Clinical trial NCT03286751
Conditions: Diabetes Mellitus, Type 2
Sponsor: Eli Lilly and Company
Start date: 2017-10-13; Completion date: 2018-02-06
Enrollment: 42 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study compares LY900014, a drug that lowers blood sugar, with insulin lispro (Humalog). Both drugs are given by injection under the skin of the abdomen. The study will be conducted in healthy people to investigate how quickly and how much LY900014 is absorbed and the effect of different doses of LY900014 on blood sugar levels in comparison with insulin lispro. The study will last about 7 to 12 weeks for each participant, including screening and follow up. Screening is required within 28 days prior to entering the study.

Detailed description:

Arms: arm 1: Single dose of 7 units (U), 15 U, and 30 U of LY900014 administered subcutaneously (SC) in three of six periods. arm 2: Single dose of 7 U, 15 U, and 30 U of insulin lispro administered SC in three of six periods.
Interventions: intervention 1: LY900014 intervention 2: Insulin Lispro
Intervention descriptions: intervention 1: Administered SC intervention 2: Administered SC

Protocol documents:
Prot_000.pdf: 
Protocol I8B-MC-ITSH 
 
A Study to Evaluate the Pharmacokinetics and Glucodynamics of LY900014 and Humalog 
across Different Subcutaneous Doses in Healthy Subjects 
 
 
NCT03286751  
 
Approval Date: 26-JUN-2017 
 
 
 


I8B-MC-ITSH Clinical Pharmacology Protocol
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Protocol I8B-MC-ITSH
A Study to Evaluate the Pharmacokinetics and 
Glucodynamics of LY900014 and Humalogacross Different 
Subcutaneous Doses in Healthy Subjects
EudraCT Number: 2017-001859-32
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: 26-Jun-2017 GMT
LY900014
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly on date 
provided below.


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Table of Contents
A Study to Evaluate the Pharmacokinetics and 
Glucodynamics of LY900014 and Humalog across Different 
Subcutaneous Doses in Healthy Subjects
Section
Page
Protocol I8B-MC-ITSH A Study to Evaluate the Pharmacokinetics and 
Glucodynamics of LY900014 and Humalog across Different 
Subcutaneous Doses 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...........................................................................20
5.5.
Justification for Dose ...................................................................................................20
6.
Study Population...............................................................................................................22
6.1.
Inclusion Criteria..........................................................................................................22
6.2.
Exclusion Criteria ........................................................................................................23
6.3.
Lifestyle and/or Dietary Requirements .........................................................................24
Meals and Dietary Restrictions.............................................................................24
6.3.1.
Caffeine, Alcohol, and Tobacco ...........................................................................25
6.3.2.
Activity................................................................................................................25
6.3.3.
6.4.
Screen Failures.............................................................................................................25
7.
Treatment..........................................................................................................................26
7.1.
Treatment Administered...............................................................................................26
Packaging and Labelling ......................................................................................26
7.1.1.
7.2.
Method of Treatment Assignment ................................................................................26
Selection and Timing of Doses.............................................................................27
7.2.1.
7.3.
Blinding .......................................................................................................................27


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7.4.
Dose Modification........................................................................................................27
7.5.
Preparation/Handling/Storage/Accountability...............................................................27
7.6.
Treatment Compliance .................................................................................................28
7.7.
Concomitant Therapy...................................................................................................28
7.8.
Treatment after the End of the Study............................................................................28
8.
Discontinuation Criteria ....................................................................................................29
8.1.
Discontinuation from Study Treatment.........................................................................29
Discontinuation of Inadvertently Enrolled Subjects ..............................................29
8.1.1.
8.2.
Discontinuation from the Study....................................................................................29
8.3.
Subjects Lost to Follow-up...........................................................................................29
9.
Study Assessments and Procedures ...................................................................................30
9.1.
Efficacy Assessments...................................................................................................30
9.2.
Adverse Events ............................................................................................................30
Serious Adverse Events........................................................................................31
9.2.1.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................32
Complaint Handling.............................................................................................32
9.2.2.
9.3.
Treatment of Overdose.................................................................................................32
9.4.
Safety...........................................................................................................................32
Laboratory Tests ..................................................................................................32
9.4.1.
Vital Signs ...........................................................................................................32
9.4.2.
Electrocardiograms ..............................................................................................33
9.4.3.
Other Tests...........................................................................................................33
9.4.4.
9.4.4.1.
Physical Examinations....................................................................................33
9.4.4.2.
Body Weight ..................................................................................................33
9.4.4.3.
Hip and Waist Circumference.........................................................................33
Safety Monitoring ................................................................................................33
9.4.5.
9.4.5.1.
Glucose Monitoring........................................................................................34
9.4.5.1.1.
Severe Hypoglycaemia .............................................................................35
9.4.5.2.
Hepatic Safety ................................................................................................35
Injection-Site Assessments (Local Tolerability)....................................................35
9.4.6.
9.5.
Pharmacokinetics .........................................................................................................36
Bioanalysis...........................................................................................................36
9.5.1.
9.6.
Glucodynamics (Euglycaemic Glucose Clamp)............................................................36
Immunogenicity Assessments ..............................................................................37
9.6.1.
9.7.
Genetics .......................................................................................................................37
9.8.
Exploratory Biomarkers ...............................................................................................38
C-Peptide .............................................................................................................38
9.8.1.
9.9.
Health Economics ........................................................................................................38


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10.
Statistical Considerations and Data Analysis .....................................................................39
10.1. Sample Size Determination for Faster PK Absorption ..................................................39
10.2. Sample Size Determination for Dose Proportionality....................................................39
Study Participant Disposition ...............................................................................39
10.2.1.
Study Participant Characteristics ..........................................................................39
10.2.2.
10.3. Statistical Analyses ......................................................................................................39
Safety Analyses....................................................................................................40
10.3.1.
10.3.1.1.
Clinical Evaluation of Safety ..........................................................................40
10.3.1.2.
Statistical Evaluation of Safety .......................................................................40
Pharmacokinetic Analyses....................................................................................40
10.3.2.
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................40
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................41
Glucodynamic Analyses.......................................................................................42
10.3.3.
10.3.3.1.
Glucodynamic Parameter Estimation ..............................................................42
10.3.3.2.
Glucodynamic Statistical Inference.................................................................42
Pharmacokinetic/Glucodynamic Analyses............................................................43
10.3.4.
Evaluation of Immunogenicity .............................................................................43
10.3.5.
C-Peptide .............................................................................................................43
10.3.6.
Data Review during the Study..............................................................................43
10.3.7.
Interim Analyses ..................................................................................................43
10.3.8.
11.
References ........................................................................................................................44


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List of Tables
Table
Page
Table ITSH.1.
Objectives and Endpoints .......................................................................17
Table ITSH.2.
Treatment Sequence Example for I8B-MC-ITSH ...................................19
Table ITSH.3.
Treatments Administered for I8B-MC-ITSH ..........................................26


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


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................45
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


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1. Protocol Synopsis
Title of Study:
A study to evaluate the pharmacokinetics and glucodynamics of LY900014 and Humalog across different 
subcutaneous doses in healthy subjects.  
Rationale: 
In clinical practice, patients with diabetes on insulin therapy will inject their prandial insulins at a range of 
individualised doses, which may or may not influence the absorption pharmacokinetics (PK), as well as, the 
glucodynamic (GD) effect.  The primary objective of this study is to evaluate the PK and GD effects across 3 dose 
levels after administration of the commercial formulation of LY900014 in comparison to after administration of 
Humalog.  It will also assess the dose proportionality of insulin lispro PK and GD after administration of the 
commercial formulation of LY900014. 
Objectives/Endpoints:
Objectives
Endpoints
Primary
To evaluate the insulin lispro PK following 
subcutaneous (SC) doses of LY900014 compared to 
Humalog (at doses of 7, 15, and 30 U) in healthy 
subjects.
Time to early half-maximal plasma concentration 
(early 50% tmax) and area under the concentration 
versus time curve (AUC) from time zero to 30 
minutes
Secondary
1.
To evaluate the dose proportionality of the 3 dose 
levels of LY900014 as assessed by insulin PK and 
GD measures.
2.
To evaluate the GD of LY900014 compared to 
Humalog following SC doses of 7, 15, and 30 U in 
healthy subjects using a euglycaemic clamp 
procedure.
3.
To evaluate the tolerability of LY900014 in 
healthy subjects.
1a. PK: AUC from time zero to 10 hours 
(AUC[0-10h]), AUC from time zero to infinity
(AUC[0-∞]), and maximum observed drug
concentration (Cmax)
1b. GD:  Total amount of glucose infused (Gtot) 
and maximum glucose infusion rate (Rmax)
2. Time to half-maximal GIR before tRmax (early 
50% tRmax), Gtot over 30 minutes
(Gtot[0-30min]), Gtot over 1 hour (Gtot([0-1h]), 
and time to onset of insulin action (Tonset)
3. Adverse events (AEs) and injection-site 
reactions
Summary of Study Design:
Study I8B-MC-ITSH is a Phase 1, randomised, subject- and investigator-blind, 6-period complete crossover study in 
up to 42 healthy subjects to evaluate the PK and GD characteristics of LY900014 doses in comparison to Humalog
at doses of 7, 15, and 30 U.
Treatment Arms and Planned Duration for an Individual Subject:
Subjects will be randomised to 1 of 6 treatment sequences to assess different doses of LY900014 (7, 15, and 30 U)
and Humalog (7, 15, and 30 U).  The study will include a 28-day screening period, followed by 6 study periods, with 


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LY900014
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 42 healthy men and women may be enrolled to target approximately 34 subjects to complete.
Statistical Analysis:
The primary statistical analyses for PK will be conducted on those subjects who receive at least 1 dose of study drug 
and have measurable insulin lispro concentrations.  The primary statistical analysis for GD will be conducted on 
those subjects who complete at least 1 clamp procedure.  Supportive analyses will be done on the key parameters for 
the subjects who complete all treatment periods with evaluable data.
Safety:
Safety analyses will be conducted for all enrolled subjects, whether or not they complete all protocol requirements.  
All investigational product and protocol-procedure AEs will be listed, and if the frequency of events allows, safety 
data will be summarised using descriptive methodology.  Safety parameters that will be assessed include safety 
laboratory parameters and vital signs, as well as evaluation of injection-site reactions.  The parameters will be listed 
and may be summarised using standard descriptive statistics.
Pharmacokinetics:
Pharmacokinetic analyses will be conducted using standard noncompartmental methods of analysis.  
Pharmacokinetic parameters will be assessed using free serum insulin lispro.
Log-transformed AUC estimates and Cmax for insulin lispro will be evaluated to estimate least-squares geometric 
means, ratios of geometric means between LY900014 and Humalog for each dose level, and their corresponding 
95% CIs using the mixed-effects model that includes treatment, dose level, dose level-by-treatment interaction, and 
period as fixed effects and subject as a random effect.  
The same model without log transformation will be used for the analysis of the PK time parameters (time to early
half-maximal plasma concentration [early 50% tmax], time to late half-maximal plasma concentration [late 50% 
tmax], time to maximum observed drug concentration [tmax], and half-life associated with the terminal rate constant 
in noncompartmental analysis [t1/2]).  Least-squares means (LSmeans), treatment differences in LSmeans, and the 
corresponding 95% confidence intervals (CIs) for the treatment differences for each dose level will be estimated 
from the model.  The treatment ratios and 95% CIs for the ratios will be calculated using Fieller’s theorem.  
The analyses described above will also be performed on the population of subjects who completed and had 
evaluable PK data for all study periods 
The degree of dose proportionality for the insulin lispro in LY900014 will be assessed by fitting the power model to 
both AUC (AUC[0-10h], and AUC[0-∞]) and Cmax versus dose for each dose level of LY900014.  The estimated 
ratio of dose-normalised geometric means of PK parameters between the highest and lowest doses will be used to 
assess dose proportionality.  In addition, the slope and its 95% CIs and the geometric LSmeans for each dose level 
tested will be produced.  In the event that the power model is not a good representation of the data over the entire 
dose range tested, alternative models may be investigated.  Log-transformed Cmax and AUC LSmeans, and 95% CI 
estimates for each dose will be back-transformed to provide the geometric means and the corresponding 95% CIs.  


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The analyses will also be performed using the subset of the subjects who complete all treatment periods with 
evaluable data.
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 
patients 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. The fitted data for each patient will 
be used to calculate the GD parameters.
The GD statistical model will be the same as the model used for the analysis of the PK parameters.  The following 
variables will be log transformed prior to analysis:  Rmax, Gtot, Gtot(0-30min), Gtot(0-1h), and Gtot over 10 hours.  
The same model without log transformation will be used for the analysis of the GD time parameters (Tonset, time to 
maximum GIR [tRmax], early 50% tRmax, time to half-maximal GIR after tRmax).  Least-squares means, treatment 
differences in LSmeans, and the corresponding 95% CIs for the treatment differences for each dose level will be 
estimated from the model.  The treatment ratios and 95% CIs for the ratios will be calculated using Fieller’s 
theorem.
The degree of dose proportionality for the GD of LY900014 will be assessed by fitting the power model to Gtot and 
Rmax parameters.  The estimated ratio of dose-normalised geometric means of PK parameters between the highest 
and lowest doses will be used to assess dose proportionality.  In addition, the slope and its 95% CIs and the 
geometric LSmeans for each dose level tested will be produced.  In the event that the power model is not a good 
representation of the data over the entire dose range tested, alternative models may be investigated.  
Log-transformed Gtot and Rmax LSmeans, and 95% CI estimates for each dose will be back transformed to provide 
the geometric means and the corresponding 95% CIs.  The degree of dose proportionality in GD following 
administration of LY900014 will be assessed by fitting the power model to Gtot and Rmax versus dose for each dose 
level of LY900014.
Pharmacokinetics and GD analyses will also be performed using the subset of the subjects who complete all 
treatment periods with evaluable data.  


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2. Schedule of Activities


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Study Schedule for Protocol I8B-MC-ITSH
Procedures
Screening
Euglycaemic Clamp Procedure
Periods 1 to 6
FU/
EDa
Comments
Up to 
Day -28
Day 
-1
Day 1
Informed consent
X
Must occur before screening procedures. Screening procedures should 
take place no later than 28 days after signing the informed consent.
Admission to CRU
X
Enrolment will occur on the first admission.
Overnight fast
X
X
Subjects are expected to fast for approximately 8 hours before 
screening, and at least 8 hours starting from the evening before each 
dose until the end of the glucose clamp procedure.
Weight
X
X
Day -1 weight for Period 1 only.
Height
X
Hip and waist circumference
X
Period 1 only. Record the average of triplicate measurements.
Physical examination/
Medical assessmentb
X
Predose and before discharge from CRU 
for each period
X
Full physical examination and medical history at screening. Thereafter, 
medical review and targeted examination, as appropriate and as deemed 
necessary by the investigator.
Vital signs (supine): blood 
pressure and pulse rateb
X
Predose and after the end of clamp 
procedure
X
12-Lead ECGb
X
Predose and after the end of clamp 
procedure
X
Single ECGs to be collected for safety. 
Clinical laboratory testsb
X
Predose of Period 1 only
X
Results not required prior to first dosing.
Pregnancy test/urine drug 
screen/alcohol breath test
X
X
X
Pregnancy test for female subjects of childbearing potential only. 
Serum pregnancy test at screening. Urine pregnancy test for all other 
visits. Alcohol breath test and drug screen may be omitted at follow up.
Study drug administration
0 minute
Time of study drug administration = 0 minute.  Study drug will be 
administered at about the same time on Day 1 of each study period.
Injection-site assessments
0, 60, 240, and 600 minutes
Assessment times are relative to study drug administration time 
(time 0).  The 0-minute assessment will start as soon as practicably 
possible (within 1 minute) following the injection.
Insulin lispro PK sampling
0, 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 70, 
90, 120, 150, 180, 210, 240, 300, 360, 
420, 480, 540, and 600 minutes
Sampling times are relative to study drug administration time (time 0). 
The 0-minute sample should be taken within 2 minutes prior to planned 
dosing. 


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Procedures
Screening
Euglycaemic Clamp Procedure
Periods 1 to 6
FU/
EDa
Comments
Up to 
Day -28
Day 
-1
Day 1
Euglycaemic clamp and 
blood glucose sampling for 
procedure
The clamp device will automatically 
sample blood at a rate of 2 mL/h after 
connection and record a blood glucose 
value every minute during the clamp 
procedure. A manual blood sample will 
also be taken at least every 30 minutes 
during the clamp for checking the correct 
functioning of the clamp device blood 
glucose readings and for safety.
Blood glucose monitoring will be done every minute starting from 
calibration after connection to the clamp device, baseline glucose 
establishment, drug dosing, and clamp up to 10 hours after dosing
C-peptide sampling
0, 60, 120, 240, 360, 480, and 600 
minutes
Sampling times are relative to study drug administration (time 0). The 
0-minute sample should be taken within 2 minutes prior to planned 
dosing. 
Pharmacogenetic sample
X
Period 1 only.
Immunogenicity sampleb
Predose for Period 1, Period 3, and
Period 5
X
Additional samples may be collected if the investigator considers there 
is a possibility that an adverse event is immunologically indicated. 
Discharge from CRU
X
After completion of all study procedures and medical assessment on 
Day 1.  Investigator’s discretion to discharge on Day 2.
Abbreviations:  CRU = clinical research unit; ECG = electrocardiogram; ED = early discontinuation; FU = follow-up; PK = pharmacokinetics.
a
Procedures should be performed at least 14 days after the last dose of study drug.
b
Predose assessments, procedures, and sampling may be performed any time before actual dosing on Day 1.
Note:  The site should schedule activities as appropriate.  In cases when several study procedures are scheduled at the same time, the order of priority will be as follows:  PK 
samples, glucose samples, injection-site assessments, vital signs, ECG, clinical laboratory samples, immunogenicity, C-peptide, and pharmacogenetic samples.  If the 
investigator decides based on clinical judgement not to dose a subject on a given day (for example, because of low blood glucose), the subject’s visit may be rescheduled; 
any procedures performed in that period may be repeated.


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3.Introduction
3.1. Study Rationale
In clinical practice, patients with diabetes on insulin therapy will inject their prandial insulins at a 
range of individualised doses, which may or may not influence the absorption pharmacokinetics 
(PK), as well as, the glucodynamic (GD) effect.  The primary objective of this study is to 
evaluate the PK and GD effects across 3 dose levels after administrationofthe commercial 
formulation of LY900014 in comparison toHumalog
®.It will alsoassess the dose 
proportionality of insulin lispro PK and GD after administration of the commercial formulation 
of LY900014. 
3.2. Background
CCI
The insulin analogue, insulin lispro (Humalog; Eli Lilly and Company), has been shown to be 
absorbed more quickly than regular human insulin (Humalog package insert, 2015).  In healthy 
volunteers given subcutaneous (SC)doses of insulin lispro ranging from 0.1 to 0.4 U/kg, peak 
serum levels were seen 30 to 90 minutes after dosing (Humalog package insert, 2015).  However, 
the general consensus is that rapid-acting insulin, administered either through pumps or 
syringes/pen injectors, is still not rapid enough to match carbohydrate absorption profiles, which 
limits efficacy and dosing flexibility.  An ultra-rapid-acting prandial insulin would shift the PK 
and GD profiles so that they have an even faster onset to better match carbohydrate absorption 
and also may allow important flexibility in the time of dosing relative to meals.
LY900014 is an ultra-rapid-acting insulin lispro formulation with treprostinil 
 
 and other ingredients.  LY900014 has an increased early absorption of insulin 
lispro compared to commercially available insulin lispro(Humalog). 
 
 
Treprostinil is a prostacyclin analogue, administered either through inhalation 
, as an 
intravenous (IV)infusion, or as a continuous SC administrationfor the treatment of symptomatic 
pulmonary arterial hypertension (PAH) and has been approved in the US since 2002 
 
.  Each of the other excipients (such as sodium citrate and magnesium 
chloride) in the LY900014 formulation is listed in the US Food and Drug Administration 
(FDA)’s Generally Recognized as Safe Food Additives database and in the FDA’s Inactive 
Ingredients in Approved Drugs database.  Furthermore, the excipient concentration in LY900014 
is within the limits identified for approved drug products in the FDA Inactive Ingredients in 
Approved Drugs database.
Safety and tolerability of LY900014 have been demonstrated in healthy subjects in 3previous 
clinical studies, in approximately 71healthy subjects across a dose range of 7.5 to 30 U.  All 
3studies were Phase 1, randomised, subject-blind studies in which the PK and GD of LY900014 
and Humalog were evaluated during a euglycaemic glucose clamp following SC administration.  
The total insulin lispro exposure and GD effect were similar for LY900014 and Humalog insulin 
CCI
CCI
CCI


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LY900014
lispro; however, LY900014 demonstrated a faster and earlier insulin lispro absorption compared 
to Humalog.LY900014 also displayed a dose proportional increase in theinsulin lispro
exposure (maximum observed drug concentration [Cmax]and area under the concentration versus 
time curve from time [AUC])across this dose range.
In addition, data from twoPhase 1b studies showed LY900014 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).  Small numbers of treatment-emergent adverse events(TEAEs) were 
reported, and there were no notable increases in these events in relation to any of the LY900014 
formulations compared to those in relation to Humalog.
More information can be found in the Investigator’s Brochure (IB) of LY900014.
3.3. Benefit–Risk Assessment
CCI
Study I8B-MC-ITSH (ITSH) will not offer any direct benefits to the healthy subjects 
participating in the study.  The data from previous studies in healthy subjects and data from 
studies in patients with T1DM and T2DM have shown that LY900014 was welltolerated 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 hypoglycaemia, hypersensitivity reactions (localised allergy and/or systemic 
allergy), undesirable effects at the injection site (injection-site reactions and lipodystrophy), and 
peripheral oedema (Humalog package insert, 2015).
Notably, across alldoses inthe Lilly clinical studies with healthy subjectsand patients with 
diabetesthat have evaluated treprostinil as a local vasodilator with or without insulin lispro, there 
was no clinically significant increase in those AEs associated with systemic absorpti
on of 
treprostinil, 
  Moreover, data from Lilly
Phase 1b patient studies showed that only 1 out of 472 plasma sampleshad detectable treprostinil 
levels taken from a total of 30patients with T1DM (doses up to  
 per SC bolus injection) and 
30 patients with T2DM (doses up to 
 per SC bolus injection)following MDI administration 
of LY900014.The exposure levels of treprostinil from the doses of LY900014 planned in this 
studyare thus expected to be undetectable and substantially lower than those observed in the 
treatment of PAH.  In preclinical safety pharmacology and toxicity studies or clinical 
pharmacology studies involving LY900014 or treprostinil alone, other than known risks 
associated with Humalog and 
, no additional risks were identified.  No known 
potential risks are associated with the use of small amounts of treprostinil 
 in the 
LY900014 formulation.  Additionally, local and systemic toxicity profiles of Humalog and 
 do not suggest the potential for additive or synergistic toxicity.  
Following administration of the study insulin, subjects will receive IV glucose infusion at a 
variable rate to maintain euglycaemia up to 10 hours after insulin lispro administration.  The aim 
of the clamp procedure is to maintain blood glucose within the normal glycaemic range.  In 
CCI
CCI
CCI
CCI
CCI


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LY900014
addition, the clamp is performed while the subject is inpatient and under the investigator’s 
supervision.  These considerations should minimise the risk of hypoglycaemia in subjects 
participating in Study ITSH.
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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LY900014
4. Objectives and Endpoints
Table ITSH.1 shows the objectives and endpoints of the study.
Table ITSH.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To evaluate the insulin lispro pharmacokinetics following SC 
doses of LY900014 compared to Humalog (at doses of 7, 15, 
and 30 U) in healthy subjects.
Early 50% tmax and AUC(0-30min)
Secondary
1.
To evaluate the dose proportionality of the 3 dose levels of
LY900014 as assessed by insulin lispro pharmacokinetics
and glucodynamic measures.
2.
To evaluate the GD during euglycaemic clamp procedure 
following SC doses of 7, 15, and 30 U of LY900014
compared to Humalog in healthy subjects.
3.
To evaluate the tolerability of LY900014 in healthy 
subjects.
1a. PK: AUC(0-10h), AUC(0-∞), and Cmax
1b. GD: Gtot and Rmax
2.
Early 50% tRmax, Gtot(0-30min), Gtot(0-1h), 
and Tonset
3. AEs and injection-site reactions
Exploratory
1.
Explore the formation of antibodies to insulin lispro.
2.
To assess C-peptide levels following administration of 
LY900014 and Humalog.
1. Anti-insulin lispro antibodies
2. C-peptide concentration
Abbreviations:  AE = adverse event; AUC(0-30min) = area under the concentration versus time curve from time 
zero to 30 minutes; AUC(0-10h) = AUC from time zero to 10 hours; AUC(0-∞) = AUC from time zero to 
infinity; Cmax = maximum observed drug concentration; early 50% tmax = time to early half-maximal plasma 
concentration; early 50% tRmax = time to half-maximal glucose infusion rate before tRmax; GD = glucodynamics; 
Gtot = total amount of glucose infused; Gtot(0-30min) = Gtot over 30 minutes; Gtot(0-1h) = Gtot over 1 hour; PK =
pharmacokinetics; Rmax = maximum glucose infusion rate; SC = subcutaneous; Tonset = time to onset of insulin 
action.


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LY900014
5. Study Design
5.1.
Overall Design
This is a Phase 1, randomised, subject- and investigator-blind, 6-period complete crossover study 
in up to 42 healthy subjects to evaluate the PK and GD characteristics across a range of 
LY900014 doses. 
Approximately 34 subjects are expected to complete the study.  Each subject will be randomised 
to 1 of 6 treatment sequences comprising single SC doses of 7, 15, and 30 U of LY900014 or
Humalog administered SC in the abdominal wall (Table ITSH.2).  A minimum of 3 days 
between study dosing of each consecutive study period will be required for an individual subject.
Figure ITSH.1 illustrates the study design.  
Study governance considerations are described in detail in Appendix 3.
*Single dose of 7, 15, or 30 U of LY900014 or Humalog administered subcutaneously 
to the abdomen. Euglycaemic clamp procedure after each dose.
Figure ITSH.1.
Illustration of study design for I8B-MC-ITSH.
Screening
Period 1
Period 2
Period 3
Period 4
Period 5
Period 6
Follow-up
Healthy 
Subjects
*LY900014 
or Humalog
*LY900014 
or Humalog
*LY900014 
or Humalog
*LY900014 
or Humalog
*LY900014 
or Humalog
*LY900014 
or Humalog
≤ 28 days
Inpatient 
Euglycaemic
Clamp
Inpatient 
Euglycaemic
Clamp
Inpatient 
Euglycaemic
Clamp
Inpatient 
Euglycaemic
Clamp
Inpatient 
Euglycaemic
Clamp
Inpatient 
Euglycaemic
Clamp
≥ 14 days
Washout duration between clamp visits ≥ 3 days


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LY900014
Table ITSH.2.
Treatment Sequence Example for I8B-MC-ITSH
Treatment 
Sequence
Period 1
Period 2
Period 3
Period 4
Period 5
Period 6
1
LY 7 U
LY 15 U
H 30 U
LY 30 U
H 15 U
H 7 U
2
LY 15 U
LY 30 U
LY 7 U
H 7 U
H 30 U
H 15 U
3
LY 30 U
H 7 U
LY 15 U
H 15 U
LY 7 U
H 30 U
4
H 7 U
H 15 U
LY 30 U
H 30 U
LY 15 U
LY 7 U
5
H 15 U
H 30 U
H 7 U
LY 7 U
LY 30 U
LY 15 U
6
H 30 U
LY 7 U
H 15 U
LY 15 U
H 7 U
LY 30 U
Abbreviations:  H = Humalog; LY = LY900014.
Note: This is only an example table for illustration purpose; subjects will be assigned a treatment sequence 
according to the actual treatment randomisation schedule provided to the unblinded site pharmacist.
Subjects will be admitted to the clinical research unit (CRU) on the evening before each dosing 
day and will remain in the CRU for the duration of the clamp period and until discharge by the 
investigator.  Subjects are expected to fast for at least 8 hours before each dose.  Following dose 
administration, each subject will undergo an euglycaemic clamp procedure of up to 10 hours.  
Upon completion of the clamp procedures, the subjects will be provided a meal and discharged 
from the CRU in the evening after medical assessments.  Subjects may remain in the CRU if 
deemed necessary for safety monitoring, as determined by the investigator.  
Subjects will be required to attend the CRU on at least 8 occasions:

screening visit (up to 28 days prior to dosing)

six treatment visits for the dosing and clamp procedure (study Periods 1 to 6) with 
a minimum period of at least 3 days between consecutive clamp visits

follow-up visit (at least 14 days after the last dose), or early discontinuation
In the study, safety assessments and an evaluation of local tolerability at injection sites will be 
performed as specified in the Schedule of Activities (Section 2).  Local tolerability assessments 
will include injection-site reactions within the following categories:  pain on palpation, itching, 
erythema, oedema, and induration/infiltration.
5.2.
Number of Participants
A total of 42 subjects may be enrolled for an approximately 34 completing subjects. For 
purposes of this study, a subject is considered as having completed the study when all scheduled 
procedures shown in the Schedule of Activities (Section 2) have been completed.  If a subject 
discontinues before completion of all 6 dosing periods, replacement subjects may be enrolled. 
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.


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5.4. Scientific Rationale for Study Design
A population of healthy subjects isselected 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.  Thestudy is subject-and investigator-blindedto minimise potential bias
related to the clamp procedure.
A euglycaemic clamp technique, the gold standard methodology for assessing insulin action, will 
be used in this study to provide data on the GD activity of LY900014(see Section9.6for a 
detailed description of the clamp methodology)relative to Humalog.Previous studieshave 
shown thatthe 10-hourduration of the euglycaemicglucose clamp will allow for a complete 
assessment of GD activity of LY900014.
Based on the PK properties of treprostinil (half-life associated with the terminal rate constant in 
noncompartmental analysis [t
1/2]=
 and Humalog (t
1/2=
, a minimumduration of3days for the washout period between clamp 
visits and at least 14-daysduration between the last dose of study drug and the follow-up visit 
are considered appropriate.  
In patients with diabetes, mealtime insulin requirementscan vary substantially depending on 
carbohydrate content, glycaemic index of the meal, and the insulin sensitivity of patient. 
Understanding the PKand GDacross a broader dose rangeis importantasreliable titration of an 
insulin product depends on anestablished dose–response relationship.  
5.5. Justification for Dose
CCI
The safety, PK, and pharmacology of LY900014 at similar doses and with the similar 
formulation composition have been assessed in clinical studies in healthy subjects, in patients 
with T1DM and T2DM using MDI.  In addition, clinical studies had evaluatedthe safety, PK, 
and pharmacology of SC bolus doses of treprostinilalone.More information can be found in the
.
All tested doses ofLY900014 (up to 50U) and treprostinil (
) were well tolerated in 
healthy subjects, patients with T1DM, and patients with T2DM.  There were no SAEs related to 
study treatment in any of the 8 studies.  No subject discontinued from the studies because of 
drug-related AEs.  Trial participants in thesestudies were monitored for changes in vital signs; 
there were no significant systemic haemodynamic effects of treprostinil at the doses administered 
based on blood pressure and heart rate.  Visual analoguescale pain scores showed that the SC 
injections of insulin lispro plus treprostinil co-formulations and treprostinil alone were well 
tolerated.In summary, 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 wereno clinically significant increase in those AEs 
associated with systemic absorption as described in the 
 (i.e., 
CCI
CCI
CCI
CCI


I8B-MC-ITSHClinical Pharmacology Protocol
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LY900014
headache, diarrhoea, nausea, jaw pain, vasodilatation, rash, oedema, and hypotension).  This is 
likely attributable to the relatively lower exposures of treprostinil demonstrated in these clinical 
studies.
Study ITSH will evaluate3 insulin lispro dose levels (7,15, and 30 U), which are within the
range of insulin doses thatare used for the treatment of both patients with T1DM and T2DM in 
clinical practice. At the highestdose level of 30U of LY900014,subjects will be expected to
receiveapproximately
 treprostinil in a single SC dose, which is within the range 
evaluated as safe and tolerated in previous studies. The PK profile of treprostinil showed that 
concentrations of treprostinil in healthy subjects (after administration of up to30U of an 
experimental LY900014 formulation which contained 
 of treprostinil)were quantifiable in
only
 of the samples at 15minutes postdose and  
 of the samples at 30minutes postdose 
occurring around Cmax.Among subjects with detectable levels, the mean concentrations were 
only slightly above the detection limit of the assay (lower limit of quantitation= 
),
and there were no detectable levels in any samples at 1 and 2 hoursafterinjection.Thus, the 
expected treprostinil Cmax
CCI
following LY900014 administration would be 
 than the 
steady-state treprostinil levels in patients with PAH treated with 
 
 from an 
average dose of 
 of  
 in clinical trials 
,
.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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LY900014
6. Study Population
Eligibility of subjects for the study will be based on the results of screening medical history, 
physical examination, vital signs, clinical laboratory tests, and electrocardiogram (ECG). 
The nature of any conditions present at the time of the physical examination and any pre-existing 
conditions will be documented.
Screening may occur up to 28 days prior to enrolment.  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 enrolment 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] male subjects:  agree to use an effective method of contraception for the 
duration of the study and for 1 month following the last dose of 
investigational product (IP)
[1b] female subjects:

women of childbearing potential may participate and include those 
who test negative for pregnancy before initiation of treatment based 
on a urine pregnancy test and agree to use 1 highly effective method 
of contraception or a combination of 2 effective methods of 
contraception during the study and for 1 month following the last dose 
of the IP

women of nonchildbearing potential may participate in the study 
without using adequate contraceptive methods, and include those who 
are:
o
infertile due to surgical sterilisation (hysterectomy, bilateral 
oophorectomy, or tubal ligation), congenital anomaly such as 
müllerian agenesis; or
o
postmenopausal, defined as women aged <52 years and being 
amenorrhoeic for more than 1 year with a serum follicle-stimulating 
hormone (FSH) level compatible with postmenopausal status 
(positive FSH level) or aged ≥52 years and being amenorrhoeic for 
less than 1 year and with a serum FSH level compatible with 
postmenopausal status or aged ≥52 years being amenorrhoeic for 
more than year.


I8B-MC-ITSH Clinical Pharmacology Protocol
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LY900014
[2]
are between 18 and 65 years of age, inclusive, at the time of screening.
[3]
have a body mass index (BMI) of 18.0 to 30.0 kg/m2, inclusive, at the time of 
screening.
[4]
have clinical laboratory test results within normal reference range for the 
population or CRU, or results with acceptable deviations that are judged to be 
not clinically significant by the investigator.
[5]
have venous access sufficient to allow for blood sampling, IV administration,
and clamp procedure as per the protocol.
[6]
are nonsmokers, have not smoked for at least 6 months before entering the 
study, and agree not to smoke (cigars, cigarettes, or pipes) or use smokeless 
tobacco or nicotine products for the duration of the study.
[7]
are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures.
[8]
are able and willing to give signed informed consent.
6.2.
Exclusion Criteria
Subjects will be excluded from study enrolment if they meet any of the following criteria at 
screening and/or enrolment:
[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 or employees of the CRU.
[11]
are currently enrolled in a clinical study involving an IP or any other type of 
medical research judged not to be scientifically or medically compatible with 
this study.
[12]
have participated, within the past 30 days, in a clinical study involving an IP.  
If the previous IP has a long half-life, 5 half-lives, or 3 months (whichever is 
longer) should have passed.
[13]
have previously completed or withdrawn from this study.
[14]
have known allergies to treprostinil or insulin lispro, related compounds, or 
any components of the formulation, or 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 an abnormal blood pressure and/or pulse rate as deemed to be clinically 
significant by the investigator.


I8B-MC-ITSH Clinical Pharmacology Protocol
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LY900014
[17]
have a history or presence of cardiovascular, respiratory, hepatic, renal, 
gastrointestinal, endocrine, haematological, or neurological disorders capable 
of significantly altering the absorption, metabolism, or elimination of drugs; 
of constituting a risk when taking the study drug; or of interfering with the 
interpretation of data.
[18]
have known or ongoing psychiatric disorders deemed to be clinically 
significant by the investigator.
[19]
regularly use known drugs of abuse and/or show positive findings on urinary 
drug screening.
[20]
show evidence of human immunodeficiency virus (HIV) infection, and/or 
positive human HIV antibodies.
[21]
show evidence of hepatitis B and/or positive hepatitis B surface antigen.
[22]
show evidence of hepatitis C and/or positive hepatitis C antibody (the
presence of hepatitis C antibodies in the setting of normal liver function tests 
and a negative hepatitis C polymerase chain reaction are not an exclusion).
[23]
use over-the-counter or prescription medication within 7 to 14 days, 
respectively, prior to dosing apart from vitamin/mineral supplements, 
occasional paracetamol, topical treatments, thyroid replacement medication, 
or birth control methods and throughout the study.  If this situation arises, 
inclusion of an otherwise suitable subject may be at the discretion of the 
investigator and sponsor.
[24]
have donated blood or have blood loss of more than 500 mL within the 
previous 3 months of study screening.
[25]
have a significant history of alcoholism or drug abuse as judged by the 
investigator or consuming more than 24 g of alcohol per day for males or 
more than 12 g of alcohol per day for females or are unwilling to stop alcohol 
consumption at least 24 hours before each CRU admission (Day -1) and 
throughout the duration of each CRU visit.
[26]
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.
Meals and Dietary Restrictions
6.3.1.
For all treatment periods, subjects will fast for at least 8 hours prior to dosing and until the 
glucose clamp procedure is completed, after which subjects will receive a meal.  Water can be 
consumed freely during this time.
When not a resident at the CRU, subjects will be encouraged to follow their normal diets.


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LY900014
Caffeine, Alcohol, and Tobacco
6.3.2.
No alcohol intake will be allowed at least 24 hours before each CRU admission and while 
resident within the CRU.
Subjects should refrain from caffeine-containing food/beverages (for example, cola, chocolate, 
tea, and coffee) for at least 12 hours before each dose and throughout the duration of each CRU 
visit.
Smoking (cigars, cigarettes, or pipes) and the use of smokeless tobacco products will not be 
permitted during the study.
Activity
6.3.3.
Subjects are encouraged to maintain their regular exercise habits; however, they should not 
undertake vigorous or prolonged exercise within 48 hours prior to dosing.  These subjects will 
have their dosing visits deferred or may 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
This studywill evaluate LY900014 (Test) and Humalog (Reference)across 3SC doses with 
reference to the amount of insulin lispro present (7, 15, and 30 U).TableITSH.3showsthe 
treatment regimens.
The CRU must have resuscitation equipment, emergency drugs, and appropriately trained staff 
available during thestudy drugadministration.
TableITSH.3.
TreatmentsAdministered for I8B-MC-ITSH
Treatment name
LY900014
Humalog
Insulin lispro dosage concentration
100 U/mL
100 U/mL
Insulin lispro dosage level
7, 15, 30U
7, 15, 30U
Route of administration
SC injection 
SC injection 
Abbreviation:SC = subcutaneous.
The investigator or designee is responsible for
explaining the correct use of the study drugsto the CRUpersonnel 
verifying that instructions are followed properly
maintaining accurate records of study drugs’dispensationand collection
and returning all unused medicationsto Lilly or its designee at the end of the study.
Note:In some cases, sites may destroy the material if, during the investigativesite selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical materials. 
Packaging and Labelling
7.1.1.
Clinical studymaterials will be labelledaccording to the country’s regulatory requirements.  
LY900014 will be supplied by Lilly or its representative in accordance with current good 
manufacturing practices and will be supplied with lot numbers. Reference drug will be 
commercially available insulin lispro (Humalog) supplied by Lilly.
The study insulins will be provided to the CRUunblinded.Each vial will contain 10 mL of 
either LY900014 or commercially available insulin lispro at a concentration of 100 U/mL.  
LY900014 will also contain treprostinil at a concentration of 
.  An unblinded pharmacist 
at the CRUor other CRUpersonnel who are unblinded will use the insulin vials provided to 
prepare the blinded syringesfor study drug administration.
7.2. Method of Treatment Assignment
CCI
The study insulin to be injected in a given treatment period will be determined according to a 
randomisation schedule.


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LY900014
Selection and Timing of Doses
7.2.1.
The actual date and time of all dose preparations will be documented, and the actual time of all 
dose administrations will be recorded in the subject’s electronic case report form (eCRF).  For 
each subject, the doses will be administered at approximately the same time on Day 1 of each 
study period.
The site of administration of each injection will be recorded.  Injection sites selected should be 
about 5 cm from the umbilicus and the treatment administered SC with the needle applied at 
about 90° to the surface of the skinfold.  An appropriately sized insulin syringe and needle shall 
be used in all dosing periods to ensure all injections are delivered to a consistent depth target into 
the SC space.  Injections will be rotated among different injection sites on the anterior abdominal 
wall during the 6 study periods (i.e., left lower quadrant and right lower quadrant).  
All study treatments will be given in the CRU by qualified CRU personnel as designated by the 
investigator.  Study injections should be given by a limited number of individuals for 
consistency.
The site of administration of each injection will be recorded in the eCRF.
7.3.
Blinding
The study is subject- and investigator-blind with reference to the identity of the study drug
administered. The CRU staff will not be blinded to the dose administered due to the difference 
in volume of injection for the 3 doses being studied.
The Lilly clinical pharmacologist (CP)/Lilly study team will be unblinded.
Emergency codes will be available to the investigator. A pharmacist or other CRU personnel 
who is unblinded will be required to prepare the insulin doses for administration. A code that 
reveals the treatment group for a specific study subject may be opened during the study only if 
the subject’s well-being requires knowledge of the subject’s treatment assignment.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a subject’s treatment assignment is warranted for medical management of the event. The 
subject’s safety must always be the first consideration in making such a determination. If the 
investigator decides that unblinding is warranted, it is the responsibility of the investigator to 
promptly document the decision and rationale and notify Lilly as soon as possible. 
Upon completion of the study, all codes must be returned to Lilly or its designee.
7.4.
Dose Modification
Dose adjustments are not allowed in this study.
7.5.
Preparation/Handling/Storage/Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained, as communicated by the sponsor, during transit for all study drugs received and any 
discrepancies are reported and resolved before use of the study treatment.


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LY900014
Only participants enrolled in the study may receive the study drugs, and only authorised CRU
personnel may supply or administer the study drug. All study drugs should be stored in an
environmentally controlled and monitored (manual or automated) area in accordance with the 
labelled storage conditions, with access limited to the investigator and authorised CRU staff.
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 the study drug accountability, reconciliation, and record 
maintenance (such as receipt, reconciliation, and final disposition records).
7.6.
Treatment Compliance
The study drug will be administered at the CRU, and documentation of treatment administration 
will occur at the CRU.
7.7.
Concomitant Therapy
Subjects should not use over-the-counter or prescription medications as described in exclusion 
criterion 23 throughout the study.  If a subject does use these medications, inclusion of the 
subject may be at the discretion of the investigator and sponsor.
If the need for concomitant medication arises, inclusion or continuation of the subject may be at 
the discretion of the investigator, and when possible, after consultation with a Lilly CP/clinical 
research physician (CRP).  Any additional medication used during the course of the study must 
be documented.
7.8.
Treatment after the End of the Study
Not applicable.


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LY900014
8. Discontinuation Criteria
Subjects discontinuing the study drug and/or study prematurely for any reason should complete 
AE and other follow-up procedures per Section 2 of this protocol.
8.1.
Discontinuation from Study Treatment
Discontinuation of Inadvertently Enrolled Subjects
8.1.1.
If the sponsor or investigator identifies a subject who did not meet enrolment criteria and was 
inadvertently enrolled, the subject must be discontinued from the study.  
8.2.
Discontinuation from the Study
Subjects will be discontinued under the following circumstances:

Enrolment in any other clinical study involving an IP or enrolment in any other type of 
medical research judged not to be scientifically or medically compatible with this study.

Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP).

Investigator Decision
o
the investigator decides that the subject should be discontinued from the study.

Subject Decision
o
the subject, or legal representative, requests to be withdrawn from the study.
8.3.
Subjects Lost to Follow-up
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the CRU.  The CRU personnel are expected to make 
diligent attempts to contact subjects who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the CRU.


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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).  The specifications in this protocol for the timings of 
safety and sample collection are given as targets to be achieved within reasonable limits.  
Modifications may be made to the time points based upon merging clinical information.  The 
scheduled time points may be subject to minor alterations; however, the actual time must be 
correctly recorded in the eCRF.  Late collection outside stipulated time allowances or failure to 
perform procedures or obtain samples due to clinical issues, such as equipment technical 
problems, venous access difficulty, or subject defaulting on an agreed scheduled procedure, will 
not be considered as protocol deviations but the CRU will still be required to notify the sponsor 
in writing via a file note.
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 the subsections below, all samples collected for specified laboratory 
tests will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may 
be retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1.
Efficacy Assessments
Not applicable for this study.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of subjects who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the subject.
The investigator is responsible for the appropriate medical care of subjects during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the study drug or the 
study, or that caused the subject to discontinue the study drug before completing the study.  The 
subject should be followed until the event resolves, stabilises with appropriate diagnostic 
evaluation, or is reasonably explained.  The frequency of follow-up evaluations of the AE is left 
to the discretion of the investigator.
After the informed consent form (ICF) is signed, CRU personnel will record, via electronic data 
entry, the occurrence and nature of each subject’s preexisting conditions, including clinically 
significant signs and symptoms of the disease under treatment in the study.  Additionally, CRU
personnel will record any change in the condition(s) and the occurrence and nature of any AEs.  


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LY900014
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 study drug, and/or study procedure and the AE.
Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study.
If a subject’s study drug is discontinued as a result of an AE, CRU personnel must report this to 
Lilly or its designee via electronic data entry.
Serious Adverse Events
9.2.1.
An SAE is any AE from this study that results in 1 of the following:

death

initial or prolonged inpatient hospitalisation

a life-threatening experience (i.e., 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 hospitalisation but may jeopardise the patient or may require intervention to prevent 1 
of the other outcomes listed in the definition above.
The CRU personnel must alert the Lilly CRP/CP, or its designee, of any SAE as soon as 
practically possible.
Additionally, CRU personnel must alert Lilly Global Patient Safety, or its designee, of any SAE 
within 24 hours of investigator awareness of the event via a sponsor-approved method.  If alerts 
are issued via telephone, they are to be immediately followed with official notification on 
study-specific SAE forms.  This 24-hour notification requirement refers to the initial SAE 
information and all follow-up SAE information.
Although all AEs are recorded in the electronic data entry after signing informed consent, SAE 
reporting to the sponsor begins after the subject has signed informed consent and has received 
study drug.  However, if an SAE occurs after signing ICF, 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 fulfil regulatory requirements any pregnancy should be reported following the 
SAE process to collect data on the outcome for both mother and foetus.
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 study drug 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.
Complaint Handling
9.2.2.
Lilly collects product complaints on IPs and drug delivery systems used in clinical studies in 
order to ensure the safety of study participants, monitor quality, and to facilitate process and 
product improvements.
Subjects should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the IP so that the situation can be assessed.
9.3.
Treatment of Overdose
For the purposes of this study, an overdose of the study drugs is considered any dose higher than 
the dose assigned through randomisation.
Excess insulin administration may cause hypoglycaemia and hypokalaemia. Mild episodes of 
hypoglycaemia usually can be treated with oral glucose. More severe episodes with coma, 
seizure, or neurologic impairment may be treated with intramuscular/SC glucagon or 
concentrated IV glucose.  Sustained carbohydrate intake and observation may be necessary 
because hypoglycaemia may recur after apparent clinical recovery. Hypokalaemia must be 
corrected appropriately.
Refer to the IB for further information.
9.4.
Safety
Laboratory Tests
9.4.1.
For each subject, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2). 
Vital Signs
9.4.2.
For each subject, vital sign measurements should be conducted according to the Schedule of 
Activities (Section 2) and as clinically indicated.
Blood pressure and pulse rate should be measured after at least 5 minutes supine.
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms.  Additional vital signs may be measured during each study period if 
warranted.


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Electrocardiograms
9.4.3.
For each subject, ECGs should be collected according to the Schedule of Activities (Section 2).
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
subject receives the first dose of the study drug, should be reported to Lilly, or its designee, as an 
AE via electronic data entry methods. 
For each subject, a single 12-lead digital ECG will be collected according to the Schedule of 
Activities (Section 2).  Subjects must be supine for approximately 5 to 10 minutes before ECG 
collection and remain supine but awake during ECG collection.  Electrocardiograms may be 
obtained at additional times, when deemed clinically necessary.  All ECGs recorded should be 
stored at the CRU.
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the CRU as soon after the time of ECG collection as possible, and ideally while the 
subject is still present, to determine whether the subject meets entry criteria at the relevant 
visit(s) and for immediate subject management, should any clinically relevant findings be 
identified.
If a clinically significant finding is identified (including, but not limited to, changes in 
QT/corrected QT interval from baseline) after enrolment, the investigator will determine if the 
subject can continue in the study.  The investigator, or qualified designee, is responsible for 
determining if any change in subject management is needed, and must document his/her review 
of the ECG printed at the time of collection.  Any new clinically relevant finding should be 
reported as an AE.
Other Tests
9.4.4.
9.4.4.1.
Physical Examinations
Physical examinations and routine medical assessments will be conducted as specified in the 
Schedule of Activities (Section 2) and as clinically indicated.
9.4.4.2.
Body Weight
Body weight will be recorded as specified in the Schedule of Activities (Section 2) and as 
clinically indicated.
9.4.4.3.
Hip and Waist Circumference 
Hip and waist circumference will be recorded as specified in the Schedule of Activities 
(Section 2). The average of triplicate measurements of waist (narrowest circumference between 
lowest aspect of the ribs and anterior superior iliac crests) and the hip (widest circumference 
between the anterior superior iliac crests and the greater trochanters) circumference will be 
measured.
Safety Monitoring
9.4.5.
The Lilly CP or CRP/scientist will monitor safety data throughout the course of the study.


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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.
9.4.5.1.
Glucose Monitoring
Hypoglycaemia will be described using the following definitions:

Documented hypoglycaemia:
o
Symptomatic hypoglycaemia: an event during which typical symptoms of 
hypoglycaemia are accompanied by plasma glucose ≤70 mg/dL (3.9 mmol/L)
o
Asymptomatic hypoglycaemia: an event not accompanied by typical 
symptoms of hypoglycaemia but with plasma glucose ≤70 mg/dL (3.9 mmol/L)

Unspecified hypoglycaemia:  an event during which plasma glucose ≤70 mg/dL 
(3.9 mmol/L) but with no available information related to symptoms of 
hypoglycaemia

Probable symptomatic hypoglycaemia: an event during which symptoms 
indicative of hypoglycaemia are observed but not accompanied by a plasma glucose 
determination (but that was presumably caused by plasma glucose ≤70 mg/dL 
[3.9 mmol/L])

Clinically significant hypoglycaemia: 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 hypoglycaemia:  an event during which patients had altered mental status,
and could not assist in their own care, or were semiconscious or unconscious, or 
experienced coma with or without seizures, and the assistance of another person was 
to actively administer carbohydrate, glucagon, or other resuscitative actions. Plasma
glucose measurements may not be available during such an event, but neurological 
recovery attributable to the restoration of plasma glucose to normal is considered
sufficient evidence that the event was induced by a low plasma glucose concentration
(≤70 mg/dL [3.9 mmol/L]). 

Nocturnal hypoglycaemia: any hypoglycaemic event (documented symptomatic, 
asymptomatic, probable symptomatic, or severe hypoglycaemia) that occurs between 
bedtime and waking

Relative hypoglycaemia: an event during which typical symptoms of 
hypoglycaemia, which do not require the assistance of another person, are 
accompanied by plasma glucose >70 mg/dL (3.9 mmol/L), but these levels may be 
quickly approaching the 70-mg/dL (3.9 mmol/L) threshold

Overall (or total) hypoglycaemia:  This optional category combines most cases of 
hypoglycaemia except relative hypoglycaemia.  Nocturnal and severe hypoglycaemia
are special cases of documented or probable hypoglycaemia. If an event of
hypoglycaemia falls into multiple subcategories, that event should only be counted 
once in this category of overall (or total) hypoglycemia.  


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The goal of the euglycaemic clamp is to maintain glucose concentrations at normoglycaemic 
levels close to a predefined target.  Therefore, the equivalence of plasma glucose concentrations 
below 70 mg/dL will not routinely be recorded as hypoglycaemic events during the glucose 
clamp procedure.  However, at the discretion of the investigator, decrease in glucose 
concentrations may be recorded as a hypoglycaemic event based on clinical concern or related to 
technical issues resulting in hypoglycaemia.
9.4.5.1.1. Severe Hypoglycaemia
The determination of a hypoglycaemic event as an episode of severe hypoglycaemia as defined 
above will be made by the investigator based on the medical need of the subject to have required 
assistance and is not predicated on the report of a subject simply having received assistance.
Only severe hypoglycaemia episodes will be reported as AEs.  All episodes of severe 
hypoglycaemia will be reported as SAEs.
9.4.5.2.
Hepatic Safety
If a study subject experiences elevated alanine aminotransferase (ALT) ≥3X upper limit of 
normal (ULN), alkaline phosphatase (ALP) ≥2X ULN, or elevated total bilirubin (TBL) ≥2X 
ULN, liver tests (Appendix 4) should be repeated within 3 to 5 days including ALT, aspartate 
aminotransferase (AST), ALP, TBL, direct bilirubin, gamma-glutamyl transferase (GGT), 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 normalise and/or are returning to approximate baseline levels. 
Additional safety data should be collected if 1 or more of the following conditions occur: 

elevation of serum ALT to ≥5X ULN on 2 or more consecutive blood tests

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.
Injection-Site Assessments (Local Tolerability)
9.4.6.
Injection-site assessments for local tolerability will be conducted as specified in the Schedule of 
Activities (Section 2) and more frequently if deemed necessary by the investigator.
If deemed necessary by the investigator, digital pictures may be taken of the injection site at the 
time of identification of local intolerability and thereafter as often as judged necessary by the 
investigator.  The pictures should include subject number, visit number, time after dosing, and a 
ruler for scaling and will be filed on site.  
Local tolerability at the injection site will be evaluated and transcribed into the eCRF by means 
of assessments within the following categories:  pain on palpation, itching, erythema, oedema, 


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LY900014
and induration/infiltration.  If 1or more symptom(s) of an injection-/infusion-site reaction is 
reportedduring the assessment, a single AE for injection-site reaction will be recorded on the AE 
page of the eCRF.  
9.5. Pharmacokinetics
At the visits and times specified in the Scheduleof Activities(Section 2), venous blood samples 
will be collected to determine the 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) of each sampling will be recorded.
Bioanalysis
9.5.1.
Samples will be analysedat a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.
Concentrations of insulin lisproin serum following LY900014 and Humalog administration will 
be assayed using a validated enzyme-linked immunosorbent assay.
Bioanalytical samples collected to measureinsulin lispro concentrationswill be retained for a 
maximum of 1 year following last subject visit for the study.  During this time, samples 
remaining may be used for other exploratory analyses on insulin lispro.
9.6. Glucodynamics(EuglycaemicGlucose Clamp)
CCI
The aim of the euglycaemicglucose 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 glucose infusion rate (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.
At least30 minutes before the planned administration of study drug, subjects will be connected 
to the clamp device 
 for continuous blood glucose monitoring to determine their 
baselineblood glucose.  Baseline is defined as the mean of blood glucose concentrations at
approximately–6, –4, and –2minutes (before study drugadministration)as measured using 
. After study drug administration,onset of action occurs whenblood glucose drops 
5mg/dL(0.3 mmol/L) from baseline(as measured by  
).Thisblood glucose level 
5mg/dL below baseline will be used as the euglycaemic glucose clamp target level throughout 
the remainder of the clamp procedure.  Subjects will not be clamped to a blood glucose target 
lower than 63 mg/dL.  Therefore, subjects with a mean predosebaselinefasting blood glucose 
below68 mg/dL (equivalent to a fasting plasma glucose of 76 mg/dL [4.21mmol/L]) will not be 
dosed to undergo the clamp procedure but may be rescheduled to a later period.  In addition, any 
study procedures conducted up to that time may be repeated in that later period. 
After the onset of action has been reached, a variable IVglucose infusion will be initiated in 
order to keep blood glucoseconstant at the target level.  The GIR necessary to keep the blood 
glucoseconcentration at the target level will be recordedevery minute throughout the glucose 
CCI
CCI


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clamp. Frequently or at least every 30 minutes throughoutthe glucose clamp, blood glucose
measurements for verification of  
 measurements will be performed using  
 
.  
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.  At the end of the clamp procedure, the subjectwill be given a meal.  
All subjects will be medically assessed before discharge from the CRU (see Schedule of 
Activities [Section2]).
Immunogenicity Assessments 
9.6.1.
Blood samples for immunogenicity testing will be collected to determine antibody production 
against insulin lispro as described in the Schedule of Activities (Section 2).  Additional samples 
may be collected if there is a possibility that an AE is immunologically mediated.
Immunogenicity will be assessed bya 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 ethics committees (ECs) allow,at a facility selected by the 
sponsor.  The duration allows the sponsor to respond to future regulatory requests related to the 
study drug.  Any samples remaining after 15 y
ears will be destroyed.
9.7. Genetics
Ablood sample will be collected for pharmacogenetic analysis as specified in the Schedule of 
Activities(Section2)
CCI
, where local regulations allow.
Samples willnotbeused toconduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable exposure or response to the 
study drugand to investigate genetic variants thought to play a role in diabetes mellitus.  
Assessment of variable response may include evaluation of AEs.
All samples will be coded with the subject number.  These samples and any data generated can 
be linked back to the subject only by the CRUpersonnel.
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period iflocal regulationsand/or ECsimpose shorter time limits, for the study at a facility 
selected byLilly.  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 LY900014or after LY900014is 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 utilised, data generated will be used only for the specific research 
scope described in this section. 
CCI


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9.8.
Exploratory Biomarkers
C-Peptide
9.8.1.
Blood samples will be obtained for determination of C-peptide concentrations as specified in the 
Schedule of Activities (Section 2).  These samples and any remaining serum after C-peptide 
analyses will be discarded.  Instructions for the collection and handling of these samples will be 
provided by the sponsor.
9.9.
Health Economics
This section is not applicable for this study.


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10.Statistical Considerations and Data Analysis
10.1.Sample SizeDeterminationfor Faster PK Absorption
Up to 42subjects may be enrolled to ensure that at least34subjects completethe study. 
Thirty-fourcompleting subjects will provide approximately 96% power to demonstrate a 
40%increase in the insulin lispro AUCfrom timezeroto 30 minutes (AUC[0-30min]) between 
LY900014 and Humalog.  Testing will be done at an alphalevel of 0.05with a 2-sided 
confidence interval (CI).  The variability was estimated using priorinternal studiesthat showed 
an averagelog-scale standard deviation of within-subject difference in AUC(0-30min)of  .  
Analysis of internal data showed a log-scale standard deviation of within-subject difference in 
time to early half-maximal plasmaconcentration (early 50% t
max) of .  This sample size 
provides approximately 98% power to show a 30% reduction in early 50% tmax, testing with an 
alphalevel of 0.05and a 2-sided CI.
In addition, the study is adequately powered to evaluate the GD parameters.  There is 
approximately 80% power to detect a 20% decrease in both time to onset of insulin action 
(Tonset) and time to half-maximal GIR before tRmax(early 50% tR
max) and at least85%power 
to detect at least a 40% increase in total amount of glucose infused (Gtot)over 30minutes 
(Gtot[0-30min]) and Gtotover 1 hour (Gtot[0-1h]).
10.2.Sample Size Determinationfor Dose Proportionality
Thirty-fourcompleting subjects will provide greater than 95%power to demonstrate dose
proportionality of AUCfrom time zeroto 10 hours (AUC[0-10h])andAUCfrom time zero to 
infinity (AUC[0-∞]).  This is basedon the assumption of a log-normal distribution and an 
estimate of intrasubject log-scale standard deviation of  .There is also approximately 90% 
power to demonstrate doseproportionality of C
max, assuming an intrasubject log-scale standard 
deviation of  .
StudyParticipant Disposition
10.2.1.
A detailed description of subjectdisposition will be provided at the end of the study. 
Study Participant Characteristics
10.2.2.
Standard baseline characteristics of age, sex, ethnicity, race, height, weight, and BMI will be
summarised for all randomised patients. 
10.3.Statistical Analyses
CCI
Statistical analysis of this study will be the responsibility of Eli Lilly and Company
 or its 
designee.
The primary statistical analyses for PK will be conducted on those subjects who receive at least 
1dose of study drug and have measurable insulin lispro concentrations.  The primary
 statistical 
analysis for GD will be conducted on those subjects who complete at least 1 clamp procedure.  
CCI
CCI
CCI


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Supportive analyses will be done on the key parameters for the subjects who complete all 
treatment periods with evaluable data.
Safety Analyses
10.3.1.
Safety analyses will be conducted for all enrolled subjects, whether or not they completed all 
protocol requirements.
Any change to the data analysis methods described in the protocol will require an amendment 
only if it changes a principal feature of the protocol.  Any other change to the data analysis 
methods described in the protocol and the justification for making the change will be described 
in the study results.
Additional exploratory analyses of the data will be conducted as deemed appropriate.  Study 
results may be pooled with the results of other studies for population PK analysis purposes to 
avoid issues with post hoc analyses and incomplete disclosures of analyses.  
10.3.1.1. Clinical Evaluation of Safety
All IP and protocol procedure AEs will be listed, and if the frequency of events allows, safety 
data will be summarised using descriptive methodology.
The incidence of symptoms for each treatment will be presented by severity and by association 
with IP as perceived by the investigator.  Symptoms reported to occur prior to enrolment 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, as 
well as evaluation of injection-site reactions.  The parameters will be listed and may be 
summarised using standard descriptive statistics.  Additional analysis will be performed if 
warranted upon review of the data.
Pharmacokinetic Analyses
10.3.2.
10.3.2.1. Pharmacokinetic Parameter Estimation
Insulin lispro PK parameter estimates for LY900014 will be calculated using standard 
noncompartmental methods of analysis.  Free serum insulin lispro concentrations will be used to 
calculate several PK parameters, including maximum observed drug concentration (Cmax), time 
to maximum observed drug concentration (tmax), half-life (t1/2), time to early half-maximal 
plasma concentration (early 50% tmax), time to late half-maximal drug concentration (late 50% 
tmax), AUC from time zero to 30 minutes [AUC(0-30min)], AUC from time zero to 1 
hour[AUC(0-1h)], AUC from time zero to 10 hours [AUC(0-10h)], AUC from time 3 to 10 
hours AUC(3-10h) and AUC from time zero to infinity [AUC(0-∞)] will be determined.  In 
addition, the apparent total body clearance of drug calculated after extra-vascular administration 


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(CL/F), and volume of distribution after extra-vascular administration (Vz/F) also will be 
determined.  Other parameters may be calculated as deemed appropriate.  Additional partial 
AUCs may be computed as necessary, such as AUC from time zero to 2 hours.
The insulin lispro PK parameters for assessing faster insulin lispro absorption are the early 50% 
tmax and AUC(0-30min).
The insulin lispro PK parameters for assessing reduction in the late insulin lispro exposure are 
the late 50% tmax and AUC(3-10h).
The insulin lispro PK parameters for assessing dose proportionality are the Cmax, AUC(0-10h)
and AUC(0-∞).  
Although attempts will be made to adhere to the scheduled collection times (Section 2), it is 
recognised that situations arise that may compromise the scheduled times.  Parameters will be 
individually calculated for each subject based on actual collection times and presented using 
summary statistics.
10.3.2.2. Pharmacokinetic Statistical Inference
Log-transformed AUCs and Cmax for insulin lispro will be evaluated to estimate least-squares 
geometric means, ratios of least-squares geometric means between LY900014 and Humalog for 
each dose level, and their corresponding 95% CIs using the mixed-effects model that includes 
treatment, dose level, dose level-by-treatment interaction, and period as fixed effects and subject 
as a random effect.  
The same model without log transformation will be used for the analysis of the PK time 
parameters (early 50% tmax, late 50% tmax, tmax, and t1/2).  Least-squares means (LSmeans), 
treatment differences in LSmeans, and the corresponding 95% CIs for the treatment differences 
for each dose will be estimated from the model.  The treatment ratios and 95% CIs for the ratios 
will be calculated using Fieller’s theorem.  As a sensitivity analysis, the PK time parameters will 
be analysed nonparametrically.  The median differences between treatments and the 95% CIs for 
the differences will be presented.
The analyses described above will also be performed on the population of subjects who 
completed and had evaluable PK data for all study periods.
In addition, the degree of dose proportionality for insulin lispro will be assessed by fitting the 
power model (Smith et al. 2000) to both AUC (AUC[0-10h] and AUC[0-∞]) and Cmax versus 
dose for each dose level of LY900014. The estimated ratio of dose-normalised geometric means 
of PK parameters between the highest and lowest doses will be used to assess dose 
proportionality. In addition, the slope and its 95% CI and the geometric least-square means for 
each dose level tested will be produced. In the event that the power model is not a good 
representation of the data over the entire dose range tested, alternative models may be 
investigated. Log-transformed Cmax and AUC LSmeans, and 95% CI estimates for each dose 
will be back-transformed to provide the geometric means and the corresponding 95% CIs.


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The analyses will also be performed using the subset of the subjectswho complete all treatment 
periods with evaluable data.
Glucodynamic Analyses
10.3.3.
10.3.3.1.Glucodynamic Parameter Estimation
Glucodynamic assessments will be determined from the glucose clamp procedure, where the 
GIR over time will be used as a measure of insulin effect.  Glucodynamicanalyses 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 patient will be used to calculate the following GD parameters:  Tonset, 
maximum GIR (Rmax), time to R
max(tRmax), time to half-maximal GIR before tRmax(early 
50% tRmax),time to half-maximal GIR after tRmax(late 50% tRmax), total amount of glucose 
infused (Gtot),Gtotover 30 minutes (Gtot[0-30min]), Gtotover 1 hour (Gtot[0-1h]), and Gtotover 10 
hours (Gtot[0-10h]).  Additional partial glucose AUCs, such as Gtotover 2hours (Gtot[0-2h]), G
tot
from 3hours to 10 hours Gtot[3-10h) may be computed as necessary.  The values of these GD 
parameters will be summarised by treatment and/or period through descriptive statistics.  Mean 
LOESSfits of GIR versus time profiles will be generated.  The primaryGD parameters for 
earlier PD onsetare early 50% tRmax, G
tot(0-30min), G
tot(0-1h), and Tonset.
10.3.3.2.Glucodynamic Statistical Inference
The GD statistical model will be the same as the model used for the analysis of the PK 
parameters.  The following variables will be logtransformed prior to analysis:  Rmax, G
tot, 
Gtot(0-30min), Gtot(0-1h), and Gtot(0-10h)along withany additional partial Gtot.  For GD parameters 
that have at least 1 subject with a value equal to zero, a value equal to the smallest non-zero 
observed GD value for that parameter divided by 2 will be added to all values, and the analysis 
of the log-transformed data will be performed.In addition, as a sensitivity analysis, a 
nonparametric methodwill be performed for that parameter.  
The same model without logtransformation will be used for the analysis of the GD time 
parameters (Tonset, tR
max, early 50% tR
max, late 50% tR
max).  Least-squares means, treatment 
differences in LSmeans, and the corresponding 95% CIs for the treatment differences for each 
dose will be estimated from the model.  The treatment ratios and 95% CIs for the ratios will be 
calculated using Fieller’s theorem.
The analyses described above will also be performed on the population of patients who 
completed and had evaluable GD data for both study periods.
The degree of dose proportionality for the insulin lispro in LY900014 will be assessed by fitting 
the power model to G
totand Rmax
CCI
versus dose for each dose level of LY900014.
The analyses will also be performed using the subset of the subjectswho complete all treatment 
periods with evaluable data.


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Pharmacokinetic/Glucodynamic Analyses
10.3.4.
Not applicable.
Evaluation of Immunogenicity
10.3.5.
The frequency of antibody formation to insulin lispro will be determined.  The relationship 
between the presence (or absence) of antibodies and AEs may be assessed.  Likewise, the 
relationship between the presence of antibodies and the PK parameters and GD response to 
insulin lispro may be assessed.
C-Peptide
10.3.6.
Mean and individual C-peptide concentration versus time plots with both treatments will be 
presented by dose level.  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 euglycaemic clamp.
Data Review during the Study
10.3.7.
This section is not applicable for this study.
Interim Analyses
10.3.8.
No formal interim analyses are planned for this study.  Data may be accessed by the unblinded 
Lilly study team and reviewed while the study is ongoing, but no changes to the study design are 
planned.  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
Humalog [package insert]. Indianapolis, IN 46285: Lilly USA, LLC; 2015.
LY900014 Investigator’s Brochure. Version approved 03 Mar 2017.
Smith BP, Vandenhende FR, DeSante KA, Farid NA, Welch PA, Callaghan JT, Forgue ST. 
Confidence interval criteria for assessment of dose proportionality. Pharm Res
CCI
. 
2000;17(10):1278-1283.


I8B-MC-ITSH Clinical Pharmacology Protocol
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LY900014
Appendix 1. Abbreviations and Definitions


I8B-MC-ITSH Clinical Pharmacology Protocol
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LY900014
Term
Definition
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavourable 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(0-30min)
AUC from time zero to 30 minutes
AUC(0-10h)
AUC from time zero to 10 hours
AUC(2-10h)
AUC from time 2 to 10 hours
AUC(3-10h)
AUC from time 3 to 10 hours
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
EC
ethics committee
ECG
Electrocardiogram


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LY900014
eCRF
electronic case report form
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
good clinical practice
GD
glucodynamic(s)
GGT
gamma-glutamyl transferase
GIR
glucose infusion rate
Gtot
total amount of glucose infused
Gtot(0-30min)
Gtot over 30 minutes
Gtot(0-1h)
Gtot over 1 hour
Gtot(0-10h)
Gtot over 10 hours
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
informed consent
A process by which a subject voluntarily confirms his or her willingness to participate in a 
particular study, after having been informed of all aspects of the study that are relevant to 
the subject’s decision to participate.  Informed consent is documented by means of a 
written, signed, and dated informed consent form.  
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigational 
product (IP)
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical study, including products already on the market when used or assembled 
(formulated or packaged) in a way different from the authorised form, or marketed products 
used for an unauthorised indication, or marketed products used to gain further information 
about the authorised form.
investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible leader 
of the team and may be called the principal investigator.
IV
Intravenous
late 50% tmax
time to late half-maximal drug concentration
late 50% tRmax
time to half-maximal GIR after tRmax


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LY900014
LOESS
locally weighted scatterplot smoothing
LSmeans
least-squares means
MDI
multiple daily injection
PAH
pulmonary arterial hypertension
PK
pharmacokinetic(s)
randomise
The process of assigning subjects/patients to an experimental group on a random basis.
Rmax
maximum glucose infusion rate
SAE
serious adverse event
SC
subcutaneous(ly)
screen
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study.
SUSAR
suspected unexpected serious adverse reaction
t1/2
half-life associated with the terminal rate constant in noncompartmental analysis
T1DM
type 1 diabetes mellitus
T2DM
type 2 diabetes mellitus
TBL
total bilirubin
TEAE
treatment-emergent adverse event:  Any untoward medical occurrence that emerges during 
a defined treatment period, having been absent pretreatment, or worsens relative to the 
pretreatment state, and does not necessarily have to have a causal relationship with this 
treatment 
tmax
time to maximum observed drug concentration
Tonset
time to onset of insulin action
tRmax
time to Rmax
ULN
upper limit of normal


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LY900014
Appendix 2. Clinical Laboratory Tests
Safety Laboratory Tests
Haematologya
Clinical Chemistrya
Haematocrit
Sodium
Haemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume 
Chloride
Mean cell haemoglobin
Calcium
Mean cell haemoglobin concentration 
Phosphate
Leucocytes (WBC) 
Glucose
Absolute counts of
Blood urea nitrogen (BUN)
Neutrophils
Total protein
Lymphocytes
Albumin
Monocytes
Total bilirubin
Eosinophils
Alkaline phosphatase (ALP)
Basophils
Aspartate aminotransferase (AST)
Platelets
Alanine aminotransferase (ALT)
Coagulationb
Gamma-glutamyl transferase (GGT)
International normalised ratio (INR)
Activated partial thromboplastin time (aPTT)
Creatinine
Uric acid
Urinalysisa
Serologyb
Specific gravity
Hepatitis B surface antigen
pH
Hepatitis C antibody
Protein
HIV
Glucose
FSHc
Ketones
Pregnancy testd
Bilirubin
Ethanol/Alcohol breath teste
Urobilinogen
Urine drug screene
Blood
Nitrite
Leucocytes
Microscopyf
Abbreviations:  CRU = clinical research unit; FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; 
RBC = red blood cell; WBC = white blood cell.
a
Performed at screening, Period 1 Day 1, and follow-up.
b
Only at screening.  Hepatitis B, hepatitis C, and HIV tests may be waived if results of the same test have been obtained from 
the subject within the past 6 months before screening.
c
Only at screening in menopausal women if necessary.
d
All females of childbearing potential: Serum pregnancy test at screening, urine pregnancy test at all other visits.
e
Performed locally at the site at screening and repeated prior to each CRU admission. Urine drug screen:  amphetamine, 
cannabis, cocaine, barbiturates, methadone, benzodiazepines, tricyclic antidepressants, methamphetamine, opiates, and 
phencyclidine.
f
If clinically indicated, per investigator’s discretion.
Note:  Results of these assays will be validated by the local laboratory at the time of testing.  Additional tests may be performed 
or auto-calculated by the laboratory as part of its standard panel that cannot be removed.  Some of the above parameters are 
calculated from measured values.  Omission of calculated values will not be considered as a protocol violation.


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


I8B-MC-ITSH Clinical Pharmacology Protocol
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LY900014
3) applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third-party organisation.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, the principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Final Report Signature
The investigator or designee will sign the clinical study report for this study, indicating 
agreement with the analyses, results, and conclusions of the report.
The sponsor’s responsible medical officer and statistician will sign/approve the final clinical 
study report for this study, confirming that, to the best of his or her knowledge, the report 
accurately describes the conduct and results of the study.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the CRU, as appropriate.

provide training to instruct the investigators and study coordinators.  This training will 
give instruction on the protocol, the completion of the eCRFs, and study procedures.

make periodic visits to the CRU.

be available for consultation and stay in contact with the CRU personnel by mail, 
telephone, and/or fax.

review and evaluate eCRF data and/or use standard computer edits to detect errors in data 
collection.

conduct a quality review of the database.
In addition, Lilly or its representatives will periodically check a sample of the subject data 
recorded against source documents at the CRU.  The study may be audited by Lilly and/or 
regulatory agencies at any time.  Investigators will be given notice before an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ECs with direct access to the original source 
documents.


I8B-MC-ITSH Clinical Pharmacology Protocol
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LY900014
Data Collection Tools/Source Data
An electronic data capture system will be used in this study.  The CRU must define and retain all 
source records and must maintain a record of any data where source data are directly entered into 
the data capture system.
Data Protection
Data systems used for the study will have controls and requirements in accordance with local 
data protection law.
The purpose and use of subject personal information collected will be provided in a written 
document to the subject by the sponsor.
Study and Site Closure
Discontinuation of Study Sites
Clinical research unit participation may be discontinued if Lilly, the investigator, or the EC of 
the CRU judges it necessary for medical, safety, regulatory, or other reasons consistent with 
applicable laws, regulations, and GCP.
Discontinuation of the Study
The study will be discontinued if Lilly judges it necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP.


I8B-MC-ITSH Clinical Pharmacology Protocol
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LY900014
Appendix 4. Hepatic Monitoring Tests for Treatment-
Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with Lilly or its designee CRP.
Hepatic Monitoring Tests
Hepatic Haematologya
Haptoglobina
Haemoglobin
Haematocrit
Hepatic Coagulationa
RBC
Prothrombin time
WBC
Prothrombin time, INR
Neutrophils
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Conjugated bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear Antibody
AST
Alkaline Phosphatase Isoenzymesa
GGT
CPK 
Anti-smooth Muscle Antibody (or Anti-actin 
Antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalised
ratio; RBC = red blood cell; WBC = white blood cell.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


I8B-MC-ITSH Clinical Pharmacology Protocol
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LY900014
Appendix 5. Blood Sampling Summary
This table summarises the approximate number of venipunctures and blood volumes for all blood 
sampling (screening, safety laboratories, and bioanalytical assays) during the study.
Protocol I8B-MC-ITSH Sampling Summary
Purpose
Blood Volume per 
Sample (mL)
Number of Blood Samples
Total Volume 
(mL)
Screening testsa
10
1
10
Clinical laboratory testsa
7
2
14
Pharmacokinetic samples serum 
insulin lispro
1
24 samples × 6 periods = 
144
144
Clamp device sampling for
glucoseb
NA
NA
138
Blood glucose during clamp 
period (Super GL)c
0.3
276
82.8
C-peptide
2
7 samples × 6 periods = 42
84
Immunogenicity
5
4
20
Pharmacogenetics
10
1
10
Total for clinical purposes 
502.8
Total for clinical purposes rounded up to the nearest 10 mL
510
a
Additional samples may be drawn if needed for safety purposes.
b
Clamp device sampling: 30- to 60-minute calibration, 30-minute baseline plus 10-hour clamp = 11.5 hours ×
6 periods = 69 hours × 2 mL/hour = 138 mL.
c
Blood glucose during clamp period (Super GL): 30- to 60-minute calibration, 30-minute baseline plus 10-hour 
clamp = 11.5 hours × 6 periods = 69 hours × up to 4 samples/hour = 276 blood samples × 0.3 mL/blood sample = 
82.8 mL.

SAP_001.pdf: 
Statistical Analysis Plan I8B-MC-ITSH 
 
A Study to Evaluate the Pharmacokinetics and Glucodynamics of LY900014 and Humalog 
across Different Subcutaneous Doses in Healthy Subjects 
 
 
NCT03286751  
 
Approval Date: 18-APR-2018 
 
 
 


Final V2, 12APR2018
             Page 1of 18
STATISTICAL ANALYSIS PLAN
A Study to Evaluate the Pharmacokinetics andGlucodynamics of LY900014 and Humalog 
across DifferentSubcutaneous Doses in Healthy Subjects
Statistical Analysis Plan Status:  FinalVersion 2
Statistical Analysis Plan Date:  12th
Approval Date: 18-Apr-2018 GMT
April 2018
Study Drug:LY900014
Sponsor Reference:  I8B-MC-ITSH
Covance CRU Study: 
Clinical Phase I
CCI


Final V2, 12APR2018
             Page 2of 18
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.
Sponsor Reference I8B-MC-ITSH
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 Exploratory Objectives............................................................................................6
5. STUDY DESIGN...........................................................................................................7
6. TREATMENTS.............................................................................................................8
7. SAMPLE SIZE JUSTIFICATION.................................................................................8
7.1 Sample Size Determination for Faster PK Absorption..............................................8
7.2 Sample Size Determination for Dose Proportionality...............................................9
8. DEFINITION OF ANALYSIS POPULATIONS............................................................9
9.
CCI
STATISTICAL METHODOLOGY.............................................................................10
9.1 General..................................................................................................................10
9.2 Demographics and Subject Disposition..................................................................10
9.3 Pharmacokinetic Assessment.................................................................................10
9.3.1
Pharmacokinetic Parameter Estimation.........................................................10
9.3.2
Pharmacokinetic Statistical Inference...........................................................11
9.4 Glucodynamic Assessment....................................................................................12
9.4.1
Glucodynamic Parameter Estimation............................................................12
9.4.2
Glucodynamic Statistical Inference...............................................................12
9.5 Safety and Tolerability Assessments......................................................................13
9.5.1
Adverse events.............................................................................................13
9.5.2
Concomitant medication...............................................................................13
9.5.3
Clinical laboratory parameters......................................................................13
9.5.4
Vital signs....................................................................................................13
9.5.5
Electrocardiogram (ECG).............................................................................13
9.5.6
Hepatic Monitoring......................................................................................13
9.5.7
Blood Glucose Monitoring and Hypoglycemia.............................................14
9.5.8
Injection Site LocalTolerability Assessment Data........................................15
9.5.9
Immunogenicity...........................................................................................15
9.5.10 C-peptide......................................................................................................15
9.5.11 Other assessments.........................................................................................16
9.5.12 Safety and Tolerability Statistical Methodology............................................16


Final V2, 12APR2018
             Page 3of 18
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 
Sponsor Reference I8B-MC-ITSH
10.INTERIM ANALYSES...............................................................................................16
11.CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES......16
12.REFERENCES............................................................................................................16
13.DATA PRESENTATION............................................................................................16
13.1Derived Parameters...............................................................................................16
13.2Missing Data.........................................................................................................17
13.3Insufficient Data for Presentation..........................................................................17
14.
CCI
BLINDING AND UNBLINDING PLAN.....................................................................17


Final V2, 12APR2018
             Page 4of 18
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 
Sponsor Reference I8B-MC-ITSH
2.ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP)only (not thetables, figures and 
listings[TFLs]).
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Aminotransferase
AUC
Area under the concentration versus time curve
AUC(0-15min)
Area under the concentration versus time curve from time zero to 
15 minutes
AUC(0-30min)
Area under the concentration versus time curve from time zero to 
30 minutes
AUC(0-1h)
Area under the concentration versus time curve from time zero to 1 
hour
AUC(0-10h)
Area under the concentration versus time curve from time zero to 
10 hours
AUC(3-10h)
Area under the concentration versus time curve from time 3 hours 
to time 10 hours
AUC(0-∞)
Area under the concentration versus time curve from time zero to 
infinity
Cmax
Maximum observed drug concentration
CI
Confidence interval
CRF
Case Report Form
CSR
Clinical Study Report
CRU
Clinical Research Unit
CV
Coefficient of variation
early 50% t
max
Time to early half-maximal drug concentration
early 50% tR
max
Time to half-maximal GIR before tRmax
EC
Early Clinical 
ECG
Electrocardiogram
e.g.
For example (Latin: exempli gratia)
GD
Glucodynamic 
GIR
Glucose infusion rate
Gtot
CCI
Total amount of glucose infused


Final V2, 12APR2018
             Page 5of 18
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 
Sponsor Reference I8B-MC-ITSH
Gtot(0-30min)
Total amount of glucose infused over 30 minutes
Gtot(0-1h)
Total amount of glucose infused over 1 hour
ICH
International Council on Harmonisation
late 50% t
max
Time to late half-maximal drug concentration
late 50% tR
max
Time to half-maximal GIR after time of maximum glucose infusion 
rate
LOESS
Locally weighted scatterplot smoothing
LS
Least square
MedDRA
Medical Dictionary for Regulatory Activities
MRE
Magnetic resonance elastography
PK
Pharmacokinetic
SAP
Statistical Analysis Plan
SC
Subcutaneous 
SD
Standard deviation 
TBL
Total bilirubin
TFLs
Tables, Figures, and Listings
t
max
Time ofmaximum observed drugconcentration
Tonset
Time to onset of insulin action
tR
max
CCI
Time of maximum glucose infusion rate
ULN
Upper limit of normal
WHO
World Health Organization


Final V2, 12APR2018
             Page 6of 18
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 
Sponsor Reference I8B-MC-ITSH
3.INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
26June 2017)and version 1 of the SAP (dated 29 September 2017).
This SAP describes the planned analysis of the safety, tolerability, glucodynamic (GD)and
pharmacokinetic(PK)data from this study. A detailed description of the planned TFLs to be 
presented in the clinical study report (CSR) is provided in the accompanying TFL shell 
document.
The intent of this document is to provide guidance for the statistical and PK analyses of data. In 
general, the analyses are based on information from the protocol, unless theyhave been modified 
by agreement between Eli Lilly and Company and Covance Early Clinical(EC)Biometrics. A 
limited amount of information concerning this study (e.g., objectives, study design) is given to 
help the reader’s interpretation. This SAP must besigned 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
Primary Objective
To evaluate the insulin lispro PKfollowing subcutaneous (SC)doses of LY900014 
compared to Humalog (at doses of 7, 15, and 30 U) in healthy subjects.
4.2
Secondary Objectives
To evaluate the dose proportionality of the 3 dose levels of LY900014 as assessed by 
insulin lispro PKand GDmeasures.
To evaluate the GD during euglycaemic clamp procedure following SC doses of 7, 15, 
and 30 U of LY900014 compared to Humalog in healthy subjects.
To evaluate the tolerability of LY900014 in healthy subjects.
4.3
Exploratory Objectives

CCI
Explore the formation of antibodies to insulin lispro.


Final V2, 12APR2018
             Page 7of 18
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.
Sponsor Reference I8B-MC-ITSH
To assess C-peptide levels following administration of LY900014 and Humalog.
5.STUDY DESIGN
This is a Phase 1, randomised, subject-and investigator-blind, 6-period complete crossover study
in up to 42 healthy subjects to evaluate the PK and GD characteristics across a range of
LY900014 doses.
Approximately 34 subjects are expected to complete the study. Each subject will be randomised
to 1 of 6 treatment sequences comprising single SC doses of 7, 15, and 30 U of LY900014 or
Humalog administered SC in the abdominal wall (Table 1). A minimum of 3 daysbetween study 
dosing of each consecutive study period will be required for an individual subject. Figure 1 
illustrates the study design.
Study governance considerations are described in detail in Appendix 3of the protocol.
Figure 1. Illustration of Study Design
Table 1. Treatment Sequence Example
Treatment 
Sequence
Period 1
Period 2
Period 3
Period 4
Period 5
Period 6
1
LY 7 U
LY 15 U
H 30 U
LY 30 U
H 15 U
H 7 U
2
LY 15 U
LY 30 U
LY 7 U
H 7 U
H 30 U
H 15 U
3
LY 30 U
H 7 U
LY 15 U
H 15 U
LY 7 U
H 30 U
4
H 7 U
H 15 U
LY 30 U
H 30 U
LY 15 U
LY 7 U
5
H 15 U
H 30 U
H 7 U
LY 7 U
LY 30 U
LY 15 U
6
H 30 U
LY 7 U
H 15 U
LY 15 U
H 7 U
LY 30 U
CCI


Final V2, 12APR2018
             Page 8of 18
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 
Sponsor Reference I8B-MC-ITSH
Abbreviations: H = Humalog; LY = LY900014.
Note: this is only an example table for illustrative purpose; subjects will be assigned a treatment sequence according 
to the actual treatment randomisation schedule provided to the unblinded site pharmacist.
Subjects will be admitted to the clinical research unit (CRU) on the evening before each dosing
day and will remain in the CRU for the duration of the clamp period and until discharge by the
investigator. Subjects are expected to fast for at least 8 hours before each dose. Following dose
administration, each subject will undergo an euglycaemic clamp procedure of up to 10 hours.
Upon completion of the clamp procedures, the subjects will be provided a meal and discharged
from the CRU in the evening after medical assessments. Subjects may remain in the CRU if
deemed necessary for safety monitoring, as determined by the investigator.
Subjects will be required to attend the CRU on at least 8 occasions:
screening visit (up to 28 days prior to dosing)
six treatment visits for the dosing and clamp procedure (study Periods 1 to 6) witha 
minimum period of at least 3 days between consecutive clamp visits
follow-up visit (at least 14 days afterthe last dose), or early discontinuation
In the study, safety assessments and an evaluation of local tolerability at injection sites will be
performed as specified in the Schedule of Activities (Section 2of the protocol). Local tolerability 
assessmentswill include injection-site reactions within the following categories: pain on 
palpation, itching,erythema, oedema, and induration/infiltration.
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
7 U LY900014SC
1
15 U LY900014SC
2
30 U LY900014SC
3
7 U HumalogSC
4
15 U HumalogSC
5
30 U HumalogSC
6
7.SAMPLE SIZE JUSTIFICATION
7.1
Sample Size Determination for Faster PK Absorption
CCI
Up to 42 subjects may be enrolled to ensure that at least 34 subjects complete the study.


Final V2, 12APR2018
             Page 9of 18
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 
Sponsor Reference I8B-MC-ITSH
Thirty-four completing subjects will provide approximately 96% power to demonstrate a40% 
increase in the insulin lispro area under the concentration versus time curve (AUC)from time 
zero to 30 minutes (AUC[0-30min]) betweenLY900014 and Humalog. Testing will be done at 
an alpha level of 0.05 with a 2-sidedconfidence interval (CI). The variability was estimated 
using prior internal studies that showedan average log-scale standard deviation(SD) of within-
subject difference in AUC(0-30min) of . Analysis of internal data showed a log-scale SDof 
within-subject difference intime to early half-maximal plasma concentration (early 50% time of 
maximum observed drug concentration [t
max]) of . This sample sizeprovides approximately 
98% power to show a 30% reduction in early 50% tmax, testing with analpha level of 0.05 and a 
2-sided CI.
In addition, the study is adequately powered to evaluate the GD parameters. There is
approximately 80% power to detect a 20% decrease in both time to onset of insulin action(T
onset) 
and time to half-maximal glucose infusion rate (GIR)before time to R
max(tR
max)(early 50% 
tR
max) and at least 85% powerto detect at least a 40% increase in total amount of glucose infused 
(G
tot) over 30 minutes(G
tot[0-30min]) and Gtotover 1 hour (Gtot[0-1h]).
7.2
Sample Size Determination for Dose Proportionality
Thirty-four completing subjects will provide greater than 95% power to demonstrate dose 
proportionality of AUC from timezero to 10 hours (AUC[0-10h]) and AUC from time zero to 
infinity (AUC[0-∞]). This is based on the assumption of a log-normal distribution and an 
estimate of intrasubject log-scale SD of . There is also approximately 90% power to 
demonstrate dose proportionality of maximum observed drug concentration (Cmax), assuming an 
intrasubject log-scale SD of 
.
8. DEFINITION OF ANALYSIS POPULATIONS
CCI
The “Safety” population will consist ofall enrolled subjectswho receive at least 1 dose of study 
drug.
The primary statistical analyses for PK will be conducted on those subjectswho receive at least 1 
dose of study drug and have measurable insulin lispro concentrations. 
The primary statisticalanalysis for GD will be conducted on those subjectswho complete at least 
1 clamp procedure.
Supportive analyses will be done on the key parameters for the subjectswho complete all
treatment periods with evaluable data.
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when subjects are assigned to analysis populations.
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9.STATISTICAL METHODOLOGY
9.1
General
Data listings will be provided for all datathat isdatabased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include thearithmetic mean, arithmetic SD, median, min, max and N; for 
log-normal data (e.g. the PK parameters: AUCs and Cmax) the geometric mean and geometric 
coefficient of variation (CV%) will also be presented. For categorical data, frequency count and 
percentages will be presented. Data listings will be provided for all subjects up to the point of 
withdrawal, with any subjects excluded from the relevant population highlighted. Summary 
statistics and statistical analyses will generally only be performed for subjects included in the 
relevant analysis population. For the calculation of summary statistics and statistical analysis, 
unrounded data will be used. 
Data analysis will be performed using 
.
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, heightandbody mass will besummarized and listed.
9.3
Pharmacokinetic Assessment
9.3.1 Pharmacokinetic Parameter Estimation
Insulin lispro PK parameter estimates for LY900014 will be calculated using standard 
noncompartmental methods of analysis. Free serum insulin lisproconcentrations will be used to 
calculate several PK parameters, including C
max, t
max, time to early half-maximal plasma 
concentration (early 50% t
max), time to late half-maximal drug concentration (late 50% tmax), 
AUC from time zero to 15 minutes [AUC(0-15min)], AUCfrom time zero to 30 minutes 
AUC(0-30min), AUC from time zero to 1 hour[AUC(0-1h)],AUC from time zero to 10 hours
AUC(0-10h), AUC from time 3 to 10 hours AUC(3-10h) and AUC(0-∞) will be determined.
Additional partial AUCs may be computed as necessary, such as AUC from time zero to 2 hours.
The insulin lispro PK parameters for assessing faster insulin lispro absorption are the early 50%
t
maxand AUC(0-30min).
The insulin lispro PK parameters for assessing reduction in the late insulin lispro exposure are
the late 50% t
maxand AUC(3-10h).
The insulin lispro PK parameters for assessing dose proportionality are the C
max
CCI
, AUC(0-10h),
and AUC(0-∞).
Although attempts will be made to adhere to the scheduled collection times (Section 2of the 
protocol), it isrecognised that situations arise that may compromise the scheduled times. 
Parameters will beindividually calculated for each subject based on actual collection times and 
presented usingsummary statistics.


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9.3.2 Pharmacokinetic Statistical Inference
Log-transformed AUCs and C
maxfor insulin lispro will be evaluated to estimate least-squares
(LS) geometric means, ratios of LSgeometric means between LY900014 and Humalog foreach 
dose level, and their corresponding 95% CIs using the mixed-effects model that includes
treatment, dose level, dose level-by-treatment interaction, and period as fixed effects and subject
as a random effect.
Example  
 code:
proc mixed data=pk;
class subject period treatment dose ;
model logpk = treatment period dose dose*treatment / ddfm=kr;
random subject;
lsmeans dose*treatment;
run;
The same model without log transformation will be used for the analysis of the PK time
parameters (early 50% t
max, late 50% t
max,andt
max). LSmeans,treatment differences in LSmeans, 
and the corresponding 95% CIs for the treatment differencesfor each dose will be estimated 
from the model. The treatment ratios and 95% CIs for the ratioswill be calculated using Fieller’s 
theorem. 
The analyses described above will also be performed on the population of subjects who
completed and had evaluable PK data for all study periods.
In addition, the degree of dose proportionality for insulin lispro will be assessed by fitting the
power model (Smith et al.2000
3) to both AUC (AUC[0-10h] and AUC[0-∞]) and Cmaxversus
dose for each dose level of LY900014. The estimated ratio of dose-normalised geometric means
of PK parameters between the highest and lowest doses will be used to assess dose
proportionality. Inaddition, the slope and its 95% CI and the geometric LSmeansforeach dose 
level tested will be produced. In the event that the power model is not a goodrepresentation of 
the data over the entire dose range tested, alternative models may beinvestigated.Log-
transformed C
max and AUC LSmeans, and 95% CI estimates for each dosewill be back-
transformed to provide the geometric means and the corresponding 95% CIs. The analyses will 
also be performed using the subset of the subjects who complete all treatmentperiods with 
evaluable data.
Example  
 code:
proc mixed data=pk1;
class subject;
model log_pk = log_dose / alpha=0.05 cl solution outpred=resids ddfm=kr;
random subject;
estimate 'xx mg' intercept 1 log_dose a / alpha=0.05 cl; /*Log value of xx*/
estimate 'yy mg' intercept 1 log_dose b / alpha=0.05 cl; /*Log value of yy*/
estimate 'zz mg' intercept 1 log_dose c / alpha=0.05 cl; /*Log value of z*/
estimate 'zz mg - xx mg' log_dose d / alpha=0.05 cl; /*Difference in log
values of zz and xx*/
estimate 'zz mg - yy mg' log_dose e / alpha=0.05 cl; 
CCI
/*Difference in log
CCI


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values of zz and yy*/
estimate 'yy mg - xx mg' log_dose f / alpha=0.05 cl; /*Difference in log
values of yy and xx*/
ods output solutionf=est;
ods output estimates=estims;
run;
9.4
GlucodynamicAssessment
9.4.1 Glucodynamic Parameter Estimation
GDassessments will be determined from the glucose clamp procedure, where the GIR over time 
will be used as a measure of insulin effect. GDanalyses 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 subjectwill be used tocalculate the following GD parameters: T
onset, 
maximum GIR (Rmax), time to R
max(tR
max), time to half-maximal GIR before tRmax(early 50% 
tR
max), time to half-maximal GIR after tRmax(late 50% tR
max), total amount of glucose infused 
(G
tot), G
totover 30 minutes (Gtot[0-30min]), and Gtotover 1 hour (Gtot[0-1h]). Additional partial 
glucose AUCs, such as Gtotover 2 hours (Gtot[0-2h]), Gtotfrom 3hours to 10 hours (G
tot[3-10h]), 
from 4 hours to 10 hours (Gtot[4-10h]) may be computed as necessary.The values of these GD 
parameters will be summarised by treatment and/or period through descriptive statistics. Mean 
LOESS fits of GIR versus time profiles will be generated. The primary GD parameters for earlier 
PD onset are early 50% tR
max, G
tot(0-30min), G
tot(0-1h), and Tonset.
9.4.2 Glucodynamic Statistical Inference
The GD statistical model will be the same as the model used for the analysis of the PK 
parameters. The following variables will be log transformed prior to analysis: Rmax, G
tot,
Gtot(0-30min), and Gtot(0-1h) along with any additional partial G
tot. For GDparameters that have 
at least 1 patient with a value equal to zero, an analysis of original scale data (not log-
transformed) will be performed as described below for the GD time parameters.  
The same model without log transformation will be used for the analysis of the GD time
parameters (T
onset, tR
max, early 50% tR
max, late 50% tR
max). LSmeans, treatmentdifferences in 
LSmeans, and the corresponding 95% CIs for the treatment differences for eachdose will be 
estimated from the model. The treatment ratios and 95% CIs for the ratios will becalculated 
using Fieller’s theorem.
The analyses described above will also be performed on the population of subjectswho
completed and had evaluable GD data for both study periods.
The degree of dose proportionality for the insulin lispro in LY900014 will be assessed by fitting
the power model to G
totand R
max
CCI
versus dose for each dose level of LY900014.
The analyses will also be performed using the subset of the subjects who complete all treatment
periods with evaluable data.
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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 consentand is ongoing at consent. A non-treatment emergent AE is 
defined as an AE which startsafter informed consent but prior to dosing. A treatment-emergent 
AE is defined as an AE which occurs postdose or which is present prior to dosing and becomes 
more severe postdose. 
All AEs will be listed. Treatment-emergentAEs will be summarized by treatment, severity and 
relationship to the study drug. The frequency (the number of AEs, the number of subjects 
experiencing an AEand the percentage of subjects experiencing an AE) of treatment-emergent 
AEswill be summarized by treatment, Medical Dictionary for Regulatory Activities (MedDRA)
version20.0 system organ class and preferred term. The summary and frequency AEtables will 
be presented for all causalities and those considered related to the study drug. Any serious AEs
will be tabulated.
9.5.2Concomitant medication
Concomitant medication will be coded using the WHO drug dictionary (VersionMarch 2017). 
Concomitant medication will be listed.
9.5.3Clinical laboratory parameters
Allclinical chemistry, hematologyand urinalysisdatawill be listed. Additionally clinical 
chemistry, hematologyand urinalysis data outside the reference ranges will be listed.
Values for any clinical chemistry, hematology and urinalysis values outside the reference ranges 
willbe flagged on the individual subject data listings.
9.5.4 Vital signs
Vital signs data will belisted for individual subjects.
9.5.5 Electrocardiogram (ECG)
The ECG data will be listedfor individual subjects.
9.5.6 Hepatic Monitoring
CCI
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.
9.5.7 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 Glucose Alert Level (Level 1), Plasma Glucose (PG) ≤70 mg/dL 
(3.9mmol/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 (3.9mmol/L) 
but no information relative to symptoms of hypoglycemia was recorded
Documented Clinically Significant Hypoglycemia (Level 2)PG <54 mg/dL 
(3.0mmol/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 (3.0mmol/L) 
but no information relative to symptoms of hypoglycemia was recorded
Severe hypoglycemia (Level 3)
CCI
: 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 


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require parenteral therapy. PGmeasurements may not be available during such an event, 
but neurological recovery attributable to the restoration of blood glucose concentration to 
normal is considered sufficient evidence that the event was induced by a low PG 
concentration (PG ≤70 mg/dL [3.9 mmol/L])
o Severe hypoglycemia requiring medical attention: a severe hypoglycemic 
event when patients require therapy by HCPs (EMTs, emergency room 
personnel, etc)
Other Hypoglycemia:
Nocturnal hypoglycemia: any hypoglycemic event (documented symptomatic, 
asymptomatic, probable symptomatic,or severe hypoglycaemia) 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 
>70mg/dL (3.9 mmol/L), but these levels may be quickly approaching the 70mg/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 oncein 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 blood glucose concentration ≤70 mg/dL (3.9 mmol/L).
9.5.8 Injection Site Local Tolerability Assessment Data
Injection-site assessment data will be listed and summarized in frequency tables by treatment and 
timepoint.
9.5.9 Immunogenicity
The frequency of antibody formation to insulin lispro will be summarized by treatment and listed 
for individual subjects.
9.5.10 C-peptide
CCI
C-peptide data will be summarized by treatment. Figuresof mean and individual C-peptide 
concentrationsversus time will be presentedby dose level for both treatments. In addition, 
individual plots overlaying the C-peptide concentration versus time with the insulin lispro serum 
concentration versus time will be presented.
Senstivity analysis removing subject(s) who could have potential confounding on the PD 
parameters will be performed as described in Section 9.4.2.Potential C-peptide confounding is 


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defined as when a substantialand implausiblerise in C-peptide over baseline while the glucose 
infusion isongoing.
9.5.11 Other assessments
Body weight, and hip and waist circumference will be listed.
All other safety assessmentsnot detailed in this section will be listed but not summarized or 
statistically analyzed. 
9.5.12 Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.
10.
INTERIM ANALYSES
No interim statistical analyses are planned.
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
There were no changes from the protocol specified statistical analyses.Between the version 1 
SAP and version 2 SAP, it was decided by Lilly to update the methodology for dealing with GD 
parameters with zero values. Additionally, some PK parameters were removed (CL/F, Vz/F and 
t½).
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 StudyReports (E3), 30 November 1995.
3. Smith BP, Vandenhende FR, DeSante KA, Farid NA, Welch PA, Callaghan JT, Forgue ST. 
Confidence interval criteria for assessment of dose proportionality. Pharm Res. 
2000;17(10):1278-1283.
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. Observedtime data, e.g. t
max
CCI
, should be reported as received. N and percentage 
valuesshould be reported as whole numbers. Median values should be treated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values.


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13.2
Missing Data
Missing data will not be displayed in listings.
13.3
Insufficient Data for Presentation
Some of the TFLs maynot 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, “Noserious adverse events occurred for this study.”
14.
BLINDING AND UNBLINDING PLAN
Levels of unblinding are indicated in the table below. This table provides general guidance as to 
who will beallowed access to blinding information (including data or documentsthat can 
potentially unblind such as randomization codes, treatment assignments, and unblinded data) at 
various steps of the trial. For Interim Analysis (IA), appropriate IA team members, including the 
statistician, programmer and data manager will be identified and agreed upon between Lilly and 
any relevant Third Party Organizations (TPO).
Blinding information is kept strictly confidential and is accessible only by authorized personnel 
until unblinding of the trial as described below.All measures possible must be taken to maintain 
the blind; which means that access to the blinding information must be restricted to authorized 
personnel as described in the protocol and summarized in the table below.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted for medical management of the event. In such 
cases, the unblinding is to be conducted according to the protocol. 
In the event of unplanned intentional unblinding, the detailed process, including information of 
the unblinded team, creating restricted access electronic folders, and measures taken to guard 
against inappropriate dissemination of treatment codes, will be described in a blinding plan 
revision or anotherappropriate document and review sought from the study team statistician.
Study Timelines
Study Team Member
Screening
Randomisation
Treatment 
Phase
Follow-Up
Database Entry 
Lock
General
Clinical Supply Coordinator
NA
U
U
U
U
Randomization Statisticians
NA
U
U
U
U
ECG Reader
NA 
NA
NA 
NA 
NA
Central Laboratory
NA
U
U
U
U
Local Laboratory
NA 
NA
NA 
NA 
NA
Bio and Sample Analysis Lab
NA
U
U
U
U
Clinical Site
Pharmacist
NA
U
U
U
U
Study/Dosing Nurse
NA
B
B
B
U
Technicians/Data entry staff
NA
B
B
B
U
Patient/Subject
NA
B
B
B
U
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Study Timelines
Study Team Member
Screening
Randomisation
Treatment 
Phase
Follow-Up
Database Entry 
Lock
Investigator(s)
NA
B
B
B
U
Study Monitor (Covance)
NA
U
U
U
U
Covance Biometrics
Project Integration
NA
U
U
U
U
Data Management
NA
U
U
U
U
Programming
NA
U
U
U
U
Statistician
NA
U
U
U
U
Medical Writing 
NA
U
U
U
U
PK Scientist/Associate
NA
U
U
U
U
Lilly
CP/CRP/CRS/Biologist
NA
U
U
U
U
Consultant CPM
NA
U
U
U
U
CPA / Study Manager
NA
U
U
U
U
DSA
NA
U
U
U
U
SDTM Core Team
NA
U
U
U
U
Statistician
NA
U
U
U
U
Statistical Analyst
NA
U
U
U
U
Medical Writing
NA
U
U
U
U
PK Scientist/Associate
NA
U
U
U
U
PK Analyst
NA
U
U
U
U
PK Data Delivery
NA
U
U
U
U
CLO Representative
NA
U
U
U
U
CCI
Abbreviations:  B = blindedto study drug but not dose; CLO = clinical laboratory operations; CP = clinical 
pharmacologist; CPA = clinical pharmacology associate; CPM = clinical project manager; CRP = clinical 
research physician; CRS = clinical research scientist; DBL = database lock; DSA = data solutions associate; ECG 
= electrocardiogram; FPET = first patient enters treatment; LPET = last patient enters treatment; N/A = not 
applicable; PK = Pharmacokinetic; SDTM = study data tabulation model; TPO = third party organization; U = 
unblinded.