Clinical trial NCT03056456
Conditions: Diabetes Mellitus, Type 1
Sponsor: Eli Lilly and Company
Start date: 2017-02-23; Completion date: 2017-06-19
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study will be conducted in participants with type 1 diabetes mellitus to investigate how the human body processes LY900014, a new blood sugar lowering insulin, and its effect on blood sugar levels when it is delivered via an insulin pump. Side effects and tolerability will be documented. The study will last about 4 to 11 weeks for each participant.

Detailed description:

Arms: arm 1: LY900014 (Treatment B) delivered via an insulin pump as a continuous infusion under the skin, with various intermittent bolus doses immediately before meals over 3-days per period. arm 2: Insulin lispro (Treatment A) delivered via an insulin pump as a continuous infusion under the skin, with various intermittent bolus doses immediately before meals over 3-days per period.
Interventions: intervention 1: LY900014 intervention 2: Insulin Lispro (Humalog)
Intervention descriptions: intervention 1: Administered subcutaneously (SC) intervention 2: Administered SC

Protocol documents:
Prot_000.pdf: 
Protocol I8B-MC-ITSC(a) 
 
A Study to Assess the Pharmacokinetics, Glucodynamics, Safety, and Tolerability of LY900014 
in Patients with Type 1 Diabetes Mellitus on Continuous Subcutaneous Insulin Infusion Therapy 
 
NCT03056456 
 
Approval Date: 06-Feb-2017 


I8B-MC-ITSC(a)Clinical Pharmacology Protocol
Page 1
LY900014
Protocol I8B-MC-ITSC(a)
A Study to Assess the Pharmacokinetics, Glucodynamics, 
Safety, and Tolerability of LY900014 in Patients with Type1 
Diabetes Mellitus on Continuous Subcutaneous Insulin 
Infusion Therapy
EudraCT Number:  2016-004093-18
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 subsidiarie
s 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: 06-Feb-2017 GMT
LY900014
Eli Lilly and Company
Indianapolis, Indiana USA46285
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly:
19November 2016
Amendment (a) Electronically Signed and Approved by Lilly
on approval date provided below.


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LY900014
Table of Contents
A Study to Assess the Pharmacokinetics, Glucodynamics, 
Safety, and Tolerability of LY900014 in Patients with Type 1 
Diabetes Mellitus on Continuous Subcutaneous Insulin 
Infusion Therapy
Section
Page
Protocol I8B-MC-ITSC(a) A Study to Assess the Pharmacokinetics, 
Glucodynamics, Safety, and Tolerability of LY900014 in Patients 
with Type 1 Diabetes Mellitus on Continuous Subcutaneous Insulin 
Infusion Therapy.................................................................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................9
2.
Schedule of Activities .......................................................................................................12
3.
Introduction ......................................................................................................................18
3.1.
Study Rationale............................................................................................................18
3.2.
Background..................................................................................................................18
3.2.1.
Clinical Studies....................................................................................................19
3.3.
Benefit/Risk Assessment..............................................................................................20
4.
Objectives and Endpoints..................................................................................................22
5.
Study Design.....................................................................................................................23
5.1.
Overall Design .............................................................................................................23
5.1.1.
Inpatient Procedures.............................................................................................26
5.1.1.1.
Day –1 Study Activities..................................................................................27
5.1.1.2.
Day 1 Study Activities....................................................................................27
5.1.1.3.
Day 2 Activities..............................................................................................28
5.1.1.4.
Day 3 Activities..............................................................................................28
5.1.2.
Outpatient Procedures ..........................................................................................29
5.2.
Number of Participants.................................................................................................29
5.3.
End of Study Definition ...............................................................................................29
5.4.
Scientific Rationale for Study Design...........................................................................29
5.5.
Justification for Dose ...................................................................................................30
6.
Study Population...............................................................................................................32
6.1.
Inclusion Criteria..........................................................................................................32
6.2.
Exclusion Criteria ........................................................................................................33
6.2.1.
Additional Exclusion Criteria for Inpatient Dosing Days......................................35
6.3.
Lifestyle and/or Dietary Requirements .........................................................................36


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LY900014
6.3.1.
Meals and Dietary Restrictions.............................................................................36
6.3.1.1.
Mixed-Meal Tolerance Test on Day 1 and Day 3............................................36
6.3.1.2.
High-Glycemic Index Meal Test on Day 2......................................................37
6.3.1.3.
Lunch and Dinner Meals.................................................................................37
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................37
6.3.3.
Activity................................................................................................................37
6.4.
Screen Failures.............................................................................................................38
7.
Treatment..........................................................................................................................39
7.1.
Treatment Administered...............................................................................................39
7.1.1.
Investigational Medicinal Product ........................................................................39
7.1.2.
Noninvestigational Medicinal Products ................................................................39
7.1.3.
Inpatient Dosing...................................................................................................39
7.1.4.
Outpatient Dosing ................................................................................................40
7.1.5.
Packaging and Labeling .......................................................................................40
7.2.
Method of Treatment Assignment ................................................................................40
7.2.1.
Selection and Timing of Doses.............................................................................40
7.3.
Blinding .......................................................................................................................40
7.4.
Dose Modification........................................................................................................41
7.5.
Preparation/Handling/Storage/Accountability...............................................................41
7.6.
Treatment Compliance .................................................................................................42
7.7.
Concomitant Therapy...................................................................................................42
7.8.
Treatment after the End of the Study............................................................................43
8.
Discontinuation Criteria ....................................................................................................44
8.1.
Discontinuation from Study Treatment.........................................................................44
8.1.1.
Discontinuation of Inadvertently Enrolled Patients...............................................44
8.2.
Discontinuation from the Study....................................................................................44
8.3.
Patients Lost to Follow-up............................................................................................45
9.
Study Assessments and Procedures ...................................................................................46
9.1.
Efficacy Assessments...................................................................................................46
9.2.
Adverse Events ............................................................................................................46
9.2.1.
Serious Adverse Events........................................................................................47
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................47
9.2.2.
Complaint Handling.............................................................................................48
9.3.
Treatment of Overdose.................................................................................................48
9.4.
Safety...........................................................................................................................48
9.4.1.
Laboratory Tests ..................................................................................................48
9.4.2.
Vital Signs ...........................................................................................................48
9.4.3.
Physical Examination...........................................................................................49


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LY900014
9.4.4.
Body Weight........................................................................................................49
9.4.5.
Electrocardiograms ..............................................................................................49
9.4.6.
Plasma Glucose Monitoring .................................................................................49
9.4.7.
Catheter Insertion-Site Assessments.....................................................................50
9.4.7.1.
Subjective Procedure:  Examination of Infusion Set and 
Catheter..........................................................................................................50
9.4.7.2.
Subjective Procedure:  Acceptability of Insulin Delivery 
Experience......................................................................................................50
9.4.8.
Pain Measurements Using the Visual Analog Scale..............................................50
9.4.9.
Safety Monitoring ................................................................................................51
9.4.9.1.
Glucose Monitoring........................................................................................51
9.4.10.
Immunogenicity Assessments ..............................................................................52
9.5.
Pharmacokinetics .........................................................................................................53
9.5.1.
Bioanalysis...........................................................................................................53
9.6.
Pharmacodynamics ......................................................................................................53
9.6.1.
Glucose Samples (Inpatient Periods) ....................................................................53
9.6.2.
Glucose Samples (Mixed-Meal Tolerance Test) ...................................................54
9.6.3.
Exploratory Continuous Glucose Monitoring .......................................................54
9.7.
Genetics .......................................................................................................................54
9.8.
Health Economics ........................................................................................................55
10.
Statistical Considerations and Data Analysis.....................................................................56
10.1. Sample Size Determination ..........................................................................................56
10.2. Populations for Analyses..............................................................................................56
10.2.1.
Study Participant Disposition ...............................................................................56
10.2.2.
Study Participant Characteristics ..........................................................................56
10.3. Statistical Analyses ......................................................................................................56
10.3.1.
Safety Analyses....................................................................................................57
10.3.1.1.
Clinical Evaluation of Safety..........................................................................57
10.3.1.2.
Statistical Evaluation of Safety.......................................................................57
10.3.2.
Pharmacokinetic Analyses....................................................................................57
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................57
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................58
10.3.3.
Glucodynamic Analyses.......................................................................................58
10.3.3.1.
Glucodynamic Parameter Estimation..............................................................58
10.3.3.2.
Glucodynamic Statistical Inference.................................................................59
10.3.4.
Exploratory Continuous Glucose Monitoring Analyses ........................................59
10.3.5.
Evaluation of Immunogenicity .............................................................................59
10.3.6.
Interim Analyses..................................................................................................59


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LY900014
11.
References ........................................................................................................................60


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List of Tables
Table
Page
Table ITSC.4.1.
Objectives and Endpoints .......................................................................22
Table ITSC.5.1.
Planned Treatment Sequences by Period.................................................25


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List of Figures
Figure
Page
Figure ITSC.5.1.
Study design...........................................................................................24


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................61
Appendix 2.
Clinical Laboratory Tests........................................................................65
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................66
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............69
Appendix 5.
Blood Sampling Summary......................................................................70
Appendix 6.
Protocol Amendment I8B-MC-ITSC(a) Summary [A Study to 
Assess the Pharmacokinetics, Glucodynamics, Safety, and 
Tolerability of LY900014 in Patients with Type 1 Diabetes 
Mellitus on Continuous Subcutaneous Insulin Infusion Therapy]............71


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LY900014
1.Protocol Synopsis
Title of Study:  A Study to Assess the Pharmacokinetics, Glucodynamics, Safety, and Tolerability of LY900014 in 
Patients with Type1 Diabetes Mellitus on Continuous Subcutaneous Insulin Infusion Therapy
Rationale: This trial is intended to test anew formulation of insulin lispro (LY900014) in patients with type1 
diabetes mellitus (T1DM) using continuous subcutaneousinsulin infusion (CSII).  The use of LY900014 will be 
compared to insulin lispro (HumalogU-100; Reference formulation) when given as a standard dual-wave bolus 
dose or as a standard (1.5 U/minute) single-wave bolus dose on both Days 1 and 3 and as a rapid (15 U/minute) or 
standard (1.5 U/minute) single-wave bolus dose on Day2, with a breakfast mealtest using an insulin pump.  In 
addition, rapid versus standard dual-wave bolus doses and rapid versus standard single-wave bolus doses will be 
comparedduring the lunch and dinner meals, respectively, using the assigned treatment (LY900014 or Humalog) for 
that period.  Humalog is already marketed and used in diabetes treatment,and its efficacy and safety as a single 
insulin preparation is well known.
Objectives/Endpoints:  
Primary Objectives
Endpoints
To evaluate the difference in insulin lispro PK when
LY900014 and Humalog areadministered as different 
test bolus doses with an insulin pump to patients with 
T1DMduring a breakfast meal test
AUC,C
max, T
max, early 50% Tmax,and late50% 
Tmax
Secondary Objectives
Endpoints
To evaluate the sustainability of any difference in 
insulin lispro PK of LY900014 and Humalogover 
3days when administered as different test bolus doses 
with an insulin pump to patients with T1DMduring a 
breakfast meal test
AUC,C
max,T
max, early 50% Tmax,and late50% 
Tmax
To evaluate the difference in GD response when
LY900014 and Humalog are administered as different 
test bolus doses withan insulin pump to patients with 
T1DMduring a breakfast meal test
∆AUC
To compare the durability of GD response over 3 days 
whenLY900014 and Humalogare administered as 
different test bolus doses withan insulin pump to 
patients with T1DMduring a breakfast meal test
∆AUC
Abbreviations:  AUC=area under the concentration versus time curve; Cmax=maximum concentration; early 
50%Tmax=time to early half-maximal concentration; GD=glucodynamics; late 50% Tmax=time to late 
half-maximal concentration; PK=pharmacokinetics; T1DM=type 1 diabetes mellitus; Tmax=time to 
maximumconcentration.
Summary of Study Design:
C
C
I
  This is a single-site, 4-period, patient-and investigator-blind, randomized, crossover 
study in patients with T1DM to evaluate the insulin lispro pharmacokinetic (PK)and glucodynamic (GD)
characteristics of LY900014 (Test)over3 dayswithCSII compared with that of Humalog (Reference) using a 
.


I8B-MC-ITSC(a) Clinical Pharmacology Protocol
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LY900014
Each patient will be randomized to 1 of 4 treatment sequences comprising CSII of LY900014 or Humalog, with 
different combinations of the modes of administration of the bolus doses relative to the breakfast, lunch, and dinner 
meals using an insulin pump.  The modes of administration are as follows:

Mode 1:  bolus dose is administered as a standard dual-wave bolus (50% immediate bolus 
delivery [speed = 1.5 U/minute] and 50% as a square wave over 3 hours)

Mode 2:  bolus dose is administered as a standard single-wave bolus (speed = 1.5 U/minute)

Mode 3:  bolus dose is administered as a rapid single-wave bolus (speed = 15 U/minute)

Mode 4:  bolus dose is administered as a rapid dual-wave bolus (50% immediate bolus 
delivery [speed = 15 U/minute] and 50% as a square wave over 3 hours)
A mixed-meal tolerance test (MMTT) will be administered at breakfast as an individually standardized solid test 
meal on Day 1 and Day 3 and as a high-glycemic index test meal on Day 2.  The assigned treatment will be 
administered as a bolus dose at time 0 relative to the start of each breakfast test meal via 3 different modes:  
Modes 1, 2, and 3.
An individually standardized solid lunch will be administered on Days 1, 2, and 3.  The assigned treatment will be 
administered as standard (Mode 1) or rapid (Mode 4) dual-wave bolus doses at time 0 relative to the start of each 
lunch meal.
An individually standardized dinner will be administered on Days 1 and 2.  The assigned treatment will be 
administered as standard (Mode 2) or rapid (Mode 3) single-wave bolus doses at time 0 relative to the start of each 
dinner meal.
Treatment Arms and Duration:  Patients will be randomly assigned to 1 of 4 dosing sequences; each sequence 
will have 4 periods.  Patients will be administered bolus doses of LY900014 or Humalog during the 3-day inpatient 
stay for each study period and bolus doses of Humalog for the lead-in and outpatient time periods.
Number of Patients: Initially, 24 patients will be enrolled to target approximately 20 patients to complete all 
4 periods of the study.  Patients who drop out may be replaced, up to a maximum of 30 total patients enrolled, to 
ensure 20 completers; the replacement patient will adopt all assigned treatments of the original patient’s 
randomization schedule and complete all 4 study periods.
Statistical Analysis:
Primary statistical analyses will be conducted on the set of patients receiving at least 1 dose of the study drug to 
which they are randomized.  Patients who complete at least 1 MMTT and have measurable insulin lispro 
concentrations will be included in the analysis dataset for the PK analyses.  Patients who receive at least 1 dose of 
study drug and have evaluable GD data will be included in the analysis set for the GD analyses.
Sample Size:  Twenty completing patients will provide approximately 80% power to demonstrate a 25% decrease in 
the time to early half-maximal concentration (early 50% Tmax) between LY900014 and Humalog.  Testing will be 
done at an -level of 0.1 with a 2-sided confidence interval (CI).  The variability was estimated as approximately 
35.9% coefficient of variation of within-subject variability for early 50% Tmax.
Safety:  All treatment- (investigational product and Humalog noninvestigational product) and procedure-related
adverse events (AEs) will be listed, and if the frequency of events allows, safety data will be summarized using 


I8B-MC-ITSC(a) Clinical Pharmacology Protocol
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LY900014
descriptive methodology.  The incidence of symptoms for each treatment will be presented by severity and by 
association with investigational product as perceived by the investigator.  The number of investigational 
product-related serious AEs (SAEs) will be reported.  Safety parameters that will be assessed include safety 
laboratory parameters and vital signs.  The parameters will be listed and summarized using standard descriptive 
statistics.
Pharmacokinetics:  PK analyses will be conducted using standard noncompartmental methods of analysis.  Serum 
insulin lispro concentrations will be used to calculate several PK parameters, including time to maximum 
concentration (Tmax), early 50% Tmax, time to late half-maximal concentration (late 50% Tmax), maximum 
concentration (Cmax), area under the plasma concentration versus time curve (AUC) from time 0 to 15 minutes 
postdose (AUC[0-15min]), AUC from time 0 to 30 minutes postdose (AUC[0-30min]), AUC from time 0 to 1 hour 
postdose (AUC[0-1h]), AUC from time 0 to the last recorded time (AUC[0-tlast]), and AUC from time 0 to 5 hours 
postdose (AUC[0-5h]).
Log-transformed insulin lispro Tmax, early 50% Tmax, late 50% Tmax, Cmax, and AUC estimates will be evaluated 
to estimate geometric means, ratios of geometric means of insulin lispro within LY900014 to Humalog, and the 
corresponding 90% CIs of the ratios.
The statistical model for Days 1 and 3 breakfast meal tests will include treatment (4 combinations of treatment and 
bolus administration mode), period, day-within-period, and treatment-by-day-within-period interaction as fixed 
effects and patient as a random effect.  A separate analysis model will be used for the Day 2 breakfast meal test, 
including treatment (4 combinations of treatment and bolus administration mode) and period as fixed effects and 
patient as a random effect.  For the primary inference, insulin lispro administered from LY900014 will be concluded 
to have a significantly decreased early 50% Tmax relative to Humalog if the upper confidence bound of the 2-sided 
90% CI of the ratio of geometric means of the early 50% Tmax is <1.  As a sensitivity analysis, early 50% Tmax will 
be analyzed using the Wilcoxon signed-rank test.
Glucodynamics: Data will be analyzed for the patients during each MMTT.  The change from baseline values for 
each patient will be calculated.  Incremental change from baseline glucose AUC values will be calculated during a 
5-hour meal test.
Summary statistics will be presented by treatment and by bolus dose administration mode (all 4 combinations of 
treatment) for Days 1 and 3 and Day 2, separately.  The same statistical model and comparisons used to analyze the 
PK parameters will be used to analyze the GD parameters on the original scale (not log-transformed) using Fieller’s 
theorem.
Exploratory Continuous Glucose Monitoring:  The continuous glucose monitoring (CGM) outcome variables (for 
example, incremental change from baseline AUC[0-5h], the change from baseline 1- and 2-hour excursions) will be 
derived based on the raw data collected from the individualized standardized lunch meals on Days 1, 2, and 3 and 
from the individualized standardized dinner meals on Days 1 and 2.
Immunogenicity:  The relationship between the status (positive or negative) of treatment-emergent anti-insulin lispro 
antibodies and treatment-emergent AEs (TEAEs) will be assessed.  Likewise, the relationship between the status of 
treatment-emergent antibodies and the PK parameters and GD response to insulin lispro may also be assessed.


I8B-MC-ITSC(a) Clinical Pharmacology Protocol
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LY900014
2. Schedule of Activities


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Study Schedule Protocol I8B-MC-ITSC
Procedure
Screena
Days 
-28 to -8
Lead-In 
Days 
-7 to -1
Periods 1 to 4
ED/
FUa,b
Comments
Day -1
Day 1
Day 2
Day 3
Informed consent
X
At least 1 day before screening procedures.  
Screening procedures should take place no 
later than 28 days after signing the informed 
consent.
Physical 
examination/medical 
assessment
X
X
Before 
discharge from 
CRU
X
Physical examination and medical history at 
screening.  Thereafter, medical review and 
targeted examination, as appropriate, including 
review of patient diary.
AE and concomitant
medication
X
X
X
X
X
X
Height and weight
X
X
Height will be measured at screening only.
Eligibility assessment
X
X
Meal test exclusion criteria (Section 6.3.1) will 
be reviewed on Day −1 at admittance to the 
CRU.
Lead-in activities
X
Patients will switch from their short-acting 
insulin used before the start of the study to 
Humalog; patients will continue to use their 
own pump to administer Humalog.  A patient 
diary will be provided for recording dosing and 
any information as required by the investigator
(refer to Section 5.1 for a detailed description).
Training
X
X
Diabetes training will include dose calculation 
for short-acting insulins; correct 
self-monitoring of plasma glucose; and 
interpretation of results, symptoms, and 
treatment of hypoglycemia.
Admission to CRU
X
Will be admitted to CRU in the early evening 
(approximately 5:00 PM).
Discharge from CRU
X
Patients will be discharged from the CRU at 
least 5 hours after the start of the lunch meal.


I8B-MC-ITSC(a)Clinical Pharmacology Protocol
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LY900014
Procedure
Screena
Days 
-28 to -8
Lead-In 
Days 
-7 to -1
Periods 1 to 4
ED/
FUa,b
Comments
Day -1
Day 1 
Day 2 
Day 3
Insert CGM
X
The CGM system will be inserted before the 
start of the Day –1standardized dinner.
Standardized dinner
X
Approximately 7:00 PMand should be 
consumed within 20minutes.Identical to the
standardized testdinner served on Days 1 
and2.
Catheter 
insertion/change
X
X
Day –1:  after the standardized dinner.
Day 3:  after the lunchmeal procedures(blood 
draws and medical assessments) are completed
(approximately 5 hours after thestart of the
lunch meal),unless the patient stays at the 
clinic untilthat evening (approximately 
5:00PM) for Day–1 procedures for next 
period; then the new catheter will beinserted 
after the standardized dinner (Day–1 for the 
following period).
Run-in/stabilization of 
glucose
X
(approximately 
1:00 AM)
X
(approximately 
1:00 AM)
From 7 hours to 30 minutes before dosing:  
infusion of glucose (dextrose solution) or 
insulin 
 to target a plasmaglucose 
concentration of 126mg/dL(7.0mM).  
Run-in/stabilization of glucose willbegin at 
approximately 1:00 AM.  Plasma glucose
concentrations will be monitored
approximately every30minutes.
Glucose monitoring 
before Day 2 meal test
X
After completion of the standardized dinnerto 
30 minutes before dosing:  plasmaglucose 
concentrations will be monitored 
approximately every hour.
C
C
I


I8B-MC-ITSC(a)Clinical Pharmacology Protocol
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LY900014
Procedure
Screena
Days 
-28 to -8
Lead-In 
Days 
-7 to -1
Periods 1 to 4
ED/
FUa,b
Comments
Day -1
Day 1 
Day 2 
Day 3
Glucose monitoring 
throughout inpatient 
period
X 
X
X
X
Regular monitoring of blood glucose using the 
 (approximately 
every2 hours) will also be performed during 
the complete inpatient period outside of the 
breakfast meal test procedures and includes 
predose before the standardized lunch and 
dinner.
Treatment 
administration
(LY900014 or Humalog)
X 
X
X
X
Day –1 prandial Humalog shall be 
administered using the patient’s own personal 
pump.  After the standardized dinner the
patient willswitch to the 
; the reservoir will be filled with the 
assigned study treatment (LY900014 or 
Humalog) by qualified staff.  Study treatment
will be administered continuously via a basal 
infusion and via a bolusdoseimmediately 
before each breakfast test mealand
standardizedlunch meal (Days 1, 2, and 3) and 
before each standardizeddinner meal (Days 1 
and 2 only),which should follow within 
1minute of dosing.
Breakfast test meals
(refer to Sections6.3.1.1
and 6.3.1.2)
X
(MMTT)
X 
(high-glycemic 
index meal 
test)
X
(MMTT)
Breakfast(Days 1, 2, and 3) will be given 
immediately after dosing (approximately 
8:00AM) and should be consumed within
20minuteson Days 1 and 3 and within 
15minutes on Day 2.
Standardizedtest lunch
(refer to Section6.3.1.3)
X
X
X
Approximately 1:00 PMand at least5 hours 
after the start of the breakfast meal; the meal
should be consumed within 20minutes.
Standardizedtest dinner
(refer to Section6.3.1.3)
X
X
Approximately 7:00 PMand at least5 hours 
after the start of the lunchmeal;the meal
should be consumed within 20minutes.
CCI
CCI


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LY900014
Procedure
Screena
Days 
-28 to -8
Lead-In 
Days 
-7 to -1
Periods 1 to 4
ED/
FUa,b
Comments
Day -1
Day 1
Day 2
Day 3
Remove CGM
X
After the Day 3 lunch meal procedures are 
completed (approximately 5 hours after the 
start of the lunch meal), the CGM system will 
be removed.
Vital signsc (minutes)
X
X
X
(predose, 30, 
120)
X
(predose, 30, 
120)
X
(predose, 30, 
120, and 
before 
discharge from 
CRU)
X
Blood pressure and pulse rate should be 
measured after at least 5 minutes supine; body 
temperature at screening only.  Time is 
referenced to bolus dose of insulin lispro 
(LY900014 or Humalog) for the breakfast 
meal tests, that is, time 0.
12-lead ECGc
X
X
(predose, 
Period 1 only)
X
(predose, 
Period 1 only)
X
Single ECGs only.  ECGs should be recorded 
before collecting any blood for safety or PK 
tests.
Clinical laboratory testsc
X
Period 1 only 
(predose)
X
Details in Appendix 2 (Clinical Laboratory 
Tests).
Alcohol breath test
X
May be repeated before every CRU admission.  
The alcohol breath test is included in the 
Day –1 eligibility assessment.
Pregnancy test/urine 
drug screen
X
X
X
Pregnancy test will be taken for female 
patients only.  Serum pregnancy test at 
screening.  Urine pregnancy test for all other 
visits.
Insulin lispro PK 
sampling (minutes)
-15, 0, 5, 10, 
15, 20, 25, 30, 
35, 40, 45, 50, 
55, 60, 70, 90, 
120, 150, 180, 
240, 300
-15, 0, 5, 10, 
15, 20, 25, 30, 
35, 40, 45, 50, 
55, 60, 70, 90, 
120, 150, 180, 
240, 300
-15, 0, 5, 10, 
15, 20, 25, 30, 
35, 40, 45, 50, 
55, 60, 70, 90, 
120, 150, 180, 
240, 300
Time is referenced to the start of the 
administration of the bolus dose of insulin 
lispro (LY900014 or Humalog) for the 
breakfast meal tests, that is, time 0.


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Procedure
Screena
Days 
-28 to -8
Lead-In 
Days 
-7 to -1
Periods 1 to 4
ED/
FUa,b
Comments
Day -1
Day 1
Day 2
Day 3
Plasma glucose 
monitoring with 
Super GL glucose 
analyzer (minutes)
-30, -15, 0, 10, 
20, 30, 40, 50, 
60, 70, 80, 90,
100, 110, 120, 
135, 150, 165, 
180, 195, 210, 
225, 240, 300
-30, -15, 0, 10, 
20, 30, 40, 50, 
60, 70, 80, 90, 
100, 110, 120, 
135, 150, 165, 
180, 195, 210, 
225, 240, 300
-30, -15, 0, 10, 
20, 30, 40, 50, 
60, 70, 80, 90, 
100, 110, 120, 
135, 150, 165, 
180, 195, 210, 
225, 240, 300
Time is referenced to the start of the 
administration of the bolus dose of insulin 
lispro (LY900014 or Humalog) for the 
breakfast meal tests, that is, time 0.
VAS and insertion-site 
assessments (minute)
0d, 20, 40, 60, 
120, 180, 240, 
300
0d, 20, 40, 60, 
120, 180, 240, 
300
0d, 20, 40, 60, 
120, 180, 240, 
300
Time is referenced to dose of insulin lispro 
(LY900014 or Humalog) for the breakfast test 
meals.
Assessment of insulin 
delivery experience
X
Subjects will be asked to provide the overall 
acceptability of their insulin delivery 
experience, either prior to CRU discharge or 
after completing Day 3 lunch procedures for 
each period.
Biomarker samplec 
(PGx)
Period 1 only 
(predose)
Sample for 
immunogenicityc
Period 1 only 
(predose)
X
Additional samples may be collected if there is 
a possibility that an AE is immunologically 
mediated.
Abbreviations:  AE = adverse event; CGM = continuous glucose monitoring; CRU = clinical research unit; ECG = electrocardiogram; ED = early 
discontinuation; FU = follow-up; MMTT = mixed-meal tolerance test; PK = pharmacokinetics; VAS = visual analog scale.
Note:  Interim telephone visits may occur at any time during the outpatient periods, as determined by the investigator, to review the safety and well-being of the 
patient.
a
Patients should be fasted for at least 8 hours before the start of screening and follow-up (or early discontinuation) activities.  Patients may consume up to 20 g 
of carbohydrates to treat or prevent hypoglycemia during the fasting periods.
b
Within 7 to 14 days after last dose or early discontinuation.
c
Predose is defined as the predose for the breakfast test meal only.  Predose measurements should be performed within approximately 2 hours before the 
planned dosing time.
d
The VAS at the 0-minute time point is to be performed as soon as practicably possible after the start of the dosing for the breakfast meal tests.


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3.Introduction
3.1. Study Rationale
There is an unmet medical need for fast prandial insulin analogs with improved pharmacokinetic 
(PK)and glucodynamic (GD)characteristics.
A new formulation of insulin lispro will be used in this study and was developed as an 
ultra-rapid–acting insulin formulation with an even faster onset of action than currently available 
rapid-acting insulin analogs.  The changes in PK and GD characteristics are achieved by 
coformulating insulin lispro with a microdose of treprostinil (the active ingredient in 
)and Generally Recognized as Safe (GRAS)excipients.
This trial is intended to test this new formulation of insulin lispro (LY900014) in patients with 
type1 diabetes mellitus (T1DM)using continuous subcutaneousinsulin infusion (CSII).  
Differentinsulin pump–delivered bolus options are assessed in this study:  asingle-wave bolus 
provides a single immediate dose of insulin in 2 speed options (rapid [15 U/minute] or standard 
[1.5 U/minute]),andadual-wave bolus delivers a combinationof an immediate single-wave 
bolus (either standard or rapid) followed by asquare-wave bolus(a single bolus administered 
evenly over an extended period of time).  The use of LY900014 will be compared to insulin 
lispro (Humalog
U-100; Reference formulation) when given as a standarddual-wave bolus 
dose oras a standard(1.5 U/minute)single-wave bolus dose onboth Days 1 and 3, and as a rapid
(15U/minute) orstandard(1.5 U/minute) single-wave bolus dose on Day2,with a breakfast 
meal test usingan insulin pump. In addition, rapidversus standarddual-wave bolus doses and 
rapidversus standardsingle-wave bolus doses will be compared during the lunch anddinner
meals, respectively, using the assigned treatment (LY900014 or Humalog) for that period. 
Humalog is already marketed and used in diabetes treatment,and its efficacy and safety as a 
single insulin preparation is well known.
This clinical trial will beconducted to gather PK/GD, safety, and compatibility (that is, catheter 
occlusions) data on LY900014 when used in CSII therapywith a pumpand administeredas 
either standardor rapiddual-waveorsingle-wave bolus doses on Days 1,2,and3.
A study using model-predicted optimized bolus delivery has shown that a bolus for a mixed meal 
containing a substantial amount of fat(approximately 40% of total calories),compared to a meal 
with the same carbohydrate content but only a minimal amount of fat,needs a larger bolus dose 
and a dual-wave delivery method to achieve optimal postprandial glucose control (Bell et 
al.2016).Therefore,testinga dual-wave bolus dose and different bolus speed options to support 
a safe and efficient use of LY900014in T1DM patients using an insulin pumpis of greatclinical 
interest.
3.2. Background
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A prandial insulin with faster-on and/orfaster-off characteristics might reduce glycemic 
excursions and the incidence of late postprandial hypoglycemia compared to currently available 
fast-acting insulin analogs.  The insulin analog, insulin lispro (Humalog), has been shown to be 
absorbed more quickly than regular human insulin (Humalog package insert 2015).  In healthy 


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LY900014
subjectsgiven subcutaneous (SC) doses of insulin lispro ranging from 0.1 to 0.4 U/kg, peak 
serum levels were seen 30 to 90minutes after dosing.  Insulin analogs are absorbed faster than 
human insulin; however, the general consensus is that rapid-acting insulin, administered either 
by pumps or syringes/pen injectors, is still not rapid enough to match carbohydrate absorption 
profiles, limiting efficacy and dosing flexibility.  It is anticipated that anultra-rapid–acting 
prandial insulin would shift the PK/GDof insulin analogs so that they have an even faster onset 
to match carbohydrate absorption and also allow greater flexibility and postmeal dosing.  This 
ultra-rapid insulin (URI) could be for use in T1DMand type 2 diabetes mellitus(T2DM) in 
adults and children when given by multiple daily injections (MDI) or by CSII.  A URI could be 
created by using additives that increase local capillary blood flow and/or alter vascular 
permeability.
This study aims to characterize the PK of insulin lispro after administration of LY900014, which 
is a formulation of insulin lispro, treprostinil, and other excipients using an insulin pump.  This 
formulation involves the novel use of a microdose of treprostinil (
 as an excipient to 
enhance the absorption of insulin lispro by local vasodilatation rather than an active 
pharmaceutical ingredient to elicit a systemic effect.  LY900014 (Test formulation) is considered 
the investigational medicinal product (IMP) for this study.
Treprostinil is a prostacyclin analog, administered either by inhalation (
), as an 
intravenous (IV) infusion, or as a continuous SC infusionfor the treatment of symptomatic 
pulmonary arterial hypertension(PAH), and has been approved in the United States since 2002 
(
) and in Germany since 2006 (
 
.  Sodium citrate and each of the other excipients (zinc chloride, magnesium 
chloride, glycerin, and m-cresol)in theLY900014 formulation arelisted in the Food and Drug 
Administration (FDA) GRASfood additives database (FDASCOGS[WWW]) and in the FDA 
Inactive Ingredients in Approved Drugs database(FDA[WWW]).  Furthermore, the excipient 
concentration in LY900014 is within the limits identified for approved drug products in the FDA 
Inactive Ingredients in Approved Drugs database.
3.2.1. Clinical Studies
Five clinical studies wereconducted that evaluated the effects ofadministration of treprostinil 
alone, insulin lispro formulated with treprostinil, and LY900014:  
 
 
All 5studies are complete(refer to the LY900014 
Investigator’s Brochure [IB]for detailed information).
The PK of treprostinil following SC bolus injection has been assessed across the 5 Phase 1a 
clinical studieslisted above. The treprostinil concentration versus time profile and PK 
parameters were consistent across studies,and treprostinil was rapidly absorbed and eliminated 
following SC bolus administration(refer to theIB).If treprostinil levels were detectable at doses 
of 
, these observations were approximatelythe maximum concentration (Cmax
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)
and were slightly above the detection limit of the assay (
); no changes in blood 
pressure or pulse rate that might suggest systemic effects of treprostinil were observed.  
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Treprostinil exposure following LY900014 administration was monitored in the 3 ongoing 
Phase1b studies (Studies
], and I8B-
 
) which evaluated the PK, GD, safety, and tolerability of MDIs of LY900014 in patients 
with T1DM and T2DM and when used in patients with T1DM using CSII.  Treprostinil exposure 
was assessed at 15minutesand 30minutespostdose (approximatelyCmax)in the Phase 1b MDI 
studies and throughout the duration of the CSII for each period in all patients who were 
administered LY900014. Preliminary data analysisshowedthatonly 1sample haddetectable 
treprostinil drug concentration levels in plasma from the approximately 967samples taken from 
a total of75T1DM and T2DM patients following MDI administration of LY900014 using doses 
up to 40U per SC bolus injectioncontaining approximately 
 of treprostinil.  Importantly, 
no detectable drug levels were observed with CSII therapyin 30 patients.
The estimated total daily treprostinil (basal and bolus) doses inLY900014 for patients with 
T1DM in this study are expected to be within the clinical dose range previously explored with 
SC bolus administration of treprostinil.  The highest daily insulinlispro/treprostinil doses are 
expected to be administered topatients with T2DMwith MDI therapy.Based on the estimated 
amount of treprostinil delivered fromrelatively largepreprandial bolus doses of LY900014 in
patients with T2DM(
 [with 50U insulin lispro]) and the
lack oftreprostinil exposures observed in the 3Phase 1b studies, treprostinil concentrations 
during use of LY900014 inCSIItherapy are expected to be minimal orundetectable.
All tested doses of treprostinil and insulin lispro were well tolerated in both healthy subjects 
(
) and patients with T2DM (
).  There were no 
serious adverse events(SAEs) related to study treatment in any of the 5 completed studies.  No 
subject discontinuedfrom the studies because ofa drug-related adverse event(AE).
In a preliminary review of data from 3 ongoing Phase 1b PK and GD studies (
 
), LY900014 was well tolerated in patients with T1DM using MDI or insulin 
pump treatment and T2DMusing MDI.  There were no SAEsrelated to study treatment or
discontinuationsfrom the studies because ofa drug-related AE.  Small numbersof 
treatment-emergent AEs (TEAEs)were reported, andthere wereno notableincreasesin these 
events in relation to any of the LY900014 formulations compared to those in relation to 
Humalog.  No significant differences were observed for injection-site tolerability and 
hypoglycemic events when LY900014 was compared to Humalog.
More information about the LY900014 clinical studies are to be found in the IB.
3.3. Benefit/Risk Assessment
CCI
The data from previous studies (
) and preliminary data from ongoing 
studies(
 [MDI] and Study 
[CSII])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 insulinlispro 
(Humalog) which is the active pharmaceutical ingredient in LY900014, are hypoglycemia, 
hypersensitivity reactions (localized allergy and/or systemic allergy), undesirable effects at the 
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injection site (injection-site reactions and lipodystrophy), and peripheral edema (Humalog 
package insert 2015).
Notably, across alldoses in the Lilly clinical studies that have evaluated treprostinil as a local 
vasodilator with or without insulin lispro, there was no clinically significant increase in those
AEsassociated with systemic absorption of treprostinil, as described in the 
 
) (that is, headache, diarrhea, nausea, jaw pain, vasodilatation, rash, edema, anorexia, 
vomiting, asthenia, abdominal pain,and hypotension).  Theexposures of treprostinil in 
LY900014 for participants in thisstudy are expected to be undetectablebased on preliminary 
data from 
.  The dose ranges previously explored with SC bolus administration of 
treprostinil resulted in treprostinil exposures that were undetectable orsubstantially lower than 
those observed forthe treatment of PAH.
No additional potential risks of LY900014 or treprostinil alone were identified in preclinical 
safety pharmacology and toxicity studies or clinical pharmacology studies.  No known potential 
risks are associated with the use of small amounts of treprostinil ( 
) in the LY900014 
formulation.
Additionally, local and systemic toxicity profiles of Humalog and 
 do not suggest the 
potential for additive or synergistic toxicity.
More information about the known andexpected benefits, risks, SAEs and reasonably 
anticipated AEs ofLY900014maybe found in the IB.
More detailed information about the known and expected benefits and risks of Humalog may be 
found in the Summary of Product Characteristics(Humalog:  EPAR [WWW]); known and 
expected benefits and risks of treprostinil may be found in the package insert for treprostinil 
).
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4. Objectives and Endpoints
Table ITSC.4.1 shows the objectives and endpoints of the study.
Table ITSC.4.1.
Objectives and Endpoints
Primary Objective
Endpoints
To evaluate the difference in insulin lispro PK when LY900014 and 
Humalog are administered as different test bolus doses with an 
insulin pump to patients with T1DM during a breakfast meal test
AUC, Cmax, Tmax, early 50% Tmax, and late
50% Tmax
Secondary Objectives
Endpoints
To evaluate the sustainability of any difference in insulin lispro PK 
of LY900014 and Humalog over 3 days when administered as 
different test bolus doses with an insulin pump to patients with 
T1DM during a breakfast meal test
AUC, Cmax, Tmax, early 50% Tmax, and late
50% Tmax
To evaluate the difference in GD response when LY900014 and 
Humalog are administered as different test bolus doses with an 
insulin pump to patients with T1DM during a breakfast meal test
∆AUC
To compare the durability of GD response over 3 days when
LY900014 and Humalog are administered as different test bolus 
doses with an insulin pump to patients with T1DM during a 
breakfast meal test
∆AUC
Exploratory Objectives
Endpoints
To evaluate the safety and tolerability of LY900014 administered 
with an insulin pump
Adverse events, anti–insulin lispro 
antibodies, infusion-site reactions/pain, and 
frequency and/or severity of hypoglycemia
To compare the GD response using CGM when LY900014 and 
Humalog are administered as different test bolus doses with an 
insulin pump to patients with T1DM during a standardized lunch 
meal
∆AUC
To compare the GD response using CGM when LY900014 and 
Humalog are administered as different test bolus doses with an 
insulin pump to patients with T1DM during a standardized dinner 
meal
∆AUC
To evaluate the intrasubject and intersubject insulin lispro PK 
variability of LY900014 compared with Humalog after 3 days of 
CSII
CV of AUC
To determine catheter occlusion rates with LY900014 and Humalog
after 3 days of CSII
Microscopic assessment of infusion tubing 
after 3 days of use or in case of suspected 
catheter occlusion
To perform an exploratory comparison of glucose fluctuations with
time in patients with euglycemia, hypoglycemia, and hyperglycemia 
receiving LY900014 and Humalog
CGM profiles during inpatient periods:  time 
in euglycemia, hypoglycemia, and 
hyperglycemia
Abbreviations:  AUC = area under the concentration versus time curve; CGM = continuous glucose monitoring; 
Cmax = maximum concentration; CSII = continuous subcutaneous insulin infusion; CV = coefficient of variation; 
early 50% Tmax = time to early half-maximal concentration; GD = glucodynamics; late 50% Tmax = time to late 
half-maximal concentration; PK = pharmacokinetics; T1DM = type 1 diabetes mellitus; Tmax = time to 
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LY900014
5.Study Design
5.1. OverallDesign
This is a single-site, 4-period, patient-and investigator-blind, randomized, crossover study in 
patients with T1DM to evaluate the insulin lispro PK and GD characteristics of LY900014 (Test)
over3 dayswith CSII compared with that of Humalog(Reference) using a 
.
Each patient will be randomized to 1 of 4treatment sequences comprising CSII of LY900014 or 
Humalog, with different combinations of the modes of administration of the bolus dosesrelative 
to the breakfast, lunch, and dinner mealsusingan insulin pump(refer toFigureITSC.5.1and 
TableITSC.5.1). The modes of administration are as follows:
Mode 1:  bolus dose is administered as a standard dual-wavebolus 
(50%immediate bolus delivery [speed = 1.5 U/minute]and 50% as a 
square-wave over 3 hours)
Mode 2:  bolus dose is administered as a standard single-wave bolus 
(speed=1.5 U/minute)
Mode 3:  bolus dose is administered as a rapid single-wave bolus 
(speed=15U/minute)
Mode 4:  bolus dose is administered as a rapiddual-wave bolus 
(50%immediate bolus delivery [speed = 15 U/minute]and 50% as a square
wave over 3 hours)
The compositions of the meals are described in Section6.3.1.
A mixed-meal tolerance test (MMTT) will beadministered atbreakfast as an individually 
standardized solid test mealon Day 1 and Day 3andas ahigh-glycemic index test meal on 
Day2.  The assigned treatment will beadministered as a bolus dose at time 0 relative to the start 
of each breakfast test mealvia 3different modes:  Modes 1, 2, and 3.
An individually standardizedsolid lunch will beadministered on Days1, 2,and 3.  The assigned 
treatment will beadministered as standard (Mode 1) orrapid (Mode 4) dual-wave bolus doses at 
time 0 relative to the start of each lunchmeal.
An individuallystandardizeddinnerwill beadministered on Days1and 2.  The assigned 
treatment will beadministered as standard (Mode 2) or rapid (Mode 3) single-wave bolus doses 
at time 0 relative to the start of each dinnermeal.
The study design is shown in FigureITSC.5.1andplanned treatment sequences are shown in 
TableITSC.5.1.  Details of the inpatient and outpatient procedures are described in Section5.1.1
and Section5.1.2
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, respectively.
Patients who are eligible to participate in the study based on the results of the screening 
procedures will proceed to a 1-week lead-in period.  During the lead-in period, patients will (if 
not receiving Humalog) switch from their short-acting insulin used before the start of the study 


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LY900014
to Humalog, which will be administered using their own personal pump.  Patients will also be 
provided with a general diabetes training including, but not limited to, dose calculation for 
short-acting insulins;correct self-monitoring of plasmaglucose;and interpretation of results, 
symptoms, and treatment of hypoglycemia.  A patient diary will alsobe provided for 
documentation of dosing, meals,and glucose monitoring outcomes.
Patients will be randomly assigned to a treatment sequence according to the actual randomization 
schedule provided to the siteat the beginning of or during the lead-in period.  The  
 
 pump willbe used for all study treatment administrations, while maintaining the 
catheter needle at the same catheter insertion-site locationfor the 3-day duration of each study 
period.  Before each MMTTon Day 1 and Day 3, a run-in period to stabilize plasma glucose
levels will occur.  Details of run-in activities are described in Section5.1.1.2and Section2.
Before the breakfast meal teston Day 2,the patients will have theirplasmaglucose monitored 
approximately every hourduring the night to ensure that the targeted plasmaglucose range is 
met before the start of the Day 2 meal test.
Note:  Patients will be randomized to 1 of 4 treatment sequences;each sequence has 
4periods.  Eachperiod comprises dosing with assigned treatment (Humalogor 
LY900014) over Days 1 to 3.
FigureITSC.5.1.
Study design.
Patients will be required to attend the clinical research unit (CRU) on at least 8occasions:
a visit for informed consent
a screening visit (may occur up to 21days before the lead-in period)
an initial CRU visit at the start of the 1-week lead-in period in which all patients 
will receive Humalog as their CSII
4 inpatient stays from Day –1 to Day3(one in each study period)
a follow-up visit (within 7 to 14 days after the last dose or early discontinuation)
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Table ITSC.5.1.
Planned Treatment Sequences by Period
Note:  Patients will be randomized to 1 of 4 treatment sequences, each comprising different administration modes 
for the prandial bolus dose for the breakfast, lunch, and dinner meals on Days 1 through 3 in each of the 
4 periods.
“Treatment A” and “Treatment B” may represent either Humalog or LY900014.  Patients will be assigned a 
treatment sequence according to the actual randomization schedule provided to the site.
Bolus dose administration modes:  RD = rapid dual-wave; RS = rapid single-wave; SD = standard dual-wave; 
SS = standard single-wave.
Patients will be discharged from the CRU on Day 3 (at least 5 hours after the start of the lunch
meal) or later, if deemed necessary for safety monitoring as determined by the investigator.  
Study treatments may be administered on consecutive days from one period to the next, and a 
maximum time of 1 week is permitted between consecutive periods.
Patients will continue their individual CSII basal rate using the insulin pump during the entire 
study including the meal test days unless safety issues arise; in this case, the investigator will 
discuss a change of the basal rate with the sponsor clinical research physician (CRP) and 
implement this change, if necessary, to prevent any medical problems.  However, during the 
MMTT (approximately 6:00 AM to 2:00 PM on Days 1 and 3) and the high-glycemic index 
breakfast meal test (approximately 6:00 AM to 2:00 PM on Day 2), the basal rate will be 
changed to a single hourly rate based on the patient’s mean basal needs during the meal test 
period.  For all lunch and dinner meals during the inpatient periods, the patients’ individual CSII 
basal rate will be continued unchanged.
Assessment of local tolerability at all catheter insertion sites will be performed as specified in the 
Study Schedule (Section 2), including visual analog scale (VAS) scores for pain and inspection 
of the catheter insertion site for signs such as edema, erythema, and rash.
For each meal test day (Days 1, 2, and 3), serial blood samples will be collected over 
approximately 300 minutes to assess the PK and GD responses following start of the breakfast 


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LY900014
meal test, as specified in the Study Schedule (Section2).  For each standardizedlunch and dinner 
mealon Days 1 through 3,the GD responsewill be assessed using continuous glucose 
monitoring (CGM)following start of the meals.
5.1.1. Inpatient Procedures
Patients will arrive at the CRU in the early evening of Day
 –1 (approximately 5:00 PM),and a 
CGM system will be inserted before the start of a standardized dinner (at approximately 
7:00PM).  Astandard system will be used for CGM (for example, 
). The 
patients will wear this device during all inpatient days. The CGM device will be calibrated using 
the plasma glucose values obtained with the 
by site personnel.
Regular monitoring of blood glucose using the 
 (approximately every 
2 hours) will be performed during the complete inpatientperiod outside of the breakfast meal test
procedures.
The catheter needle will be inserted during the evening of Day –1 and should stay at the same 
catheter insertion-site location for the duration of each period (3 days).  If the patient needs to 
change the catheter during the study period (between Day1 to Day 3), the patient may repeat that 
study period onceonly if the maximum blood loss over the entire study (that is, the blood loss 
during the past periods and the expected blood loss of upcoming periods) will not exceed 
approximately 550mL.  The patient will not be withdrawnfrom the studyeven if theperiod 
cannot be repeated.
AbreakfastMMTTof fixed nutrient composition will be administered on Day 1 and Day 3, and 
a high-glycemic index breakfast test mealwill be administered on Day 2for each of the 
4treatment periods.  Additionally, a standardizedlunch will beadministered on Days1, 2,and 3,
and a standardizeddinner will be administered on Days 1 and 2.  A detailed description of the 
test mealsispresented in Section6.3.1.  Patients will be without further oral food intake from the 
start of eachmeal to completion of blood collection for the breakfast meals and to 5hoursafter 
the start of the mealfor the lunch and dinnermeals (approximately 300minutes) unless required 
to treat hypoglycemia, as defined by a plasma glucoselevel 
CCI
56mg/dL (3.1mM) or symptoms 
that require treatment as assessed by the investigator during the inpatient period that is reversed 
with either rapidly absorbable oral carbohydrates or IV glucose.  If a patient’s plasma glucose
concentration rises above 306 mg/dL (17 mM) for more than 1 hour, insulin glulisine (
) 
will be administered IV.  In both cases, blood samples for plasma glucose(for safety) will be 
taken,and PK samples will be collected as planned.
All LY900014 andHumalogdosesfor standardized meals as well as for snacks outside of the 
defined postmeal assessment periodswill be administered by qualified site staff using a 
 pump during the inpatient period (Day–1, starting after the 
administration of the standardized dinner,and continuingto Day 3).  Patients will use their own 
personal pump to administer Humalog during the lead-in and outpatient periods, including the 
Day–1 prandial Humalog dose taken before the start of the standardized dinner.
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5.1.1.1. Day –1 Study Activities
On Day –1 in each of the 4 periods, patients will arrive at the CRU in the early evening (at 
approximately 5:00 PM),and a CGM system will be inserted.  The patient’s short-acting insulin 
(Humalog) may be administered with their own pump before the start of a standardized dinner 
(at approximately 7:00 PM).  After the standardizeddinner, the 
pump 
reservoir will be filled by a qualified site staff member with either LY900014 or Humalog,and a 
standard infusion set and catheter will be inserted after a priming dose has been given to test the 
catheter.  The catheter should remain unchanged from approximately 8 hours beforethe startof 
the breakfastmeal on Day 1 to approximately 5hours after the start of the lunch mealon Day 3.  
In case of immediate infusion set intolerance, a new needle can be inserted up until 7 hours 
before bolus dosing.  Up to 6U of LY900014 or Humalogmay be administered as a bolus with 
the pump between 7and 12hours before the scheduled meal test.  Before the start of a run-in 
period, the cannulation of 2veins will be performed.
5.1.1.2. Day 1Study Activities
On Day 1, approximately 7hours before dosing, the run-in period will start with IV infusion of 
glucose (20% dextrose solution) or insulin (
) as needed to reach a target 
plasma glucoselevel of 126(±20)mg/dL (7.0[±1.1]mM).  If this target glucose level is not 
attained before 11:00 AM, the meal test will be halted and may be performed on a separate 
inpatient period; each meal test can only be repeated once.  During the run-in period, plasma 
glucoseconcentrations will be monitored approximately every30minutes.
The run-in period will end at approximately 30 minutes before the scheduled start time of the 
MMTTon Day 1.  The MMTT will start in the early morning at approximately 8:00 AM with 
allowance up to 11:00 AM, if required, to ensure the patient’s plasma glucoseis stable and at 
target, with the premeal activities as specified in the Study Schedule (Section2).  LY900014 or 
Humalogwill be given as a bolusdoseby a qualified staff member usingthe insulin pump 
(time0) according to the assignedtreatment administration mode (Mode 1 or Mode 2) 
immediately before the start of the test meal.  The prandial insulin dose (LY900014 or Humalog) 
will be 30% greater than the dose calculated from the patients’ individual insulin:carbohydrate 
ratioif the patients’ current insulin:carbohydrate ratio does not take into account the necessary 
dose adaptation for the fat content of the test meal(refer to Section5.5
CCI
for rationale).For each 
MMTT, the patient should stay in a semi-supine position for 2hours postdose,and the patient 
will not be allowed to consume water for 2 hours after dosing.
If a catheter occlusion alarm occurs <5 hoursafter the start of the MMTT, the data will not be 
used for analysis,and the MMTT can be repeated a maximum of 1 time.  Only data from the 
repeat MMTT will be used for analysis.
Patients will receive a standardizedlunch meal (the same standardizedlunch provided on Days 2 
and 3)at approximately 1:00 PMand at least5 hours after the start of the breakfast meal.  
LY900014 or Humalog bolus dose will be administered by a qualified staff memberas a 
standard or rapid dual-wave bolus usingthe insulin pump according to the assignedtreatment 
administration mode (Mode 1 or Mode4) immediately before the start of the lunch meal.  The 
prandial insulin dose (LY900014 or Humalog) will be 30% greater than the dose calculated from 
CCI


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the patients’ individual insulin:carbohydrate ratio if the patients’ current insulin:carbohydrate 
ratio does not take into account the necessary dose adaptation for the fat content of the test meal.
Patients will receive a standardizeddinner meal(the same standardizeddinner provided on 
Day–1and Day 2) at approximately 7:00 PMand at least 5hours after the start of the lunch 
meal.  LY900014 or Humalog will be given as a standard or rapid single-wave bolus dose using
the insulin pump according to the assignedtreatment administration mode (Mode 2or Mode 3) 
immediately before the start of thedinnermeal.  The prandial insulin dose (LY900014 or 
Humalog) is individually selected by the patient according to their individually calculated dose 
and/or insulin:carbohydrate ratio.
5.1.1.3. Day 2Activities
Patients stay at the CRU overnight and will be testedfor plasma glucoseapproximately every 
hourduring the night (from completion of the Day–1 standardized dinnerto 30 minutes before 
Day 2 dosing)by qualified site staff. If plasma glucoselevels fall outside the targeted glucose 
range(that is, hyperglycemia or hypoglycemia), the site staff willintervene by administering 
glucose orallyor IV,or insulin (
) SCor IVup to 6 hours beforethe start 
of the planned test meal(approximately 2AM on Day 2).  If the patient requires glucose or 
insulin treatment duringthe 6 hours before the meal,the Day2 high-glycemic test meal will not 
be performed (test will be handled as missing data). In this case,patientswill receive a 
standardized breakfast (same breakfast as on Days 1 and 3)using a bolus dose selected by the 
investigator based on the preprandial glucose level and the patients’ individual 
insulin:carbohydrate ratio,but no PK,GD,or other assessments (for example,local tolerability) 
will be performed.  After the overnight fast,the target plasma glucoselevel before the start of the 
test meal should be between71and180mg/dL (3.9to 10.0mM).The same reservoir and 
catheter inserted on Day–1 will be used by the site staff to administer the patient’sbolusdose
using the 
 with the single-wave, standard or rapid bolus delivery 
mode as per the randomization schedulebefore the start of the standardized high-glycemic index 
breakfast.  The patient should stay in a semi-supine position for 2hours postdose,and the patient 
will not be allowed to consume water for 2 hours after dosing.
The lunch meal and dinner meal procedureswill be performed as described above for the Day1 
procedures.
5.1.1.4. Day 3Activities
CCI
Before the start of the run-in period, the cannulation of 2veins will be performed.  On Day3, 
approximately 7hours before dosing(approximately 1:00AM), the run-in period for the Day3 
MMTT will start.  The run-in period,breakfast MMTT, and lunch meal procedureswill be 
performed as described above for the Day1 procedures.
If a catheter occlusion alarm occurs <5hours after the start of the MMTT on Day 3, the data will 
not be used for analysis and the entire periodcan be repeated a maximum of 1 time.  If catheter 
occlusion occurs >5 hours after the start of the MMTT on Day 3, the data will be used for 
analysisfor the breakfast meal test,but the lunch test meal on Day 3 willbe omitted and handled 
CCI


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as missing data,and the patient will have the catheter and CGM system removed.  A new 
catheter will be inserted for use with the patient’s own insulin pump.
After the Day 3 lunch meal procedures are completed(approximately 5 hours after the start of 
the lunch meal), the catheter and CGM system will be removed.  A newcatheter will be inserted 
for use with the patient’s own insulin pump.  However, if the patient plans to stay at the clinic 
until that evening (approximately 5:00 PM) for Day –1procedures for the next period, the new 
catheter and reservoir will not be inserted until after the standardizeddinner (at approximately 
7:00PM) is given (Day –1for the following period).
Additionally, a macroscopic andmicroscopic check of the removedcatheter and catheter tubing 
will be performed on site, ideally immediately after removing but within 120 minutesto exclude 
micro-occlusions and/or particles in the tubing.
5.1.2. Outpatient Procedures
For the time between consecutive periods, patients will continue their CSII therapy with their 
own pump using Humalog until the evening of Day –1(after completing the Day–1standardized
dinner) of the next meal test period when they will receive either the LY900014 or Humalog
with a 
, according to their assigned treatment.  Patients will be 
instructed to perform regular blood glucose monitoring consisting of a minimum of daily 4-point 
self-measured plasma glucoseprofiles (preprandial for 3 meals [that is,breakfast, lunch, and 
dinner] and at bedtime) using their own glucose meters.  Patients will be instructed to use a diary 
to document any AEs, hypoglycemic events,meals(time, units of carbohydrate equivalent), 
insulin bolus dosesand basal rate changes, and the self-measured plasmaglucose values.  The 
source data for self-measured plasmaglucose values will be the patient’s diary.  Upon return to 
the CRU on the evening of Day –1, the diary will be reviewed and checked for hy
poglycemic 
events and AEs.  The individual insulin doses may be adapted by the investigator for the 
outpatient period if clinically indicated to prevent significant hyperglycemia or hypoglycemia.  
Additionally, as determined by the investigator, interim telephone visits may occur at any time 
during the outpatient periods to review the safety and well-being of the patient.
5.2. Number of Participants
Initially, 24patients will be enrolled to target approximately 20patients to complete all 4periods 
of the study.  Patients who drop out may be replaced, up to a maximum of 30 total patients 
enrolled, to ensure 20completers; the replacement patient will adopt all assigned treatments of 
the original patient’s randomization scheduleand complete all 4study periods.
5.3. End of Study Definition
End of the studyis the date of thelast visit or last scheduled procedure shown in the Schedule of 
Activities(Section2) for the last patient.
5.4. Scientific Rationale for Study Design
CCI
The study is a 4-period crossover design to reduce thevariability of insulin PKand GDas each 
patient will act as his/her own control. On Days 1 and 3,each patient will undergo an insulin 


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administration using different bolus delivery modes (standard single-wave or standard dual-wave
boluses) with LY900014 and Humalog before a solid, individually standardized breakfast test
meal (MMTT) is administered; the standard dual-wave mode of administration will be compared
to a standard single-wave (traditional) insulin administration via CSII. This design enables the 
optimization of a bolus delivery for both LY900014 and Humalog by monitoring the PK and GD
properties (Luijf et al. 2013). To improve the comparability of the GD effects on Days 1 and 3,
an overnight run-in period using a variable insulin and glucose IV infusion has been introduced. 
This run-in aims to achieve similar preprandial glucose levels for all patients before the start of 
the test meal and thereby reduces the variability of the postprandial glucose response. Insulin 
glulisine has been chosen for the IV optimization of plasma glucose during the run-in because 
insulin glulisine does not cross-react with the insulin lispro–specific assay used for the PK 
analysis. Because this run-in procedure requires a 7-hour fasting interval before the start of a test
meal procedure, the run-in can only be implemented overnight and not for the planned lunch and 
dinner test meals. The run-in is also not implemented the night before the Day 2 test meal to 
better mimic the Phase 3 environment in which this meal will be used.
On Day 2, a high–glycemic index breakfast test meal will be administered, comparable to the 
one chosen for future Phase 3 studies, to test if a rapid or a standard single-wave bolus delivery 
will have an impact on the postprandial glucose excursions. Since LY900014 is a new 
formulation of the already marketed short-acting analog, Humalog, the latter is the best 
comparator to assess potential differences in clinical utility of this novel formulation.
On Days 1, 2, and 3, standardized lunches will be served, and on Days 1 and 2, standardized 
dinners will be served. The postprandial glucose profiles after these lunches and dinners will be 
assessed using CGM. For these meals, additional bolus administration options will be tested: 
standard versus rapid dual-wave bolus administration for lunch test meals and standard versus
rapid single-wave bolus administration for dinner test meals. The standardization of the lunch 
and dinner meals allows the testing of other bolus delivery forms in a controlled environment,
and the use of CGM enables the analysis of postprandial glycemic excursions while minimizing
the blood loss associated with multiple blood glucose samples.
Under this design, for any 2 consecutive days of a period, the interval between the last bolus on 
the first day and the first bolus on the second day is much longer compared to the length of time 
that the treatment (LY900014 or Humalog) lasts in the bloodstream; therefore, no carryover 
effect is assumed (from Day 1 to Day 2 or from Day 2 to Day 3). This enables PK and GD data 
from the breakfast meal tests on Days 1 and 3 and Day 2 to be analyzed independently and 
separately.
5.5.
Justification for Dose
The bolus dose of insulin lispro (LY900014 or Humalog) will be individualized per patient to 
cover the carbohydrate content of both the standardized meals while inpatient at the CRU and 
meals consumed during the outpatient time period(s) and will be based on the patient’s 
individually calculated dose and/or insulin:carbohydrate ratio; the doses used for the MMTTs 
(Days 1 and 3) and lunch meals (Days 1, 2, and 3) during the inpatient periods will be 


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30% greater than the dose calculated from the patient’s individual insulin:carbohydrate ratio if 
the patient’s current insulin:carbohydrate ratio does not take into account the necessary dose 
adaptation for the fat content of the test meal because literature data show that the prandial 
insulin requirements for MMTTs are 17% to 124% greater for a mixed meal containing a 
substantial amount of fat compared to a meal with the same carbohydrate content but only a 
minimal amount of fat (Bell et al. 2016). For each patient, the individualized prandial insulin 
lispro dose in LY900014 and Humalog for each test meal must be kept identical throughout the 
crossover periods.  The prandial doses of Humalog can be adapted during the outpatient period if 
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6. Study Population
Eligibility of patients for study enrollment will be based on the results of a screening medical 
history, physical examination, vital signs, clinical laboratory tests, and electrocardiograms 
(ECGs).  The nature of any conditions present at the time of the physical examination and any 
preexisting conditions will be documented.
Screening may occur up to 21 days before the lead-in period.  Patients who are not enrolled 
within 21 days of screening may be subjected to an additional medical assessment and/or clinical 
measurements to confirm their eligibility.
Individuals who do not meet the criteria for participation in this study (screen failure) will not be 
rescreened.
Prospective approval of protocol deviations from recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Patients are eligible for enrollment in the study only if they meet all of the following criteria at 
screening and/or enrollment:
[1]
are male or female patients with T1DM for at least 1 year.  A diagnosis of 
T1DM is based on medical history with a fasting C-peptide ≤0.30 nmol/L
[1a] male patients:  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
[1b] female patients:

women of childbearing potential may participate and include those 
who test negative for pregnancy before initiation of treatment based 
on a serum pregnancy test and agree to use 1 highly effective method 
of contraception or a combination of 2 effective methods of 
contraception during the study and for 1 month following the last dose 
of the investigational product

women of nonchildbearing potential may participate in the study 
without using adequate contraceptive methods and include those who 
are:
o
infertile due to surgical sterilization (hysterectomy, bilateral 
oophorectomy, or tubal ligation) or congenital anomaly such as 
Müllerian agenesis; or


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o postmenopausal,defined aswomen aged <52 years and being 
amenorrheic for more than 1year with aserum follicle-stimulating 
hormone (FSH)level compatible with postmenopausal status
(positive FSH level),or aged ≥52 years and being amenorrheic for 
<1year and with a serum FSH level compatiblewith 
postmenopausal status or aged ≥52 years being amenorrheic for 
more than 1year
[2] are aged between 18 and 70years, inclusive, at the time of screening
[3] have a body mass index (BMI) ranging from 18.5 to 33.0kg/m2at screening,
inclusive
[4] haveclinical laboratory test results within normal reference range for the 
population or investigator site or results with acceptable deviations that are 
judged to be not clinically significant by the investigator
[5] have a hemoglobin A1c (HbA1c) of <9.0% atscreening
[6] have had no episodes of severe hypoglycemia in the past 6 months (severe 
hypoglycemia is defined as having neurological symptoms consistent with 
neuroglycopenia and having required assistance in treatment by a second 
party)
[7] are currentlyon CSIItherapy,with a total insulin dose ≤1.5U/kg/day and are 
willing to use a standard pump 
) and standard 
catheter and infusion set for the duration of the study
[8] have venous access sufficient to allow for blood sampling andIV infusions as 
per the protocol
[9] are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures
[10]have given written informed consent approved by Lilly and the ethical review 
board (ERB) governing the site
6.2. Exclusion Criteria
CCI
Patients will be excluded from study enrollment if they meet any of the following criteriaat 
screening and/or enrollment:
[11]are investigativesite personnel directly affiliated with this study and their 
immediate families.  Immediate family is defined as a spouse, parent, child, or 
sibling, whether biological or legally adopted
[12]are Lilly employees or employees of the investigator site/CRU
[13]are currently enrolled in a clinical trial involving an investigational product or
any other type of medical research judged not to be scientifically or medically 
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CCI
[14]have participated, within the last 30 days, in a clinical trial involving an 
investigational product.  If the previous investigational product has a long 
half-life, 3 months or 5 half-lives (whichever is longer) should have passed
[15]are persons who have previously completed or withdrawn from this study
[16]have known allergies to treprostinil ( 
), insulin lispro,  
 
, related compounds, or any components of the formulation;
or have a history of significant atopy
[17]have an abnormality in the 12-lead ECG that, in the opinion of the 
investigator, increases the risks associated with participating in the study
[18]have an abnormal blood pressure as determined by the investigator, or results 
with unacceptable deviations that are judged by the investigator to be 
clinically significant for the population
[19]have a significant history of or current cardiovascular, respiratory, hepatic, 
renal, gastrointestinal, endocrine (apart from T1DM), hematological, or 
neurological disorders capable of significantly altering the absorption, 
metabolism, or elimination of drugs; of constituting a risk when taking the 
investigational product; or of interfering with the interpretation of data
[20]have known slowing of gastric emptying and or gastrointestinal surgery that, 
in the opinion of the investigator, might change gastrointestinal motility and 
food absorption
[21]have significant lipohypertrophy in the target abdominal injection area as 
judged by the investigator
[22]have proliferative retinopathy or maculopathy and/or severe neuropathy; in 
particular, autonomic neuropathy as judged by the investigator based on a 
recent (<1.5 years) ophthalmologic examination
[23]have known or ongoing psychiatric disorder(s)
[24]regularly use known drugs of abuse and/or show positive findings on urinary 
drugscreening
[25]show evidence of human immunodeficiency virus (HIV) infection and/or 
positive HIV antibodies
[26]show evidence of hepatitis C and/or positive hepatitis C antibody
[27]show evidence of hepatitis B and/or positive hepatitis B surface antigen
[28]are women who are lactating
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[29] have, except for current regimen of insulin therapy and concomitant 
medication (for example, antihypertensives, lipid-lowering agents), regular 
use of or intended use of any over-the-counter or prescription medications or 
nutritional supplements that treat hyperglycemia or insulin resistance or that 
promote weight loss within 14 days before dosing (apart from vitamin/mineral 
supplements, ibuprofen, hormone/thyroid-replacement therapy, or hormonal 
contraceptives)
[30] have intended use of over-the-counter or prescription medications containing 
acetaminophen (paracetamol) during the study
[31] have regular use of or intended use of known inducers or inhibitors of 
cytochrome P450 [CYP]2C8 or niacin.  Patients taking these medications 
before study enrollment will be eligible with an appropriate washout period 
which will be evaluated by the investigator in consultation with the Lilly CRP
[32] had blood loss of more than 500 mL within the last month
[33] 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
[34] are currently a smoker, used tobacco products on a regular basis in the 
6 months before screening, or are intending to smoke during the study period
[35] are receiving chronic (lasting longer than 14 consecutive days), systemic, or 
inhaled glucocorticoid therapy (excluding topical, intra-articular, and 
intraocular preparations); or have received such therapy within the 4 weeks 
before screening
[36] in the opinion of the investigator or sponsor, are unsuitable for inclusion in the 
study
6.2.1. Additional Exclusion Criteria for Inpatient Dosing Days
Patients who fulfill 1 or more inpatient dosing-day exclusion criteria will be excluded from the 
MMTT(s) for that treatment period.  For each patient, 1 treatment period can be rescheduled 1 to 
7 days later.  A patient may be replaced if he/she has already missed more than 1 period.
The following exclusion criteria apply to before each inpatient visit:
[37] consumption of alcohol within 24 hours before each of the inpatient periods or 
a positive result of the alcohol breath test
[38] positive drug screen
[39] positive pregnancy test


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[40] consumption of coffee, tea, chocolate, cola, and/or energy drinks containing 
methylxanthine (caffeine, theophylline, or theobromine) within 12 hours 
before each test meal
[41] strenuous exercise within 24 hours before each test meal
[42] any medical condition or AE that could interfere with glucose metabolism, as 
judged by the investigator
[43] any use of prescription or nonprescription medication according to Exclusion 
Criteria [29] through [31]
[44] hypoglycemia during the treatment period and <24 hours before dosing that 
poses a significant risk to patient safety, as judged by the investigator
[45] injection of a bolus of more than 6 U of a fast-acting insulin analog between 
7 and 12 hours before dosing
[46] change of catheter site during a treatment period from approximately 8 hours 
before the start of the breakfast meal on Day 1 to approximately 5 hours after 
the start of the lunch meal on Day 3
6.3.
Lifestyle and/or Dietary Requirements
Before beginning the study, the patients will complete an informed consent form (ICF) and 
screening tests.
Throughout the study, patients may undergo medical assessments and/or a review of compliance 
with requirements before continuing in the study.  Patients should continue to meet the 
restrictions related to meals, alcohol, tobacco, caffeine, and medication use.
6.3.1. Meals and Dietary Restrictions
While resident in the CRU, patients may not consume any food or caloric drinks other than that 
provided by the CRU.  When not resident in the CRU, patients may resume their regular diet.
6.3.1.1.
Mixed-Meal Tolerance Test on Day 1 and Day 3
Patients will be provided individualized breakfast meals for the MMTTs on Day 1 and Day 3, as 
outlined in the Study Schedule (Section 2).  The total caloric content will be approximately 
30% of the daily estimated caloric need for weight maintenance.  The macronutrient composition 
of the meals should be targeted to provide approximately 50% of the calories from carbohydrate, 
30% of the calories from fat, and 20% of the calories from protein.  Patients will be fasted 
(except for water) for at least 10 hours before each test meal and consume each meal within 
approximately 20 minutes.  Test meals for each patient will be kept consistent with respect to 
calorie and nutrient content across Day 1 and Day 3 MMTT assessments in the study.  The 
patient will not be allowed to consume water for 2 hours after dosing apart from fluid provided 
with the meal; however, water may be consumed freely after 2 hours postdose.
The time of meal start and completion, the total calories and grams of carbohydrates consumed
in the MMTT, the high-glycemic index meal (Section 6.3.1.2), and the standardized lunch and 


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dinner meals (Section6.3.1.3) during theinpatient stays will be captured in the study case report 
form (CRF).
6.3.1.2. High-Glycemic Index Meal Test on Day 2
In the morningof Day 2 in each period, patients will be provided a high-glycemic index
breakfast meal (Section2)consisting of a solid nutrition bar(such as 
) and a liquid nutrition shake(such as
)
that has atotal caloric content of approximately 550 kcal and is expected to be representative of 
the test meal planned forfuturePhase 3 studies.  The macronutrient composition of the meals 
should be targeted to provide approximately 50% of the calories from carbohydrate, 30% of the 
calories from fat, and 20% of the calories from protein.  Patientswill be fasted (except for water) 
for at least 10 hours beforeeachtest meal and consume each meal within approximately 
15minutes.  Test meals for each patient will bekept consistent with respect to calorie and 
nutrient content across all Day 2 meal testassessments in the study.  The patient will not be 
allowed to consume water for 2 hours after dosing apart from fluid provided with the meal; 
however, water may be consumed freely after 2 hours postdose.
6.3.1.3. Lunch and Dinner Meals
Patients will be provided individualized standardizedlunchmeals on Days 1, 2, and 3 and 
individualized standardizeddinnermeals on Days 1 and 2, as outlined in the Study
 Schedule 
(Section2).  The macronutrient composition of the meals should be targeted to provide 
approximately 50% of the calories from carbohydrate, 30% of the calories from fat, and 20% of 
the calories from protein.  Patients will consume each meal within approximately 20minutes.  
Lunch and dinnermeals for each patient will be kept consistent with respect to calorie and 
nutrient content.
6.3.2. Caffeine, Alcohol, and Tobacco
Patients should refrain from food/beverages containing caffeine(for example, cola, chocolate 
drinks, tea, coffee, energy drinks containing methylxanthine [caffeine, theophylline, or 
theobromine]) for at least 12 hours before each CRU admissionand throughout the duration of 
each CRU visit.
No alcohol will be allowed at least 24 hours before each CRU admission (Day–1) and 
throughout the duration of each CRU visit.  Between CRU visits, daily alcohol consumption
should not exceed 3 units for males and 2 units for females (a unit is defined in Exclusion 
Criterion [33], Section6.2).
No cigarette smoking will be permitted during the study.
6.3.3. Activity
CCI
Patients will be encouraged to maintain their regular exercise and insulin regimen adaptation 
related to exercise during the outpatient period; however, they should not undertake vigorous or 
prolonged exercise at least 24 hours before each dosing day at the CRU.  Movement will be 
restricted to retain the integrity of connections to infusion(s) and the study procedures.
CCI


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6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) will not be 
rescreened.


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7.Treatment
7.1. TreatmentAdministered
7.1.1. Investigational Medicinal Product
The drug product, LY900014,will be providedasasolution formulation in sterile glass vials. 
LY900014 is composed of insulin lispro drug substance and the followingexcipients: sodium 
citrate, zinc chloride, magnesium chloride, glycerin, m-cresol, andtreprostinil.The vial is 
formulated to deliver 100 units of insulin lispro per milliliter ofLY900014.
Humalog administered as aReference during the inpatient treatment (Periods 1 to 4)will be 
considered as an investigational medicinal product. Commercially available10-mL vials will be 
over-labeled.  The vial is formulated to deliver 100units of insulin lispro per milliliter of 
Humalog.An unblinded pharmacist at the site will fill the pump reservoirs and attribute them to 
the respective patientsas per randomization schedule.
Both LY900014 and theReference (Humalog) used during the inpatient periods of the study will 
be supplied by the sponsor; bothwill be packaged and labeled for clinical trialuse.
7.1.2. Noninvestigational Medicinal Products
For daily dosing during the 1-week lead-in period and between study periods, patients will be 
provided with commercially available Humalog 10-mL vials for infusion; in these situations, 
Humalog will be considered as a noninvestigational medicinal productfor study procedures.  
Commercially available 
) and 20% dextrose will be used for the 7-hour 
run-in period before the start of the MMTTs on Days 1 and 3 and can be used up to 
approximately 6hoursbefore the start of the Day2 breakfasttest meal.  Inaddition, if a patient’s 
plasma glucoseconcentration rises above 306mg/dL(17mM) for more than 1hour during the 
meal test,
 will be administered.Apidra or IVglucose can also be administered during the 
complete inpatient period outside of the testmeal procedures if required to treat hypo-or 
hyperglycemia at the discretion of the investigator.
The dosesof Humalog, 
,and glucoseadministered during the trial must be recorded in the 
CRF.
Humalog used as a noninvestigational medicinal product will be supplied by the sponsor.  All 
othernoninvestigational medicinal products will be sourced locally by the siteand will be used 
from theiroriginal packaging.
7.1.3. Inpatient Dosing
CCI
During inpatient stays(Day –1, starting after the administration of the standardized dinner, to 
Day 3), all study drug will be administered with a 
.  A 
standardized catheter with a 6-mm needle length will be inserted on the day before the first meal 
test is administered (Day –1) during each period, and the catheter site must remain the same until 
the lunch meal procedureson Day3 havebeen completed.  Catheter insertion sites selected 
should be in the abdominal area,and the treatment will be administered SC.  Catheter insertions 
CCI
CCI
CCI


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LY900014
should be performed by a limited number of qualified and appropriately trained site personnel as 
designated by the investigatorfor consistency.
The insulin pump reservoir will be filled with either LY900014or Humalog by qualified site 
staff while maintaining the blind for the investigator and patient.
Unless the patient decides to stay in the CRU for the next study period, after each period, the 
 will be changed to the patient’s own personal pump and the 
catheter will be changed.
7.1.4. Outpatient Dosing
For the time between consecutive periods, patients will continue their CSII therapy with their 
personal pump using Humalog until the evening of Day –1(after administration of the 
standardized dinner) of the next meal test period when they will receive either the LY900014or 
Humalog, according to their assigned treatment.
Patients will be asked to record the date,time,and dosagesof prandial and basal Humalogdoses
in a patient diarybetween study periods.
7.1.5. Packaging and Labeling
LY900014 will be supplied by Lilly or its representative in accordance with current good 
manufacturing practicesand will be supplied with lot numbers.  Reference drug will be 
commercially available insulin lispro (HumalogU-100) supplied by Lilly.
The study insulinswill be provided to the site unblinded. The glass vialswill each contain 
10mL ofeither LY900014 or Humalogwithan insulin lisproconcentration of 100 U/mL.An 
unblinded pharmacist at the site or other site personnel who are unblinded will use the insulin 
vials provided to prepare the blinded vials.
7.2. Method of Treatment Assignment
Each patient will be randomized to 1 of 4 treatmentsequences (4 periods per sequence) 
comprising of LY900014 or Humalog, administered as a CSII with different bolus administration 
modes, determined according to a randomization schedule.
7.2.1. Selection and Timing of Doses
For each meal test, the doses will be administered at time “0,” immediately before the start of a 
test meal.  The test meal will be given at approximately the same time on Days 1, 2,and 3 of 
each study period.  Specific patient restrictions are described in Section6.3.  The actual time of 
all dose and test meal administrations will be recorded in the patient’s CRF.
7.3. Blinding
CCI
This is a patient-and investigator-blind study.  Blinding will be maintained throughout the 
conduct of the trial until all data are cleaned to an acceptable level of quality and locked.  The 
details are included in the blinding/unblinding plan.


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To preserve the blinding of the study, only a minimum number of personnel at the site will see 
the randomization table and codes before the study is complete.
Emergency codes will be available to the CRU.  A code, which reveals the treatment group for a 
specific study patient, may be opened during the study only if the patient’s well-being requires 
knowledge of the patient’s treatment assignment.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted for medical management of the event.  Patient 
safety must always be the first consideration in making such a determination.  If the investigator 
decides that unblinding is warranted, the investigator should make every effort to contact the 
Lilly clinical pharmacologist or CRP before unblinding a study patient’s treatment assignment
unless this could delay emergency treatment of the patient.  If a study patient’s treatment 
assignment is unblinded, Lilly must be notified immediately.
Upon completion of the study, all codes must be returned to Lilly or its designee.
7.4.
Dose Modification
For the inpatient period, there will be no dose modifications of LY900014 for the meal tests and 
basal rates unless medically indicated and confirmed between the sponsor CRP and the 
investigator.
For the outpatient period, the individual insulin doses may be adapted by the investigator if 
clinically indicated to prevent significant hyperglycemia or hypoglycemia.
7.5.
Preparation/Handling/Storage/Accountability
LY900014 and Humalog will be provided to the site by the sponsor.
Patients will be supplied with a standard infusion set at the lead-in visit.
The investigator or designee is responsible for:

explaining the correct use of the investigational agents to the site personnel;

verifying that instructions are followed properly;

maintaining accurate records of investigational product dispensing and collection; and 

returning all unused medication to Lilly or its designee at the end of the study.
Note:  In some cases, sites may destroy the material if, during the investigator site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose clinical trial materials.
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
All clinical study material provided to the investigator will be stored in a secure place and 
allocated and dispensed by appropriately trained persons.  The allocation and dispensing of the 


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investigational products will be fully documented and verified by a second person.  Detailed 
records of the amounts of the investigational product received, dispensed, and remaining at the 
end of the study will be maintained. The investigator site will be permitted to destroy the 
investigational material after written approval is obtained from the sponsor and must retain 
appropriate documentation for the destruction of the material.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (such as
receipt, reconciliation, and final disposition records).
7.6.
Treatment Compliance
Every attempt will be made to select patients who have the ability to understand and comply with 
instructions.  Noncompliant patients may be discontinued from the study.  The time and day of 
drug administration will be recorded.  Drug accountability records will be maintained by the 
study site.
The specifications in this protocol for the timings of safety (including pain and insertion-site 
assessments), PK, and GD sampling are given as targets, to be achieved within the time windows 
described in the study-specific CRF completion guidelines. Modifications may be made to the 
time points based upon the safety and PK information obtained.  The scheduled time points may 
be subject to minor alterations; however, the actual time must be correctly recorded in the CRF.  
Failure to obtain samples and perform protocol-specific procedures outside the allowable time 
window because of clinical issues, such as problems with venous access, technical problems with 
equipment, or problems with patient no-show for scheduled procedures, will not be considered a 
protocol deviation but the site will still be required to notify the sponsor in writing.  Written 
documentation (for example, a note-to-file) will have to be provided to the sponsor for all 
missing or delayed samples and procedures (regardless of reasons) to facilitate data 
reconciliation before study completion.
Any major modifications that might affect the conduct of the study, patient safety, and/or data 
integrity will be detailed in a protocol amendment.
7.7.
Concomitant Therapy
Patients on stable concomitant medication at the time of study entry should continue their 
regular, unchanged dose throughout the study.  Patients will continue their basal insulin infusion 
rate during the entire study except when presenting safety issues and during the breakfast test 
meal period as defined in Section 5.1; in case of safety-driven indications for a basal-rate 
adaptation, the investigator will discuss a change of the regimen of insulin basal rate to prevent 
any medical problems.  Any change in the basal rate will be captured in the patient diary and 
CRF.
Patients should not use over-the-counter or prescription medication (other than their current 
regimen of insulin therapy and concomitant medication [for example, antihypertensives, 
lipid-lowering agents] at enrollment) or nutritional supplements that affect blood glucose or the 
body’s sensitivity to insulin or that promote weight loss 14 days before dosing (apart from 


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vitamin/mineral supplements, ibuprofen, hormone/thyroid-replacement therapy, or hormonal 
contraceptives) or throughout the study (refer to Section 6.2).  Drugs or supplements that are 
known inducers or inhibitors of CYP2C8 are not permitted as they may alter the PK of 
treprostinil.
Patients should not use over-the-counter or prescription medications containing acetaminophen 
(paracetamol) because it is known to interfere with CGM sensing, resulting in falsely elevated 
CGM glucose values.
Patients should not apply any creams or lotions to the abdominal skin on the morning of the 
catheter insertion or during the inpatient study procedure.
If the need for concomitant medication arises (for example, to treat an AE or infusion-site pain), 
inclusion or continuation of the patient may be at the discretion of the investigator, preferably 
after consultation with a Lilly clinical pharmacologist or CRP.  Any additional medication used 
during the course of the study must be documented.
7.8.
Treatment after the End of the Study
LY900014 will not be made available to subjects after conclusion of the study.


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8. Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
Discontinuation of the investigational product for abnormal liver tests should be considered by 
the investigator when a patient meets one of the following conditions after consultation with the 
Lilly designated medical monitor:

alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) >5X upper limit of normal (ULN)

ALT or AST >3X ULN along with one of the following criteria
o
sustained for more than 2 weeks or
o
total bilirubin level >2X ULN or
o
prothrombin time >1.5X ULN or
o
appearance of fatigue, nausea, vomiting, right upper-quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%)

alkaline phosphatase (ALP) >3X ULN

ALP>2.5X ULN and total bilirubin level >2X ULN

ALP>2.5X ULN with the appearance of fatigue, nausea, vomiting, right 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
Patients who discontinue the investigational product early will have procedures performed as 
shown in the Schedule of Activities (Section 2).
8.1.1. Discontinuation of Inadvertently Enrolled Patients
If the sponsor or investigator identifies a patient who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Lilly clinical pharmacologist/CRP
and the investigator to determine if the patient may continue in the study.  If both agree it is 
medically appropriate to continue, the investigator must obtain documented approval from the 
Lilly clinical pharmacologist/CRP to allow the inadvertently enrolled patient to continue in the 
study with or without continued treatment with investigational product.
8.2.
Discontinuation from the Study
Patients will be discontinued in the following circumstances:

enrollment in any other clinical trial involving an investigational product or 
enrollment in any other type of medical research judged not to be 
scientifically or medically compatible with this study

participation in the study needs to be stopped for medical, safety, regulatory, 
or other reasons consistent with applicable laws, regulations, and good clinical 
practice (GCP)

investigator decision


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o
the investigator decides that the patient should be discontinued from 
the study
o
if the patient, for any reason, requires treatment with another 
therapeutic agent that has been demonstrated to be effective for 
treatment of the study indication, discontinuation from the study 
occurs before introduction of the new agent

subject decision
o
the patient or designee (for example, parents or legal guardian)
requests to be withdrawn from the study
Patients who discontinue the study early will have end-of-study procedures performed as shown 
in the Schedule of Activities (Section 2).
8.3.
Patients Lost to Follow-up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.


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9. Study Assessments and Procedures
Section 2 lists the Schedule of Activities, detailing the study procedures and their timing 
(including tolerance limits for timing).
Appendix 2 lists the laboratory tests that will be performed for this study.
Appendix 4 provides a summary of the maximum number and volume of invasive samples for all 
sampling during the study.
Unless otherwise stated in subsections below, all samples collected for specified laboratory tests 
will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may be 
retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
Investigators must document their review of each laboratory safety report.
9.1.
Efficacy Assessments
This section is not applicable for this study.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.
The investigator is responsible for the appropriate medical care of patients during the study.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important; that are considered related to the 
investigational product, the Humalog noninvestigational product, or the study; or that caused the 
patient to discontinue the investigational product before completing the study.  The patient 
should be followed until the event resolves, stabilizes with appropriate diagnostic evaluation, or 
is reasonably explained.  The frequency of follow-up evaluations of the AE is left to the 
discretion of the investigator.
After the ICF is signed, study site personnel will record, via the CRF, the occurrence and nature 
of each patient’s preexisting conditions, including clinically significant signs and symptoms of 
the disease under treatment in the study.  Additionally, site personnel will record any change in 
the condition(s) and the occurrence and nature of any AEs.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment or a study procedure, taking into account the disease, 
concomitant treatment, or pathologies.
A “reasonable possibility” means that there is a cause and effect relationship between the 
investigational product and/or study procedure and the AE.


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Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study.
If a patient’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via the CRF.
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

events considered significant by the investigator based upon appropriate 
medical judgment
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms.  This 
24-hour notification requirement refers to the initial SAE information and all follow-up SAE 
information.
Although all AEs are recorded in the CRF after signing informed consent, SAE reporting begins 
after the patient has signed informed consent and has received investigational product.  However, 
if an SAE occurs after signing informed consent but before receiving investigational product
AND is considered Reasonably Possibly Related to a study procedure, then it MUST be reported.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued from and/or completed the study (the patient summary CRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a patient has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly.
Pregnancy (maternal or paternal exposure to investigational product) does not meet the definition 
of an AE.  However, to fulfill regulatory requirements, any pregnancy should be reported 
following the SAE process to collect data on the outcome for both mother and fetus.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to investigational product or procedure. 
US 21 CFR 312.32 and EU Clinical Trial Directive 2001/20/EC and the associated detailed 
guidances or national regulatory requirements in participating countries require the reporting of 


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SUSARs.  Lilly has procedures that will be followed for the recording and expedited reporting of 
SUSARs that are consistent with global regulations and the associated detailed guidances.
9.2.2. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical trials in order to ensure the safety of study participants, to monitor quality, and to 
facilitate process and product improvements.
Patients should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
9.3.
Treatment of Overdose
Excess insulin administration may cause hypoglycemia. For the purposes of this study, an 
overdose of LY900014 is considered any dose higher than the calculated individualized dose to 
cover the carbohydrate content of meals consumed during the study.
Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug 
dosage, meal patterns, or exercise may be needed. More severe episodes with coma, seizure, or 
neurologic impairment may be treated with intramuscular/SC glucagon or concentrated IV 
glucose. Sustained carbohydrate intake and observation may be necessary because 
hypoglycemia may recur after apparent clinical recovery.
Refer to the IB for LY900014 and the package insert for insulin lispro (Humalog package 
insert 2015).
9.4.
Safety
9.4.1. Laboratory Tests
For each patient, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2).
Blood and urine samples will be collected to determine whether patients meet 
inclusion/exclusion criteria and to monitor patient health.  Routine clinical laboratory tests will 
be analyzed by a local laboratory.
9.4.2. Vital Signs
For each patient, vital signs 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.
If orthostatic measurements are required, patients should be supine for at least 5 minutes and 
stand for at least 2 minutes.
If the patient feels unable to stand, supine vital signs only will be recorded.


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Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms.  Additional vital signs may be measured during each study period if 
warranted and agreed upon between the sponsor and investigator.
Body temperature will be measured as specified in the Schedule of Activities(Section2) and as 
clinically indicated.
9.4.3. Physical Examination
Physical examinations and routine medical assessments will be conducted as specified in the
Schedule of Activities(Section2) and as clinically indicated.
9.4.4. Body Weight
Body weight will be recorded as specified in theSchedule of Activities(Section2) and as 
clinically indicated.
9.4.5. Electrocardiograms
For each patient, single 12-lead digital ECGs will be collected according to the Schedule of 
Activities(Section2).  ECGs must be recorded before collecting any blood for safety or PK tests.  
Patients must be supine for approximately 5 to 10 minutes before ECG collection and remain 
supine but awake during ECG collection.  ECGs may be obtained at additional times when 
deemed clinically necessary.  All ECGs recorded should be stored at the investigational site.
ECGs will be interpreted by a qualified physician (the investigator or qualified designee) at the
site as soon after the time of ECG collection as possible and ideally while the patient is still 
presentto determine whether the patient meets entry criteria at the relevant visit(s) and for 
immediate patient management, should any clinically relevant findings be identified.
If a clinically significant finding is identified (including, but not limited to, changes in QT/QT 
corrected for heart rate [QTc] interval from baseline) after enrollment, the investigator will 
determine if the patient can continue inthe study.  The investigator or qualified designee is 
responsible for determining if any change in patient management is needed and must document
his/her review of the ECG printed at the time of collection.  Any new clinically relevant finding 
should be reported as an AE.
9.4.6. Plasma GlucoseMonitoring
The patient’s plasma glucoseconcentrations will be monitored frequently at the times specified
in the Schedule of Activities(Section2
CCI
)using a 
 available at the site 
for safety assessments.
Additionally, patients will be instructed to conduct daily self-plasma glucosemonitoring at a 
minimum of 4time points (premeals:  breakfast, lunch, dinner;and bedtime) during the 
outpatient phase of the study.  Patients will be instructed to immediately report any episodes of 
hyperglycemia or hypoglycemia requiring an adaptation of the treatment regimen to the 
investigator, who will be responsible for advising the patient on what further actions to take.  


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Patients will be instructed to record the date, time, and result of each self-plasma glucose
monitoring test.  Additional monitoring may be requested at the investigator’s discretion.
Hypoglycemic episodes will be defined as clinical events with or without symptoms typical of 
hypoglycemia, accompanied by a plasma glucose level of ≤70 mg/dL (3.9 mM), which are 
reversed by oral carbohydrates or IV glucose.  These episodes will be captured in the CRF.  In 
addition, episodes that fulfillthe criteria of severe hypoglycemia as defined in Section9.4.9.1
will bereported as an SAE.  Investigator review of glucose results clinically indicative of 
hypoglycemia will be required.
Hypoglycemia is considered a therapeutic effect of insulin lispro and will generally not be 
considered a clinically significant drug-related AE but will be treated appropriately.  Additional 
monitoring of plasma glucoselevels may be performed at the discretion of the investigator.
9.4.7. Catheter Insertion-Site Assessments
Catheter insertion-site assessments, including inspection of the site for signs such as edema, 
erythema, and rash,will be conducted as specified in the Schedule of Activities(Section2)and 
as clinically indicated.
9.4.7.1. Subjective Procedure:  Examination of Infusion Set and Catheter
When the infusion set and reservoir are changed (except for Period 1, Day –1) at the site, a 
macroscopic (visual) and microscopic examination (ideally immediately after removing the 
catheter, but no longer than 120 minutes)will be performed including the following:
a check on the infusion set or the catheter for signs of kinking or other damage.  
In case of damage, the damage should be described in the CRF and photographic 
evidence should be taken
a check of the insulin in the reservoir and infusion-set tubing for color change and 
crystals and/or particles including the location of these (that is, reservoir, infusion set)
a microscopic check of the catheter tubing to exclude micro-occlusions and/or 
particles in the tubing
9.4.7.2. Subjective Procedure:  Acceptability of Insulin Delivery Experience
Subjects will be asked to providethe acceptability of their overall experience with the study 
insulin delivery via the 
 at the end of each study period, prior to 
discharge from theCRU.  If the subject plans to stay on after Day 3 and continue on to Day-1 
activities for the next period, the assessment will be performed after the Day 3 lunch meal 
procedures are completed (approximately 5 hours after the start of the lunch meal).
9.4.8. Pain Measurements Using the Visual Analog Scale
CCI
Pain measurements during bolus application will be assessed using the electronic version of the 
100-mm validated VAS (or electronic VAS [eVAS]) for pain.  The VAS is a well-validated tool 
(Williamson and Hoggart2005) to assess catheter insertion-site pain.  The eVAS (vanDuinen 
etal. 2008) is presented as a10-cm (100-mm) line, anchored by verbal descriptors, usually “no 
pain” and “worst imaginable pain.”  The patient is asked to mark the 100-mm line electronically 


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to indicate pain intensity.  The patient will be asked to rate any pain associated during each 
inpatient infusion on a scale of 0 to 100 mm immediately (within 1 minute) following the start of 
the infusion and will be asked to rate the pain at the catheter insertion site at time points 
according to the Schedule of Activities (Section 2) and as clinically indicated.
As catheter insertion-site pain is an expected AE, insertion-site pain (especially transient 
episodes of pain) will generally not be considered a clinically significant event unless the 
duration or intensity of the pain interferes with normal activities of daily living or constitutes a 
risk to the well-being of the patient.  Analgesia can be prescribed in response to pain and must be 
documented in the concomitant medication section of the CRF.
9.4.9. Safety Monitoring
The Lilly clinical pharmacologist or CRP/scientist will monitor safety data throughout the course 
of the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly clinical 
pharmacologist or CRP will consult with the functionally independent Global Patient Safety 
therapeutic area physician or clinical research scientist when appropriate and periodically 
review:

trends in safety data

laboratory analytes

AEs
If a study patient experiences elevated ALT ≥3X ULN, ALP ≥2X ULN, or elevated total 
bilirubin ≥2X ULN, clinical and laboratory monitoring should be initiated by the investigator.  
Details for hepatic monitoring depend on the severity and persistence of observed laboratory test 
abnormalities.  To ensure patient safety and compliance with regulatory guidance, the 
investigator is to consult with the Lilly designated CRP regarding collection of specific 
recommended clinical information and follow-up laboratory tests (Appendix 4).
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the group level, additional analyses of the safety data will be conducted by the personnel 
included in the unblinding/blinding plan.
9.4.9.1.
Glucose Monitoring
Hypoglycemia will be described using the following definitions:

Documented hypoglycemia:  
o
Symptomatic hypoglycemia: an event during which typical symptoms of 
hypoglycemia are accompanied by plasma glucose ≤70 mg/dL (3.9 mM)
o
Asymptomatic hypoglycemia: an event not accompanied by typical 
symptoms of hypoglycemia but with plasma glucose ≤70 mg/dL (3.9 mM)


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
Unspecified hypoglycemia:  an event during which plasma glucose 
≤70 mg/dL (3.9 mM) but no information relative to symptoms of 
hypoglycemia was recorded

Probable symptomatic hypoglycemia: an event during which symptoms 
indicative of hypoglycemia are not accompanied by a plasma glucose 
determination (but that was presumably caused by plasma glucose ≤70 mg/dL 
[3.9 mM])

Severe hypoglycemia:  an event requiring assistance of another person to 
actively administer carbohydrate, glucagon, or other resuscitative actions.  
During these episodes, the subject has an altered mental status and cannot 
assist in their own care, is semiconscious or unconscious, or experienced 
coma with or without seizures and may require parenteral therapy.  Plasma 
glucose measurements may not be available during such an event, but 
neurological recovery attributable to the restoration of blood glucose 
concentration to normal is considered sufficient evidence that the event was 
induced by a low plasma glucose concentration (≤70 mg/dL [3.9 mM])

Nocturnal hypoglycemia: any hypoglycemic event (documented 
symptomatic, asymptomatic, probable symptomatic, or severe hypoglycemia) 
that occurs between bedtime and waking

Relative hypoglycemia: an event during which typical symptoms of 
hypoglycemia, that do not require the assistance of another person, are 
accompanied by plasma glucose >70 mg/dL (3.9 mM), but these levels may 
be quickly approaching the 70-mg/dL (3.9 mM) threshold

Total hypoglycemia:  an optional category that combines all cases of 
hypoglycemia.  If an event which hypoglycemia falls into multiple 
subcategories, the event is only counted once in this category
Investigator review of documented glucose results in the diary or during the inpatient period that 
are clinically indicative of hypoglycemia will be required.
9.4.10. Immunogenicity Assessments
Blood samples for immunogenicity testing will be collected to determine antibody production 
against insulin lispro at the times specified in the Schedule of Activities (Section 2).  Additional 
samples may be collected if there is a possibility that an AE is immunologically mediated.  
Immunogenicity will be assessed using a validated radioligand-binding assay designed to detect 
anti-insulin lispro antibodies and characterize cross-reactivity to insulin.
Since the characterization of insulin antibodies is readily available, reliable on-market data exists 
showing that anti-insulin antibodies, while present, do not appear to be clinically consequential 
(Fineberg et al. 2003), and in vivo measures exist to allow for identification of those patients 
who may lose efficacy to insulin lispro; Lilly intends to use these measures (that is, HbA1c and 
serum glucose) as direct measures of a neutralizing effect.


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Samples will be retained for a maximum of 15 years after the last patientvisit, or for a shorter 
period if local regulations and ERBs allow,at a facility selected by the sponsor.  The duration 
allows the sponsor to respond to future regulatory requests related to the investigationalproduct.  
Any samples remaining after 15 years will be destroyed.
9.5. Pharmacokinetics
Venous blood samples of approximately 1mL each will be collected to determine the serum 
concentrations of insulin lispro at the visits and times specified in the Schedule of Activities
(Section2).  The actual date and time (24-hour clock time) of each sampling will be recorded.
The time points for insulin lispro blood sampling may be modified during the study if warranted 
and agreed upon between both the investigator and sponsor, but no additional samples will be 
drawn.  Instructions for the collection and handling of blood samples will be provided by the 
sponsor.
Drug concentrationinformation that would unblind the study will not bereported to the 
investigative siteor blinded personnel until the study has been unblinded.
9.5.1. Bioanalysis
Samples will be analyzed at a laboratoryapproved by the sponsor and stored at a facility 
designated by the sponsor.  Serum samples will be analyzed for insulin lispro concentrations 
using a validated enzyme-linked immunosorbent assay (ELISA)thatis specific for insulin lispro.  
Samples remaining after the bioanalyses may be used for exploratory analyses.
Bioanalytical samples collected to measure insulin lisproconcentrations will be retained for a 
maximum of 1 year following last patient visit for the study.
9.6. Pharmacodynamics
Blood samples (approximately 0.2 mL each) will be collectedfor the measurement of plasma 
glucose at the times specifiedin the Schedule of Activities(Section2)using a validated method 
(for example, 
) that will be readily available at the investigative site 
during the inpatient periods in order to provide real-time glucose measurement.  Repeat samples 
for counterchecking of apparent spurious results may be taken whenindicated.
The sampleswill be discarded after analysis and/or confirmation of results.
9.6.1. Glucose Samples (Inpatient Periods)
CCI
Plasmaglucose concentrations will be monitored approximately every30minutesduring the 
run-in period on Days 1 and 3 (approximately 7 hours before dosing)for the MMTTs.
Plasmaglucose concentrations will be monitored approximately every hourduring the night on 
Day 2 (approximately 6hours before dosing)for the high-glycemic index meal test.
Regular monitoring of blood glucose using the 
 (approximately every 
2 hours) will also be performed during the complete inpatientperiod outside of the breakfast 
CCI


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meal testprocedures and includes predose before the standardized lunch and dinneras well as for 
the calibration of the CGM system.
9.6.2. Glucose Samples (Mixed-Meal Tolerance Test)
Blood samples will be obtained for the measurement of plasma glucose concentrations 
(
) at the times specifiedin the Schedule of Activities(Section2).  
These glucose measurements will be used for patient safety management (Section9.4.6) as well 
as for GD evaluations.
9.6.3. Exploratory Continuous Glucose Monitoring
For the CGM, a standard system (for example, the 
) will be used in 
a blinded mode (that is, patients will not be able to see their glucose values).  TheCGM sensor 
will be inserted by qualified site personnel,and the patients will be instructed to always carry the 
receiver with them. The CGM device will be calibrated using the plasma glucose values 
obtained with the 
 by qualified site personnel.  The patients will wear 
this device from approximately 12hours beforethe start of the breakfast mealon Day1 to 
approximately 5hours after the start of the lunch mealon Day3for each inpatient period.  The 
monitor will record continuous glucose measurements.  Atthe end of the recording, theCGM 
sensor will be removed,and the receiver will be used to download the glucose data.
9.7. Genetics
A bloodsample 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 response to the investigational 
product and to investigate genetic variants thought to play a role in the disease under 
investigation in this study.  Assessment of variable response may include evaluation of AEsor 
differences in efficacy.
All samples will be coded with the patientnumber.  These samples and any data generated can 
be linked back to the patientonly by the investigativesite personnel.
Samples will be retained for a maximum of 15 years after the lastpatientvisit or for a shorter 
period iflocal regulationsand/or ERBsimpose shorter time limitsfor the study at a facility 
selected byLilly or its designee.This retention period enables use of new technologies, response 
to regulatory questions, and investigation of variable response that 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, and candidate gene studies. Regardlessof 
technology utilized, data generated will be used only for the specific research scope described in 
this section.
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9.8.
Health Economics
This section is not applicable for this study.


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10. Statistical Considerations and Data Analysis
10.1.Sample SizeDetermination
An initial 24 patients may be randomizedin order that approximately 20patients complete the 
study.  Twenty completing patients will provide approximately80% power to demonstrate a 25% 
decrease in the time to early half-maximal concentration (early 50% Tmax) between LY900014 
and Humalog.  Testing will be done at an -level of 0.1 with a 2-sided confidence interval (CI).  
The variability was estimated by analyzing internal Lilly data (
) for 
LY900014 andHumalogadministeredon CSIItherapy, resulting in approximately 35.9% 
coefficient of variation of within-subjectvariability for early 50% Tmax.
Patients who are randomized but drop out before completing assigned treatment may be replaced 
to ensure that approximately 20patientscomplete the study (refer to Section5.1).
10.2.Populations for Analyses
10.2.1.Study Participant Disposition
The patient’s disposition will be recorded.  Allpatients who discontinue from the study will be 
identified, and the extent of their participation in the study will be reported.  If known, a reason 
for their discontinuation will be given.
10.2.2.Study Participant Characteristics
The patient’s age, sex, weight,BMI, height, race/subrace, smoking habits, and other 
demographic characteristics will be recorded.
10.3.Statistical Analyses
Statistical analysis of this study will be the responsibility of Eli Lilly and Company.
Primary statisticalanalyses will be conducted on the set of patients receiving at least 1 dose of 
the study drug to which they are randomized.  The populations for the PK or GD analyses are 
definedin more detail in Section10.3.2.1and Section10.3.3.1, respectively. Supportive 
analyses will be conducted on the set of patients who complete the study according to the 
sequence/treatment to which they are randomized. Safetyanalyses will be conducted on the set 
of patients receiving at least 1 dose of the study drug to which they are randomizedand have at 
least 1postdose safety assessment, regardless of whether or not they complete all protocol 
requirements.
For all PK/GD analyses(only applicable forbreakfastmeal tests), Days1 and3 and Day 2 will 
be analyzed using 2separate and independent statistical models, assuming no carryover effect of
the bolus administrationmode from Day 1 to Day 2 or from Day 2 to Day 3(refer to
Section5.4
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).
The CGM analyses for lunch and dinner will be documented in the statistical analysis plan.


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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 may be conducted as deemed appropriate.  Analyses 
will be fully detailed in the statistical analysis plan.  Study results may be pooled with the results 
of other studies for population PK analysis purposes to avoid issues with posthoc analyses and 
incomplete disclosures of analyses.  Analyses will be fully detailed in the clinical study report, 
synopsis, and/or manuscript.
10.3.1. Safety Analyses
10.3.1.1. Clinical Evaluation of Safety
All treatment- (investigational product and Humalog noninvestigational product) and 
procedure-related AEs will be listed, and if the frequency of events allows, safety data will be 
summarized using descriptive methodology.
The incidence of symptoms for each treatment will be presented by severity and by association 
with investigational product as perceived by the investigator.  Symptoms reported to occur 
before study enrollment will be distinguished from those reported as new or increased in severity 
during the study.  Each symptom will be classified by the most suitable term from the medical 
regulatory dictionary.
The number of investigational product-related SAEs will be reported.
10.3.1.2. Statistical Evaluation of Safety
Safety parameters that will be assessed include safety laboratory parameters and vital signs.  The 
parameters will be listed and summarized using standard descriptive statistics.  Additional 
analysis will be performed if warranted upon review of the data.
10.3.2. Pharmacokinetic Analyses
10.3.2.1. Pharmacokinetic Parameter Estimation
Patients who complete at least 1 MMTT and have measurable insulin lispro concentrations will 
be included in the analysis dataset for the PK analyses.  Patients who did not keep identical 
insulin lispro doses for the MMTTs (Days 1 and 3) will be excluded from the PK analysis on the 
MMTT days.  In addition, patients who did not keep identical insulin lispro doses for the 
high-glycemic index meal tests (Day 2) will be excluded from the PK analysis on the Day 2 meal 
test days.
PK analyses will be conducted using standard noncompartmental methods of analysis on a 
computer that meets or exceeds the minimum system requirements for these programs.  It is 
possible that other validated equivalent PK software programs may be used if appropriate, 
warranted, and approved by global PK management.  The version of any software used for the


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analysis will be documented, and the program will meet the Lilly requirements of software 
validation.
Serum insulin lispro concentrations will be used to calculate several PK parameters, including 
time to maximum concentration (Tmax), early 50% Tmax, time to late half-maximal concentration 
(late 50% Tmax), Cmax, area under the plasma concentration versus time curve (AUC) from time 
0 to 15 minutes postdose (AUC[0-15min]), AUC from time 0 to 30 minutes postdose 
(AUC[0-30min]), AUC from time 0 to 1 hour postdose (AUC[0-1h]), AUC from time 0 to the 
last recorded time (AUC[0-tlast]), and AUC from time 0 to 5 hours postdose (AUC[0-5h]).  
These will be the key parameters for analysis; other parameters (that is, partial AUCs) may be 
calculated as deemed appropriate.
Although attempts will be made to adhere to the scheduled collection times (Section 2), it is 
recognized that situations arise that may compromise sample collection at the scheduled times.  
Parameters will be individually calculated for each patient based on actual collection times and 
presented by summary statistics.
10.3.2.2. Pharmacokinetic Statistical Inference
Log-transformed insulin lispro Tmax, early 50% Tmax, late 50% Tmax, Cmax, and AUC estimates 
will be evaluated to estimate geometric means, ratios of geometric means of insulin lispro within 
LY900014 to Humalog, and the corresponding 90% CIs of the ratios.
The statistical model for the Day 1 and Day 3 breakfast meal tests will include treatment
(4 combinations of treatment and bolus administration mode: LY900014 dual-wave, Humalog
dual-wave, LY900014 single-wave, or Humalog single-wave), period, day-within-period, and 
treatment-by-day-within-period interaction as fixed effects and patient as a random effect. A 
separate analysis model will be used for the Day 2 breakfast meal test, including treatment
(4 combinations of treatment and bolus administration mode: LY900014 rapid, LY900014 
standard, Humalog rapid, or Humalog standard, all given as a single-wave bolus) and period as 
fixed effects and patient as a random effect. The variance-covariance structure considerations 
will be detailed in the statistical analysis plan.  For the primary inference, insulin lispro 
administered from LY900014 will be concluded to have a significantly decreased early 50% 
Tmax relative to Humalog if the upper confidence bound of the 2-sided 90% CI of the ratio of 
geometric means of the early 50% Tmax is <1.
As a sensitivity analysis, early 50% Tmax will be analyzed using the Wilcoxon signed-rank test.  
The difference in median early 50% Tmax between LY900014 and Humalog and the 90% CIs for 
the difference will be presented.
10.3.3. Glucodynamic Analyses
10.3.3.1. Glucodynamic Parameter Estimation
Patients who receive at least 1 dose of study drug and have evaluable GD data will be included in 
the analysis set for the GD analyses.  Also, for Days 1 and 3 and Day 2, separately, patients who 
did not complete the entire test meal or had significant changes in nutrient consumption of the 


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test meal or dose changes during the breakfast test meal will be excluded from all the GD 
analyses.
Data will be analyzed for the patients during each MMTT.  The change from baseline values (the 
average of -30, -15, and 0 minutes represented as the 0-hour time point) for each patient will be 
calculated.  Incremental change from baseline glucose AUC values will be calculated during a 
5-hour meal test.  Partial AUCs may be calculated as deemed appropriate.
10.3.3.2. Glucodynamic Statistical Inference
Summary statistics (including number of patients, mean, standard deviation or standard error, 
minimum, and maximum) will be presented by treatment and by bolus dose administration mode
(all 4 combinations of treatment) for Days 1 and 3 and Day 2, separately.  The same statistical 
model and comparisons used to analyze the PK parameters will be used to analyze the GD
parameters on the original scale (not log-transformed) using Fieller’s theorem (Chow and 
Liu 2009).
10.3.4. Exploratory Continuous Glucose Monitoring Analyses
The CGM outcome variables (for example, incremental change from baseline AUC[0-5h], the 
change from baseline 1- and 2-hour excursions) will be derived based on the raw data collected 
from the individualized standardized lunch meals on Days 1, 2, and 3 and from the 
individualized standardized dinner meals on Days 1 and 2. These will be the key parameters for 
analysis; other parameters (for example, partial AUCs) may be calculated as deemed appropriate.
The CGM analysis details will be documented in the statistical analysis plan.
10.3.5. Evaluation of Immunogenicity
The relationship between the status (positive or negative) of treatment-emergent anti-insulin 
lispro antibodies and TEAEs will be assessed.  Likewise, the relationship between the status of 
treatment-emergent antibodies and the PK parameters and GD response to insulin lispro may
also be assessed.
10.3.6. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the Lilly clinical pharmacologist, CRP, investigator, or designee will consult with the 
appropriate medical director or designee to determine if it is necessary to amend the protocol.
The Lilly clinical pharmacologist/CRP/Lilly study team is unblinded.  Data may be accessed and 
analyzed while the trial is ongoing, but no changes to the study design are planned.  The results 
may help Lilly expedite final delivery and enable planning of future studies.  Information that 
may unblind the study during the analyses will not be reported to the study site until the study 
has been unblinded.  An assessment committee will not be formed.


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11. References
Bell KJ,Toschi E, Steil GM, Wolpert HA.Optimized mealtime insulin dosing for fat and protein 
in type 1 diabetes: application of a model-based approach to derive insulin doses for open-loop 
diabetes management. Diabetes Care. 2016;39(9):1631-1634.
Chow SC, Liu JP. Design and analysis of bioavailability and bioequivalence studies. 3rd ed.
Florida: Taylor and Francis Group, LLC;2009:88-90.
[FDA] USFood and Drug Administration. Inactive ingredients in approved drug products. 
Available at: http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm. Accessed 
December15,2015.
[FDASCOGS] USFood and Drug Administration. SCOGS (Select Committee on GRAS 
Substances). Available at: http://www.accessdata.fda.gov/scripts/fdcc/?set=SCOGS. Accessed 
December 15,2015.
Fineberg SE, Huang J, Brunelle R, Gulliya KS, Anderson JH Jr. Effect of long-term exposure to 
insulin lispro on the induction of antibody response in patients with type 1 or type 2 diabetes. 
Diabetes Care. 2003;26(1):89-96.
[Humalog: EPAR]Product information. European Medicines Agency web site. Available at: 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000088/hu
man_med_000820.jsp&mid=WC0b01ac058001d124. Accessed September 9, 2015.
Humalog [package insert]. Indianapolis, IN: Eli Lilly and Company; 2015.
LuijfYM, ArnoldsS, AvogaroA, BeneschC,BruttomessoD, FarretA, HeinemannL, PlaceJ, 
RenardE, ScottonR, DeVriesJH; AP@home consortium. Patch pump versus conventional 
pump: postprandial glycemic excursions and the influence of wear time.Diabetes Technol
Ther.2013;15(7):575-579.
]. Research Triangle Park, NC: United Therapeutics Corp; 
2014.
]. Unither House, Chertsey, Great Britain: United 
Therapeutics Corp; 2014.
van Duinen M, Rickelt J, Griez E. Validation of the electronic Visual Analogue Scale of 
Anxiety. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(4):1045-1047.
Williamson A, Hoggart B. Pain: a review of three commonly used pain rating scales. J Clin 
Nurs
CCI
. 2005;14(7):798-804.
CCI


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Appendix 1.
Abbreviations and Definitions
Term
Definition
AE
adverse event:  any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
AUC(0-15min)
AUC from time 0 to 15 minutes postdose
AUC(0-30min)
AUC from time 0 to 30 minutes postdose
AUC(0-1h)
AUC from time 0 to 1 hour postdose
AUC(0-5h)
AUC from time 0 to 5 hours postdose
AUC(0-tlast)
AUC from time 0 to the last recorded time
audit
A systematic and independent examination of the trial-related activities and documents to 
determine whether the evaluated trial-related activities were conducted, and the data were 
recorded, analyzed, and accurately reported according to the protocol, sponsor’s standard 
operating procedures (SOPs), good clinical practice (GCP), and the applicable regulatory 
requirement(s).
blinding
A procedure in which one or more parties to the trial are kept unaware of the treatment 
assignment(s).  Unless otherwise specified, blinding will remain in effect until final 
database lock.
A single-blind trial is one in which the investigator and/or his staff are aware of the 
treatment but the patient is not, or vice versa, or when the sponsor is aware of the treatment 
but the investigator and/his staff and the patient are not.  A double-blind trial is one in 
which neither the subject nor any of the investigator or sponsor staff who are involved in 
the treatment or clinical evaluation of the subjects are aware of the treatment received.
BMI
body mass index
CGM
continuous glucose monitoring
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences


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Cmax
maximum concentration
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the trial-related requirements, good clinical practice (GCP) requirements, 
and the applicable regulatory requirements.
confirmation
A process used to confirm that laboratory test results meet the quality requirements defined 
by the laboratory generating the data and that Lilly is confident that results are accurate.  
Confirmation will either occur immediately after initial testing or will require that samples 
be held to be retested at some defined time point, depending on the steps required to obtain 
confirmed results.
CRF
case report form:  Sometimes referred to as clinical report form.  A printed or electronic 
form for recording study participants’ data during a clinical study, as required by the 
protocol.
CRP
clinical research physician:  Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research scientist, 
global safety physician, or other medical officer.
CRU
clinical research unit
CSII
continuous subcutaneous insulin infusion
CYP
cytochrome P450
early 50% Tmax
time to early half-maximal concentration
ECG
electrocardiogram
ELISA
enzyme-linked immunosorbent assay
end of study (trial)
End of study is the date of the last visit or last scheduled procedure shown in the Study 
Schedule for the last patient.
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are those 
who have been assigned to a treatment.
enter
Patients entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ERB
ethical review board:  A board or committee (institutional, regional, or national) composed 
of medical professionals and nonmedical members whose responsibility is to verify that the 
safety, welfare, and human rights of the subjects participating in a clinical trial are 
protected.
eVAS
electronic visual analog scale
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone


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GCP
good clinical practice:  A standard for the design, conduct, performance, monitoring, 
auditing, recording, analyses, and reporting of clinical trials that provides assurance that the 
data and reported results are credible and accurate, and that the rights, integrity, and 
confidentiality of trial patients are protected.
GD
glucodynamic(s)
GRAS
Generally Recognized as Safe
HbA1c
hemoglobin A1c
HIV
human immunodeficiency virus
ICF
informed consent form:  A Lilly term used to describe (1) information regarding the trial for 
the subject/patient, and (2) the document that the subject/patient signs to indicate consent to 
participate in the clinical trial.
ICH
International Council on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use
IMP
investigational medicinal product
informed consent
A process by which a patient voluntarily confirms his or her willingness to participate in a 
particular trial, after having been informed of all aspects of the trial that are relevant to the 
subject's decision to participate.  Informed consent is documented by means of a written, 
signed and dated informed consent form.
interim analysis
An interim analysis is an analysis of clinical trial data, separated into treatment groups, that 
is conducted before the final reporting database is created/locked.
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical trial, including products already on the market when used or assembled 
(formulated or packaged) in a way different from the authorized form, or marketed products 
used for an unauthorized indication, or marketed products used to gain further information 
about the authorized form.
investigator
A person responsible for the conduct of the clinical trial at a trial site.  If a trial is conducted 
by a team of individuals at a trial site, the investigator is the responsible leader of the team 
and may be called the principal investigator.
IV
intravenous
late 50% Tmax
time to late half-maximal concentration
legal 
representative
An individual or judicial or other body authorized under applicable law to consent, on 
behalf of a prospective patient, to the patient’s participation in the clinical trial.
MDI
multiple daily injections
MMTT
mixed-meal tolerance test


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noninvestigational 
product
A product that is not being tested or used as a reference in the clinical trial, but is provided 
to patients and used in accordance with the protocol, such as:  concomitant or rescue/escape 
medication for preventative, diagnostic, or therapeutic reasons, medication to ensure 
adequate medical care, and/or products used to induce a physiological response.
PAH
pulmonary arterial hypertension
patient
A study participant who has the disease or condition for which the investigational product is 
targeted.
PK
pharmacokinetic(s)
randomize
The process of assigning subjects to an experimental group according to the randomization 
schedule for the trial.
rescreen
To screen a patient who was previously declared a screen failure for the same study.
SAE
serious adverse event:  Any untoward medical occurrence that at any dose:  results in death, 
is life threatening, requires inpatient hospitalization or prolongation of existing 
hospitalization, results in persistent or significant disability/incapacity, or is a congenital 
anomaly/birth defect.
SC
subcutaneous
screen
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical trial.  In this trial, screening 
involves invasive or diagnostic procedures and/or tests (for example, blood draws).  For this 
type of screening, informed consent for these screening procedures and/or tests shall be 
obtained; this consent may be separate from obtaining consent for the study.
SUSARs
suspected unexpected serious adverse reactions
T1DM
type 1 diabetes mellitus
T2DM
type 2 diabetes mellitus
TEAE
treatment-emergent adverse event: Any untoward medical occurrence that either occurs or 
worsens at any time after treatment baseline and which does not necessarily have to have a 
causal relationship with this treatment.
Tmax
time to maximum concentration
ULN
upper limit of normal
URI
ultra-rapid insulin
VAS
visual analog scale


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Appendix 2.
Clinical Laboratory Tests
Laboratory Tests
Hematologya
Clinical Chemistrya
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume 
Chloride
Mean cell hemoglobin 
Calcium
Mean cell hemoglobin concentration 
Phosphorus
Leukocytes (WBC)
Glucose (fasting)
Absolute counts of:
Blood urea nitrogen (BUN)
Neutrophils
Uric acid
Lymphocytes
Total cholesterol
Monocytes
Total protein
Eosinophils
Albumin
Basophils
Total bilirubin
Platelets
Alkaline phosphatase
HbA1cb
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Urinalysisa
Creatinine
Specific gravity
Gamma-glutamyl transferase (GGT)
pH
C-peptideb (fasting)
Protein
Glucose
Serology
Ketones
Hepatitis B surface antigenb
Bilirubin
Hepatitis C antibodyb
Urobilinogen
HIVb
Nitrite
Erythrocytes/hemoglobin
Pregnancy testd
Leucocytes
Urine drug screene,f
Microscopyc
Follicle-stimulating hormoneb
Coagulationb
International normalized ratio (INR)
Partial thromboplastin time (PTT)
Abbreviations:  HbA1c = hemoglobin A1c; HIV = human immunodeficiency virus; RBC = red blood cells; 
WBC = white blood cells.
a
Results will be validated by the local laboratory at the time of initial testing.
b
Performed at screening only.  Hepatitis B and HIV tests may be waived if they have been performed within the 
6 months before screening (with reports available for review).
c
If clinically indicated, per investigator’s discretion.
d
Females only:  serum pregnancy test at screening; urine pregnancy test for all other visits.
e
Urine drug screen may be repeated before any admission to the clinical research unit.
f
Urine drug screen:  amphetamine, cannabis, cocaine, barbiturates, methadone, benzodiazepines, tricyclic 
antidepressants, methamphetamine, opiates, and phencyclidine.


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Appendix 3.
Study Governance, Regulatory and Ethical 
Considerations
Informed Consent
The investigator is responsible for:

ensuring that the patient understands the potential risks and benefits of participating in 
the study

ensuring that informed consent is given by each patient or legal representative.  This 
includes obtaining the appropriate signatures and dates on the informed consent form 
(ICF) before the performance of any protocol procedures and before the administration 
of investigational product

answering any questions the patient may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the patient’s willingness to 
continue his or her participation in the trial
A legal representative must give informed consent for a child to participate in this study.  In 
addition to informed consent given by the legal representative, the child may be required to give 
documented assent, if capable.
Ethical Review
The investigator must give assurance that the ethical review board (ERB) was properly 
constituted and convened as required by International Council on Harmonisation (ICH)
guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site.  Lilly or its representatives must approve the ICF 
before it is used at the investigative site. All ICFs must be compliant with the ICH guideline on 
good clinical practice (GCP).
The study site’s ERB should be provided with the following:

the current Investigator’s Brochure (IB) and updates during the course of the study

ICF

relevant curricula vitae
Regulatory Considerations
This study will be conducted in accordance with:
1) consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International
Organizations of Medical Sciences (CIOMS) international ethical guidelines


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


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Data Collection Tools/Source Data
An electronic data capture system will be used in this study.  The site must define and retain all 
source records and must maintain a record of any data where source data are directly entered into 
the data capture system.
Study and Site Closure
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ERB of the study 
site judges it necessary for medical, safety, regulatory, or other reasons consistent with 
applicable laws, regulations, and GCP.
Discontinuation of the Study
The study will be discontinued if Lilly judges it necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP.


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Appendix 4.
Hepatic Monitoring Tests for 
Treatment-Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with Lilly or its designee clinical research 
physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin time
WBC
Prothrombin time, INR
Neutrophils, segmented
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Conjugated bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
GGT
Anti-smooth muscle antibody (or anti-actin antibody)a
CPK
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gammaglutamyl transferase; Ig = immunoglobulin; INR = international normalized ratio; 
RBC = red blood cells; WBC = white blood cells.
a
Assayed by a Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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Appendix 5.
Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.  Fewer 
venipunctures and blood draws may actually occur, but this will not require a protocol 
amendment.
Protocol I8B-MC-ITSC Sampling Summary
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa
12
1
12
Clinical laboratory testsa
9
2
18
Pharmacokinetics (insulin lispro)
1.0
21 x 3 MMTT days 
x 4 periods
252
Blood for glucosea
0.2
24 x 3 MMTT days 
x 4 periods
57.6
Sample for immunogenicity
5
2
10
Pharmacogenetics
10
1
10
Blood for glucose during run-in period for 
Days 1 and 3 only (30-minute interval 
sampling)
0.2
14 x 2 MMTT days 
x 4 periods
22.4
Blood for glucose before Day 2 meal test
0.2
12 x 4 periods
9.6
Blood for glucose every 2 hours during 
inpatient and predose for lunch and dinner 
meals and CGM calibration
0.2
(2 [CGM calibration]
plus 5 [premeal] plus 
33 [every 2 hours]) 
x 4 periods
32
Total
423.6
Total for clinical purposes (rounded up to nearest 10 mL)
430
a
Additional samples may be drawn if needed for safety purposes.


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Appendix 6.
Protocol Amendment I8B-MC-ITSC(a) 
Summary [A Study to Assess the Pharmacokinetics, 
Glucodynamics, Safety, and Tolerability of LY900014 in 
Patients with Type 1 Diabetes Mellitus on Continuous 
Subcutaneous Insulin Infusion Therapy]
Protocol I8B-MC-ITSC, A Study to Assess the Pharmacokinetics, Glucodynamics, Safety, and 
Tolerability of LY900014 in Patients with Type 1 Diabetes Mellitus on Continuous 
Subcutaneous Insulin Infusion Therapy, has been amended.  The new protocol is indicated by 
Amendment (a) and will be used to conduct the study in place of any preceding version of the 
protocol.
The overall changes and rationale for the changes made to this protocol are as follows:

Removed reference to a separate manual for instructions to the site for 
examination of the infusion set and catheter, as these details have been included in 
the Protocol (Section 9.4.7.1), and hence no longer required.

Added a subject assessment procedure to enable the site to collect overall 
acceptability of insulin delivery experience for each study period.

Corrected minor formatting and grammatical inconsistencies and updated the full name 
of ICH (“Conference” to “Council”) although these had not been put in tracked changes.


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Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
2.
Schedule of Activities
Study Schedule Protocol I8B-MC-ITSC
Procedure
…
… … … …
Day 3
…
Comment
…
…
… … … … 
… 
…
Assessment of insulin 
delivery experience
X
Subjects will be asked to providethe overall 
acceptability of their insulin delivery experience, 
either prior to CRU discharge or after completing 
Day 3 lunch procedures for each period.
…
…
… … … … 
… 
…
5.1.1.4.  Day 3 Activities
Additionally, a macroscopic and microscopic check of the removed catheter and catheter tubing 
will be performed on site, ideally immediately after removing but within 120 minutes to exclude 
micro-occlusions and/or particles in the tubingaccording to instructions provided to the site in a 
separate manual. 
9.4.7.1.  Subjective Procedure:  Examination of Infusion Set and Catheter
When the infusion set and reservoir are changed (except for Period 1, Day –1) at the site, a 
macroscopic (visual) and microscopic examination (ideally immediately after removing the 
catheter, but no longer than 120 minutes)will be performed (according to instructions provided 
to the site in a separate manual)including the following:
a check on the infusion set or the catheter for signs of kinking or other damage.  
In case of damage, the damage should be described in the CRF and photographic 
evidence should be taken
a check of the insulin in the reservoir and infusion-set tubing for color change and 
crystals and/or particles including the location of these (that is, reservoir, infusion set)
a microscopic check of the catheter tubing to exclude micro-occlusions and/or 
particles in the tubing
9.4.7.2.  Subjective Procedure:  Acceptability of Insulin Delivery Experience
Subjects will be asked to providethe acceptability of their overall experience with the study 
insulin delivery via the 
 at the end of each study period, prior to 
discharge from the CRU.  If the subject plans to stay on after Day3 and continue on to Day-1 
activities for the next period, the assessment will be performed after the Day 3 lunch meal 
procedures are completed (approximately 5 hours after the start of the lunch meal).  
CCI

SAP_001.pdf: 
Statisitcal Analysis Plan  I8B-MC-ITSC 
 
A Study to Assess the Pharmacokinetics, Glucodynamics, Safety, and Tolerability of LY900014 
in Patients with Type 1 Diabetes Mellitus on Continuous Subcutaneous Insulin Infusion Therapy 
 
NCT03056456 
 
Approval Date: 24-Feb-2017 
 


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             Page 1of 24
STATISTICAL ANALYSIS PLAN
A Study to Assess the Pharmacokinetics, Glucodynamics, Safety, and Tolerability of 
LY900014 in Patients with Type 1 Diabetes Mellitus on Continuous Subcutaneous Insulin 
Infusion Therapy 
Approval Date: 24-Feb-2017 GMT
Statistical Analysis Plan Status:Final
Statistical Analysis Plan Date:22-February-2017
Study Drug: LY900014
Sponsor Reference:I8B-MC-ITSC
Covance CRU Study: 1001215-8356636
Clinical Phase I


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Statistical Analysis Plan 
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1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS .....................................................................................................2
2.
ABBREVIATIONS..............................................................................................................4
3.
INTRODUCTION ...............................................................................................................6
4.
STUDY OBJECTIVES........................................................................................................6
4.1
Primary Objective..........................................................................................................6
4.2
Secondary Objectives ....................................................................................................6
4.3
Exploratory Objectives ..................................................................................................7
5.
STUDY DESIGN.................................................................................................................7
6.
TREATMENTS .................................................................................................................11
7.
SAMPLE SIZE JUSTIFICATION .....................................................................................12
8.
DEFINITION OF ANALYSIS POPULATIONS................................................................12
9.
STATISTICAL METHODOLOGY ...................................................................................12
9.1
General........................................................................................................................12
9.2
Demographics and Patient Disposition.........................................................................13
9.3
Pharmacokinetic Assessment.......................................................................................13
9.3.1
Pharmacokinetic Parameter Estimation...............................................................13
9.3.2
Pharmacokinetic Statistical Inference .................................................................14
9.4
Glucodynamic Assessment ..........................................................................................15
9.4.1
Glucodynamic Parameter Estimation ..................................................................15
9.4.2
Glucodynamic Statistical Inference.....................................................................16
9.5
Safety and Tolerability Assessments ............................................................................16
9.5.1
Adverse events ...................................................................................................16
9.5.2
Concomitant medication.....................................................................................16
9.5.3
Clinical laboratory parameters ............................................................................16
9.5.4
Vital signs ..........................................................................................................17
9.5.5
Dosing information.............................................................................................17
9.5.6
Immunogenicity .................................................................................................17
9.5.7
Blood glucose monitoring and Hypoglycemia.....................................................17
9.5.8
Catheter Injection-site assessment.......................................................................18
9.5.9
Pain Measurements using the Visual Analog Scale (VAS)..................................18
9.5.10
Exploratory Continuous Glucose Monitoring Analyses.......................................18
9.5.11
Acceptability of Insulin Delivery Experience......................................................21
9.5.12
Other assessments...............................................................................................21


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10. INTERIM ANALYSES .....................................................................................................21
11. REFERENCES ..................................................................................................................21
12. DATA PRESENTATION ..................................................................................................22
12.1 Derived Parameters .....................................................................................................22
12.2 Missing Data ...............................................................................................................22
12.3 Insufficient Data for Presentation ................................................................................22
13. BLINDING AND UNBLINDING PLAN...........................................................................22


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2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
AE
Adverse event
AUC
Area under the concentration versus time curve
AUC[0-15 min]
Area under the concentration versus time curve from time zero to 15 
minutes
AUC[0-30 min]
Area under the concentration versus time curve from time zero to 30 
minutes
AUC[0-1 h]
Area under the concentration versus time curve from time zero to 1 
hour
AUC[2-5 h]
AUC[0-5 h]
Area under the concentration versus time curve from time 2 to 5 
hours
Area under the concentration versus time curve from time zero to 5 
hours
AUC(0-tlast)
Area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable concentration
BGRI
Sum of the LBGI and HBGI
CGM
Continuous glucose monitoring
CI
Confidence interval
Cmax
Maximum observed drug concentration
CRF
Case Report Form
CSR
Clinical Study Report
CRU
Clinical Research Unit
CRP
Clinical research physician
CSII
Continuous subcutaneous insulin infusion
CV
Coefficient of variation
Early 50% Tmax
Time to early half-maximal concentration
EC
Early Clinical 
ECG
Electrocardiogram
e.g.
For example (Latin: exempli gratia)
GD
Glucodynamic 


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HbA1c
Hemoglobin A1c
HBGI
High blood glucose index
ICH
International Council on Harmonization
Late 50% Tmax
Time to early half-maximal concentration
LBGI
Low blood glucose index
MedDRA
Medical Dictionary for Regulatory Activities
MMTT
Mixed meal tolerance test
PK
Pharmacokinetic
SAP
Statistical Analysis Plan
SOP
Standard Operating Procedure
T1DM
Type 1 diabetes mellitus
TFLs
Tables, Figures, and Listings
t1/2
Half-life associated with the terminal rate constant (λz) in non-
compartmental analysis
tmax
Time of maximum observed drug concentration
VAS
Visual analog scale
WHO
World Health Organization


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3.INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 19 
November 2016and amendment (a), dated 6 February 2017).
This SAP describes the planned analysisof the safety
, tol
erability, pharmacokinetic(PK)and 
glucodynamic (GD)data from this study.A detailed description of the planned TFLs to be 
presented in theclinical study report (CSR) is provided in the accompanying TFL shell 
document.
The intent of this document is to provide guidance for the statistical and PK analyses of data.In 
general, the analyses are based on information from the protocol, unless they have been modified 
by agreement between Eli Lilly and Company and 
.A 
limited amount of information concerning this study (e.g., objectives, study design) is given to 
help the reader’s interpretation.This SAP must be signed off prior to first patientadministration
for this study.When the SAP and TFL shells are agreed upon and finalized, they will
 serve as the 
template for this study’s CSR.
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they
 will be so i
dentified.If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR.Any substantial deviations from this SAP will be agreed upon 
between Eli Lilly and Company and 
and identified in the CSR.Any 
minor deviations from the TFLs may not be documented in the CSR.
This SAP is written with consideration of the recommendations outlined in the International 
Council on Harmonization(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 difference in insulin lispro PK when LY900014 and Humalog are 
administered as different test bolus doses with an insulin pump to patients with type 1 
diabetes mellitus (T1DM)during a breakfast meal test.
4.2
Secondary Objectives
To evaluate the sustainability of any difference in insulin lispro PK of LY900014 and 
Humalog over 3 days when administered as different test bolus doses with an insulin 
pump to patients with T1DM during a breakfast meal test.

CCI
To evaluate the difference in GD response when LY900014 and Humalog are 
administered as different test bolus doses with an insulin pump to patients with T1DM 
during a breakfast meal test.
CCI


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To compare the durability of GD response over 3 days when LY900014 and Humalog are 
administered as different test bolus doses with an insulin pump to patients with T1DM 
during a breakfast meal test.
4.3
Exploratory Objectives
To evaluate the safety and tolerability of
 LY900014 administered with an insulin pump.
To compare the GD response using continuous glucose monitoring (CGM)when 
LY900014 and Humalog are administered as different test bolus doses with an insulin 
pump to patients with T1DM during a standardized lunch meal.
To compare the GD response using CGM when LY900014 and Humalog are 
administered as different test bolus doses with an insulin pump to patients with T1DM 
during a standardized dinner meal.
To evaluate the intrapatientand interpatientinsulin lispro PK variability of LY900014 
compared with Humal
og after 3 days of continuous subcutaneous insulin infusion (CSII).
To determine catheter occlusion rates with LY900014 and Humalog after 3 days of CSII.
To perform an exploratory com
parison of glucose fluctuations with time in patients with 
euglycemic, hypoglycemia, and hyperglycemia receiving LY900014 and Humalog.
5.STUDY DESIGN
This is a single-site, 4-period, patient-and investigator-blind, randomized, crossover study in 
patients with T1DM to evaluate the insulin lispro PK and GD characteristics of LY900014 (Test) 
over 3 days with CSII compared with that of Humal
og (Reference) using a 
 
Each patient will be randomized to 1 of 4 treatment sequences comprising CSII of LY900014 or 
Humalog, with different combinations of the modes of administrati
onof the bolus doses relative 
to the breakfast, lunch, and dinner meals using an insulin pump (refer to Figure 1 and Table 1). 
The modes of administration are as follows:
Mode 1: bolus dose is administered as a standard dual-wave bolus (50% immediate bolus 
delivery [speed = 1.5 U/minute] and 50% as a square-wave over 3 hours)
Mode 2: bolus dose is administered as a standard single-wave bolus (speed = 1.5 
U/minute)
Mode 3: bolus dose is administered as a rapid single-wave bolus (speed = 15 U/minute)

CCI
Mode 4: bolus dose is administered as a rapid dual-wave bolus (50% immediate bolus 
delivery [speed = 15 U/minute] and 50% as a square wave over 3 hours)
The compositions of the meals are described in Section 6.3.1of the protocol.


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CCI
A mixed-meal tolerance test (MMTT)will be administered at breakfast as an individually 
standardized solid test meal on Day 1 and Day 3 and as a high-glycemic index test meal on Day 
2. The assigned treatment will be administered as a bolus dose at time 0 relative to the start of 
each breakfast test meal via 3 different modes: Modes 1, 2, and 3.
An individually standardized solid lunch will be administered on Days 1, 2, and 3. The assigned 
treatment will be administered as standard (Mode 1) or rapid (Mode 4) dual-wave bolus doses at 
time 0 relative to the start of each lunch meal.
An individually standardized dinner will be administered on Days 1 and 2. The assigned 
treatment will be administered as standard (Mode 2) or rapid (Mode 3) single-wave bolus doses 
at time 0 relative to the start ofeach dinner meal.
The study design i
s shown in Figure 1 and planned treatment sequences are shown in Table 1. 
Details of the inpatient and outpatient procedures are described in Section 5.1.1 and Section 5.1.2
of the protocol, respectively.
Patients who are eligible to participate in the study based on the results of the screening 
procedures will proceed to a 1-week lead-in period. During the lead-in period, patients will (if 
not receiving Humalog) switch from their short-acting insulin used before the start of the study 
to Humalog, which will be administered using their own personal pump. Patients will also be 
provided with a general
 diabetes training including, but not limitedto, dose calculation for 
short-acting insulins; correct self-monitoring of plasma glucose; and interpretation of results, 
symptoms, and treatment of hypoglycemia. A patient diary will also be provided for 
documentation of dosing, m
eals, and glucose monitoring outcomes.
Patients will be randomly assigned to a treatment sequence according to the actual randomization 
schedule provided to the site at the beginning of or during the lead-in period. The Medtronic 
 will be used for all study treatm
ent administrations, while maintaining the 
catheter needle at the same catheter insertion-site location for the 3-day durati
on of each study
 
period. Before each MMTT on Day 1 and Day
 3, a run-in period to stabilize plasma glucose 
levels will occur. Details of run-in activities are described in Section 5.1.1.2 and Section 2of the
protocol. Before the breakfast meal test on Day 2, the patients will have their plasma glucose 
monitored approximately every
 hour during the night to ensure that the targeted plasma glucose 
range is met before the start of the Day 2 m
eal test.


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Figure 1. Study design
Patients will be required to attend the clinical research unit (CRU) on at least 8 occasions:

a visit for informed consent

a screening visit (may occur up to 21 days before the lead-in period)

an initial CRU visit at the start of the 1-week lead-in period in which all patients will 
receive Humalog as their CSII

4 inpatient stays from Day –1 to Day 3 (one in each study period)

a follow-up visit (within 7 to 14 days after the last dose or early discontinuation)


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Table 1. Planned Treatment Sequences by Period
Patients will be discharged from the CRU on Day 3 (at least 5 hours after the st art of the lunch 
meal) or later, if deemed necessary for safety monitoring as determined by the investigator.
Study treatments may be administered on consecutive days from one period to the next, and a
maximum time of 1 week is permitted between consecutive periods.
Patients will continue their individual CSII basal rate using the insulin pump during the entire
study including the meal test days unless safety issues arise; in this case, the investigator will
discuss a change of the basal rate with the sponsor clinical research physician (CRP) and
implement this change, if necessary, to prevent any medical problems. However, during the
MMTT (approximately 6:00 AM to 2:00 PM on Days 1 and 3) and the high-glycemic index
breakfast meal test (approximately 6:00 AM to 2:00 PM on Day 2), the basal rate will be
changed to a single hourly rate based on the patient’s mean basal needs during the meal test
period. For all lunch and dinner meals during the inpatient periods, the patients’ individual CSII
basal rate will be continued unchanged.
Assessment of local tolerability at all catheter insertion sites will be performed as specified in the
Study Schedule (Section 2) of the protocol, including visual analog scale (VAS) scores for pain 
and inspection of the catheter insertion site for signs such as edema, erythema, and rash.


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For each meal test day (Days 1, 2, and 3), serial blood samples will be collected over
approximately 300 minutes to assess the PK and GD responses following start of the breakfast
meal test, as specified in the Study Schedule (Section 2) of the protocol. For each standardized 
lunch and dinner meal on Days 1 through 3, the GD response will be assessed using CGM 
following start of the meals.
6. TREATMENTS
The following is a list of the study treatment abbreviations that will be used in the TFLs.
For Safety outputs
Study Treatment Name
Treatment order in TFLs
Humalog 
1
LY900014
2
Bolus Dose Administration Method
Method order in TFLs
Standard dual-wave
1
Standard single-wave
2
Rapid single-wave
3
Rapid dual-wave
4
Statistical analysis treatment names
Study Treatment Name
Treatment order in TFL
Humalog standard dual-wave
1
Humalog standard single-wave
2
Humalog rapid dual-wave
3
Humalog rapid single-wave
4
LY900014 standard dual-wave
5
LY900014 standard single-wave
6


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LY900014 rapid dual-wave
7
LY900014 rapid single-wave
8
7.SAMPLE SIZE JUSTIFICATION
An initial 24 patients may be randomized in order that approximately 20 patients complete the 
study. Twenty completing patients will provide approximately 80% power to dem
onstrate a 25% 
decrease in the time to early half-maximal concentration (early 50% Tm
ax) between LY900014 
and Humalog. Testing will be done at an α-level of 0.1 with a 2-sided confidence interval (CI). 
The variability was estimated by analyzing internal Lilly data (
) for 
LY900014 and Humalog administered on CSII therapy, resul
ting in approximately 35.9% 
coefficient of variation of within-patientvariability for early 50% Tmax. Patients who are 
randomized but drop out before completing assigned treatment may be replaced to ensure that 
approximately 20 pati
ents complete the study (ref
er to Section 5.1).
8. DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all patients who received at least one dose of study drug, 
and have at least one postdose safety assessment.
The “PK” population for the statistical inference will consist of all
 patients who complete the 
study according to the sequence/treatment to which they are randomized. In addition, a 
sensitivity analysis will be performed on the population consistingof all patients who complete 
at least 1 MMTTand have measurable insulin lispro concentrations.
The “GD” population for the statistical inference will consist of all patients who complete the 
study according to the sequence/treatment to which they are randomized.In addition, a 
sensitivity analysis will be performed on thepopulation consisting ofall patients who complete 
at least 1 MMTTand have measurable GDconcentrations.
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when patients are assigned to analysis populations.
9.STATISTICAL METHODOLOGY
9.1
General
Data listings will be provided for all datathat isdatabased.Summary statistics and stati
stical 
analysis will only be presented for data where detailed in this SAP.For continuous data, 
summary statistics will include thearithmetic mean, arithmetic standard deviation, m
edian, min, 
max and N; for log-normal data (e.g. the PK parameters: AUCs and C
max
CCI
) the geometric mean 
and geometric coefficient of variation (CV%) will also be presented.For categorical data, 
frequency count and percentages will be presented.Data listings will be provided for all patients 
up to the point of withdrawal, with any patients excluded from the rel
evant population 


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highlighted. Summary statistics and statistical analyses will generally only be performed for 
patients included in the relevant analysis population.For the calculation of summary statistics 
and statistical analysis, unrounded data will be used. 
Mean change from baseline is the mean of all individual patients’ change from baseline values.
Each individual change from baseline will be calculated by subtracting the individual patient’s 
baseline value from the value at the timepoint.The individual patient’s change from baseline 
values will be used tocalculate the mean change from baseline using a 
 
.
Unless otherwise specified, testing for significance is all done at an α-level of 0.1 with 2-sided 
confidence intervals (CIs).Statistical significance will be claimed if the p-value of a test is less 
than 0.1. 
Data analysis will be performed using 
.
9.2
Demographics and PatientDisposition
Patientdisposition will be listed. The demographic variables age, sex, race/subrace, ethnicity,
country of
 enrolment, site ID,body weight, height and body m
ass index will be summarized and 
listed.In addition,screeningHbA1c, fasting blood glucose, total daily
 insulin doseat screening,
bolus dose at randomization, basal dose at randomization,fasting C-peptide and duration of 
T1DM will be summarized and listed.
Alcohol consumption will be reported in the SDTMs in units of alcohol and will be converted to 
grams for the TFLs, where 1 unit is equal to 8 grams of pure alcohol.
9.3
Pharmacokinetic Assessment
9.3.1Pharmacokinetic Parameter Estimation
Patients who complete at least 1 MMTT and have measurable insulin lispro concentrations will
be included in the analysis dataset for the PK analyses. Patients who did not keep identical
insulin lispro doses for the MMTTs (Days 1 and 3) will be excluded from the PK analysis on the
MMTT days. In addition, patients who did not keep identical insulin lispro doses for thehigh-
glycemic index meal tests (Day 2) will
 be excluded from the PK analysis on the Day 2 m
ealtest 
days.
PK analyses will be conducted using standard noncompartmental m
ethods of analysis on a
computer that meets or exceeds the minimum system requirements for these programs. It is
possible that other validated equivalent PK software programs may be used if appropriate,
warranted, and approved by global PK management. The version of any software used for the
analysis will be documented, and the program will meet the Lilly requirements of software
validation.
Serum insulin lispro concentrations will be usedto calculate several PK parameters, including
time to maximum concentration (T
max), early 50% T
max, time to late half-maximal concentration
(late 50% Tmax), C
max
CCI
, area under the plasma concentration versus time curve (AUC) from time0 
C
C
I


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to 15 minutes postdose (AUC[0-15min]), AUC from time 0 to 30 minutes postdose
(AUC[0-30min]), AUC from time 0 to 1 hour postdose (AUC[0-1h]), AUC from time 0 to the
last recorded time (AUC[0-tlast]), AUC from time 0 to 5 hours postdose (AUC[0-5h]), change 
from baseline PK parameters such as change from baseline AUC (CFBLAUC[0-5], and CFBL 
AUC[0-∞]). These will be the key parameters for analysis; other parameters (that is, partial 
AUCs and CL/F) may be calculated as deemed appropriate.
Although attempts will be made to adhere to the scheduled collection times (Section 2) detailed 
in the protocol, it is recognized that situations arise that may compromise sample collection at 
the scheduled times. Parameters will be individually calculated for each patient based on actual 
collection times and presented by summary statistics.
9.3.2 Pharmacokinetic Statistical Inference
The “PK” population for the statistical inference is defined in Section 8.
Log-transformed insulin lispro Tmax, early 50% Tmax, late 50% Tmax, Cmax, t1/2, and AUC 
estimates will be evaluated to estimate geometric means, ratios of geometric means of insulin 
lispro within LY900014 to Humalog by day and bolus administration mode, and the 
corresponding 90% CIs of the ratios.
The statistical model for the Day 1 and Day 3 breakfas t meal tests will include treatment (4 
combinations of treatment and bolus administration mode: LY900014 dual-wave, Humalog
dual-wave, LY900014 single-wave, or Humalog single-wave), period, day (Day 1 or Day 3), and
treatment-by-day interaction as fixed effects and patient as a random effect.
Example SAS code:
proc mixed data=pk;
class patient treatment period day ;
model logpk = treatment period day treatment*day / ddfm=kr;
  lsmeans trt*day;
  random patient / grp= treatment;
  repeated / grp= treatment;
run;
A separate analysis model will be used for the Day 2 breakfast meal test, including treatment (4 
combinations of treatment and bolus administration mode: LY900014 rapid, LY900014 standard, 
Humalog rapid, or Humalog standard, all given as a single-wave bolus) and period as fixed 
effects and patient as a random effect. 
Example SAS code:
proc mixed data=pk;
class patient treatment period;
model logpk = treatment period / ddfm=kr;
  random patient / grp= treatment;
  repeated / grp= treatment;
run;


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Statistical Analysis Plan 
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For the primary inference, insulin lispro administered from LY900014 will be concluded to have 
a significantly decreased early 50% Tmax relative to Humalog if the upper confidence bound of 
the 2-sided 90% CI of the ratio of geometric means of the early 50% Tmax is <1.
If possible, the above models will also be used to calculate the intra-patient and inter-patient
variability of LY900014, however if convergence issues occur, then the model will be 
appropriately updated to account for these issues.
As a sensitivity analysis, early 50% Tmax will be analyzed by day using the Wilcoxon signed-
rank test. The difference in median early 50% Tmax between LY900014 and Humalog and the 
90% CIs for the difference will be presented.
An exploratory analysis of Early 50% Tmax, from breakfast on Days 1, 2 and 3 based on the 
standard single-wave data only will also be performed. The model will include sequence, 
treatment and day within period and treatment by day as fixed effects, and patient as a random 
effect.
9.4
Glucodynamic Assessment
9.4.1 Glucodynamic Parameter Estimation
The “GD” population for the statistical inference is defined in Section 8.
Also, for Days 1 and 3 and Day 2, separately, patients who did not complete the entire test meal 
or had significant changes in nutrient consumption (greater than 10%) of the test meal or dose 
changes during the breakfast test meal will be excluded from all the GD analyses.
Data will be analyzed for the patients during each MMTT. The change from baseline values (the
average of -30, -15, and 0 minutes represented as the 0 -hour time point) for each patient will be
calculated. Incremental change from baseline glucose
AUC values will be calculated during a
5-hour meal test. Partial AUCs may be calculated as deemed appropriate. Parameters will be 
calculated and provided to Covance by Lilly. Parameters will include:

BGAUC(0-30 min)

BGAUC(0-1 h)

BGAUC(0-2 h)

BGAUC(0-3 h)

BGAUC(0-4 h)

BGAUC(0-5 h)

BGAUC(2.5-5 h)

Maximum change from baseline (BG max)

Maximum change from baseline up to 1 h (BG1h)

Maximum change from baseline up to 2 h (BG2h)


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Statistical Analysis Plan 
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9.4.2 Glucodynamic Statistical Inference
Summary statistics (including number of patients, mean, standard deviation or standard error,
minimum, and maximum) will be presented by treatment and by bolus dose administration mode
(all 4 combinations of treatment) for Days 1 and 3 (and combined) and Day 2, separately. The 
same statistical model and comparisons used to analyze the PK parameters will be used to 
analyze the GD parameters on the original scale (not log -transformed) using Fieller’s theorem 
(Chow and Liu 20093). A macro provided by Lilly will be used to complete the Fieller’s theorem 
analysis.
The analysis will be repeated for the completers population.
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 patient has 
provided written informed consent and is ongoing at consent. A non-treatment emergent AE is 
defined as an AE which starts after informed consent but prior to dosing. A treatment-emergent 
AE is defined as an AE which occurs postdose or which is present prior to the first dose and 
becomes more severe postdose. Any AE that occurs during the outpatient period will be 
associated with open-label Humalog (and not treatment).
All AEs will be listed. Treatment-emergent AEs will be summarized by treatment , bolus 
administration mode, meal, severity and relationship to the study drug. The frequency (the 
number of adverse events, the number of patients experiencing an adverse event and the 
percentage of patients experiencing an adverse event) of treatment-emergent adverse events will 
be summarized by treatment, bolus administration mode, meal, Medical Dictionary for 
Regulatory Activities (MedDRA) version 19.1 system organ class and preferred term. The 
summary and frequency adverse event tables will be presented for all causalities and those 
considered related to the study drug. Any serious adverse events will be tabulated.
9.5.2 Concomitant medication
Concomitant medication will be coded using the WHO drug dictionary (Version September
2016). Concomitant medication will be listed.
9.5.3 Clinical laboratory parameters
Clinical chemistry, hematology and urinalysis data outside the reference ranges will be listed.
Values for any clinical chemistry, hematology and urinalysis values outside the reference ranges 
will be flagged on the individual patient data listings.


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Statistical Analysis Plan 
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9.5.4 Vital signs
Vital signs data will be summarized by treatment and bolus administration mode, together with 
changes from baseline, where baseline is defined as predose of Day 1. Furthermore, values for 
individual patients will be listed.
9.5.5 Dosing information
Daily bolus dosing and basal dosing information will be listed.
9.5.6 Immunogenicity
Immunogenicity data will be listed. The number of patients who have detected anti-insulin lispro 
antibodies at predose and follow-up, and number of patients who have anti-insulin lispro 
antibodies that become cross-reactive with human insulin at follow-up will be summarized by 
overall population.
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, and the time of occur rence relative to the patient’s last meal. Each 
category of hypoglycemic events (defined below) will be listed and summarized for the 
outpatient, inpatient before the MMTT, inpatient during the MMTT, or inpatient after the MMTT 
periods and overall. Severe hypoglycemic events will be reported as SAEs. “During MMTT” 
refers to 0-300 minutes postdose. Events will be summarized by treatment, bolus dose 
administration method and meal.
Hypoglycemia is defined as follows:

Documented Hypoglycemia:
o
Symptomatic hypoglycemia: An event during which typical symptoms of 
hypoglycemia are accompanied by plasma glucose ≤70 mg/dL (≤3.9 mmol/L)
o
Asymptomatic hypoglycemia: An event not accompanied by typical symptoms of 
hypoglycemia but with plasma glucose ≤70 mg/dL (≤3.9 mmol/L)

Unspecified hypoglycemia: An event during which plasma glucose ≤70 mg/dL (≤3.9 
mmol/L) but no information relative to symptoms of hypoglycemia was recorded.

Probable symptomatic hypoglycemia: An event during which symptoms indicative of 
hypoglycemia are not accompanied by a plasma glucose determination (but that was 
presumably caused by PG ≤70 mg/dL [≤3.9 mmol/L]).

Severe hypoglycemia: An event requiring assistance of another person to actively 
administer carbohydrate, glucagon, or other resuscitative actions.


Final, 22 Feb 2017
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Statistical Analysis Plan 
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
Nocturnal hypoglycemia: Any hypoglycemic event (documented symptomatic, 
asymptomatic, probable symptomatic, or severe hypoglycemia) that occurs between 
bedtime and waking

Relative hypoglycemia: an event during which typical symptoms of hypoglycemi a, that 
do not require the assistance of another person, are accompanied by plasma glucose 
>70 mg/dL (3.9 mmol/L), but these levels may be quickly approaching the 70 mg/dL 
(3.9 mmol/L) threshold

Total hypoglycemia: an optional category that combines all cases of hypoglycemia. If an 
event which hypoglycemia falls into multiple subcategories, the event is only counted 
once in this category

Overall hypoglycemia: This category combines all cases of hypoglycemia (documented
hypoglycemia and probable symptomatic hypoglycemia, including severe hypoglycemia). 
If an event of hypoglycemia falls into multiple subcategories, then the event is only 
counted once in this category.    

Serious and clinical important hypoglycemia: A hypoglycemia that is accompanied by a 
measured plasma glucose <54 mg/dl (<3.0 mmol/L).                                                                              
9.5.8 Catheter Injection-site assessment
Injection-site assessment data will be listed and summarized in frequency tables by treatment, 
bolus administration mode and day.
9.5.9 Pain Measurements using the Visual Analog Scale (VAS)
Pain measurements during bolus application will be assessed using the electronic version of the 
100-mm validated VAS (or electronic VAS [eVAS]) for pain. Data will be listed and 
summarized by treatment and bolus administration mode. 
VAS data will also be summarized based on the following categories of score: 0 mm, 1-10 mm, 
11-20 mm, 21-30 mm, 31-40 mm, etc. up to the maximum category by treatment and timepoint, 
and also the categories <=10 mm, <=20 mm and <=45 mm. The table will show number and 
percent of patients with observations in each category.
9.5.10 Exploratory Continuous Glucose Monitoring Analyses
The CGM outcome variables will be derived based on the raw data collected from the 
individualized standardized lunch meals on Days 1, 2, and 3 and from the individualized 
standardized dinner meals on Days 1 and 2. 
The following incremental glucose AUCs will be calculated:

AUC(0-1 h)

AUC(0-2 h)

AUC(0-5 h)


Final, 22 Feb 2017
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Statistical Analysis Plan 
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Covance Clinical Study No. 8356636
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
AUC(2.5-5 h)
The incremental glucoseAUCs will be calculated using the linear trapezoidal method (with 
negative areas included in the calculation of the trapezoidal areas). For the calculation of the 
incremental glucose AUC parameters, baseline is defined as the average of all CGM values 
recorded in the 19 minutes prior to each meal.
For the CGM data, time in range parameters will be derived from the raw data collected through 
the 3 days of CGM device use by patient, treatment, bolus dose administration method and 
meal. The following ranges will be calculated:

Normal range (>70 mg/dL and <=180 mg/dL) for each day, normalized to 5 hours 
(duration and % of 5 hours)

Strict normal range (>70 mg/dL and <=140 mg/dL) for each day, normalized to 5 hours 
(duration and % of 5 hours)

Hyperglycemia (>180 mg/dL) during the treatment period, normalized to 5 hours 
(duration and also as % of 5 hours)

Hypoglycemia ( ≤70 mg/dL) during the treatment period, normalized to 5 hours 
(duration and % of 5 hours)

Severe hypoglycemia ( ≤55 mg/dL) during the treatment period, normalized to 5 hours 
(duration and % of 5 hours)
For the calculation of the incremental glucose AUCs and range parameters, the following rules 
will be used to define a valid CGM session prior to parameter calculation:

Minimum number of measures for each parameter must be greater than 70% of the total 
measures obtained. For example, for iAUC(0-2 h), there will be 24 measurements during 
this period so a patient must have at least 17 valid measurements to be able to calculate 
the parameter. Similarly, for the time in range parameters calculated over 5 hours, there 
will be 60 measurements so must be at least 42 valid measurements to be able to calculate 
these parameters

The maximum allowable continuous missing interval will be 10 minutes for incremental 
glucose AUC(0-1 h), 20 minutes for incremental glucose AUC(0-2 h) and incremental 
glucose AUC(2.5-5 h), and 25 minutes for incremental glucose AUC(0-5 h), Low blood 
glucose index (LBGI), high blood glucose index (HBGI), combined blood glucose risk 
index (BGRI, sum of the LBGI and HBGI), and the time in range parameters
The incremental glucose AUCs and time in range parameters will also be analyzed statistically 
with separate analyses based on the parameters at lunch times on Days 1, 2 and 3 only, and based 
on the parameters at Dinner times on Days 1 and 2 only. The model will include treatment 
(combination of treatment and bolus administration mode), period and day within period and 
treatment- by-day within period as fixed effects, and patient as a random effect. The model will 
be used to estimate least squares means, differences of least squares means of insulin lispro 
within LY900014 to Humalog by bolus administration mode, and the corresponding 90% CIs of 
the ratios.


Final, 22 Feb 2017
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Statistical Analysis Plan 
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In addition to the above parameters, within-day and between-day CGM variability parameters 
will be calculated. The within-day parameters (derived by day and meal) will include the 
standard deviation, CV% and Mean amplitude of glycemic excursions (MAGE). The between-
day parameters will be based on the lunch data on Day 1-3 and dinner data on Days 1-2 
separately, and will include the standard deviation, CV% and mean of daily differences 
(MODD).
The LBGI, HBGI and BGRI will also be derived. The LBGI has been developed to quantitate 
both frequency and severity of hypoglycemia.  The LBGI has been validated as a predictor of 
severe hypoglycemia, which is a serious adverse event and could result in coma or death if 
unrecognized and untreated.  The HBGI quantifies both frequency and severity of hyperglycemia 
and has been related to HbA1c and risk for hyperglycemia (Kovatchev et al. 2005).  
Additionally, both the LBGI and HBGI have a high sensitivity to changes in glycemic profiles 
and control (Kovatchev et al. 2005).  LBGI is a non-negative number that increases as the 
number of low readings increases.  HBGI is a non-negative number that increases as the number 
of high readings increases.
The LBGI, HBGI, and BGRI will be derived in the following steps:
Step 1:  For each blood glucose (BG [mg/dL]) at the ith time point, compute the 
following:
f(BGi)=1.509×[(ln(BGi))1.084-5.381]
Transform the BG data using a nonlinear transformation that maps the BG range
of 20 to 600 mg/dL  to a symmetric interval of

10
,
10

The center of the BG scale is 112.5 mg/dL  and is mapped to 0
Step 2:  Compute BG risk for each reading




2
i
i
BG
f
10
BG
rl


if f(BG) < 0; otherwise rl(BGi) = 0




2
i
i
BG
f
10
BG
rh


if f(BG) > 0; otherwise rh(BGi) = 0
Assign the risk of each BG value by applying the above quadratic risk function
Range from 0 (achieved when BG = 112.5, the center) to 100
Left side of the parabola is risk of hypoglycemia, where the right side is risk of 
hyperglycemia
Step 3:  Compute LBGI and HBGI


Final, 22 Feb 2017
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Statistical Analysis Plan 
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Covance Clinical Study No. 8356636
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


n
1
i
i)
rl(BG
n
1
LBGI
, where n is the number of measurements



n
1
i
i)
rh(BG
n
1
HBGI
, where n is the number of measurements
    Step 4: Compute BGRI
BGRIm=LBGI + HBGI
The calculated parameters will be summarized and listed by treatment, bolus dose administration 
mode, day and meal. In addition, the average across the three days for lunch and two days of 
dinner will be calculated separately.
9.5.11 Acceptability of Insulin Delivery Experience
Acceptability of patient overall experience with the study insulin delivery will be summarized 
(yes/no) by treatment.
9.5.12 Other assessments
To determine catheter occlusion rates with LY900014 and Humalog after 3 days of CSII, the 
frequency of “occlusions observed on macroscopic examination of the catheter and catheter 
tubing” from the CRF will be.
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed. 
10.
INTERIM ANALYSES
No interim analyses are planned for this study. If an unplanned interim analysis is deemed 
necessary, the Lilly clinical pharmacologist, CRP, investigator, or designee will consult with the 
appropriate medical director or designee to determine if it is necessary to amend the protocol.
The Lilly clinical pharmacologist/CRP/Lilly study team is unblinded. Data may be accessed and 
analyzed while the trial is ongoing, but no changes to the study design are planned. The results 
may help Lilly expedite final delivery and enable planning of f uture studies. Information that 
may unblind the study during the analyses will not be reported to the study site until the study 
has been unblinded. An assessment committee will not be formed.
11.
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.


Final, 22 Feb 2017
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8356636
    Sponsor Reference I8B-MC-ITSC
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.
3. Chow SC, Liu JP. Design and analysis of bioavailability and bioequivalence studies. 3 rd ed. 
Florida: Taylor and Francis Group, LLC; 2009:88-90.
4. Kovatchev BP, Clarke WL, Breton M, Brayman K, McCall A. Quantifying temporal glucose 
variability in diabetes via continuous glucose monitoring: mathematical methods and clinical 
application. Diabetes Technol Ther. 2005 Dec;7(6):849-62.
12.
DATA PRESENTATION
12.1
Derived Parameters
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be 
reported to three significant figures. Observed concentration data, e.g. Cmax, should be reported 
as received. Observed time data, e.g. tmax, should be reported as received. N and percentage 
values should be reported as whole numbers. Median values should be treated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values.
12.2
Missing Data
Missing data will not be displayed in listings.
12.3
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of patients or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the center of the table, 
such as, “No serious adverse events occurred for this study.”
13.
BLINDING AND UNBLINDING PLAN
Levels of unblinding are indicated in the table below. This table provides general guidance as to 
who will be allowed access to blinding information (including data or documents that 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. 


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Statistical Analysis Plan 
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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 another appropriate 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
U
U
U
U
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
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


Final, 22 Feb 2017
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8356636
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Abbreviations:  B = blinded; 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.