obtained at additional times, when deemed 
clinically necessary.  All ECGs recorded should be stored (as printed reports) at the CRU.
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the CRU as soon after the time of ECG collection as possible, and ideally while the 
subject is still present, to determine whether the subject meets entry criteria at the relevant 
visit(s) and for immediate subject management, should any clinically relevant findings be 
identified.  
If a clinically significant finding is identified (including, but not limited to, changes in 
QT/corrected QT interval from baseline) after enrollment, the investigator will determine if the 
subject can continue in the study.  The investigator, or qualified designee, is responsible for 
determining if any change in subject management is needed, and must document his/her review 
of the ECG printed at the time of collection.  Any new clinically relevant finding should be 
reported as an AE.
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 


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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.
9.4.5.1.
Glucose Monitoring
Hypoglycemia will be described using the following definitions (IHSG 2017):

Documented Glucose Alert Level (Level 1), plasma glucose (PG) ≤70 mg/dL 
(3.9 mmol/L):
o
Symptomatic hypoglycemia:  an event during which typical symptoms of 
hypoglycemia are accompanied by PG ≤70 mg/dL (3.9 mmol/L)
o
Asymptomatic hypoglycemia:  an event not accompanied by typical symptoms of 
hypoglycemia but with PG ≤70 mg/dL (3.9 mmol/L)
o
Unspecified hypoglycemia:  an event during which PG ≤70 mg/dL (3.9 mmol/L) but 
no information relative to symptoms of hypoglycemia was recorded.

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 requiring assistance of another person to 
actively administer carbohydrate, glucagon, or other resuscitative actions.  During these 
episodes, the patient has an altered mental status and cannot assist in their care, is 
semiconscious or unconscious, or experienced coma with or without seizures and may 
require parenteral therapy.  Plasma glucose measurements may not be available during 
such an event, but neurological recovery attributable to the restoration of PG
concentration to normal is considered sufficient evidence that the event was induced by a 
low PG concentration (PG ≤70 mg/dL [3.9 mmol/L])


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o
Severe hypoglycemia requiring medical attention:  a severe hypoglycemic event when 
patients require therapy by health care providers (emergency medical technicians, 
emergency room personnel, etc.).
Other Hypoglycemia:

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, 
which do not require the assistance of another person, are accompanied by PG 
>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 all cases of 
hypoglycemia.  If an event of hypoglycemia falls into multiple subcategories, the event is 
counted only once in this category

Probable symptomatic hypoglycemia: An event during which symptoms of 
hypoglycemia are not accompanied by a PG measurement but that was presumably 
caused by a PG concentration ≤70 mg/dL (3.9 mmol/L).
The goal of the euglycemic clamp is to maintain glucose concentrations at normoglycemic levels 
close to a predefined target.  Therefore, the equivalence of PG 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.
9.4.5.2.
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 patient to have required 
assistance and is not predicated on the report of a patient simply having received assistance.  
Hypoglycemic events will be recorded in the hypoglycemia module of the eCRF (see Section 9.2
for details).  All episodes of severe hypoglycemia must be reported as SAEs.
9.4.5.3.
Hepatic Safety
If a study subject experiences elevated ALT ≥3X ULN, ALP ≥2X ULN, or elevated total 
bilirubin (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: 


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
elevation of serum ALT to ≥5X ULN on 2 or more consecutive blood tests

elevated 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)
If the investigator determines that any injection-site reaction (ISR) has occurred or if a subject 
indicates symptoms are indicative of an ISR (unsolicited event; volunteered by subject), the 
event will be captured as an AE.  The investigator or the CRU personnel will then ask the 
following question: 
Has the subject reported/experienced an injection-site reaction (For example: redness, 
pain, swelling, induration, or itching)?
If the answer is yes to the above question, then the ISR questionnaire and VAS pain 
measurements will be completed.
9.4.6.1.
Pain Measurements Using the Visual Analog Scale
In case of an AE of ISR pain (see Section 9.4.6), pain 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 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.
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.


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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.
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  (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 (0.3 mmol/L) 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 (3.5 mmol/L; whole 
blood).  Therefore, subjects with a mean predose fasting blood glucose less than 68 mg/dL 
(3.8 mmol/L; equivalent to a fasting PG 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 Section 2).  


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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 
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. 
C-peptide samples will not be collected after the clamp has terminated if a meal has been 
provided.


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


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10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
Up to 72 subjects may be enrolled so that approximately 58 subjects complete the study.  Fifty-
eight completing 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 deviation for within-subject difference of 0.28 and 
up to a 5% difference in geometric LSmean ratio.  There is also at least 80% power to show the 
2-sided 90% CI of the ratio of the geometric means for Cmax between the 2 formulations also 
within 0.80 to 1.25.  This calculation assumes a log-scale standard deviation for within-subject 
difference of 0.59 and an 8% 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 is 
approximately 90% 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 maximum GIR (Rmax) 
are within 0.80 to 1.25.  This calculation assumes a log-scale standard deviation for within-
subject difference of 0.57 for Gtot and 0.64 for Rmax and up to a 5% difference in the LSmean 
ratios.
Subjects who are randomized but not administered treatment may be replaced to ensure that 
approximately 58 subjects 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 subject disposition 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
Statistical analysis of this study will be the responsibility of Lilly or its designee.
Pharmacokinetic/pharmacodynamic analyses will be conducted on data from all subjects who 
receive at least 1 dose of the study drug and have evaluable PK. Data from individual treatment 
periods may be excluded from the analysis for the following reasons:

the clamp was terminated early (e.g., due to an AE, technical issues, or subject 
withdrawal),


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
failure to administer full dose (e.g., appearance of liquid on the skin after withdrawing 
the needle)or

failure to collect sufficient PK or GD samples in order to define key endpoints (e.g.,
Cmax, Rmax).
Primary statistical analyses will be conducted on the set of subjects who complete at least the 
first period of treatment with evaluable parameters.  Supportive analyses may be done on the key 
parameters for the subjects who complete all treatment periods and have evaluable parameters.  
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.
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
Visual analog scale data for pain intensity, collected as described in Section 9.4.6.1, will be 
summarized using standard descriptive statistics and using 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. 


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10.3.2.Pharmacokinetic Analyses
10.3.2.1.Pharmacokinetic Parameter Estimation
Subjects who completed at least 1 period and had evaluable insulin lispro concentrations will be 
included in the PK analysis dataset.  Pharmacokinetic analyses will be conducted using standard 
noncompartmental methods of analysis using 
on a computer that meets or exceeds 
the minimum system requirements for these programs.  The version of any software used for the 
analysis will be documented and the program will meet the Lilly requirements of software 
validation.  It is possible that other validated equivalent PK software programs may be utilized if 
appropriate, warranted, and approved by global PK management.
Free serum insulin lispro concentrations will be used to calculate several PK parameters, 
including C
max, time of Cmax(tmax), time to early half-maximal drug concentration (early 50% 
t
max), time to late half-maximal drug concentration (late 50% tmax), and AUC
(0-tlast), AUCfrom 
time zero to 10 hours (AUC
[0-10h]), and AUC(0-∞). The apparent total body clearance of drug 
calculated after extravascular administration (CL/F), half-life (t
1/2), apparent volume of 
distribution during the terminal phase after extra-vascular administration (Vz/F), maybe 
determined.Other parameters may be calculated as deemed appropriate, 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
To compare PK parameters between LY900014 U-200 relative to LY900014 U-100, 
log-transformed AUC parameter estimates (AUC[0-tlast], AUC
[0-∞], and C
max) will be analyzed 
using a repeated measures, linearmixed-effects model wheretreatment, sequence, and period 
will be considered as fixed effects and subject as a random effect.  From the model, the 
difference in LSmeans and the corresponding 2-sided 90% CIs for the treatment 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).
AUC(0-tlast)and AUC(0-∞)will also be analyzed using a linear fixed-effects model. The 
parameter estimates will be log-transformed before analysis. The model will include fixed 
effects for sequence, period, treatment, and subject nested within sequence. The LSmeans for 
each formulation, the difference in means between treatments, and the 90% CIs will be estimated 
from the model and back-transformed from the log scale to provide estimates of the geometric 
LSmeans, the ratio of the geometric LSmeans, and the 90% CIs. This analysis will only include 
completers.
A model with fixed effects for sequence, period, treatment, and subject nested within sequence 
without log transformation will be used for the analysis of the PK time parameters (early 50% 
t
maxand tmax
C
C
I
).  The LSmeans, treatment differences in LSmeans, and the corresponding 90% 
CIs for the treatment differences will be estimated from the model.  The treatment ratios and 


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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.
10.3.3.Pharmacodynamic Analyses
10.3.3.1.Pharmacodynamic Parameter Estimation
Glucodynamic assessments will be determined from the glucose clamp procedure, where the 
GIR over time will be used as a measure of insulin effect.  Glucodynamic analyses will be 
conducted on those subjects who complete at least 1 clamp procedure.
A locally weighted scatterplot smoothing (LOESS) function will be applied to all individual GIR 
versus time profiles in each treatment group and/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), maximal GIR (Rmax), time to Rmax(tRmax), time to half-maximal 
GIR before tRmax(early 50% tRmax),time to half-maximal GIR after tRmax(late 50% tRmax), 
total glucose infused over the duration of the clamp (Gtot).  Additional partial glucose AUCs, 
such as Gtotover 30 minutes (Gtot0-30min), and Gtot over 1hour (Gtot0-1h)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-100 formulations, log-transformed G
totand Rmaxestimates 
will be analyzed using a repeated measures, linear mixed-effects model where treatment, 
sequence, and period will be considered as fixed effects and subject as a random effect.  From 
the model, the difference in LSmeans and the corresponding 2-sided 90% CIs for the treatment 
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.
A model with fixed effects for sequence, period, treatment, and subject nested within sequence 
without log transformation will be used for the analysis of the GD time parameters (tRmaxand 
early 50% t
Rmax).  The 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 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.
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 


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LY900014
relationship between the presence of antibodies and the PK parameters and GD response to 
insulin lispro may be assessed.
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.


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11. References
AMIS database. 13 June 2006. DIMDI (Deutsches Institut für medizinische Dokumentation und 
Information. Available at: https://www.dimdi.de/dynamic/de/db/recherche/index.htm. 
Accessed: November 07, 2017.
Humalog [package insert]. Indianapolis, IN 46285: Lilly USA, LLC; 2017.
[IHSG] International Hypoglycaemia Study Group. Glucose concentrations of less than 3.0 
mmol/l (54 mg/dl) should be reported in clinical trials: a joint position statement of the 
American Diabetes Association and the European Association for the Study of Diabetes. 
Diabetes Care. 2017;40(1):155-157.
 
.
Williamson A, Hoggart B. Pain: a review of three commonly used pain rating scales. 
JClinNurs.
CCI
2005;14(7):798-804.


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Appendix 1.
Abbreviations and Definitions
Term
Definition
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
AUC(0-10h)
AUC from time zero to 10 hours
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


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Term
Definition
FDA
Food and Drug Administration
GCP
good clinical practice
GD
glucodynamic(s)
GIR
glucose infusion rate
Gtot
total amount of glucose infused
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
informed 
consent
A process by which a subject voluntarily confirms his or her willingness to participate in a 
particular study, after having been informed of all aspects of the study that are relevant to 
the subject’s decision to participate.  Informed consent is documented by means of a 
written, signed, and dated informed consent form.  
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigational 
product
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.
ISR
injection-site reaction
IV
intravenous
late 50% tmax
time to late half-maximal drug concentration
LOESS
locally weighted scatterplot smoothing
LSmeans
least-squares means
MDI
multiple daily injection
PAH
pulmonary arterial hypertension
PG
plasma glucose
PK
pharmacokinetic(s)
randomize
The process of assigning subjects to an experimental group on a random basis.
Rmax
maximum glucose infusion rate


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Term
Definition
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 
tmax
time of maximum observed drug concentration
tRmax
time to Rmax
U
units
ULN
upper limit of normal
VAS
visual analog scale


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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
  Microscopye
FSHd
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
A urine and blood test (HCG, rapid) for pregnancy will be done at screening for all females; a urine pregnancy 
test (HCG, urine) will be done during the study and at follow-up/ED for women of child bearing potential only,
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.  


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Appendix 3.
Study Governance, Regulatory, and 
Ethical Considerations
Informed Consent
The investigator is responsible for

ensuring that the subject understands the nature of the study, the potential risks and 
benefits of participating in the study, and that their participation is voluntary.

ensuring that informed consent is given by each subject.  This includes obtaining the 
appropriate signatures and dates on the ICF prior to the performance of any protocol 
procedures 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 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 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 investigative site.  Lilly or its representatives must approve the ICF 
before it is used at the investigative site.  All ICFs must be compliant with the ICH guideline on 
GCP.
The study site’s ERB should be provided with the following:

the current IB and updates during the course of the study

ICF 

relevant curricula vitae
Regulatory Considerations
This study will be conducted in accordance with the protocol and with


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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 site, as appropriate.

provide training to instruct the investigators and study coordinators.  This training will 
give instruction on the protocol, the completion of the CRFs, and study procedures.

make periodic visits to the study site.

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax.

review and evaluate CRF data and/or use standard computer edits to detect errors in data 
collection.

conduct a quality review of the database.
In addition, Lilly or its representatives will periodically check a sample of the subject data 
recorded against source documents at the 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, 


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applicable regulatory agencies, and applicable ERBs with direct access to the original source 
documents.
Data Collection Tools/Source Data
An electronic data capture system will be used in this study.  The site must define and retain all 
source records and must maintain a record of any data where source data are directly entered into 
the data capture system.
Data Protection
Data systems used for the study will have controls and requirements in accordance with local 
data protection law.  
The purpose and use of subject personal information collected will be provided in a written 
document to the subject by the sponsor.
Study and Site Closure
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ERB of the study 
site judges it necessary for medical, safety, regulatory, or other reasons consistent with 
applicable laws, regulations, and GCP.
Discontinuation of the Study
The study will be discontinued if Lilly judges it necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP.


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Appendix 4.
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 patients 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 Antibodya
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.


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Appendix 5.
Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.  
Protocol I8B-MC-ITSS 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 the 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.


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Appendix 6.
Protocol Amendment I8B-MC-ITSS(a) 
Summary 
Bioequivalence Study Comparing 2 Formulations of 
LY900014 in Healthy Subjects
Overview
Protocol I8B-MC-ITSS, Bioequivalence Study Comparing 2 Formulations of LY900014 in 
Healthy Subjects, has been amended.  The new protocol is indicated by Amendment (a) and will 
be used to conduct the study in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:
Per the FDA guidance “Statistical Approaches to Establishing Bioequivalence”
(https://www.fda.gov/downloads/Drugs/Guidances/ucm070244.pdf), a 4-period, 2-sequence 
design is recommended for replicated bioequivalence studies; therefore in the protocol, the 4-
sequence design is replaced by 2-sequence design.


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Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
1
Protocol Synopsis
Summary of Study Design:  
Study I8B-MC-ITSS is a Phase 1, single-center, subject- and investigator-blind, 42-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 2 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). 
5.1
Overall Design
This is a Phase 1, single-center, investigator- and subject-blind, 42-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.
……
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 2 dosing 
sequences (Table ITSS.2).
Table ITSS.2.
Treatment Sequence Example for I8B-MC-ITSS
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.

SAP_001.pdf: 
Statistical Analysis Plan I8B-MC-ITSS v2 
 
Bioequivalence Study Comparing 2 Formulations of LY900014 in Healthy Subjects 
 
NCT03616977 
 
Approval Date: 12-Oct-2018 
 
 


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STATISTICAL ANALYSIS PLAN
Bioequivalence Study Comparing 2 Formulations ofLY900014 in Healthy Subjects
Approval Date: 12-Oct-2018 GMT
Statistical Analysis Plan Status:  FinalVersion 2
Statistical Analysis Plan Date:  01-October-2018
Study Drug:LY900014
Sponsor Reference:  I8B-MC-ITSS
Covance CRU Study: 1001215-8391985
Clinical Phase I


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             Page 2 of 16
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8391985
Sponsor Reference I8B-MC-ITSS
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS .....................................................................................................2
2.
ABBREVIATIONS..............................................................................................................4
3.
INTRODUCTION ...............................................................................................................6
4.
STUDY OBJECTIVES........................................................................................................6
4.1
Primary Objective..........................................................................................................6
4.2
Secondary Objectives ....................................................................................................6
4.3
Tertiary/Exploratory Objectives.....................................................................................7
5.
STUDY DESIGN.................................................................................................................7
6.
TREATMENTS...................................................................................................................8
7.
SAMPLE SIZE JUSTIFICATION .......................................................................................8
8.
DEFINITION OF ANALYSIS POPULATIONS..................................................................9
9.
STATISTICAL METHODOLOGY .....................................................................................9
9.1
General..........................................................................................................................9
9.2
Demographics and Subject Disposition........................................................................10
9.3
Pharmacokinetic Analyses...........................................................................................10
9.3.1
Pharmacokinetic Parameter Estimation...............................................................10
9.3.2
Pharmacokinetic Statistical Inference .................................................................10
9.4
Pharmacodynamic Analyses ........................................................................................12
9.4.1
Pharmacodynamic Parameter Estimation............................................................12
9.4.2
Pharmacodynamic Statistical Inference...............................................................12
9.5
Safety and Tolerability Assessments............................................................................13
9.5.1
Adverse events ...................................................................................................13
9.5.2
Concomitant medication.....................................................................................13
9.5.3
Clinical laboratory parameters............................................................................13
9.5.4
Vital signs ..........................................................................................................13
9.5.5
Electrocardiogram (ECG)...................................................................................14
9.5.6
Blood Glucose Monitoring and Hypoglycemia ...................................................14
9.5.7
Hepatic Monitoring ............................................................................................14
9.5.8
Injection Site Local Tolerability Assessment Data..............................................15
9.5.9
Pain Measurements using the Visual Analog Scale .............................................15
9.5.10
Immunogenicity .................................................................................................15
9.5.11
C-Peptide ...........................................................................................................15
9.5.12
Safety and Tolerability Statistical Methodology..................................................15


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8391985
Sponsor Reference I8B-MC-ITSS
10. INTERIM ANALYSES .....................................................................................................15
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ............16
12. REFERENCES ..................................................................................................................16
13. DATA PRESENTATION ..................................................................................................16
13.1 Derived Parameters .....................................................................................................16
13.2 Missing Data ...............................................................................................................16
13.3 Insufficient Data for Presentation ................................................................................16


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8391985
Sponsor Reference I8B-MC-ITSS
2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
AE
Adverse event
AUC
Area under the concentration versus time curve
AUC
Area under the concentration versus time curve during one dosing 
interval
AUC(0-tlast)
Area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable concentration
AUC(0-10 h)
Area under the concentration versus time curve from time zero to 
time 10 h
AUC(0-∞)
Area under the concentration versus time curve from time zero to 
infinity
Cmax
Maximum observed drug concentration
CI
Confidence interval
CL/F
Apparent total body clearance of drug calculated after extra-vascular
administration
CRF
Case Report Form
CSR
Clinical Study Report
CRU
Clinical Research Unit
CV
Coefficient of variation
Early 50% tmax
Time to early half-maximal drug concentration
Early 50% tRmax
Time to half-maximal glucose infusion rate before tRmax
EC
Early Clinical 
ECG
Electrocardiogram
e.g.
For example (Latin: exempli gratia)
GD
Glucodynamic 
GIR
Glucose infusion rate
Gtot
Total amount of glucose infused
ICH
International Council on Harmonisation
Late 50% tmax
Time to late half-maximal drug concentration
LOESS
Locally weighted scatterplot smoothing


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8391985
Sponsor Reference I8B-MC-ITSS
LS
Least square
MedDRA
Medical Dictionary for Regulatory Activities
NA
Not applicable
PK
Pharmacokinetic
SAP
Statistical Analysis Plan
SC
Subcutaneous 
SD
Standard deviation 
SOP
Standard Operating Procedure
TFLs
Tables, Figures, and Listings
t1/2
Half-life associated with the terminal rate constant (λz) in non-
compartmental analysis
tmax
Time of maximum observed drug concentration
tRmax
Time to Rmax
Vz/F
Apparent volume of distribution during the terminal phase after 
extra-vascular administration
WHO
World Health Organization


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8391985
Sponsor Reference I8B-MC-ITSS
3.INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 14 
June 2018and amendment (a) dated 20 July 2018).
This SAP describes the planned analysis of the safety, tolerability andpharmacokinetic(PK)and 
glucodynamic(GD)data fromthis study. A detailed description of the planned TFLs to be 
presented in the clinical study report (CSR) is provided in the accompanying TFL shell 
document.
The intent of this document is to provide guidance for the statistical and PK analyses of data. In 
general, the analyses are based on information from the protocol, unless they have been modified 
by agreement between Eli Lilly and Company and 
. A 
limited amount of information concerning this study (e.g., objectives, study design) is given to 
help the reader’s interpretation. This SAP must be signed off prior to first subjectadministration
for this study. When the SAP and TFL shells are agreed upon and finalized, they will serve as the 
template for this study’s CSR.
This SAP supersedesthe statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon 
between Eli Lilly and Company and Covance ECBiometricsand identified in the CSR. Any 
minor deviations from the TFLs may not be documented in the CSR.
This SAP is written with consideration of the recommendations outlined in the International 
Council on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials1and the ICH E3 Guideline entitled Guidance for Industry: Structure 
and Content of Clinical Study Reports
2.
4.STUDY OBJECTIVES
4.1
PrimaryObjective
To demonstrate the bioequivalence of PK parameters for the LY900014 U-200 versus 
LY900014 U-100 formulations after subcutaneous (SC)administration to healthy 
subjects.
4.2
SecondaryObjectives
To compare the GD responses to LY900014 U-200 versus LY900014 U-100 
formulations afterSC administration.

CCI
To assess the safety and tolerability of the LY900014 U-200 and LY900014 U-100 
formulations.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8391985
Sponsor Reference I8B-MC-ITSS
4.3
Tertiary/Exploratory Objectives

To compare other PK and GD parameters for LY900014 U-200 versus LY900014 U-100 
after SC administration.

Explore the formation of antidrug antibodies to insulin lispro.

To assess C-peptide levels following administration of LY900014.
5. STUDY DESIGN
This is a Phase 1, single-center, investigator- and subject-blind, 2-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 1 illustrates the study design.
Figure 1. Illustration of study design
Abbreviation: CRU = clinical research unit; 
*Single dose of LY900014 U-200 or LY900014 U-100 administered subcutaneously to the abdomen
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 2
dosing sequences (Table 1).
Table 1. Treatment Sequences Example for I8B-MC-ITSS
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
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)


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
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

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 a 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 adverse events (AEs), clinical 
laboratory tests, electrocardiograms (ECGs), vital sign measurement, and through medical 
assessments.
6. TREATMENTS
The following is a list of the study treatment abbreviations that will be used in the TFLs.
Study Treatment Name
Treatment order in TFL
15 U LY900014 U-100
1
15 U LY900014 U-200
2
7. SAMPLE SIZE JUSTIFICATION
Up to 72 subjects may be enrolled so that approximately 58 subjects complete the study. 
Fifty-eight completing subjects in a replicated design will provide at least 95% power to show 
the 2-sided 90% confidence intervals (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 deviation for 
within-subject difference of 0.28 and up to a 5% difference in geometric LSmean ratio. There is 
also at least 80% power to show the 2-sided 90% CI of the ratio of the geometric means for Cmax
between the 2 formulations also within 0.80 to 1.25. This calculation assumes a log-scale 
standard deviation for within-subject difference of 0.59 and an 8% 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 is
approximately 90% 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 maximum glucose 
infusion rate (GIR) (Rmax) are within 0.80 to 1.25. This calculation assumes a log-scale standard 


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deviation for withinsubject difference of 0.57 for Gtot and 0.64 for Rmax and up to a 5% difference 
in the LSmean ratios.
Subjects who are randomized but not administered treatment may be replaced to ensure that
approximately 58 subjects 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.
8. DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all subjects who received at least one dose of study drug.
The PK population will consist of all subjects who received at least one dose of study drug and 
have evaluable PK data. 
The GD population will consist of all subjects who received at least one dose of study drug and 
have evaluable GD data. 
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when subjects are assigned to analysis populations.
Data from individual treatment periods may be excluded from the analysis for the following 
reasons:

the clamp was terminated early (e.g., due to an AE, technical issues, or subject 
withdrawal), 

failure to administer full dose (e.g., appearance of liquid on the skin after withdrawing 
the needle) or

failure to collect sufficient PK or GD samples in order to define key endpoints (e.g., Cmax, 
Rmax).
9. STATISTICAL METHODOLOGY
9.1
General
Data listings will be provided for all data that is databased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include the arithmetic mean, arithmetic standard deviation (SD), median, 
min, max and N; for log-normal data (e.g. the PK parameters: area under the concentration time 
curve [AUCs] and maximum observed drug concentration [Cmax]) the geometric mean and 
geometric coefficient of variation (CV%) will also be presented. For categorical data, frequency 
count and percentages will be presented. Data listings will be provided for all subjects up to the 
point of withdrawal, with any subjects excluded from the relevant population highlighted. 
Summary statistics and statistical analyses will generally only be performed for subjects included 
in the relevant analysis population. For the calculation of summary statistics and statistical 
analysis, unrounded data will be used. 


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Mean change from baseline is the mean of all individual subjects’ change from baseline values. 
Each individual change from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint. The individual subject’s change from baseline 
values will be used to calculate the mean change from baseline using a SAS procedure such as 
Proc Univariate.
Data analysis will be performed using 
or greater.
9.2 Demographics and Subject Disposition
Subject disposition will be listed. The demographic variables age, sex, race, ethnicity,country of 
enrolment, site ID,body weight, height, body mass indexand hip and waist circumferencewill 
be summarized and listed.
9.3 Pharmacokinetic Analyses
9.3.1Pharmacokinetic Parameter Estimation
Subjects who completed at least 1 period and had evaluable insulin lispro concentrations will be
included in the PK analysis dataset. Pharmacokinetic analyses will be conducted using standard
noncompartmental methods of analysis using 
 on a computer that meets or exceeds
the minimum system requirements for these programs. The version of any software used for the
analysis will be documented and the program will meet the Lilly requirements of software
validation. It is possible that other validated equivalent PK software programs may be utilized if
appropriate, warranted, and approved by global PK management.
Free serum insulin lispro concentrations will be used to calculate several PK parameters,
including C
max, time of C
max(t
max), time to early half-maximal drug concentration (early 50%
t
max), and AUC(0-t
last), AUC fromtime zero to 10 hours (AUC[0-10h]), and AUC(0-∞). The 
apparent total body clearance of drugcalculated after extravascular administration (CL/F), half-
life (t
1/2), apparent volume ofdistribution during the terminal phase after extra-vascular 
administration (Vz/F),time to late half-maximal drug concentration (late 50% tmax),may be
determined. Other parameters may be calculated as deemed appropriate, such as partial AUCs.
Although attempts will be made to adhere to the scheduled collectiontimes, 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.
9.3.2Pharmacokinetic Statistical Inference
To compare PK parameters between LY900014 U-200 relative to LY900014 U-100,
log-transformed AUC parameter estimates (AUC[0-tlast], AUC[0-∞],AUC[0-15min], 
AUC[0-30min]and C
max
C
C
I
) will be analysed using a repeated measures, linear mixed-effects model 
where treatment, sequence, and periodwill be considered as fixed effects and subject as a 
random effect. From the model, thedifference in LSmeans and the corresponding 2-sided 90% 
CIs for the treatment difference willbe estimated and back-transformed from thelog scale to 
provide estimates of the ratio ofgeometric LSmeans and 90% CI for the ratio of the LSmeans. 
Bioequivalence will be concludedif the 2-sided 90% CI is completely contained within the 
CCI


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interval (0.80, 1.25). This method is consistent with the FDA recommended methodology of 
analysis and will involve all available data. The within- and between-subject variability of both 
treatments will also be estimated directly from the model for all AUC parameters and Cmax.
Example SAS code:
PROC MIXED;
CLASS SEQ SUBJ PER TRT;
MODEL Y = SEQ PER TRT / DDFM=SATTERTH;
RANDOM TRT / TYPE=FA0(2) SUB=SUBJ G;
REPEATED / GRP=TRT SUB=SUBJ;
ESTIMATE 'T vs. R' TRT 1 -1 / CL ALPHA=0.1;
RUN;
Should the model produce the SAS warning “Estimated G matrix is not positive definite” then 
the following code will be used:
PROC MIXED;
CLASS SEQ SUBJ PER TRT;
MODEL Y = SEQ PER TRT / DDFM=KR;
RANDOM INTERCEPT / SUB=SUBJ G GROUP=TRT;
REPEATED / GRP=TRT SUB=SUBJ;
ESTIMATE 'T vs. R' TRT 1 -1 / CL ALPHA=0.1;
RUN;
AUC(0-tlast), AUC(0-∞), and Cmax) will also be analyzed using a linear fixed-effects model. The
parameter estimates will be log-transformed before analysis. The model will include fixed effects 
for sequence, period, treatment, and subject nested within sequence. The LSmeans for each 
formulation, the difference in means between treatments, and the 90% CIs will be estimated from 
the model and back-transformed from the log scale to provide estimates of the geometric
LSmeans, the ratio of the geometric LSmeans, and the 90% CIs. This method is consistent with 
the EMA recommended methodology of analysis and will involve only study completers.
Example SAS code:
PROC MIXED;
CLASS SEQ SUBJ PER TRT;
MODEL Y = SEQ PER TRT SUBJ(SEQ) / DDFM=SATTERTH;
ESTIMATE 'T vs. R' TRT 1 -1 / CL ALPHA=0.1;
RUN;
The PK time parameters time parameters (early 50% tmax and tmax) will be analyzed 
nonparametrically using the Wilcoxon signed rank test.


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9.4 Pharmacodynamic Analyses
9.4.1Pharmacodynamic Parameter Estimation
Glucodynamic assessments will be determined from theglucose clamp procedure, where the
GIR over time will be used as a measure of insulin effect. Glucodynamic analyses will be
conducted on those subjects who complete at least 1 clamp procedure.
A locally weighted scatterplot smoothing (LOESS) function willbe 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), maximal GIR (R
max), time to R
max(tR
max), time to half maximal
GIR before tRmax (early 50% tR
max), total glucose infused over the duration of the clamp (Gtot). 
Additional time to half-maximal GIR after tRmax(late 50% tR
max),and partial glucose AUCs,
such as Gtot over 30 minutes (Gtot0-30min), and Gtot over 1 hour (Gtot0-1h) may be computed 
asnecessary. 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.
9.4.2Pharmacodynamic Statistical Inference
To address the secondary objective of comparing GD parameters (G
totand R
max) between the
LY900014 U-200 and LY900014 U-100 formulations, log-transformed G
totand R
maxestimates
will be analyzed using a repeated measures, linear mixed-effects model where treatment,
sequence, and period will be considered as fixed effects and subject as a random effect. Fromthe 
model, the difference in LSmeans and the corresponding 2-sided 90% CIs for the treatment
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.The SAS code will be the 
similar to the PK analysis code and is consistent with the FDArecommended methodology of 
analysis and will involve all available data.The within-and between-subject variability of both 
treatments will also be estimated directly from the model for Gtot,R
maxand early insulin activity 
(i.e G
tot[0-30min], G
tot[0-1h])
The GD parameters (Gtotand R
max) will also be analyzed using a linear fixed-effects model. The 
parameter estimates will be log-transformed before analysis. The model will include fixed effects 
for sequence, period, treatment, and subject nested within sequence. The LSmeans for each 
formulation, the difference in means between treatments, and the 90% CIs will be estimated from 
the model and back-transformed from the log scale to provide estimates of the geometric 
LSmeans, the ratio of the geometric LSmeans, and the 90% CIs. The SAS code will be the 
similar to the PK analysis code andis consistent with the EMA recommended methodology of 
analysis and will involve only study completers.In addition, 95% CIs and p-values will also be 
provided for this analysisin a separate table.
An additional sensitivity analysis will be performed for the GD parameters using the FDA 
methodology, based on C-peptide confounders. This sensitivity analysis will involve all available 
data.
The GDtime parameters(tR
maxand early50% tRmax
CCI
)will be analyzed nonparametrically using 
the Wilcoxon signed rank test.


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Should any of the GD parameters have zero values, a model with fixed effects for sequence, 
period and treatment, and subject nested within sequence as a random effect, without log 
transformation will be used for the analysis. The 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 
GD time parameters may be analyzed in a similar manner. In addition, 
9.5
Safety and Tolerability Assessments
9.5.1 Adverse events
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the adverse event (AE) will be reported in the listings, only the most severe will be used in the 
summary tables. A pre-existing condition is defined as an AE that starts before the subject has 
provided written informed consent and is ongoing at consent. A non-treatment emergent AE is 
defined as an AE which starts after informed consent but prior to dosing. A treatment-emergent 
AE is defined as an AE which occurs postdose or which is present prior to dosing and becomes 
more severe postdose. 
All AEs will be listed. Treatment-emergent AEs will be summarized by treatment, severity and 
relationship to the study drug. The frequency (the number of AEs, the number of subjects 
experiencing an AE and the percentage of subjects experiencing an AE) of treatment-emergent 
AEs will be summarized by treatment, Medical Dictionary for Regulatory Activities (MedDRA)
version 21.0 system organ class and preferred term. The summary and frequency AE tables will 
be presented for all causalities and those considered related to the study drug. Any serious AEs
will be tabulated.
9.5.2 Concomitant medication
Concomitant medication will be coded using the WHO drug dictionary (Version March 2018). 
Concomitant medication will be listed.
9.5.3 Clinical laboratory parameters
All clinical chemistry, hematology, serology and urinalysis data will be listed. Additionally 
clinical chemistry, hematology, serology and urinalysis data outside the reference ranges will be 
listed.
Values for any clinical chemistry, hematology and urinalysis values outside the reference ranges 
will be flagged on the individual subject data listings.
9.5.4 Vital signs
Vital signs data will be summarized by treatment together with changes from baseline, where 
baseline is defined as Day 1 predose. 
Furthermore, values for individual subjects will be listed.


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9.5.5 Electrocardiogram (ECG)
The ECG data will be listed for individual subjects. 
9.5.6 Blood Glucose Monitoring and Hypoglycemia
Hypoglycemic events will be appropriately recorded in the CRF. In the case of a hypoglycemic 
event, the actual blood glucose value, if measured, will be recorded in the CRF, together with 
any treatments administered. Each category of hypoglycemic events (defined below) will be 
listed and summarized by treatment.
Hypoglycemia is defined as follows:
•Documented Hypoglycemia:
o Documented symptomatic hypoglycemia: An event during which typical symptoms of 
hypoglycemia are accompanied by plasma glucose (PG) ≤70 mg/dL (≤3.9 mmol/L).
o Asymptomatic hypoglycemia: An event not accompanied by typical symptoms of
hypoglycemia but with PG ≤70 mg/dL (≤3.9 mmol/L).
• Unspecified hypoglycemia: An event during which PG ≤70 mg/dL (≤3.9 mmol/L) but no
information relative to symptoms of hypoglycemia was recorded
• Probable symptomatic hypoglycemia: An event during which symptoms indicative of
hypoglycemia are not accompanied by a PG determination (but that was presumably caused by 
PG ≤70 mg/dL [≤3.9 mmol/L]).
• Clinically significant hypoglycemia: 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: An event requiring assistance of another person to actively administer 
carbohydrate, glucagon, or other resuscitative actions.
• Nocturnal hypoglycemia: Any hypoglycemic event (documented symptomatic, asymptomatic, 
probable symptomatic or severe hypoglycemia) that occurs between bedtime and waking.
• Overall hypoglycemia: This optional category combines all cases of hypoglycemia. If an event 
of hypoglycemia falls into multiple subcategories, the event is only counted once in this 
category.
9.5.7 Hepatic Monitoring
If a subject experiences elevated alanine aminotransferase (ALT) ≥3× upper limit of normal 
(ULN), alkaline phosphatase (ALP) ≥2× ULN, or elevated total bilirubin (TBL) ≥2× ULN, liver 
tests will be performed to confirm the abnormality. 


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The subjects’ liver disease history and associated person liver disease history data will be listed. 
Any concomitant medication of acetaminophen/paracetamol will be listed. Results from any 
hepatic monitoring procedures, such as a magnetic resonance elastography (MRE) scan, and a 
biopsy assessment will be listed, if performed.
Hepatic risk factor assessment data will be listed. Liver related signs and symptoms data will be 
summarized by treatment and listed. Alcohol and recreational drug use data will also be listed.
All hepatic chemistry, hematology, coagulation, and serology data will be listed. Values outside 
the reference ranges will be flagged on the individual subject data listings.
9.5.8 Injection Site Local Tolerability Assessment Data
Injection-site assessment data will be listed and summarized in frequency tables by treatment.
9.5.9 Pain Measurements using the Visual Analog Scale
In case of an AE of injection-site reaction, pain will be assessed using a 100-mm validated visual 
analog scale for pain and will be listed and summarized by treatment.
9.5.10
Immunogenicity
The frequency of antibody formation to insulin lispro will be determined. The number of patients 
who have not-detected anti-insulin lispro antibody at pre-dose for period 1 and detected anti-
insulin lispro antibody at post-dose (measured at pre-dose for period 2, 3, or follow-up) will be 
summarized for combined treatments. The number of patients who have detected anti-insulin 
lispro antibody at pre-dose for period 1 and 57% increase from the pre-dose to post-dose 
(measured at pre-dose for period 2, 3, or follow-up) will also be summarized in a similar way.
The relationship between the presence (or absence) of antibodies and AEs will be assessed and 
listed. 
9.5.11
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 serum insulin lispro concentration versus time will be presented. Other plots that may be
explored.
9.5.12
Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.
10.
INTERIM ANALYSES
No interim statistical analyses are planned.


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