A Prospective, Randomized, Double-Blind Comparison of LY900014 to Insulin Lispro in Combination With Insulin Glargine or Insulin Degludec in Adults With Type 1 Diabetes
Phase: PHASE3
Conditions: Type 1 Diabetes Mellitus
Sponsor: Eli Lilly and Company

 
 
 
Protocol I8B-FH-ITSD 
 
 
A Prospective, Randomized, Double-Blind Comparison of LY900014 to Insulin Lispro in 
Combination with Insulin Glargine or Insulin Degludec in Adults with Type 1 Diabetes 
 
 
NCT03952130 
 
 
Approval Date: 13-Jul-2018 

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LY900014
Protocol I8B-FH-ITSD
A Prospective, Randomized, Double-Blind Comparison of 
LY900014 to Insulin Lispro in Combination with Insulin 
Glargine or Insulin Degludec in Adults with Type 1 Diabetes
Confidential Information
The information contained in this document is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
LY900014, unless such persons are bound by a confidentiality agreement with Eli Lilly and 
Company or its subsidiaries.  
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure. Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
LY900014
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Approval Date: 13-Jul-2018 GMT

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Table of Contents
Section
Page
1.
Synopsis .............................................................................................................................8
2.
Schedule of Activities .......................................................................................................12
3.
Introduction ......................................................................................................................17
3.1.
Study Rationale............................................................................................................17
3.2.
Background..................................................................................................................17
3.3.
Benefit/Risk Assessment..............................................................................................19
4.
Objectives and Endpoints..................................................................................................20
5.
Study Design.....................................................................................................................22
5.1.
Overall Design .............................................................................................................22
5.2.
Number of Participants.................................................................................................23
5.3.
End of Study Definition ...............................................................................................23
5.3.1.
Safety Follow-Up.................................................................................................23
5.4.
Scientific Rationale for Study Design...........................................................................24
5.5.
Justification for Dose ...................................................................................................24
6.
Study Population...............................................................................................................25
6.1.
Inclusion Criteria..........................................................................................................25
6.2.
Exclusion Criteria ........................................................................................................27
6.3.
Lifestyle Restrictions....................................................................................................30
6.4.
Screen Failures.............................................................................................................30
7.
Treatments........................................................................................................................31
7.1.
Treatments Administered .............................................................................................31
7.1.1.
Packaging and Labeling .......................................................................................31
7.1.2.
Medical Devices...................................................................................................32
7.2.
Method of Treatment Assignment ................................................................................32
7.2.1.
Selection and Timing of Doses.............................................................................32
7.2.1.1.
Target Glucose Values for Titration of Insulin Therapy ..................................32
7.2.1.2.
Basal Insulin Therapy.....................................................................................33
7.2.1.3.
Basal Insulin Titration ....................................................................................33
7.2.1.4.
Study Prandial Insulin Therapy.......................................................................34
7.2.1.5.
Transitioning off Study Insulin Therapy .........................................................37
7.3.
Blinding .......................................................................................................................37
7.4.
Dosage Modification....................................................................................................38
7.5.
Preparation/Handling/Storage/Accountability...............................................................38
7.6.
Treatment Compliance .................................................................................................38

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7.7.
Concomitant Therapy...................................................................................................38
7.8.
Treatment after the End of the Study............................................................................39
7.8.1.
Continued Access.................................................................................................39
7.8.2.
Special Treatment Considerations ........................................................................39
8.
Discontinuation Criteria ....................................................................................................40
8.1.
Discontinuation from Study Treatment.........................................................................40
8.1.1.
Permanent Discontinuation from Study Treatment ...............................................40
8.1.2.
Temporary Discontinuation from Study Treatment...............................................41
8.1.3.
Discontinuation of Inadvertently Enrolled Patients...............................................41
8.2.
Discontinuation from the Study....................................................................................41
8.3.
Lost to Follow-Up........................................................................................................42
9.
Study Assessments and Procedures ...................................................................................43
9.1.
Efficacy Assessments...................................................................................................43
9.1.1.
Primary Efficacy Assessments .............................................................................43
9.1.2.
Secondary Efficacy Assessments..........................................................................43
9.1.3.
Appropriateness of Assessments ..........................................................................44
9.1.4.
Study Procedures .................................................................................................44
9.1.4.1.
Four-Point Self-Monitoring Blood Glucose ....................................................44
9.1.4.2.
Ten-Point Self-Monitoring Blood Glucose......................................................44
9.1.4.3.
Mixed-Meal Tolerance Test............................................................................44
9.1.4.4.
Diabetes Education and Nutritional Counseling ..............................................46
9.2.
Adverse Events ............................................................................................................46
9.2.1.
Serious Adverse Events........................................................................................47
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................48
9.2.2.
Complaint Handling.............................................................................................48
9.3.
Treatment of Overdose.................................................................................................49
9.4.
Safety...........................................................................................................................49
9.4.1.
Hypoglycemia......................................................................................................49
9.4.2.
Severe Hypoglycemia ..........................................................................................50
9.4.3.
Electrocardiograms ..............................................................................................50
9.4.4.
Vital Signs ...........................................................................................................51
9.4.5.
Laboratory Tests ..................................................................................................51
9.4.6.
Safety Monitoring ................................................................................................51
9.5.
Pharmacokinetics .........................................................................................................51
9.6.
Pharmacodynamics ......................................................................................................52
9.7.
Pharmacogenomics ......................................................................................................52
9.8.
Biomarkers and Predictive or Other Analyses...............................................................52
9.8.1.
Samples for Immunogenicity Testing ...................................................................52

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9.9.
Health Economics ........................................................................................................52
9.9.1.
EQ-5D-5L............................................................................................................52
9.9.2.
Insulin Treatment Satisfaction Questionnaire .......................................................53
9.9.3.
Work Productivity and Activity Impairment Questionnaire 
General Health.....................................................................................................53
10.
Statistical Considerations ..................................................................................................54
10.1. Sample Size Determination ..........................................................................................54
10.2. Populations for Analyses..............................................................................................54
10.3. Statistical Analyses ......................................................................................................54
10.3.1.
General Statistical Considerations ........................................................................54
10.3.2.
Treatment Group Comparability...........................................................................56
10.3.2.1.
Patient Disposition..........................................................................................56
10.3.2.2.
Patient Characteristics ....................................................................................56
10.3.2.3.
Concomitant Therapy .....................................................................................57
10.3.3.
Efficacy Analyses ................................................................................................57
10.3.3.1.
Primary Analyses ...........................................................................................57
10.3.3.1.1.
Additional Analyses for the Primary Endpoint ..........................................57
10.3.3.2.
Secondary Analyses........................................................................................57
10.3.3.3.
Tertiary/Exploratory Analyses ........................................................................58
10.3.4.
Safety Analyses....................................................................................................58
10.3.5.
Other Analyses.....................................................................................................59
10.3.5.1.
Health Economics...........................................................................................59
10.3.6.
Interim Analyses..................................................................................................60
11.
References ........................................................................................................................61

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List of Tables
Table
Page
Table ITSD.1.
Objectives and Endpoints...............................................................................20
Table ITSD.2.
Treatment Regimens......................................................................................31
Table ITSD.3.
Target Glucose Values for Adjustment of Insulin Therapy.............................32
Table ITSD.4.
Basal Insulin Hypoglycemia Assessment .......................................................34
Table ITSD.5.
Summary of Basal Insulin Adjustments after Hypoglycemia 
Assessment....................................................................................................34
Table ITSD.6.
Prandial Insulin Doses and Corresponding Self Monitored Blood 
Glucose Values Pattern Adjustment Plan .......................................................36
Table ITSD.7.
LY900014 or Insulin Lispro Adjustment Algorithm Pattern Adjustment 
Plan ...............................................................................................................36
Table ITSD.8.
Concomitant Medications ..............................................................................39
Table ITSD.9.
Insulin to Carbohydrate Ratio for Determining the Prandial Insulin 
Dose for the Mixed-Meal Tolerance Test:  For Use with Patients Who 
Use Pattern Adjustment to Determine Prandial Insulin Doses ........................46

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List of Figures
Figure
Page
Figure ITSD.1.
Illustration of study design for Clinical Protocol I8B-FH-ITSD. ....................23

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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................63
Appendix 2.
Clinical Laboratory Tests...............................................................................67
Appendix 3.
Study Governance Considerations..................................................................68
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................72
Appendix 5.
World Health Organization Classification for Diabetes..................................73
Appendix 6.
New York Heart Association Cardiac Disease Classification .........................74
Appendix 7.
Classification of Contraceptive Methods........................................................75

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1.
Synopsis
Title of Study: 
A Prospective, Randomized, Double-Blind Comparison of LY900014 to Insulin Lispro, in Combination with Insulin 
Glargine or Insulin Degludec in Adults with Type 1 Diabetes
Rationale: 
A prandial insulin with faster-onset and/or faster-offset characteristics might reduce glycemic excursions and the 
incidence of delayed postprandial hypoglycemia compared to currently available rapid-acting insulin analogs.  
Rapid-acting insulins, such as Humalog®, have been shown to have a more rapid onset of action compared to 
human insulin; however, the general consensus is that they are not rapid enough to match carbohydrate absorption, 
whether delivered by pump or syringe/pen injector, thereby limiting efficacy.  An ultra-rapid-acting prandial insulin 
that shifts the pharmacokinetic (PK) and glucodynamic profiles of insulin to provide an even faster onset of action 
would better match carbohydrate absorption and allow for efficacious dosing immediately prior to meals or even
after meals. Ultra-rapid insulin (URI) could be useful in the treatment of type 1 diabetes (T1D) and type 2 diabetes
(T2D) in adults and children when delivered by multiple daily injections (MDI) or by continuous subcutaneous 
insulin infusion (CSII).  
The aim of this study is to demonstrate that an ultra-rapid formulation of insulin lispro, LY900014, is noninferior to 
insulin lispro on glycemic control as measured by change from baseline to Week 26 in hemoglobin A1c (HbA1c) in 
patients with T1D when administered in a double-blind manner as prandial insulin in combination with basal insulin 
glargine or insulin degludec in accordance with local regulations.
Objectives/Endpoints:
Objectives
Endpoints
Primary Objective

To test the hypothesis that LY900014 is 
noninferior to insulin lispro on glycemic control 
(non-inferiority margin [NIM]=0.4% for HbA1c) 
in patients with T1D when administered as 
prandial insulin (0 to 2 minutes prior to the meal), 
in combination with basal insulin glargine or 
insulin degludec for 26 weeks
[1] Difference between LY900014 and insulin lispro 
in change from baseline to Week 26 in HbA1c 
Multiplicity-Adjusted Objectives

To test the hypothesis that LY900014 is superior 
to insulin lispro in controlling 1-hour postprandial 
glucose (PPG) excursions when administered as 
prandial insulin
[2] Difference between LY900014 and insulin lispro 
in the 1-hour PPG excursion (serum glucose 
measured 1 hour after the start of the meal minus 
fasting serum glucose) from a mixed-meal 
tolerance test (MMTT) at Week 26

To test the hypothesis that LY900014 is superior 
to insulin lispro in controlling 2-hour PPG 
excursions when administered as prandial insulin 
[3] Difference between LY900014 and insulin lispro 
in the 2-hour PPG excursion (serum glucose 
measured 2 hours after the start of the meal minus 
fasting serum glucose) from an MMTT at Week 
26

To test the hypothesis that LY900014 is superior 
to insulin lispro on improving glycemic control 
(HbA1c) when administered as prandial insulin
[4] Difference between LY900014 and insulin lispro 
in change from baseline to Week 26 in HbA1c 

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Other Secondary Objectives
[5] To compare LY900014 and insulin lispro with 
respect to the rate of severe hypoglycemic events 
[6] Rate (events/patient/100 years) of severe 
hypoglycemic events from baseline through Week 
26 
[7] To compare LY900014 and insulin lispro with 
respect to the incidence and rate of documented 
symptomatic postmeal hypoglycemia
[8] Rate (events/patient/year and/or events/patient/30 
days) and incidence (percent of patients with at 
least 1 event) of documented symptomatic 
postmeal hypoglycemia within 1 and 2 hours after 
start of a meal from Week 12 through Week 26 
and Week 0 through Week 26 
[9] To compare LY900014 and insulin lispro with 
respect to the incidence and rate of documented 
symptomatic hypoglycemia
[10]Rate (events/patient/year and/or events/patient/30 
days) and incidence (percent of patients with 
events) of documented symptomatic 
hypoglycemic events from Week 12 through 
Week 26 and Week 0 through Week 26
[11]To compare LY900014 and insulin lispro with 
respect to 1,5-Anhydroglucitol (1,5-AG)
[12]Change from baseline in 1,5-AG values at 
Week 26 
[13]To compare LY900014 and insulin lispro with 
respect to 10-point self-monitored blood glucose 
(SMBG) profiles
[14]Change from baseline in 10-point SMBG values 
at Week 26 
[15]To compare LY900014 and insulin lispro with 
respect to total, basal, and prandial insulin dose 
[16]Change from baseline in total, basal and prandial 
insulin doses and prandial/total insulin dose ratios 
at Week 26 
[17]To compare LY900014 and insulin lispro with 
respect to the proportion of patients achieving 
HbA1c targets
[18]The proportion of patients with HbA1c <7% and 
≤6.5% at Week 26
Summary of Study Design:  
Study I8B-FH-ITSD is a Phase 3, prospective, randomized, double-blind, outpatient, multinational, multicenter 
2-treatment group, parallel, active-controlled study conducted in patients with T1D currently using an MDI regimen
OR premixed insulin with at least 2 injections daily.
Treatment Groups and Duration:  
The study includes a 1-week screening period and an 8-week lead-in period.  In the 2 treatment groups, LY900014 
and insulin lispro will be administered immediately (0-2 minutes) prior to each meal in a double-blind manner.  
Patients will complete a 26-week treatment period and a 4-week safety follow-up period.  
Number of Patients:
Approximately 438 participants will be screened to achieve 350 randomized patients and 298 patients completing 26 
weeks of treatment.  Approximately 280 Chinese patients will be randomized.  The other 70 randomized patients are 
planned to be from other countries, which may include Mexico, Argentina, Brazil, India and Ukraine.  The final 
participating countries and allocated patient numbers will be adjusted based on the actual condition.

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Statistical Analysis:
The primary analysis is for the treatment period through Week 26.  
Efficacy analyses will be conducted on all randomized patients using an intention-to-treat (ITT) approach according 
to the treatment the patients are assigned.  The analyses for the primary and multiplicity-adjusted objectives will 
include data collected prior to permanent discontinuation of investigational product (IP) through Week 26.  When 
change from baseline is included as a response variable of analysis models, the patient will be included in the 
analysis only if a baseline and at least 1 post-baseline measurement are available.  Selected efficacy analyses will 
also be conducted using the Per Protocol (PP) and Completer populations.  
Safety analyses will be conducted on the Safety population.  Analyses of adverse events (AEs) will include 2 sets of 
analyses, unless otherwise specified.  The first set of analyses will include data collected prior to permanent 
discontinuation of IP.  The second set of analyses will include all data collected during the course of the entire study 
regardless of IP use. Analyses of hypoglycemia will be conducted on data collected prior to permanent 
discontinuation of IP, while analyses for post-treatment may be conducted as needed.  Analyses of safety laboratory 
measurements will be performed on all data collected during the planned treatment period regardless of IP use.  
Week 26 analyses will include treatment comparisons between two treatment groups.
Baseline is defined as the last nonmissing measurement at or before the randomization visit (Visit 8), unless 
otherwise specified.
The primary efficacy comparison will be based on the contrast between LY900014 and insulin lispro at Week 26 
(Visit 18) from the mixed-effect model repeated measure (MMRM) analysis of change from baseline in HbA1c 
using all randomized patients.  If the upper limit of the 2-sided 95% confidence interval (CI) for the least squares 
(LS) mean difference in the change from baseline in HbA1c for LY900014 minus insulin lispro is below +0.4%, 
LY900014 will be declared noninferior to insulin lispro.  The model for this analysis will include the fixed class
effects of treatment, strata (country, type of basal insulin, and metformin use at study entry), visit, and treatment-by-
visit interaction, as well as the continuous, fixed covariate of baseline value.  
A graphical approach (Bretz et al. 2011) for multiple comparisons will be used to strongly control the overall Type I 
error (2-sided alpha level of 0.05) for testing the treatment effect for the primary and the following multiplicity-
adjusted objectives:  superiority of LY900014 compared with insulin lispro for 1-hour PPG excursion at Week 26, 
2-hour PPG excursion at Week 26, and change from baseline to Week 26 in HbA1c.  
An analysis of covariance (ANCOVA) model with strata (country, type of basal insulin, baseline HbA1c strata 
[≤8.5%, >8.5%], and metformin use at study entry), and treatment as fixed effects and baseline as a covariate will be 
used to analyze the 1-hour and 2-hour PPG excursions.  However, if the percentage of the patients with missing 
MMTT data at baseline is higher than 15%, a constrained longitudinal data analysis model (Liu et al. 2009; Lu 
2010) will be used instead.  Analyses details will be documented in the statistical analysis plan (SAP).
Hypoglycemia rates will be summarized for periods of 30 days, 1 year, and 100 years (severe hypoglycemia only).  
The rate of severe hypoglycemia per 100 years will be compared between treatment groups using the empirical 
method.  For each of the other categories of hypoglycemia, the number of hypoglycemia events during a specific 
period (rate) after randomization (for example, 0-12 weeks of treatment period) will be analyzed by using a negative 
binomial regression model.  The model will include treatment and the baseline hypoglycemia rate (measured during 
lead-in) as a covariate.  An offset defined as the log transformation of treatment exposure in the specific period 

I8B-FH-ITSD Clinical Protocol
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(days)/365.25 days (or 30 days) will be included in the model to estimate the rate of hypoglycemia per year (or per 
30 days).  The proportion of patients with at least 1 hypoglycemic event in each category (incidence) during a 
specific period after randomization will be analyzed using a logistic regression model including treatment and 
baseline hypoglycemia rate value in the model. 
Continuous safety variables, as well as the change from baseline for these variables, will be analyzed by MMRM or 
ANCOVA models.  For categorical variables, Fisher’s exact test will be used to compare treatment groups unless 
otherwise specified. 
Change from baseline to last-observation-carried forward endpoints for the European Quality of Life –
5 Dimensions 5 Level (EQ-5D-5L), Insulin Treatment Satisfaction Questionnaire (ITSQ), and Work Productivity 
and Activity Impairment Questionnaire General Health (WPAI-GH) will be analyzed using ANCOVA models. 
References:
Bretz F, Posch M, Glimm E, Klinglmueller F, Maurer W, Rohmeyer K. Graphical approaches for multiple 
comparison procedures using weighted Bonferroni, Simes, or parametric tests. Biom J. 2011;53(6):894-913.
Liu GF, Lu K, Mogg R, Mallick M, Mehrotra DV. Should baseline be a covariate or dependent variable in analyses 
of change from baseline in clinical trials? Stat Med. 2009;28(20):2509-2530.
Lu K. On efficiency of constrained longitudinal data analysis versus longitudinal analysis of covariance. Biometrics. 
2010;66(3):891-896.

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2. Schedule of Activities

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Study Procedure
Study 
Screening
Lead-In Period
Intensive Titration Period
Maintenance 
Period
Safety 
Follow-Up
ED
Treatment Period
eCRF Visit Number
1
2
3a
4a
5
6a
7
8
9a
10
11
12a
13
14a
15
16
17
18
801
EDb
Visit Window (± days)
3
3
3
3
3
3
4
3
3
7
7
7
7
7
7
7
7
7
Time on Study Relative to First Active 
Treatment Dose (weeks)
-9
-8
-7
-6
-4
-2
-1
0
1
2
4
6
8
10
12
18
22
26
30
Informed consent signed
X
IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient eligibility review 
X
Randomizationc
X
Clinical Assessments
Patient demographics
X
Medical historyand  preexisting conditions
X
Physical exam/heightd
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events and product complaints
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body weighte
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs:  blood pressure/pulse ratef
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG (12-lead; local)
X
Diabetes and nutrition counselingg
X
Transfer to insulin lisproh
X
Transfer to allowed study basal insulin 
regimeni
X
Basal and prandial insulin dose assessmentj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Titrate basal insulinj
X
X
X
X
X
X
Titrate prandial insulink
X
X
X
X
X
X
X
X

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Study Procedure
Study 
Screening
Lead-In Period
Intensive Titration Period
Maintenance 
Period
Safety 
Follow-Up
ED
Treatment Period
eCRF Visit Number
1
2
3a
4a
5
6a
7
8
9a
10
11
12a
13
14a
15
16
17
18
801
EDb
Visit Window (± days)
3
3
3
3
3
3
4
3
3
7
7
7
7
7
7
7
7
7
Time on Study Relative to First Active 
Treatment Dose (weeks)
-9
-8
-7
-6
-4
-2
-1
0
1
2
4
6
8
10
12
18
22
26
30
Ancillary Supplies/Diaries/IP
Dispense blood glucose meter and ancillary 
supplies and complete trainingl,m
X
X
X
X
X
X
X
X
X
Dispense study diary 
X
X
X
X
X
X
X
X
X
X
X
Diary use trainingm
X
Collect Study Diary and Transfer Diary Data 
to eCRF (InForm)n
X
X
X
X
X
X
X
X
X
X
X
X
Train on collecting 4- and 10-point SMBG 
profilesm
X
Review 4-point SMBG profileso
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Remind patient of 10-point SMBG 
requirementsp
X
X
X
X
Review 10-point SMBG profiles
X
X
X
Xq
Review/discuss hypo data 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense IP 
X
X
X
X
X
X
X
X
Patient returns used and unused study drug 
supplies
X
X
X
X
X
X
X
X
X
Drug accountability
X
X
X
X
X
X
X
X
X
Laboratory Assessments
Patient fasts prior to visit
X
X
X
X
MMTT
r
X
X
Urinalysis panel
X
Pregnancy tests
X
X
Follicle-stimulating hormone testt
X
Chemistry panel
X
X
X
X
Fasting serum glucose
X
Hematology
X
X
X
X

I8B-FH-ITSD Clinical Protocol
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LY900014
Study Procedure
Study 
Screening
Lead-In Period
Intensive Titration Period
Maintenance 
Period
Safety 
Follow-Up
ED
Treatment Period
eCRF Visit Number
1
2
3a
4a
5
6a
7
8
9a
10
11
12a
13
14a
15
16
17
18
801
EDb
Visit Window (± days)
3
3
3
3
3
3
4
3
3
7
7
7
7
7
7
7
7
7
Time on Study Relative to First Active 
Treatment Dose (weeks)
-9
-8
-7
-6
-4
-2
-1
0
1
2
4
6
8
10
12
18
22
26
30
1,5-Anhydroglucitol
X
X
X
X
X
Hemoglobin A1c
X
X
X
X
X
X
X
X
X
Lipid profile
X
X
X
Anti-insulin lispro antibodies
X
X
X
X
X
X
X
X
Health Outcomes Questionnairesu
EQ-5D-5L
X
X
X
X
ITSQ
X
X
X
X
WPAI-GH
X
X
X
X
Abbreviations:  ECG = electrocardiogram; eCRF = electronic case report form; ED = early discontinuation; EQ-5D-5L = European Quality of Life – 5 
Dimensions 5 Level;; hypo = hypoglycemia; IP = investigational product; ITSQ = Insulin Treatment Satisfaction Questionnaire; IWRS = interactive web 
response system; MMTT = mixed-meal tolerance test; SMBG = self-monitored blood glucose; WPAI-GH = Work Productivity and Activity Impairment 
Questionnaire General Health.
a
Telephone visits are indicated by shaded columns.  Activities include: 

Record visit in the IWRS.

Collect adverse events and concomitant medications.

Review blood glucose readings and study drug doses. 

Adjust prandial insulin or basal insulin doses as needed.

Review hypoglycemic events. 

Provide reminders regarding scheduled visits, fasting, and SMBG profiles, as applicable.
b
Patients who have been randomized will be asked to return for the ED visit in a fasting state unless patient is already fasting and at the site when the decision 
to discontinue is made.  Patients who discontinue during the lead-in period prior to randomization, and who are not already at the site, will be asked to return 
for the ED in a nonfasting state and all activities should be completed except for laboratory tests and questionnaires (ITSQ, EQ-5D-5L, and WPAI-GH). 
c
Randomization should occur after all Visit 8 procedures including MMTT.  If MMTT is rescheduled post Visit 8, randomization should not occur until 
baseline MMTT is completed.  The patient will administer their first dose of study insulin with the first meal after the MMTT has been completed and 
randomization has occurred.  
d  Physical examination shall be performed at Visit 1. It shall be performed at other visits if deemed necessary by the investigator. 
e
Patients should be advised to remove their shoes and empty their pockets before the body weight is obtained.

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f
Vital sign measurements must be taken before obtaining an ECG tracing and before collection of blood samples for laboratory testing.  These measurements 
should be determined after patients have been seated quietly for at least 5 minutes in a chair with feet on the floor.  The arm used for blood pressure 
measurement should be supported at heart level.  
g
Initial training at Visit 2 will include diabetes education and nutrition counseling.  Appropriate site personnel will administer training and education using 
locally approved diabetes education/training materials or other materials provided by the Sponsor.  Patients may be provided abbreviated training and 
education at visits following Visit 2 as appropriate.
h
Only applies to patients taking insulin glulisine, insulin aspart, or regular human insulin.
i
Patients will be transferred to a study basal insulin regimen at Visit 2.  Investigators will determine the appropriate basal insulin regimen for each patient. It is 
expected that most of the basal insulin dose adjustments should occur during the lead-in period.  However, basal insulin titration may continue during the 
intensive titration period for patients who need more intensification to achieve glycemic targets.  Basal insulin dose adjustments during the maintenance 
period should be made for safety reasons such as hypoglycemia and unacceptable hyperglycemia. 
j
Assessments of the basal insulin dose should be made, at minimum, weekly during the lead-in period, including Weeks -5 and -3. Assessment of the prandial 
insulin dose should be made, at minimum, weekly during the initial 12 weeks after randomization, including Weeks 3, 5, 7, 9, and 11. 
k
During the lead-in period, prandial doses, correction factors, and insulin to carbohydrate ratios should be evaluated and adjustments should be made for safety 
reasons such as hypoglycemia and unacceptable hyperglycemia.  During the intensive titration period, prandial insulin dose should be adjusted in order to 
meet the target SMBG levels.  Further adjustments during the maintenance period should be made for safety reasons such as hypoglycemia and unacceptable 
hyperglycemia.  
l
Glucose monitoring supplies will be dispensed at other visits, as needed.
m Training may be repeated at other visits, as needed.
n
Study sites will retain study diaries.
o
Patients should be encouraged to measure a minimum of 4 SMBG readings daily to satisfy dose titration. 4-point SMBG is required on three nonconsecutive 
days before each visit.
p
Patients in both study arms should be instructed to perform three 10-point SMBG profiles during a 2-week period.  The 10-point profile is completed over a 1-
day period, preferably on 3 nonconsecutive days (weekdays and weekends).  Ten-point SMBG profiles should not be performed on the day of MMTT.
q
Review of 10-point SMBG profiles at the ED visit will take place only for patients randomized into the study.
r
MMTT can occur 0 to 4 days prior to the visit, and patient must be fasting prior to start of the MMTT.  Time 0 of the MMTT will be when the patient starts to 
consume the meal.  Serial venous blood samples to measure serum glucose will be taken at time -15, 0, 15, 30, 60, 120, 180, and 240 minutes after the start of 
the meal.
s
Serum pregnancy test that is analyzed by central laboratory must be performed in women of childbearing potential at Visit 1 followed by a local urine or 
serum pregnancy test within 24 hours prior to IP exposure at randomization (Visit 8) and at other times at the investigator’s discretion. When required per 
local regulations and/or institutional guidelines, local pregnancy testing will occur at mandatory times during the study treatment period, and the local 
pregnancy test must be kept at site.
t
Follicle-stimulating hormone test must be performed at Visit 1 for a postmenopausal woman who is between 50 and 54 years of age (inclusive) with an intact 
uterus, not on hormone therapy, and who has had at least 6 months of spontaneous amenorrhea. 
u
Health outcomes questionnaires will be administered at the study sites based on the availability of appropriate translations.  The questionnaires should be 
administered prior to other study procedures except at Visit 8 and Visit 18 when questionnaires may be administered following the start of the MMTT.

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3.
Introduction
3.1.
Study Rationale
A prandial insulin with faster-onset and/or faster-offset characteristics might reduce glycemic
excursions and decrease the incidence of delayed postprandial hypoglycemia compared to 
currently available rapid-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 volunteers given subcutaneous (SC) doses of insulin lispro ranging 
from 0.1 to 0.4 U/kg, peak serum levels were seen 30 to 90 minutes after dosing. Rapid-acting 
insulins have been shown to have a more rapid onset of action compared to human insulin; 
however, the general consensus is that they are not rapid enough to match carbohydrate 
absorption and many patients are unable to achieve optimal glycemic control.  An ultra-rapid-
acting prandial insulin with pharmacokinetic (PK) and glucodynamic (GD) profiles that 
demonstrate faster absorption and onset of action may better match carbohydrate absorption and
lead to improved postprandial control.  The time action profile of rapid-acting insulin could be 
enhanced through the addition of excipients to an existing formulation to increase capillary blood 
flow and/or enhance vascular permeability.  An ultra-rapid insulin (URI) would be useful in the 
treatment of type 1 diabetes (T1D) and type 2 diabetes (T2D) when delivered by multiple daily 
injections (MDI), by continuous subcutaneous insulin infusion (CSII), and in the development of 
closed loop insulin delivery systems.
The aim of this study is to demonstrate that an ultra-rapid formulation of insulin lispro, 
LY900014, is noninferior to insulin lispro on glycemic control as measured by change from 
baseline to Week 26 in hemoglobin A1c (HbA1c) in patients with T1D, when administered in a 
double-blind manner as prandial insulin in combination with basal insulin glargine or insulin 
degludec.  The study will expand the evaluation of the efficacy and safety of LY900014 to a 
broader race/ethnic spectrum of patients with T1D.
3.2.
Background
Type 1 diabetes is an autoimmune disease mediated by a combination of genetic and 
environmental triggers resulting in lymphocytic infiltration of pancreatic islets, destruction of 
beta cells, and lifelong dependency on exogenous insulin. <<Source: ITRM CSR>> Globally, 
there were an estimated 422 million adults with diabetes in 2014, compared to 108 million in 
1980 (WHO, 2016).  Diabetes caused 1.5 million deaths in 2012 (WHO, 2016).  
There have been many advances in the treatment of T1D in the last 20 years; however, reaching 
and maintaining glycemic goals remains challenging even under intensive insulin therapy 
regimens. Although estimates on the number of patients with diabetes not meeting targets vary, 
the values are consistently high.  An analysis of NHANES data from 2007-2010 found that 
almost half of US adults with diabetes do not meet the HbA1c target of ≤7.0% (Ali et al. 2013).  
Another analysis of NHANES data showed that after improvements in glycemic control between 
1999 and 2006, the HbA1c level plateaued through 2014 and the proportion of patients achieving 
HbA1c <7% has remained relatively unchanged between the two most recent waves of data 
(Carls et al. 2017).  The UK National Diabetes Audit 2015–2016 reported that HbA1c levels 

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were >7.5% in more than two thirds (70.8%) of people with T1D and in more than one third 
(34.3%) of those with T2D (NHS 2017). Currently available rapid-acting insulin analogs 
continue to be unable to match the kinetics of physiological postmeal insulin secretion, which is 
biphasic.  Normal first-phase insulin response is a rapid but short-lived increase in secretion, 
which is then followed by a more slowly developing prolonged increase (Barrett et al. 2016).  
First phase insulin release prevents the rapid development of postprandial hyperglycemia, while 
second phase release of insulin ensures that glucose enters tissues in a steady, controlled manner 
throughout the late postprandial period.  Thus, there remains a need to continue to develop 
formulations with a time action profile that more closely approximates that of endogenous 
insulin section. 
Insulin lispro is indicated to be administrated within 15 minutes before a meal or immediately 
after a meal (Humalog package insert, 2015).  Ideally, currently available rapid-acting insulin 
analogs should be injected 10 to 15 minutes prior to meal consumption in order to control
postprandial glucose (PPG).  However, many people inject their rapid-acting insulin at the time 
of the meal or after the meal.  According to survey data from the T1D Exchange on the timing of 
prandial insulin injection, 21% of patients reported administering insulin several
minutes before meals, 44% immediately before meals, 10% during meals, and 24% after meals
(Dayte et al. 2017).Because patients often inject later than recommended, there is a greater 
mismatch between insulin action and postprandial blood glucose (BG) elevations. With 
postmeal dosing, the mismatch between the rise in BG and the onset of insulin action is even 
more pronounced.  For the development of a URI, it will be important to understand the 
relationship between time action profile of the insulin, insulin injection timing, and meal timing 
in order to maximize improvements in postprandial glycemic control and minimize 
hypoglycemia risk. A URI with higher early insulin concentration and peak exposure, and 
shorter duration should improve early postprandial control and limit postmeal hyperglycemia, 
while reducing late postprandial hypoglycemia due to lower insulin exposure.  Patients will 
administer Humalog at 0 to 2 minutes before the start of the meal to maintain the study blind. 
Hemoglobin A1c provides an integrated measurement of both fasting and postprandial glycemic 
control and is the most reliable marker for overall glucose exposure.  Elevation in HbA1c is the 
best predictor of diabetes complications. Control of both fasting and postprandial hyperglycemia 
is essential to reach HbA1c goals. The relative contribution of postprandial hyperglycemia is
predominant with moderate to fairly well controlled HbA1c levels (Monnier et al. 2003). 
A new pharmaceutical innovation that may allow more effective control of PPG levels is 
LY900014, a new formulation of insulin lispro developed as an ultra-rapid acting insulin with a 
faster onset of action and shorter duration of action compared to currently available rapid-acting 
insulin analogs.  The changes in PK and GD characteristics are achieved by coformulating 
insulin lispro with treprostinil and ingredients Generally Recognized As Safe (GRAS) by the US 
Food and Drug Administration (FDA) as excipients.
LY900014 is a formulation of insulin lispro that contains the prostacyclin analog treprostinil, 
citrate, and other excipients.  Treprostinil as an excipient enhances the absorption of insulin 

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lispro by local vasodilatation rather than as an active pharmaceutical ingredient that elicits a 
systemic effect.  Treprostinil is a prostacyclin analog administered either by inhalation 
(Tyvaso®), intravenous (IV) infusion, or continuous SC infusion (Remodulin®) for the 
treatment of symptomatic pulmonary arterial hypertension, and has been approved in the United 
States since 2002 (Remodulin package insert, 2014) and in Europe since 2005 (PMR [WWW]).  
Sodium citrate, an excipient that speeds insulin absorption, is also included in the formulation to 
further enhance the absorption of insulin lispro.  Sodium citrate and the other excipients in the 
LY900014 formulation are listed in the FDA GRAS food additives database and in the FDA 
Inactive Ingredients in Approved Drugs database. Furthermore, the excipient concentration in 
LY900014 is within the limits identified for approved drug products in the FDA Inactive 
Ingredients in Approved Drugs database.
Refer to the Humalog local product labeling (for example, Humalog package insert, 2015; 
Humalog Summary of Product Characteristics, 2016) for more information regarding insulin 
lispro. 
The Investigator’s Brochure (IB) describes the clinical and nonclinical development of 
LY900014. 
3.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks of insulin lispro may 
be found in the country-specific product labeling (for example, Patient Information Leaflet, 
Package Insert, or Summary of Product Characteristics).
Across all doses in the Eli Lilly and Company (Lilly) clinical studies that have evaluated 
treprostinil as a local vasodilator with or without insulin lispro, there was no clinically significant 
increase in those adverse events (AEs) associated with systemic absorption of treprostinil, as 
described in the Remodulin package insert (2014) (that is, headache, diarrhea, nausea, jaw pain, 
vasodilatation, rash, edema, anorexia, vomiting, asthenia, abdominal pain, and hypotension).  
The exposures of treprostinil in LY900014 for participants in upcoming and future clinical trials 
are expected to be much lower than those observed in the dose ranges previously explored with 
SC bolus administration of treprostinil and are expected to be substantially lower than those 
observed in the treatment of pulmonary artery hypertension (PAH).  Treprostinil is 
unmeasureable in the serum after administration of LY900014 in doses expected to be used in 
the clinical setting.
More information about the known and expected benefits, risks, serious adverse events (SAEs),
and reasonably anticipated AEs of LY900014 can be found in the IB.  

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4.
Objectives and Endpoints
Table ITSD.1 shows the objectives and endpoints of the study.  
Table ITSD.1.
Objectives and Endpoints
Objectives
Endpoints
Primary Objective

To test the hypothesis that LY900014 is 
noninferior to insulin lispro on glycemic control 
(NIM=0.4% for HbA1c) in patients with T1D, 
when administered as prandial insulin (0 to 
2 minutes prior to the meal), in combination with 
basal insulin glargine or insulin degludec for 26 
weeks

Difference between LY900014 and insulin lispro 
in change from baseline to Week 26 in HbA1c 
Multiplicity-Adjusted Objectives

To test the hypothesis that LY900014 is superior to 
insulin lispro in controlling 1-hour PPG excursions 
when administered as prandial insulin

Difference between LY900014 and insulin lispro 
in the 1-hour PPG excursion (serum glucose 
measured 1 hour after the start of the meal minus 
fasting serum glucose) from an MMTT at Week 26

To test the hypothesis that LY900014 is superior to 
insulin lispro in controlling 2-hour PPG excursions 
when administered as prandial insulin 

Difference between LY900014 and insulin lispro 
in the 2-hour PPG excursion (serum glucose 
measured 2 hours after the start of the meal minus 
fasting serum glucose) from an MMTT at Week 26

To test the hypothesis that LY900014 is superior to 
insulin lispro on improving glycemic control 
(HbA1c) when administered as prandial insulin

Difference between LY900014 and insulin lispro 
in change from baseline to Week 26 in HbA1c 
Other Secondary Objectives

To compare LY900014 and insulin lispro with 
respect to the rate of severe hypoglycemic events 

Rate (events/patient/100 years) of severe 
hypoglycemic events from baseline through Week 
26

To compare LY900014 and insulin lispro with 
respect to the incidence and rate of documented 
symptomatic postmeal hypoglycemia

Rate (events/patient/year and/or events/patient/30 
days) and incidence (percent of patients with at 
least 1 event) of documented symptomatic 
postmeal hypoglycemia within 1 and 2 hours after 
start of a meal from Week 12 through Week 26 and 
Week 0 through Week 26

To compare LY900014 and insulin lispro with 
respect to the incidence and rate of documented 
symptomatic hypoglycemia

Rate (events/patient/year and/or events/patient/30 
days) and incidence (percent of patients with 
events) of documented symptomatic hypoglycemic 
events from Week 12 through Week 26 and Week 
0 through Week 26

To compare LY900014 and insulin lispro with 
respect to 1,5-AG 

Change from baseline in 1,5-AG values at 
Week 26

To compare LY900014 and insulin lispro with 
respect to 10-point SMBG profiles

Change from baseline in 10-point SMBG values at 
Week 26

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Objectives and Endpoints
Objectives
Endpoints
Other Secondary Objectives (continued)

To compare LY900014 and insulin lispro with 
respect to total, basal, and prandial insulin dose 

Change from baseline in total, basal and prandial 
insulin doses and prandial/total insulin dose ratios
at Week 26 

To compare LY900014 and insulin lispro with 
respect to the proportion of patients achieving 
HbA1c targets

The proportion of patients with HbA1c <7% and 
≤6.5% at Week 26
Tertiary/Exploratory Objectives

To compare the safety of LY900014 and insulin 
lispro

Adverse events, vital signs, chemistry, and 
hematology laboratory measures

To compare the incidence of treatment-emergent 
positive anti-insulin lispro antibodies for 
LY900014 and insulin lispro

Incidence of treatment-emergent positive anti-
insulin lispro antibodies

To compare LY900014 and insulin lispro with 
respect to quality of life as measured by the EQ-
5D-5L

Change from baseline in EQ-5D-5L 
UK-population based health state index score and 
EQ-VAS score at Week 26

To compare LY900014 and insulin lispro with 
respect to diabetes treatment satisfaction as 
measured by the ITSQ

Change from baseline in ITSQ regimen 
inconvenience and lifestyle flexibility domain 
scores at Week 26

To compare LY900014 and insulin lispro with 
respect to the impact that diabetes has on the 
ability to work and perform regular activities as 
measured by the WPAI-GH

Change from baseline in WPAI-GH item scores at 
Week 26

To compare LY900014 and insulin lispro with 
respect to changes in body weight

Change in weight (kg) from baseline to Week 26

To compare LY900014 and insulin lispro with 
respect to glycemic variability 

Within-day and between-day glycemic variability 
measured by the standard deviation and the 
coefficient of variation of 10-point SMBG profiles
Abbreviations:  1,5-AG = 1,5-Anhydroglucitol; EQ-5D-5L = European Quality of Life – 5 Dimensions 5 Level; EQ-
VAS = EuroQol visual analog scale; HbA1c = hemoglobin A1c; ITSQ = Insulin Treatment Satisfaction 
Questionnaire; MMTT = mixed-meal tolerance test; NIM = non-inferiority margin; PPG = postprandial glucose;
SMBG = self-monitored blood glucose; T1D = type 1 diabetes mellitus; WPAI-GH = Work Productivity and 
Activity Impairment General Health.

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5.
Study Design
5.1.
Overall Design
Study I8B-FH-ITSD (ITSD) is a Phase 3, prospective, randomized, outpatient, multinational, 
multicenter, parallel, active-controlled study conducted in patients with T1D currently using an 
MDI regimen or premixed insulin with at least 2 injections daily.  In the 2 treatment groups, 
LY900014 and insulin lispro will be administered immediately (0-2 minutes) prior to each meal 
in a double-blind manner.  
The study is designed to demonstrate noninferiority of LY900014 when compared with insulin 
lispro in change from baseline to Week 26 in HbA1c, when both are administered at the start of 
the meal.  The study includes a 1-week screening period and an 8-week lead-in period followed 
by a 26-week treatment period and a 4-week safety follow-up period.  
Patients who have been treated with either a) a MDI therapy, including a mealtime insulin (rapid 
acting insulin analog or regular human insulin) and insulin glargine U-100 once daily, insulin 
degludec U-100 once daily, insulin detemir U-100 once or twice daily, or neutral protamine 
Hagedorn (NPH) once or twice daily, or b) a premixed therapy with at least 2 injections of
premixed human insulin or insulin analog (premixed patients), will be eligible for inclusion in 
the trial.  The purpose of the lead-in period (prior to randomization) will be to titrate basal insulin 
in the MDI regimen, obtain preliminary diagnostic laboratory tests, and determine baseline 
hypoglycemia rates.  
At Visit 2, all patients will be transferred to a MDI regimen with insulin lispro thrice daily and 
an allowed study basal insulins regimen as below:
Basal insulin:  glargine U-100 once daily (Basaglar/Abasaglar or LANTUS, either in the 
morning or evening), or insulin degludec U-100 once daily as determined by the investigator in 
accordance with local regulation. 
The brand of insulin glargine chosen at Visit 2 should remain the same throughout the study; 
switching brands should be avoided.  Insulin glargine or insulin degludec will be titrated during 
the 8-week lead-in period using a titration algorithm that should enable patients to reach the 
target fasting blood glucose (FBG) by the end of this period.
Prandial insulin doses or insulin to carbohydrate ratio (ICR) and correction factor (CF) should 
not be changed during the lead-in period except for safety reasons (hypoglycemia or 
unacceptable hyperglycemia) or to facilitate basal insulin optimization.  
At Visit 8, patients will be randomized to either LY900014 or insulin lispro at mealtime.  During 
the initial 12 weeks after randomization (intensive titration period), prandial insulin dose should 
be adjusted as necessary in order to meet the target self-monitored blood glucose (SMBG) levels.
Basal insulin may be titrated as needed to facilitate optimal prandial dosing or for safety reasons 
such as hypoglycemia or unacceptable hyperglycemia. Thereafter, during the maintenance 
period (Weeks 12-26 of treatment), it is expected that adjustments to prandial and basal insulin 

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doses would be to maintain glycemic control or for safety reasons such as hypoglycemia or 
unacceptable hyperglycemia.
Figure ITSD.1 illustrates the study design.
Abbreviation:  T = telephone visit.
a
At Visit 2, patients on insulin glulisine, insulin aspart, regular human insulin, or 
premixed insulin will be transferred to insulin lispro.  The patients’ basal insulin 
regimen will be switched to insulin glargine U-100 once daily or to insulin degludec U-
100 once daily.  At Visit 8, patients will be randomized to either premeal insulin lispro
or premeal LY900014 and continue their basal insulin regimen.
b
Titrate basal insulin (see Section 7.2.1.3).
c
Titrate prandial insulin (insulin lispro or LY900014) (see Section 7.2.1.4).
d
Patients will discontinue study insulins at Week 26.  
Figure ITSD.1.
Illustration of study design for Clinical Protocol I8B-FH-ITSD.
5.2.
Number of Participants
Approximately 438 participants will be screened to achieve 350 randomized patients and 
298 patients completing 26 weeks.  Approximately 280 Chinese patients will be randomized.  
The other 70 randomized patients are planned to be from other countries, which may include 
Mexico, Argentina, Brazil, India and Ukraine  The final participating countries and allocated 
patient numbers will be adjusted based on the actual condition.
5.3.
End of Study Definition
End of the study is the last scheduled procedure shown in the Schedule of Activities (Section 2)
for the last patient.
5.3.1. Safety Follow-Up
Safety follow-up visit guidelines are as follows (see Section 2):

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LY900014

Patients who discontinue from the study early during the lead-in period (prior to 
randomization) should complete an early discontinuation visit only.

Patients who discontinue from investigational product (IP) early, but remain in the 
study, should complete all remaining visits per the Schedule of Activities (Section 
2), including Visit 801.

Patients who discontinue from the study early (regardless of whether they 
discontinue IP at the same time or have discontinued IP at an earlier visit) should 
complete an early discontinuation visit followed by the safety follow-up visit 
(Visit 801) per the Schedule of Activities (Section 2).

Patients who finish Visit 18 without early discontinuation of IP should complete a 
safety follow-up visit (Visit 801) 4 weeks after Visit 18.
5.4.
Scientific Rationale for Study Design
Study ITSD is a Phase 3 study to evaluate LY900014 compared to insulin lispro each in 
combination with basal insulin in patients with T1D.  The trial has 2 double-blind treatment 
groups, to allow comparison of LY900014 and insulin lispro when injected at the start of the 
meal.  
The study is designed to compare HbA1c lowering as the primary endpoint, a measure of 
glycemic control accepted by health care providers and regulatory authorities as a validated 
measure of BG control over time and is the best marker for development and progression of 
diabetes complications.  The lead-in period consists of 8 weeks to allow for optimization of basal 
insulin dosing.  The 26-week treatment period consists of a 12-week intensive titration phase to 
optimize prandial insulin dosing followed by a 14-week maintenance phase; therefore, the 
primary endpoint HbA1c reflects glucose control during the 3-month time period when there are 
minimal changes to insulin dose.  
5.5.
Justification for Dose
LY900014 will have the same insulin lispro concentration (100 U/mL) as that of commercially 
available Humalog.  The addition of treprostinil to the insulin lispro formulation does not modify 
the physical, chemical, or biological integrity of insulin lispro.  The dosage of basal and prandial 
insulins used in this study should be determined based on the individual needs of each patient.  

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6.
Study Population
This study will include patients who have been diagnosed with T1D for at least 1 year, using 
insulin continuously for at least 1 year, currently on MDI therapy or at least 2 injections of 
premixed insulin for at least 90 days, and having an HbA1c value of ≥7.0 and ≤10.0% at 
screening.  Patients’ basal insulin may be insulin glargine U-100 once daily, insulin degludec U-
100 once daily, insulin detemir U-100 once or twice daily, or NPH once or twice daily.  Patients 
may be taking any approved injectable rapid-acting insulin analog or regular human insulin.
Patients must give written informed consent (approved by Lilly or its designee and the ethical 
review board [ERB] governing the site) before being allowed to participate in the study and 
before any screening assessments are performed.  
Study investigator(s) will review the patient’s records and/or history and screening test 
results/measurements to determine if the patient meets all inclusion criteria and no exclusion 
criteria to qualify for participation in the study.  All screening activities must be completed and 
reviewed before the patient begins the lead-in period.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria at 
screen
Type of Patient and Disease Characteristics
[1]
Men or women diagnosed (clinically) with T1D, based on the World Health 
Organization classification (Appendix 5) for at least 1 year prior to screening, 
and continuously using insulin for at least 1 year
Patient Characteristics
[2]
Are at least 18 years of age 
[3]
meet either criteria (3a) or (3b).
(3a) Have been on MDI therapy including any rapid acting insulin analog for at 
least 90 days, and the same rapid acting insulin analog (insulin lispro U-100, 
insulin aspart, insulin glulisine) for at least 30 days, or regular human insulin
for at least 90 days
AND 
Have been treated for at least 60 days prior to screening with 1 of the 
following, in accordance with local regulations:
o
Insulin glargine U-100 once daily
o
Insulin detemir U-100 once or twice daily
o
Insulin degludec U-100 once daily

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o
NPH once or twice daily
Or
(3b) Have been treated for at least 90 days prior to screening with premixed insulin 
or insulin analog regimen with at least 2 injections daily
[4]
Have an HbA1c value ≥7.0 and ≤10.0%, according to the central laboratory at 
screening (Visit 1).
[5]
Have a body mass index (BMI) of ≤35.0 kg/m2 at screening (Visit 1).
[6]
Male patients:
o
No male contraception required except in compliance with specific local 
government study
[7]
Female patients:
o
Women not of childbearing potential may participate and include those who
are:

infertile due to surgical sterilization (hysterectomy, bilateral 
oophorectomy, or tubal ligation), congenital anomaly such as 
Mullerian agenesis; 
Or

postmenopausal – defined as either

a woman 50 to 54 years of age (inclusive) with an intact uterus, not 
on hormone therapy who has had either
o
cessation of menses for at least 1 year; 
Or
o
at least 6 months of spontaneous amenorrhea with a follicle-
stimulating hormone >40 mIU/mL; 
Or

a woman 55 years of age or older not on hormone therapy, who has 
had at least 6 months of spontaneous amenorrhea; 
Or

a woman at least 55 years of age with a diagnosis of menopause 
prior to starting hormone replacement therapy
o
Women of childbearing potential participating:

Cannot be pregnant or intend to become pregnant

Cannot be breastfeeding (including the use of a breast pump)

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LY900014

Must remain abstinent or use 1 highly effective method of contraception 
or a combination of 2 effective methods of contraception for the entirety 
of the study (Appendix 7)

Test negative for pregnancy at the time of screening (Visit 1). Note: a 
local urine or serum pregnancy test is conducted at Visit 8.  
[8]
Have access to a telephone or alternative means for close monitoring and 
communications
[9]
Have refrigeration in the home or have ready access to refrigeration for storage 
of insulin therapy
[10] Is a patient who the investigator has determined can be randomized and 
maintain the treatment regimens based on their previous medical history,
including insulin dosing regimens, hypoglycemic episodes, and glycemic 
control
[11] Capable of, willing, and desirous to do the following:
o
Inject insulin with the use of an insulin injection device (insulin pen) 
according to included directions
o
Perform self-BG monitoring, including 10-point SMBG on designated days
(patients using a personal continuous glucose monitoring [CGM] or flash 
glucose monitoring [FGM] device for insulin dosing decisions must still use 
the study glucose meter according to the protocol)
o
Participate in two 4-hour mixed-meal tolerance tests (MMTTs) and consume 
a standardized meal for the tests 
o
Follow an algorithm for basal insulin adjustment and individualized prandial 
insulin dosing using fixed pattern adjustment or carbohydrate counting as 
agreed upon with the investigator  
o
Comply with the use of the study insulin and scheduled visits 
o
Complete the patient diary and questionnaires 
[12] Considered healthy (apart from T1D) upon completion of medical history, 
physical examination, vital signs, electrocardiogram (ECG), and analysis of 
laboratory safety variables, as judged by the investigator
Informed Consent
[13] Have given written informed consent to participate in this study in accordance 
with local regulations.
6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at 
screening:
Medical Conditions

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LY900014
[14] Have any other condition (including known drug or alcohol abuse, or 
psychiatric disorder including eating disorder) that precludes the patient from 
following and completing the protocol
[15] Have hypoglycemia unawareness, as judged by the investigator
[16] Have had more than 1 episode of severe hypoglycemia (defined as requiring 
assistance due to neurologically disabling hypoglycemia) within the last 
6 months prior to screening
[17] Have had more than 1 emergency room visit or hospitalization due to poor 
glucose control (hyperglycemia or diabetic ketoacidosis) within 6 months prior 
to screening (Visit 1)
[18] Have clinically significant cardiovascular disease within the last 6 months prior 
to screening, defined as stroke, decompensated heart failure New York Heart 
Association class III or IV (Appendix 6), myocardial infarction, unstable angina 
pectoris, or coronary arterial bypass graft
[19] Renal:  
o
History of renal transplantation
o
Currently receiving renal dialysis
o
Serum creatinine >2.0 mg/dL (177 mol/L) at screening 
[20] Hepatic:  Have obvious clinical signs or symptoms of liver disease (for 
example, acute or chronic hepatitis, or cirrhosis) or elevated liver enzyme 
measurements as indicated below at screening (Visit 1):
o
Total bilirubin level (TBL) ≥2X the upper limit of normal (ULN) (with the 
exception of Gilbert’s syndrome) as defined by the central laboratory,
OR
o
Alanine aminotransferase (ALT) ≥3X ULN as defined by the central 
laboratory
OR
o
Aspartate aminotransferase (AST) ≥3X ULN as defined by the central 
laboratory
[21] Malignancy: Have active or untreated malignancy, have been in remission from 
clinically significant malignancy (other than basal cell or squamous cell skin 
cancer) for less than 5 years, or are at an increased risk for developing cancer or 
a recurrence of cancer, in the opinion of the investigator
[22] Have any hypersensitivity or allergy to any of the insulins or excipients used in 
this trial
[23] Have hypersensitivity or allergy to any of the ingredients in the standardized 
test meal (MMTT) (for example, nut allergy)  

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LY900014
[24]
Hematologic:  Have had a blood transfusion or severe blood loss within 90 
days prior to screening or have known hemoglobinopathy, hemolytic anemia,
or any other traits of hemoglobin abnormalities known to interfere with 
measurement of HbA1c  
[25] Have presence of clinically significant gastrointestinal disease (for example, 
clinically active gastroparesis associated with wide glucose fluctuations), in the 
opinion of the investigator
[26] Have excessive insulin resistance defined as having received a total daily dose 
of insulin >1.5 U/kg at the time of screening
Prior/Concomitant Therapy
[27] Glucocorticoid therapy:  Receiving chronic (lasting longer than 14 consecutive 
days) systemic glucocorticoid therapy (including IV, intramuscular, SC, or oral, 
but excluding topical, intraocular, intranasal, intra-articular and inhaled 
preparations) or have received such therapy within 8 weeks immediately prior to 
screening (Visit 1) with the exception of replacement therapy for adrenal 
insufficiency
[28] Have used insulin human inhalation powder (Afrezza®) within 90 days prior to 
screening (Visit 1)
[29] Are currently taking traditional medicine (herbal medicine or patent medicine) 
with known/specified content of anti-hyperglycemic effects within 90 days prior 
to screening
[30] Have used CSII for more than 14 days within the 90 days prior to screening
(Visit 1)
[31] Receiving any oral or injectable medication intended for the treatment of 
diabetes mellitus other than insulins in the 90 days prior to screening (Visit 1),
EXCEPT for those patients with metformin at a stable dose for more than 90 
days prior to Visit 1. Metformin will be discontinued at Visit 2 in accordance 
with local regulation
Prior/Concurrent Clinical Trial Experience
[32] Are currently enrolled in any other clinical trial involving an IP or any other 
type of medical research judged not to be scientifically or medically compatible 
with this study
[33] Have participated in a clinical trial involving an IP within the last 30 days.  If 
the previous IP has a long half-life, 3 months or 5 half-lives (whichever is 
longer) should have passed
[34] Have previously completed or withdrawn from this study or any other study 
investigating LY900014 after receiving at least 1 dose of the IP
Other Exclusions

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[35] Are investigator site personnel directly affiliated with this study and/or their 
immediate families.  Immediate family is defined as a spouse, parent, child, or 
sibling, whether biological or legally adopted
[36] Are Lilly employees (including employees, temporary contract workers, or 
designees responsible for the conduct of the study)
[37] Are unable and/or unwilling to provide informed consent, to make themselves 
available for the duration of the study, or to abide by study procedures
6.3.
Lifestyle Restrictions

Patients should be instructed not to donate blood or blood products during the 
study. 

Patients should be instructed to avoid major changes in dietary intake or physical 
activity during the 3 days prior to MMTT.  
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened.  Retests are also not allowed, except for cases when results are not available from the 
original sample.

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7. Treatments
7.1.
Treatments Administered
This study involves a comparison of LY900014 and insulin lispro administered SC 0 to 2 
minutes prior to the start of the meal for 26 weeks.  
Table ITSD.2 shows the treatment regimens.
Table ITSD.2.
Treatment Regimens
Regimen
Dose
Strength
Dose
Administration
Route of
Administration
Timing of 
Administration
LY900014
100 U/mL
Individualized 
dosing
Subcutaneous
0 to 2 minutes before start of the meal
Insulin lispro
100 U/mL
Individualized 
dosing
Subcutaneous
0 to 2 minutes before start of the meal
The investigator or his/her designee is responsible for the following:

explaining the correct use of the IP to the patient including the importance of 
injection site rotation for both basal and prandial insulin

explaining requirements for recording insulin doses and injection times to the 
patient

verifying that instructions are followed properly

maintaining accurate records of IP dispensing and collection

at the end of the study, returning all used and unused IP to Lilly, or its designee, 
unless the sponsor and sites have agreed all unused medication is to be destroyed 
by the site, as allowed by local law
7.1.1. Packaging and Labeling
Clinical trial materials will be labeled as IP as appropriate, and according to the country’s 
regulatory requirements.  Study insulins (LY900014 and insulin lispro) will be supplied by Lilly 
or its representative, in accordance with current good manufacturing practices, and will be 
supplied with clinical trial lot numbers.  Instructions for Use for the prefilled devices will be 
provided.
The blinded prefilled pens will contain a concentration of 100 U/mL in 3-mL cartridges of either 
LY900014 or insulin lispro.  
During the lead-in period, 100 U/mL insulin lispro will be provided using open-label prefilled 
pens. 

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7.1.2. Medical Devices 
The medical devices provided for use in the study are prefilled pens.  LY900014 prefilled pens 
are new investigational combination products.
7.2.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will be randomized to double-blind treatment at 
Visit 8.  Assignment to treatment groups will be determined by a computer-generated random 
sequence using an interactive web-response system (IWRS).  Patients will be randomized to 1 of 
the 2 treatment groups in a 1:1 ratio.  Stratification will be by country (China vs. Other), HbA1c 
stratum (≤8.5% vs. >8.5% at Visit 7), type of basal insulin during the lead-in period (glargine U-
100 vs. degludec U-100), and use of metformin at study entry (yes vs. no).  
The IWRS will be used to assign all IP during the study, including insulin lispro during the 
lead-in period.  The IWRS will be used to assign prefilled pens containing double-blind IP to 
each patient randomized to the 2 blinded treatment groups. Site personnel will confirm that they 
have located the correct prefilled pens by entering a confirmation number found on the prefilled 
pens into the IWRS.
7.2.1. Selection and Timing of Doses
7.2.1.1.
Target Glucose Values for Titration of Insulin Therapy
The overall glycemic control goals for all patients enrolled in the study are similar to those 
recommended by the American Association of Clinical Endocrinologists (Bailey et al. 2016).  
Fasting, prandial, postprandial, and bedtime glucose target values used to reach the SMBG goals 
and for determination of titration in insulin therapy are listed in Table ITSD.3.
Table ITSD.3.
Target Glucose Values for Adjustment of Insulin Therapy
Time of Target Blood Glucose Measurement
Self-Monitored Blood Glucose (SMBG) Target (Range)
Fasting or pre morning meal
Target:  100 mg/dL or 5.6 mmol/L
Range:  80 to <110 mg/dL or 4.4 to 6.1 mmol/L
Pre midday meal
Target:  100 mg/dL or 5.6 mmol/L
Range:  80 to <110 mg/dL or 4.4 to 6.1 mmol/L
Pre evening meal
Target:  100 mg/dL or 5.6 mmol/L 
Range:  80 to <110 mg/dL or 4.4 to 6.1 mmol/L
Pre bedtime
Range:  90 to 130 mg/dL or 5.0 to 7.2 mmol/L
1-2 hour postprandial 
Target:  <140 mg/dL or 7.8 mmol/L 
Note:  Every effort should be made to reach the targets while avoiding hypoglycemia.

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7.2.1.2.
Basal Insulin Therapy
At Visit 2, patients will be transferred to insulin glargine U-100 (Basaglar/Abasaglar or 
LANTUS) once daily or to degludec U-100 once daily in accordance with local regulations if the 
patient enters the study on any other basal insulin regimen.  The initial basal insulin dose may be 
unit-for-unit of the prestudy basal insulin regimen or 80% of the prior basal insulin daily dose if 
the patient was previously treated with twice-daily NPH.
At Visit 2, patients treated with premixed insulin will be transferred to an allowed study basal 
insulin and to insulin lispro (see Section 7.2.1.4).  Patients transitioning from regular human 
insulin or human insulin mixtures should be reminded about the importance of injecting insulin 
lispro immediately prior to meals. The total daily insulin dose will be divided between basal and 
bolus insulin doses at the discretion of the investigator.  The initial basal insulin dose may be 
approximately 40% to 60% of the total daily dose.  The initial prandial insulin dose may be 
approximately 40% to 60% of the total daily dose.  The distribution for use across the 3 main 
meals is at the discretion of the investigator. The basal insulin dose may be influenced by other 
clinical circumstances and safety considerations known to the investigator; thus, the prescribed 
basal insulin dose during the study is determined by, and the responsibility of the investigator.  
Patients should use the same study basal insulin regimen throughout the trial. The study basal 
insulin can be dosed at any time during the day and should be taken at approximately the same 
time of day throughout the course of the study.  
7.2.1.3.
Basal Insulin Titration
At all clinic and telephone visits during the 8-week lead-in period, basal insulin dose adjustments 
should be determined by the investigator in discussion with the patient based on SMBG and 
hypoglycemia data.  Additional discussion between visits may be required to enable the patient
to reach the FBG target.  Patients’ basal insulin should be titrated using the titration algorithm to 
reach the FBG target of 100 mg/dL (5.6 mmol/L). 
Decreases to the basal insulin dose may be made at any time based upon the judgment of the 
investigator (for example, in response to hypoglycemia). Modifications in the calculation of the 
basal insulin dose may also be influenced by other clinical circumstances and safety 
considerations known to the investigator; thus, the prescribed basal insulin dose during the study 
is determined by, and the responsibility of, the investigator.  
Every effort should be made to reach the FBG target during the lead-in period to allow enough 
time for prandial insulin dose adjustments during the titration period; however, basal insulin dose 
may be adjusted if needed to facilitate optimal prandial insulin dosing during the intensive
titration period (Weeks 0 to 12) or for safety reasons.  Thereafter, during the maintenance period
(Weeks 12 to 26), it is expected that adjustments to basal insulin doses would be to maintain 
glycemic control or for safety reasons such as hypoglycemia or unacceptable hyperglycemia.  
Assessments of the basal insulin dose should be made at least at weekly intervals based upon the 
occurrence of hypoglycemia events during the previous week (Table ITSD.4). After the 
hypoglycemia assessment, the median FBG value from the 3 previous corresponding FBG values 
can be used for basal insulin adjustment as in Table ITSD.5.  Additional discussion between 

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LY900014
visits may be required to enable the patient to reach the FBG target.  The basal insulin dose may 
be adjusted every 3 to 4 days (twice per week) when appropriate, based on the patient’s glycemic 
needs and SMBG levels.  Investigators may use discretion and provide direction for patients to 
adjust the basal insulin dose.
Table ITSD.4.
Basal Insulin Hypoglycemia Assessment
Hypoglycemic Events in the Previous Week
Basal Insulin Change (units)
2 or more nocturnal hypoglycemia events occur or 1 severe 
hypoglycemia event occurs at any time of the day
Titrate the basal dose down to the previous basal 
insulin dose (or by 10% if this is first dose)
1 nocturnal hypoglycemia event occurs
Do not increase basal insulin dose and consider 
reducing the dose if clinically indicated
No nocturnal events occur
Titrate the basal insulin up based upon the median 
FBG for the previous 3 FBG values.  See 
Table ITSD.5
Abbreviation:  FBG = fasting blood glucose.
Table ITSD.5.
Summary of Basal Insulin Adjustments after Hypoglycemia 
Assessment
When Basal Insulin ≤14 units
When Basal Insulin ≥15 units
If median FBG from the 3 
previous FBG values is:
Adjust the basal dose by:
Adjust the basal dose by:
<80 mg/dL 
(<4.4 mmol/L)
Decreasing dose to previous lower dosea
Decreasing dose to previous lower dosea
80–100 mg/dL 
(4.4–5.6 mmol/L)
No adjustment
No adjustment
101–139 mg/dL 
(5.7–7.7 mmol/L)
Increasing by 1 unit
Increasing by 2 units
140–179 mg/dL 
(7.8–9.9 mmol/L)
Increasing by 2 units
Increasing by 3 units
180 mg/dL 
(10 mmol/L)
Increasing by 3 units
Increasing by 4 units
Abbreviation:  FBG = fasting blood glucose.
a
If there is no previous dose because this was the first assigned dose after randomization, then the basal dose 
should be decreased by 10% in consultation with the investigator.
Sources:  Adapted from Bartley et al. 2008 and Bolli et al. 2009.
7.2.1.4.
Study Prandial Insulin Therapy
Patients treated with insulin aspart, insulin glulisine, or regular human insulin as their prestudy 
prandial insulin will be transferred to insulin lispro (unit for unit or decreased by 10% to 20% for 
regular human insulin to avoid hypoglycemia at investigator discretion) at Visit 2.  Insulin lispro 
will be dispensed to all patients for use throughout the lead-in period. 
At Visit 2, patients treated with premixed insulin will transition to 3 injections of prandial insulin 
with 3 main meals a day.  The total daily insulin dose will be divided between basal and bolus 
insulin doses at the discretion of the investigator.  The initial basal insulin dose may be 
approximately 40% to 60% of the total daily dose.  The initial prandial insulin dose may be 
approximately 40% to 60% of the total daily dose.  The initial distribution of prandial insulin 

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LY900014
may be equal (33% of total daily prandial dose prior to each meal).  Otherwise, the investigator, 
in consultation with the patient, may alter the percentage of prandial insulin prescribed at each 
meal as clinically indicated, such as by the patient’s history of prandial insulin administration, 
SMBG levels, and meal pattern.  The prandial insulin dose may be adjusted if needed (for safety 
reasons such as hypoglycemia or unacceptable hyperglycemia) during the lead-in as clinically 
indicated.
Patients will be randomized (Visit 8) to either LY900014 or insulin lispro at mealtime.  Patients 
will administer their first study prandial insulin with the next meal following the baseline MMTT.  
Patients should have 3 doses of prandial insulin per day and eat 3 main meals per day (morning, 
midday, and evening) on a regular basis.  Patients may also eat a snack and cover with bolus 
insulin if that is their usual practice.  
This study will use 2 possible plans for determining prandial insulin dosing including:
[1] Pattern adjustment:  The patient is prescribed a fixed dose or dose range of insulin for each 
meal. The fixed insulin dose may be individualized for each meal.
[2] Carbohydrate counting: The patient performs carbohydrate counting for prandial insulin 
dosing (ICR plan) and prandial insulin dose is based upon the estimated carbohydrate content 
of the meal (as unit insulin per grams carbohydrate).
The patient should maintain the same prandial insulin dosing plan throughout the study.  
Correction factor(s) (for example, 1 unit of insulin per glucose [mg/dL or mmol/L] above target 
goal) may be implemented with either prandial insulin dosing plan.  Adjustments in insulin 
dosage should also take into account conditions of stress and/or exercise and should be made 
individually.
At randomization (Visit 8), the starting study insulin doses may be initiated unit for unit; 
however, investigators may consider reducing the prandial or correction insulin doses 
approximately 10% to 20% based on the patient’s overall glycemic status or other considerations 
known to the investigator in order to reduce risk of postprandial hypoglycemia.
For patients who are carbohydrate counting, the ICR and CF should be assessed and adjusted as 
needed, at least weekly, in order to meet the target SMBG levels described in Table ITSD.3
during the initial 12 weeks after randomization (the intensive titration period). The ICR may be 
adjusted every 3 to 4 days (twice per week) when appropriate, based on the patient’s glycemic 
needs and SMBG levels.  Postprandial SMBG levels from 10-point SMBG profiles should also 
be evaluated for optimization of prandial insulin dosing.  Additional 2-hour postprandial SMBG 
monitoring should be considered during the days following transition to study insulin beginning 
at Visit 8.  During the maintenance period (Weeks 12 to 26), it is expected that prandial insulin 
dose adjustments should be made to maintain glycemic control and for safety reasons such as 
hypoglycemia or unacceptable hyperglycemia; however, if SMBG targets have not been 
achieved, titration of prandial insulin should continue. 
For patients who are using pattern adjustment, the prandial insulin dose should be assessed and 
adjusted as needed 1 to 2 times each week, and the CF should be assessed and adjusted weekly 

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LY900014
as needed during the initial 12 weeks after randomization (the intensive titration period).  In 
addition to the weekly investigator dose assessment, investigators may use discretion and
encourage patients to make 1 additional prandial insulin dose adjustment per week.  Prandial 
insulin dose adjustments for more than twice per week will not constitute a protocol violation.  
During the maintenance period (Weeks 12-26), prandial insulin dose adjustments should be 
made in order to maintain glycemic control and for safety reasons such as hypoglycemia or 
unacceptable hyperglycemia; however, if glycemic and SMBG targets have not been achieved, 
titration of prandial insulin should continue.  Modifications in the calculation of the insulin dose 
may also be influenced by other clinical circumstances and safety considerations known to the 
investigator.  Therefore, the prescribed prandial insulin dose is determined by, and the 
responsibility of, the investigator.  
In the pattern adjustment plan, assessment of the prandial insulin dose includes review of the 
previous 3 to 7 days of SMBG levels for the corresponding meal or bedtime (Table ITSD.6).  
For example, if assessing the need to adjust the fasting (pre morning meal) prandial insulin 
dose, review the preceding 3 to 7 pre midday meal SMBG levels. 
Table ITSD.6.
Prandial Insulin Doses and Corresponding Self Monitored Blood 
Glucose Values Pattern Adjustment Plan
Prandial Insulin Dose Assessed
Corresponding SMBG Values for Review
Fasting or morning premeal
3-7 previous midday premeal SMBG values
Midday premeal
3-7 previous evening premeal SMBG values
Evening premeal
3-7 previous bedtime SMBG values
Abbreviation:  SMBG = self-monitored blood glucose.
The median value from premeal glucose readings from the 3 to 7 previous days is chosen as the 
“adjustment value” and the change in dose (either increase or decrease) is based upon this value 
(Table ITSD.7). 
Table ITSD.7.
LY900014 or Insulin Lispro Adjustment Algorithm Pattern 
Adjustment Plan
If Meal Time Dose of 
Insulin Lispro is:
Median SMBG Value 
Below Target Range
Median SMBG Value at 
Target Rangea
Median SMBG Value 
Above Target Range
<10 units
Decrease by 1 unit
No change
Increase by 1 unit
11–19 units 
Decrease by 2 units
No change
Increase by 2 units
>20 units 
Decrease by 3 units
No change
Increase by 3 units
Abbreviation:  SMBG = self-monitored blood glucose.
a
Median SMBG value at target range OR experienced 1 unexplained hypoglycemic event (70 mg/dL
[3.9 mmol/L]) or signs/symptoms consistent with hypoglycemia noted. 
Target Range: Premeal: 80 to <110 mg/dL (4.4 to 6.1 mmol/L)
Bedtime:  90 to 130 mg/dL (5.0 to 7.2 mmol/L)
1-2 hour postprandial:  <140 mg/dL (7.8 mmol/L).
Source:  Adapted from Bergenstal et al. 2008.

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Patients who wear their personal CGM/FGM device prior to study entry will be allowed to 
continue to wear their CGM/FGM device during the study. However, these patients should be 
instructed to perform SMBG monitoring using the study glucose meter according to the protocol.  
Investigators must use the SMBG levels to make treatment decisions. Patients should not start 
using a personal CGM/FGM device after Visit 2.
7.2.1.5.
Transitioning off Study Insulin Therapy
Patients should take their last dose of study insulin (LY900014 or insulin lispro) at Visit 18 with 
the MMTT if performed the same date as Visit 18 or the evening the day prior to Visit 18 if the 
MMTT is performed prior to Visit 18 or at early discontinuation.
No special instructions for transition to nonstudy prandial insulin are necessary for patients who 
were using basal bolus therapy prior to study entry.  After completion of study treatment, these
patients will restart the prandial insulin therapy used prior to study entry or may transition to a 
rapid-acting insulin analog other than insulin lispro if the patient was treated with regular human 
insulin prestudy.  Patients may remain on the basal insulin used during the study (if it was 
changed at Visit 2) at the discretion of the investigator or return to their prestudy basal insulin.
Patients who were using premixed insulins prior to study entry may choose to stay on basal bolus 
regimen at the discretion of the investigator.  However, patients who were not on lispro product 
prior to entry should NOT use lispro product during the safety follow-up period.
Additional guidance for insulin therapy after the treatment period is provided in Section 7.8.2.
7.3.
Blinding
This is a double-blind study in which LY900014 or insulin lispro will be administered 
immediately (0-2 minutes) prior to each meal in a double-blind manner.  Investigators, patients, 
and study site personnel will be blinded to assigned dosing regimens throughout the study.  
To preserve the blinding of the study, the Lilly study team will remain blinded throughout the 
study; only a minimum number of Lilly personnel will see the randomization table and treatment 
assignments before the study is complete.
Emergency unblinding for AEs may be performed through the IWRS, which may supplement or 
take the place of emergency codes generated by a computer drug-labeling system.  This option 
may be used ONLY if the patient’s well-being requires knowledge of the patient’s treatment 
assignment.  Unblinding events are recorded and reported by the IWRS.
If an investigator, site personnel performing assessments, or patient is unblinded, the patient
must be discontinued from IP and should remain in the study.
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.  The 
patient safety must always be the first consideration in making such a determination.  If a 
patient’s treatment assignment is unblinded, Lilly must be notified immediately.  If the 
investigator decides that unblinding is warranted, it is the responsibility of the investigator to 
promptly document the decision and rationale and notify Lilly as soon as possible.

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7.4.
Dosage Modification
See Section 7.2.1.
7.5.
Preparation/Handling/Storage/Accountability
The investigator or his/her designee is responsible for confirming appropriate temperature 
conditions have been maintained during transit for all study treatment received and any 
discrepancies are reported and resolved before use of the study treatment. 
Only patients enrolled in the study may receive IP, and only authorized site staff may supply or 
administer study treatment.  All study treatments should be stored in an environmentally 
controlled and monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff.
All insulin products must be stored at the investigative site under refrigerated conditions 
(between 2°C and 8°C) in a locked and secure place.  Insulin must not be frozen.
In-use insulins should be maintained at room temperature, and refrigerated material should be 
warmed to near room temperature before injection.  In-use insulin must not be used after 
28 days.
The investigator is responsible for study treatment accountability, reconciliation, and record 
maintenance (such as receipt, reconciliation, and final disposition records).  
7.6.
Treatment Compliance
The investigator or designee will assess compliance of the patient at each visit, based on a review 
of the patient’s glycemic control, adherence to the visit and treatment schedule, and completion 
of patient diary.  Patients who are deemed noncompliant will receive additional diabetes 
education and training, as required, and the importance of compliance with the protocol will be 
reinforced.  Patients who, in the opinion of the investigator, are deemed consistently 
noncompliant may be discontinued from IP or from the study.  
7.7.
Concomitant Therapy
Guidance on restrictions for concomitant therapies is provided in Table ITSD.8.

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Table ITSD.8.
Concomitant Medications
Drug Class
Acute 
Use
Chronic 
Use
Safety Follow-Up Period
Conditions for Use
NPH, insulin glargine U-300, 
insulin detemir, insulin 
degludec U-200
No
No
Yes
Regular human insulin
No
No
Yes
May be used in 
emergencies for up to 14 
consecutive days 
Premixed insulin or premixed 
insulin analog
No
No
Yesa
May be used in 
emergencies for up to 14 
consecutive days
Affreza(inhaled insulin), or 
premixed human or premixed 
analog insulin
No
No
No
May be used in 
emergencies for up to 14 
consecutive days
Any noninsulin diabetes 
treatment therapy
No
No
No
Systemic glucocorticosteroid 
(including IV, intramuscular, 
SC, or oral preparations, but 
excluding topical, inhaled, 
intraocular, intra-articular, or 
intranasal preparations)
Yes
No
No
During the lead-in period, 
allow 1-time use for 
≤14 consecutive days.  
During all other study 
periods, allow use for a 
total of ≤21 days.
Abbreviations:  IV = intravenous; NPH = neutral protamine Hagedorn; SC = subcutaneous.
a
Patients who were using premixed insulins prior to study entry may choose to stay on basal bolus regimen.  
However, patients who were not on insulin lispro product prior to entry should NOT use insulin lispro product 
during the safety follow-up period.
7.8.
Treatment after the End of the Study
7.8.1. Continued Access
LY900014 will not be made available to patients after conclusion of the study.  Rapid-acting 
insulin analogs are available in all countries for use as prandial insulin.  
7.8.2.Special Treatment Considerations
Refer to Section 7.2.1.5 for information regarding transitioning off study insulin therapy after 
discontinuation of study insulin at the end of the treatment period or earlier.
Investigators should provide patients with appropriate guidance for glucose monitoring and 
insulin dose adjustment throughout the follow-up period in order to maintain glycemic control.

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8.
Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
In the event that a patient is discontinued from the study treatment, the investigator should 
encourage the patient to remain in the study for continued safety monitoring.  
Lilly recognizes the importance of complete data collection.  This study includes elements to 
minimize missing data.  Randomized patients who are discontinued from IP before study 
completion are encouraged to remain in the study for continued monitoring.  For patients who 
remain in the study after early discontinuation of IP, both efficacy (except MMTT) and safety 
data will be collected at scheduled visits. MMTT assessment will NOT be performed for these 
patients. The difference between stopping IP and discontinuing the study will be explained to 
patients as part of the informed consent, and patients will be encouraged to continue in the study 
even if they stop study drug.  In addition, study site investigators will be trained on the 
importance of complete data collection, with additional re-education of sites and patients as 
necessary.  
8.1.1. Permanent Discontinuation from Study Treatment
Patients will be discontinued from the IP in the following circumstances:

The investigator may decide that the patient should stop IP.  If this decision is 
made because of an AE, SAE, or a clinically significant laboratory value, the 
study drug is discontinued for that patient and appropriate measures are to be 
taken.  Lilly or its designee is to be alerted.

The patient requests to discontinue IP.

If the patient becomes pregnant.

If an investigator, study site personnel performing assessments, or patient is 
unblinded, the patient must discontinue IP.

If the patient, for any reason, requires treatment with another therapeutic regimen 
or therapeutic agent that has been demonstrated to be effective for treatment of 
the study indication.  Discontinuation from IP should occur prior to introduction 
of the new agent.

Use of prohibited concomitant medication (see Table ITSD.8).

If the patient has not taken IP for more than 14 consecutive days.  

Discontinuation due to a hepatic event or liver test abnormality.  Patients who are 
discontinued from investigational product due to a hepatic event or liver test abnormality 
should have additional hepatic safety data collected via CRF.
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:

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
alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8X 
upper limit of normal (ULN)

ALT or AST >5X ULN for more than 2 weeks

ALT or AST >3X ULN and total bilirubin level (TBL) >2X ULN or 
international normalized ratio (INR) >1.5 

ALT or AST >3X ULN with the appearance of fatigue, nausea, vomiting, 
right upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(>5%)

alkaline phosphatase (ALP) >3X ULN

ALP >2.5X ULN and TBL >2X ULN

ALP >2.5X ULN with the appearance of fatigue, nausea, vomiting, right 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
Patients discontinuing from the investigational product prematurely for any reason should 
complete adverse event and other follow-up procedures per Section 2 (Schedule of Activities), 
Section 9.2 (Adverse Events), and Section 9.4 (Safety) of this protocol.
8.1.2. Temporary Discontinuation from Study Treatment
During the study, patients who temporarily discontinue the IP may be able to resume IP based on 
the following scenario:  
Patient has not taken IP for 14 consecutive days or less:

If the treatment regimen restarts within 14 days of when the patient initially stopped 
taking IP, patient may continue in the study and begin treatment again with IP.  
During this time, nonstudy insulins may have been used.  If the patient decides to 
continue in the study, no early termination procedures will be completed.  Patients 
will continue study visits through the safety follow-up.
8.1.3. Discontinuation of Inadvertently Enrolled Patients
If the sponsor or investigator identify a patient who did not meet enrollment criteria and was 
inadvertently enrolled, then the patient should be discontinued from study treatment unless there 
are extenuating circumstances that make it medically necessary for the patient to continue on 
study treatment.  If the investigator and the sponsor CRP agree it is medically appropriate to 
continue, the investigator must obtain documented approval from the sponsor CRP to allow the 
inadvertently enrolled patient to continue in the study with or without treatment with
investigational product.  Safety follow up is as outlined in Section 2 (Schedule of Activities), 
Section 9.2 (Adverse Events), and Section 9.4 (Safety) of the protocol.
8.2.
Discontinuation from the Study
Some possible reasons that may lead to permanent discontinuation include:

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
Enrollment in any other clinical trial involving an IP or enrollment in any other type of 
medical research judged not to be scientifically or medically compatible with this study

Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP)

The investigator decides that the patient should be discontinued from the study

The patient requests to be discontinued from the study

The patient discontinues insulin lispro or study-allowed basal insulin regimen for 
>14 consecutive days in the lead-in period.
Patients who discontinue the study early, but after randomization, will have early discontinuation 
procedures performed as shown in the Schedule of Activities (Section 2).  
Patients who discontinue during the lead-in period will not need to fast, have laboratory tests 
drawn, or complete questionnaires, but will have all other early discontinuation procedures
performed.
Patients discontinuing from the study prematurely for any reason should complete AE and other 
safety follow-up per Section 2 (Schedule of Activities), Section 9.2 (Adverse Events), and 
Section 9.4 (Safety) of this protocol.
8.3.
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, with the study procedures and their timing (including 
tolerance limits for timing).
Appendix 2 lists the laboratory tests that will be performed for this study.
Unless otherwise stated in the subsections below, all samples collected for specified laboratory 
tests will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may 
be retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1.
Efficacy Assessments
9.1.1. Primary Efficacy Assessments
The primary efficacy measure is the change from baseline to Week 26 in HbA1c.
9.1.2. Secondary Efficacy Assessments
The following secondary efficacy measures will be collected at the times shown in the Schedule 
of Activities (Section 2).  

Fasting and PPG collected during the MMTT
o
1-hour and 2-hour PPG excursions: serum glucose measured 1 hour and 2 hours 
after the start of a meal minus fasting serum glucose
o
Incremental areas under the serum glucose concentration-time curve from 0 to 30 
minutes, 0 to 1 hour, 0 to 2 hours, 0 to 3 hours, and 0 to 4 hours after a meal; 
maximum serum glucose after a meal
o
Glucose variability measured by the coefficient of variation and standard 
deviation (SD)

1,5-Anhydroglucitol (1,5-AG)

SMBG 10-point profiles (fasting, 1 hour post morning meal, 2 hours post morning meal, 
pre midday meal, 1 hour post midday meal, 2 hours post midday meal, pre evening meal, 
1 hour post evening meal, 2 hours post evening meal, and bedtime)
o
1-hour and 2-hour PPG excursions
o
Within- and between-day glucose variability measured by the coefficient of 
variation and SD

Proportion of patients with HbA1c ≤6.5% and <7.0%

Prandial, basal, and total insulin dose (units and units/kg), and prandial/total insulin ratio 

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9.1.3. Appropriateness of Assessments
All efficacy and safety assessments included in this study are generally regarded as reliable and 
accurate with respect to diabetes.
9.1.4. Study Procedures
The following procedures will be performed at the times shown in the Schedule of Activities 
(Section 2). 
9.1.4.1.
Four-Point Self-Monitoring Blood Glucose
Patients should be encouraged to measure a minimum of 4 SMBG readings daily to facilitate
dose titration (consists of fasting [pre morning meal], pre midday meal, pre evening meal, and 
pre bedtime), with additional readings as needed for glucose self-management. 4-point SMBG is 
required on three nonconsecutive days in the one week before each visit. Site personnel may 
request additional SMBG monitoring from patients and/or assess SMBG values at other times
(such as postprandial SMBG measurements) to make clinical management decisions.  Missing 
values in 4-point SMBG profiles will not be considered protocol deviations unless, in the opinion 
of the investigator, they are excessive and reflect noncompliance with the protocol.
9.1.4.2.
Ten-Point Self-Monitoring Blood Glucose
Patients in both study arms should be instructed to perform 10-point SMBG profiles prior to 
3 visits during the study (Visits 8, 15, and 18). Three 10-point profiles should be done during the 
2 weeks prior to each visit.  Each 10-point profile during this 2-week time interval should be 
completed over a 1-day period, preferably on 3 nonconsecutive days (weekdays and weekends), 
as per the Schedule of Activities (Section 2).  The 10-point profile consists of 10 SMBG 
measurements on the same day at premeal; 1 hour and 2 hours after the start of the morning, 
midday, and evening meals; and at bedtime.  The 10-point SMBG profile is inclusive of the daily 
4-point SMBG readings.  Patients should be encouraged to eat a morning, midday, and evening 
meal on the days that the 10-point SMBG is monitored.  Premeal measurements should be taken 
before the patient begins eating the meal.  Patients may eat a snack and cover with bolus insulin 
if that is their usual practice.  Missing values in 10-point SMBG profiles will not be considered 
protocol deviations unless, in the opinion of the investigator, they are excessive and reflect 
noncompliance with the protocol.
9.1.4.3.
Mixed-Meal Tolerance Test
A 4-hour MMTT will be performed in all patients at baseline (Week 0, Visit 8) and at the end of 
the 26 weeks of treatment (Visit 18). For patients who remain in the study after early 
discontinuation of IP, MMTT assessment will NOT be performed. Patients will be instructed to 
fast for at least 8 hours prior to the administration of the MMTT at the study site.  
The MMTT can occur 0 to 4 days prior to the visit.  The MMTT can be rescheduled up to 2 
times within the visit window, ideally at 24-hour intervals, if the patient does not meet the target 
FBG.  It is preferred for the rescheduled MMTT to occur as close to the visit date as possible.  

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Target FBG prior to the MMTT:  Patients must have an FBG in the range of 71 to 180 mg/dL 
(3.9 to 10.0 mmol/L) prior to starting the MMTT.  If the glucose is outside of this range, the 
MMTT should be rescheduled.
In order to increase the likelihood of having patients arrive on the morning of the MMTT within 
the target FBG range, note the following:

Patients should be instructed to avoid major changes in dietary intake or physical activity 
during the 3 days prior to the MMTT.

Patients should be instructed to inject basal insulin according to their usual schedule, but 
should not administer correction doses with their rapid-acting insulin within 4 hours of 
the start of the MMTT.
During the 8-hour fasting period and up to 2 hours prior to the start of the MMTT, episodes of 
non-severe hypoglycemia (symptoms or BG ≤70 mg/dL [3.9 mmol/L]) can be treated with 15 to 
20 grams of carbohydrate.  If an episode requires more than approximately 20 grams of 
carbohydrate within 8 hours of the start of the MMTT or the patient experiences a severe episode 
requiring assistance, the patient should be instructed to notify the site and the MMTT must be 
rescheduled.
Test Meal:  The MMTT meal will consist of a standardized liquid nutrition shake(s) 
(approximately total energy 700 kcal and 100 grams of carbohydrates, such as Ensure Plus®, 
Abbott Nutrition),  Patients are expected to consume the meal within 15 minutes.  Patients 
should consume the same test meal for both the baseline and end of primary treatment period 
MMTT, if possible.
Insulin Injection:  During the Visit 8 MMTT, all patients will have insulin lispro injected 
0 to 2 minutes before the start of the meal.  During the Visit 18 MMTT, patients randomized to 
either of the 2 blinded arms will have their blinded study insulin, either LY900014 or insulin 
lispro, injected 0 to 2 minutes before the start of the meal. The prandial insulin dose 
administered during the MMTT will be individualized for each patient.  

If the patient uses the carbohydrate counting prandial dosing plan, the morning 
meal ICR will be used to calculate the prandial insulin dose for the MMTT.  

If the patient does not use carbohydrate counting, the prandial insulin dose for the 
MMTT should be calculated based on the average total daily insulin dose for the 
3 days prior to the MMTT per Table ITSD.9.

Modifications in the calculation of the insulin dose may also be influenced by 
other clinical circumstances and safety considerations known to the investigator; 
thus, the MMTT prandial insulin dose is determined by, and the responsibility of, 
the investigator. 

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Table ITSD.9.
Insulin to Carbohydrate Ratio for Determining the Prandial Insulin 
Dose for the Mixed-Meal Tolerance Test: For Use with Patients 
Who Use Pattern Adjustment to Determine Prandial Insulin Doses
Average Total (Basal+Bolus) Insulin Dose 
(units) in the Last 3 Days
Insulin to Carbohydrate Ratio 
(1 unit per number of grams carbohydrate)
8-11 units
1unit : 50 grams
12-14
1:40 
15-18
1:30 
19-21
1:25 
22-27
1:20 
28-35
1:15 
36-45
1:12 
46-55
1:10 
56-65
1:8 
66-80
1:6 
81-120
1:5 
>120
1:4 
Source: Scheiner [WWW].
Hypoglycemia during the MMTT:  If the patient has signs or symptoms of hypoglycemia 
during the MMTT, BG should be measured with a glucometer.  If the patient’s BG is ≤70 mg/dL 
(3.9 mmol/L), then the patient should receive 15 grams of rapidly absorbable oral carbohydrate.  
The patient’s BG should be retested in 15 minutes or as clinically indicated, and if still 
≤70 mg/dL (3.9 mmol/L), treatment with another 15 grams of carbohydrate should be given until 
BG is >70 mg/dL (3.9 mmol/L).  Sample collection should continue per the schedule if possible.  
Sample Collection:  Time 0 of the MMTT will be when the patient starts to consume the meal.  
Serial venous blood samples to measure serum glucose will be taken at time -15, 0 (immediately 
before the start of the meal), 15, 30, 60, 120, 180, and 240 minutes after the start of the meal. 
9.1.4.4.
Diabetes Education and Nutritional Counseling
Initial training at Visit 2 will include diabetes education and nutrition counseling, as well as 
hypoglycemia recognition and management.  Appropriate site personnel will administer training 
and education using locally approved diabetes education/training materials and programs or by 
using other materials that may be provided by the sponsor.  Patients may be provided abbreviated 
training and education at visits following Visit 2 based upon patient needs.
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.
Investigators must document their review of each laboratory safety report.

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The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the IP or the study, 
or that caused the patient to discontinue the IP 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.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect.
After the informed consent form (ICF) is signed, study site personnel will record via electronic 
data entry the occurrence and nature of each patient’s preexisting conditions, including clinically 
significant signs and symptoms of the disease under treatment in the study.  In addition, site 
personnel will record any change in the condition(s) and any new conditions as AEs. 
Investigators should record their assessment of the potential relatedness of each AE to protocol 
procedure and/or IP, via electronic data entry.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, 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 IP, 
study device, and/or study procedure and the AE.
The investigator answers yes/no when making this assessment.
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.
If a patient’s IP is discontinued as a result of an AE, study site personnel must report this to Lilly 
or its designee via electronic data entry, clarifying, if possible, the circumstances leading to any 
dosage modifications or discontinuations of treatment. 
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following outcomes:

Death

Initial or prolonged inpatient hospitalization

A life-threatening experience (that is, immediate risk of dying)

Persistent or significant disability/incapacity

Congenital anomaly/birth defect

Important medical events that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed in the definition above.  Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 

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emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse.

When a condition related to the prefilled pen necessitates medical or surgical 
intervention to preclude either permanent impairment of a body function or 
permanent damage to a body structure, the serious outcome of “required 
intervention” will be assigned.

Severe hypoglycemia events: episodes of severe hypoglycemia as determined 
by the investigator according to the definition provided in Sections 9.4.1 and 
9.4.2 must be reported as SAEs.
Although all AEs occurring after signing the ICF are recorded in the case report form (CRF), 
SAE reporting begins after the patient has signed the ICF and has received IP.  However, if an 
SAE occurs after signing the ICF, but prior to receiving IP, it needs to be reported ONLY if it is 
considered reasonably possibly related to study procedure.
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. Patients with a serious hepatic adverse event should have additional data collected 
using the CRF.
Pregnancy (during maternal or paternal exposure to IP) does not meet the definition of an AE.  
However, to fulfill regulatory requirements, any pregnancy should be reported following the 
SAE process to collect data on the outcome for both mother and fetus.
Investigators are not obligated to actively seek AEs or SAEs in patients once they have 
discontinued 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 the investigator considers the event reasonably possibly 
related to the study treatment or study participation, he/she must promptly notify Lilly.
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 IP or procedure.  United States 21 CFR 
312.32 and European Union Clinical Trial Directive 2001/20/EC and the associated detailed 
guidances or national regulatory requirements in participating countries require the reporting of 
SUSARs.  Lilly has procedures that will be followed for the identification, 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 IPs and drug delivery systems used in clinical studies in 
order to ensure the safety of study participants, monitor quality, and to facilitate process and 
product improvements.

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Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the IP and/or drug delivery system so that the situation can be 
assessed.
o
Complaints must be reported by site staff within 24 hours of notification to the 
clinical site/study personnel, or within 24 hours of study/site personnel becoming 
aware of a product issue, regardless of the availability of the complaint sample.  
o
Retain the IP under appropriate storage conditions, if available or when obtained, 
until instructed to return it to Lilly.  
o
Product complaints for non-Lilly Products (including concomitant drugs) that do 
not have a Lilly Product Batch or Control number, are reported directly to the 
manufacturer per product label.
o
Follow the instructions outlined in the Product Complaint Form for other reporting 
requirements.
9.3.
Treatment of Overdose
Excess insulin administration may result in hypoglycemia.  Refer to the IB for LY900014 and 
product label for insulin lispro.  
9.4.
Safety
9.4.1. Hypoglycemia
Patients are encouraged to perform SMBG, whenever hypoglycemia may be suspected, either by 
symptoms experienced or perceived increased risk as related to dietary intake, physical activity, 
or inadvertent or atypical insulin dosing.  All patients will be instructed to treat a BG ≤70 mg/dL 
(3.9 mmol/L) as hypoglycemia.
Hypoglycemia events will be collected in the patient diaries provided by the sponsor via the 
investigator.  If a hypoglycemia event is suspected, the patient should record the BG value, any 
associated symptoms, and the treatment administered in the patient diary.  The patient should 
contact the site as necessary.  Reports of hypoglycemia will be classified by the investigator as 
“severe” or “not severe” based upon data collected in the patient diary and in consultation with 
the patient; see below and Section 9.2.1.  All episodes of severe hypoglycemia must be collected
as AEs via electronic data entry and reported as SAEs.  
Hypoglycemia will be described using the following definitions:
Documented Glucose Alert Level, BG ≤70 mg/dL (3.9 mmol/L)

Documented symptomatic hypoglycemia: with typical symptoms of hypoglycemia.

Documented asymptomatic hypoglycemia: without typical symptoms of hypoglycemia.

Documented unspecified hypoglycemia: with no information about symptoms of 
hypoglycemia available. 
Documented Clinically Significant Hypoglycemia  with similar criterion as above except for 
threshold BG <54 mg/dL (3.0 mmol/L)

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
Documented symptomatic hypoglycemia 

Documented asymptomatic hypoglycemia

Documented unspecified hypoglycemia
Severe hypoglycemia 

Severe hypoglycemia (in adults): Patients had altered mental status, and could not assist in 
their own care, or were semiconscious or unconscious, or experienced coma with or without
seizures, and the assistance of another person was to actively administer carbohydrate, 
glucagon, or other resuscitative actions. Plasma glucose measurements may not be available 
during such an event, but neurological recovery attributable to the restoration of BG 
concentration to normal is considered sufficient evidence that the event was induced by a low
BG concentration (BG ≤70 mg/dL [3.9 mmol/L]).  
Other hypoglycemia:

Nocturnal hypoglycemia: Any documented hypoglycemic event (including severe 
hypoglycemia) that occurs between bedtime and waking.

Relative hypoglycemia: An event during which typical symptoms of hypoglycemia occur,
that does not require the assistance of another person and is accompanied by BG >70 mg/dL
(3.9 mmol/L).

Probable symptomatic hypoglycemia: Symptoms of hypoglycemia were present, but BG
measurement was not reported.

Overall hypoglycemia: This optional category combines most cases of hypoglycemia
(documented hypoglycemia and probable symptomatic hypoglycemia, including severe
hypoglycemia).  It does not include relative hypoglycemia.  Nocturnal and severe
hypoglycemia are special cases of documented or probable hypoglycemia. If an event of
hypoglycemia falls into multiple subcategories, that event should only be counted once in the
category of overall hypoglycemia.
9.4.2. Severe Hypoglycemia
The determination of a hypoglycemic event as an episode of severe hypoglycemia, as defined in 
Section 9.4.1, is made by the investigator based upon the medical need of the patient to have 
required assistance and is not predicated on the report of a patient simply having received 
assistance.
9.4.3. Electrocardiograms
For each patient, ECGs should be performed at Visit 1 according to the study-specific 
requirements described in the Schedule of Activities (Section 2).  
Electrocardiograms 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 present, to determine whether the patient meets entry criteria and for immediate 
patient management, should any clinically relevant findings be identified. 
Electrocardiograms may be obtained at additional times when deemed clinically necessary. 

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9.4.4. Vital Signs
For each patient, vital sign measurements should be conducted according to the Schedule of 
Activities (Section 2) including the study specific requirements.
9.4.5. Laboratory Tests
For each patient, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2). 
With the exception of laboratory test results that may unblind the study, Lilly or its designee will 
provide the investigator with the results of laboratory tests analyzed by a central vendor, if a 
central vendor is used for the clinical trial.  
Any clinically significant findings from laboratory tests that result in a diagnosis and that occur 
after the patient receives the first dose of IP should be reported to Lilly or its designee as an AE
via electronic data entry.
9.4.6. Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.
9.4.6.1.
Hepatic Safety Monitoring
If a study patient experiences elevated ALT ≥3X ULN, ALP ≥2X ULN, or elevated TBL 
≥2X ULN, liver testing (Appendix 4) should be repeated within 3 to 5 days, including ALT, 
AST, ALP, TBL, direct bilirubin, gamma-glutamyl transferase, and creatine kinase to confirm 
the abnormality and to determine if it is increasing or decreasing.  If the abnormality persists or 
worsens, clinical and laboratory monitoring should be initiated by the investigator and in 
consultation with the study medical monitor.  Monitoring of ALT, AST, TBL, and ALP should 
continue until levels normalize or return to approximate baseline levels.
Hepatic Safety Data Collection
Additional safety data should be collected via the CRF if 1 or more of the following conditions 
occur:  
o
elevation of serum ALT to ≥5X ULN on 2 or more consecutive blood tests
o
elevated serum TBL to ≥ 2X ULN (except for cases of known Gilbert’s 
syndrome)
o
elevation of serum ALP to ≥2X ULN on 2 or more consecutive blood tests
o
patient discontinued from treatment due to a hepatic event or abnormality of 
liver tests
o
hepatic event considered to be an SAE.
9.5.
Pharmacokinetics
Not applicable.

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9.6.
Pharmacodynamics
Not applicable.
9.7.
Pharmacogenomics
Not applicable.
9.8.
Biomarkers and Predictive or Other Analyses
9.8.1. Samples for Immunogenicity Testing
Blood samples for immunogenicity testing will be collected to determine antibody production 
against insulin lispro as specified in the Schedule of Activities (Section 2). 
9.9.
Health Economics
The self-reported questionnaires will be administered according to the Schedule of Activities
(Section 2) in countries where the questionnaires have been translated into the native language of 
the region and linguistically validated.
9.9.1. EQ-5D-5L
The European Quality of Life – 5 Dimensions 5 Level (EQ-5D-5L; van Reenen and Janssen 
[WWW]) is a patient-rated questionnaire used to evaluate health status.  The questionnaire 
consists of 2 parts.  The first part assesses 5 dimensions (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression) that have 5 possible levels of response (no problems, 
slight problems, moderate problems, severe problems, extreme problems).  This part of the EQ-
5D can be used to generate a health state index score, which is often used to compute quality-
adjusted life years for utilization in health economic analyses.  The health state index score is 
CCI
CCI
CCI

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calculated based on the responses to the 5 dimensions, providing a single value on a scale from 
less than 0 (where 0 is a health state equivalent to death; negative values are valued as worse 
than dead) to 1 (perfect health), with higher scores indicating better health utility.  The second 
part of the questionnaire consists of a visual analog scale (VAS) on which the patient rates their 
perceived health state from 0 (worst imaginable health state/the worst health you can imagine) to 
100 (best imaginable health state/the best health you can imagine).
9.9.2. Insulin Treatment Satisfaction Questionnaire
The Insulin Treatment Satisfaction Questionnaire (ITSQ; Anderson et al. 2004) is a validated 
instrument containing 22 items that assesses treatment satisfaction for persons with diabetes on 
insulin.  Items are measured on a 7-point Likert-type scale, where lower scores reflect better 
outcomes.  In addition to an overall score, the items that make up the 5 domains of satisfaction 
are categorized as:
o
Inconvenience of Regimen (5 items)
o
Lifestyle Flexibility (3 items)
o
Glycemic Control (3 items)
o
Hypoglycemic Control (5 items)
o
Insulin Delivery Device Satisfaction (6 items).
All individual patient-domain scores will be calculated as the mean of nonmissing items in the 
domain if <20% of the items within the relevant domain are missing; otherwise, the domain 
score will be missing.  The domain scores will be transformed to a scale of 0 to 100 (derived as 
100*[7-raw score]/6).  An overall score is calculated as the mean of the nonmissing transformed 
domain score and only calculated when all 5 domain scores are nonmissing.  A higher score 
indicates better treatment satisfaction.
9.9.3. Work Productivity and Activity Impairment Questionnaire 
General Health
The Work Productivity and Activity Impairment Questionnaire General Health (WPAI-GH; 
Reilly et al. 1993) consists of 6 questions to determine employment status, hours missed from 
work because of problems associated with diabetes, hours missed from work for other reasons, 
hours actually worked, the degree to which diabetes affected work productivity while at work, 
and the degree to which diabetes affected activities outside of work.  Four scores are derived:  
percentage of absenteeism, percentage of presenteeism (reduced productivity while at work), an 
overall work impairment score that combines absenteeism and presenteeism, and percentage of 
impairment in activities performed outside of work.  Greater scores indicate greater impairment 
and less productivity.

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10. Statistical Considerations
10.1. Sample Size Determination
Approximately 350 patients will be randomized in order that 298 patients complete the study 
through the primary endpoint at Week 26.
The primary objective of this study is to test the hypothesis that LY900014 is noninferior to 
insulin lispro on glycemic control as measured by change from baseline to Week 26 in HbA1c in 
patients with T1D when administered in a double-blind manner as prandial insulin (0-2 minutes 
before meals) in combination with basal insulin.  
Patients will be randomized in a 1:1 ratio to double-blind LY900014 dosed 0 to 2 minutes before 
meals, or double-blind insulin lispro dosed 0 to 2 minutes before meals.  Assuming a non-
inferiority margin (NIM) of 0.4%, no true difference between treatment arms, and an SD of 
1.1%, 298 completers (149 in each treatment group) will provide 87% power to show 
noninferiority between LY900014 and insulin lispro in change from baseline to 26 weeks in 
HbA1c using the upper limit of a 2-sided 95% confidence interval (CI; LY900014 – insulin 
lispro).  Assuming a 15% dropout rate for 26 weeks, approximately 350 patients will need to be 
randomized.  
10.2. Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Entered
All patients who sign informed consent.
Enrolled
All patients who receive at least 1 dose of open-label insulin lispro in the 8-week lead-in period.
Randomized
All patients who are randomly assigned to study treatment at Visit 8.  Treatment group will be 
defined on the basis of the treatment the patients are assigned.
Safety
All randomized patients who receive at least 1 dose of the randomly assigned IP.
Completer
Patients included in the randomized population who have completed Week 26 of study treatment 
without permanent discontinuation of IP.  
Per Protocol
Patients included in the randomized population who have completed Week 26 of study treatment 
without permanent discontinuation of IP and without significant protocol deviations through 
Week 26 that would significantly impact the primary objective.  
Treatment group will be defined on the basis of the treatment the patients actually receive.
10.3. Statistical Analyses
10.3.1. General Statistical Considerations
Statistical analysis of this study will be the responsibility of Lilly or its designee.  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 
SAP or the clinical study report (CSR).  Additional exploratory analyses of data will be 
conducted as deemed appropriate.

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The primary analysis is for the treatment period through Week 26. The primary endpoint is the 
HbA1c measurement obtained at Week 26 (Visit 18).  
Efficacy analyses will be conducted on all randomized patients using an intention-to-treat (ITT) 
approach according to the treatment the patients are assigned.  Efficacy analyses, including the 
analyses for the primary and multiplicity adjusted objectives, will include data collected prior to
permanent discontinuation of IP through Week 26. When change from baseline is included as a 
response variable of analysis models, the patient will be included in the analysis only if he/she 
has a baseline and a postbaseline measurement.  Selected efficacy analyses will also be 
conducted using the Per-Protocol (PP) and Completer populations.  
Safety analyses will be conducted on the Safety population. Analyses of AEs will include 2 sets 
of analyses, unless otherwise specified.  The first set of analyses will include data collected prior 
to permanent discontinuation of IP.  The second set of analyses will include all data collected 
during the course of the entire study regardless of IP use. Analyses of hypoglycemia will be 
conducted on data collected prior to permanent discontinuation of IP, while analyses for post-
treatment may be conducted as needed. Analyses of safety laboratory measurements will be 
performed on all data collected during the planned treatment period regardless of IP use. Week 
26 analyses will include treatment comparisons between the 2 treatment groups.
Unless otherwise noted, all tests of treatment effects will be conducted at a 2-sided alpha level of 
0.05, and CIs will be calculated at 95%, 2-sided.  All tests of interactions between treatment 
groups and other factors will be conducted at a 2-sided alpha level of 0.10. 
A graphical approach for multiple comparisons (Bretz et al. 2011) will be used to strongly 
control the overall Type I error (2-sided alpha level of 0.05) for testing the treatment effect for 
the primary and multiplicity adjusted objectives.  
Baseline is defined as the last nonmissing measurement at or before the randomization visit, 
(Visit 8) unless otherwise specified.  
The primary analysis method will be a restricted maximum likelihood-based, mixed-effect model 
repeated measure (MMRM) analysis using all the longitudinal observations at each scheduled 
postbaseline visit.  The model for the analysis of the primary efficacy endpoint of change from 
baseline in HbA1c will include the fixed class effects of treatment, strata (country, type of basal 
insulin, and metformin use at study entry), visit, and treatment-by-visit interaction, as well as the 
continuous, fixed covariate of baseline value.  For analyses of variables other than HbA1c, the 
HbA1c stratum (≤8.5%, >8.5%) will be included in the model.  An unstructured covariance 
structure will be used to model the within-patient errors.  Significance tests will be based on least
squares (LS) means and Type III tests.  SAS PROC MIXED will be used to perform the analysis. 
If this analysis fails to converge, the following covariance structures will be tested in order:

Toeplitz with heterogeneity

Autoregressive with heterogeneity

Compound symmetry with heterogeneous variances

Toeplitz

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
Autoregressive

Compound symmetry without heterogeneous variances.
The first covariance structure that converges will be used.  The Kenward-Roger approximation 
will be used to estimate denominator degrees of freedom.  
An analysis of covariance (ANCOVA) model for the change from baseline to the Week 26 
HbA1c endpoint with strata (country, type of basal insulin, and metformin use at study entry), 
and treatment as fixed effects and baseline as a covariate will be conducted as supportive 
analyses.  Missing endpoints will be imputed using the last-observation-carried-forward (LOCF) 
approach, using only postbaseline data.  For analyses of variables other than HbA1c, the HbA1c 
stratum (≤8.5%, >8.5%) will be included in the model.
For continuous measures, summary statistics will include sample size, mean, SD, median, 
minimum, and maximum for both the actual and the change from baseline measurements.  Least 
squares means and standard errors derived from the analysis models will also be displayed for 
the change from baseline measurements.  Treatment comparisons will be displayed showing the 
treatment difference LS means and the 95% CIs for the treatment differences, along with the p-
values for the treatment comparisons.
For categorical measures, summary statistics will include sample size, frequency, and 
percentages.  Fisher’s exact test will be used for treatment comparisons.
10.3.2. Treatment Group Comparability
10.3.2.1. Patient Disposition
A detailed description of patient disposition will be provided.  Frequency counts and percentages 
of all patients entered, enrolled, randomized, completing, and/or discontinuing from the study 
will be presented for each treatment group.  Reasons for discontinuation from study treatment 
and from the study during the treatment period will be summarized and compared between 
treatment groups using Fisher’s exact test.  Reasons for discontinuation from the study during the 
lead-in and follow-up periods will be summarized.  
10.3.2.2. Patient Characteristics
Standard baseline characteristics of age, sex, ethnicity, race, height, weight, and BMI will be 
summarized for all randomized patients.  Summary statistics will include sample size, mean, SD, 
median, minimum, and maximum for continuous measures and sample size, frequency, and 
percent for categorical measures.  Comparisons between treatment groups will be performed 
using Fisher’s exact test for categorical data and an analysis of variance (ANOVA) with 
treatment in the model for continuous data.  Baseline diabetes characteristics will be summarized 
in a similar manner.  
Medical history and AEs at baseline will be summarized by preferred term (PT) within system 
organ class (SOC), and comparison between treatment groups will be performed using Fisher’s 
exact test.  

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10.3.2.3. Concomitant Therapy
The type of insulin therapy at study entry and at baseline will be compared between treatment 
groups using Fisher’s exact tests.  The dose of basal and bolus insulin therapy during the lead-in 
period will be compared between treatment groups using an ANOVA with treatment in the 
model.  
Concomitant medications used during the treatment period will be summarized and compared 
between treatment groups using Fisher’s exact test.  
10.3.3. Efficacy Analyses
10.3.3.1. Primary Analyses
The primary objective of this study is to test the hypothesis that LY900014 is noninferior to 
insulin lispro on glycemic control (NIM=0.4% for HbA1c) in patients with T1D, when 
administered as prandial insulin (0-2 minutes prior to the meal), in combination with basal 
insulin for 26 weeks.
The primary efficacy comparison will be based on the contrast between LY900014 and insulin 
lispro at Week 26 (Visit 18) from the MMRM analysis of change from baseline in HbA1c using 
all randomized patients.  If the upper limit of the 2-sided 95% CI for the LS mean difference in 
the change from baseline in HbA1c for LY900014 minus insulin lispro is below +0.4%, 
LY900014 will be declared noninferior to insulin lispro.  The analysis model and selection of 
covariance structure is described in Section 10.3.1.  
10.3.3.1.1.Additional Analyses for the Primary Endpoint
The primary analysis model, MMRM, will be repeated using the PP and Completer populations
to check the sensitivity of the analysis.  If the conclusion differs from that of all randomized 
patients, the data and analyses will be further investigated.  
A secondary analysis model will be an ANCOVA for HbA1c change from baseline to Week 26 
(Visit 18), using the model described in Section 10.3.1. Missing endpoints will be imputed using 
the LOCF approach using postbaseline data only.  
In addition to the primary objective, the superiority of LY900014 in controlling HbA1c 
compared to insulin lispro will also be assessed with the same model using all randomized 
patients.  If the p-value is less than the alpha level from the graphical approach allocated to this 
hypothesis, LY900014 will be declared superior to insulin lispro.
10.3.3.2. Secondary Analyses
A graphical approach for multiple comparisons will be used to strongly control the overall 
Type I error (2-sided alpha level of 0.05) for testing the treatment effect for the primary and the 
following multiplicity adjusted objectives:  superiority of LY900014 compared with insulin 
lispro for 1-hour PPG excursion at Week 26, 2-hour PPG excursion at Week 26, and change 
from baseline to Week 26 in HbA1c. 
An ANCOVA model with strata (country, type of basal insulin, metformin use at study entry, 
and baseline HbA1c strata [≤8.5%, >8.5%]) and treatment as fixed effects and baseline as a 

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covariate will be used to analyze the 1-hour and 2-hour PPG excursions.  However, if the 
percentage of the patients with missing MMTT data at baseline is higher than 15%, a constrained 
longitudinal data analysis model (Liu et al. 2009; Lu 2010) will be used instead.  Analyses 
details will be documented in the SAP.
Hemoglobin A1c and change from baseline in HbA1c at all time points will be analyzed by the 
same MMRM model used for the primary analysis.  
Additional continuous secondary efficacy variables, as well as the change from baseline for these 
variables, will be analyzed either by the MMRM or ANCOVA models described in 
Section 10.3.1.
Treatment comparisons for the proportion of patients with HbA1c <7.0% and ≤6.5% will be 
analyzed using a longitudinal logistic regression with repeated measurements conducted by a 
generalized linear mixed model including independent variables of treatment, baseline HbA1c 
value, visit, baseline HbA1c by visit interaction, and treatment by visit interaction.  An 
unstructured covariance structure will be used.  As a sensitivity analysis, the proportion of 
patients with HbA1c <7.0% and ≤6.5% at Week 26 (Visit 18), imputed using LOCF, will be 
compared using a logistic regression model including treatment and baseline HbA1c value in the 
model.  
Actual and change from baseline in basal, prandial, and total dose, as well as the prandial/total 
insulin dose ratio, will be analyzed by the MMRM models described in Section 10.3.1.
10.3.3.3. Tertiary/Exploratory Analyses
Continuous variables and the change from baseline for these variables will be analyzed either by 
the MMRM or ANCOVA models described in Section 10.3.1.  Categorical variables will be 
analyzed either by model (for example, logistic regression) or by Fisher’s exact test.  Analysis 
details for the tertiary endpoints will be described in the SAP.
10.3.4. Safety Analyses
Safety measures will include AEs, hypoglycemia, vital signs and weight, treatment exposure, 
laboratory measures, and antibodies to insulin lispro.  Analyses will be performed on data 
collected from randomization through Week 26 for all 2 treatment groups.  
Events that are newly reported after the first dose of IP or reported to worsen in severity from 
baseline will be considered treatment-emergent adverse events (TEAEs).  The Medical 
Dictionary for Regulatory Activities (MedDRA) lowest level term (LLT) will be used in the 
treatment-emergent assessment.  The maximum severity for each LLT during the baseline period 
will be used as baseline severity.
Serious adverse events, AEs reported as reason for discontinuation from the IP or study, and
TEAEs will be summarized in tables using the MedDRA PT, sorted by decreasing frequency 
within the LY900014 treatment group.  Treatment-emergent adverse events will also be 
summarized by PT sorted by decreasing frequency within SOC for all TEAEs and TEAEs by 
maximum severity.  For events that are specific to only 1 sex, the denominator and computation 

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of the percentage will include only patients from the given sex.  The number and proportion of 
patients with at least 1 event for each type of event will be summarized and compared between 
treatment groups using Fisher’s exact test.  Serious adverse events, AEs reported as reason for 
discontinuation from the IP or study, and TEAEs will also be summarized for open-label insulin 
lispro during the lead-in period. Symptoms solicited by questionnaires will not be considered 
spontaneous AEs for analysis.
Hypoglycemia rates will be summarized for periods of 30 days, 1 year, and 100 years (severe 
hypoglycemia only).  The rate of severe hypoglycemia per 100 years will be compared between 
treatment groups using the empirical method (details will be described in the SAP).  For each of 
the other categories of hypoglycemia, the number of hypoglycemia events during a specific 
period (rate) after randomization (for example, Weeks 0-12 of treatment period) will be analyzed 
by using a negative binomial regression model.  The model will include treatment and the 
baseline hypoglycemia rate (measured during lead-in) as a covariate.  An offset defined as the 
log transformation of treatment exposure in the specific period (days)/365.25 days (or 30 days) 
will be included in the model to estimate the rate of hypoglycemia per year (or per 30 days).  The 
proportion of patients with at least 1 hypoglycemic event in each category (incidence) during a 
specific period after randomization will be analyzed using a logistic regression model including 
treatment and baseline hypoglycemia rate value in the model. 
Continuous safety variables, as well as the change from baseline for these variables, will be 
analyzed by MMRM or ANCOVA models.  For categorical variables, Fisher’s exact test will be 
used to compare treatment groups unless otherwise specified.  The analyses for assessing 
immunogenicity data will be described in the SAP.
10.3.5. Other Analyses
10.3.5.1. Health Economics
Summary statistics, including number of patients and proportion of categorical outcomes 
(5 levels) for the 5 dimensions (mobility, self-care, usual activity, pain/discomfort, and 
anxiety/depression) of the EQ-5D-5L will be provided by visit and by treatment.  The change 
from baseline to LOCF endpoint (Week 26, Visit 18) in the EQ-5D-5L UK population-based 
health state index score and EuroQol VAS score will be analyzed using the ANCOVA model 
described in Section 10.3.1.
For the ITSQ, the change from baseline to LOCF endpoint while on treatment in each domain 
transformed score (inconvenience, lifestyle, hypoglycemic control, glycemic control, delivery 
system) and overall transformed score will be analyzed using the ANCOVA model described in 
Section 10.3.1.
For the WPAI-GH, the change from baseline to LOCF endpoint in each score (absenteeism, 
presenteeism, work productivity loss, and activity impairment) will be analyzed using the 
ANCOVA model described in Section 10.3.1.

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10.3.6. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the appropriate Lilly medical director, or designee, will be consulted to determine 
whether it is necessary to amend the protocol.

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11.
References
Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its 
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Ali MK, Bullard KM, Saaddine JB, Cowie CC, Imperatore G, Gregg EW. Achievement of goals 
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Anderson RT, Skovlund SE, Marrero D, Levine DW, Meadows K, Brod M, Balkrishnan R. 
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Bailey TS, Grunberger G, Bode BW, Handelsman Y, Hirsch IB, Jovanovič L, Roberts VL,
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Barrett KE, Barman SM, Boitano S, Brooks HL. Ganong’s review of medical physiology. 25th 
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Bennett P. Classification and diagnosis of diabetes mellitus and impaired glucose tolerance. In: 
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Bergenstal RM, Johnson M, Powers MA, Wynne A, Vlajnic A, Hollander P, Rendell M. Adjust 
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Bolli GB, Kerr D, Thomas R, Torlone E, Sola-Gazagnes S, Vitacolonna E, Selam JL, Home PD.
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2009;32(10):1944]. Diabetes Care. 2009;32(7):1170-1176.
Bretz F, Posch M, Glimm E, Klinglmueller F, Maurer W, Rohmeyer K. Graphical approaches for 
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Carls G, Huynh J, Tuttle E, Yee J, Edelman SV. Achievement of glycated hemoglobin goals in 
the US remains unchanged through 2014. Diabetes Ther. 2017;8(4):863-873.
Datye KA, Boyle CT, Simmons J, Moore DJ, Jaser SS, Sheanon M, Kittelsrud JM, Woerner SE, 
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Fineberg NS, Fineberg SE, Anderson JH, Birkett MA, Gibson RG, Hufferd S. Immunologic 
effects of insulin lispro [Lys (B28), Pro (B29) human insulin] in IDDM and NIDDM patients 
previously treated with insulin. Diabetes. 1996;45(12):1750-1754.
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insulin lispro on the induction of antibody response in patients with type 1 or type 2 diabetes. 
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Humalog [summary of product characteristics]. The Netherlands. Eli Lilly Nederland B.V; 2016.
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variable in analyses of change from baseline in clinical trials? Stat Med. 2009;28(20):2509-
2530.
Lu K. On efficiency of constrained longitudinal data analysis versus longitudinal analysis of 
covariance. Biometrics. 2010;66(3):891-896.
Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose 
increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with 
increasing levels of HbA(1c). Diabetes Care. 2003;26(3):881-885.
[NHS] National Diabetes Audit, 2015-2016. Report 1: Care Processes and Treatment Targets. 
Available at: https://files.digital.nhs.uk/publicationimport/pub23xxx/pub23241/nati-diab-rep1-
audi-2015-16.pdf. Accessed April 24, 2018.
[PMR] Pharmaceutical and healthcare market in CEE and CIS. Remodulin approved in 22 
European countries, also Poland. PMR web site. Available at 
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poland. Published September 1, 2005. Accessed September 16, 2016.
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and 
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Remodulin [package insert]. Research Triangle Park, NC: United Therapeutics Corp; 2014.
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van Reenen M, Janssen B. EQ-5D-5L User Guide:Basic information on how to use the EQ-5D-
5L instrument. Available at: https://euroqol.org/wp-content/uploads/2016/09/EQ-5D-
5L_UserGuide_2015.pdf. Accessed July 28, 2017.
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Accessed April 24, 2018.Appendices

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Appendix 1.
Abbreviations and Definitions
Term
Definition
1,5-AG
1,5-Anhydroglucitol
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
ANCOVA
analysis of covariance
ANOVA
analysis of variance
AST
aspartate aminotransferase
BG
blood glucose
blinding/maskin
g
A single-blind study 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 study is one in which neither the patient nor any of the investigator or sponsor 
staff who are involved in the treatment or clinical evaluation of the patients are aware of the 
treatment received.
BMI
body mass index
CF
correction factor
CGM
continuous glucose monitoring
CI
confidence interval
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.
CRF
case report form
CRP
clinical research physician: Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research scientist, 
global safety physician, or other medical officer.
CSII
continuous subcutaneous insulin infusion

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CSR
clinical study report
ECG
electrocardiogram
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.
EQ-5D-5L
European Quality of Life – 5 Dimensions 5 Level 
ERB
ethical review board
FBG
fasting blood glucose 
FDA
US Food and Drug Administration
FGM
flash glucose monitoring
GCP
good clinical practice
GD
glucodynamic(s)
GRAS
Generally Recognized As Safe
HbA1c
hemoglobin A1c
IB
Investigator’s Brochure
ICF
informed consent form
ICR
insulin to carbohydrate ratio
IP
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.
ITSQ
Insulin Treatment Satisfaction Questionnaire
ITT
intention-to-treat:  The principle that asserts that the effect of a treatment policy can be best 
assessed by evaluating on the basis of the intention to treat a patient (that is, the planned 
treatment regimen) rather than the actual treatment given.  It has the consequence that patients 
allocated to a treatment group should be followed up, assessed, and analyzed as members of 
that group irrespective of their compliance to the planned course of treatment.
IV
intravenous
IWRS
interactive web-response system
LLT
lowest level term

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LOCF
last-observation-carried-forward
LS
least squares
MDI
multiple daily injection(s)
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed-effect model repeated measure
MMTT
mixed-meal tolerance test
NIM
non-inferiority margin
NPH
neutral protamine Hagedorn
PAH
pulmonary artery hypertension
PK
pharmacokinetic(s)
PP
per protocol
PPG
postprandial glucose
PT
preferred term
RBA
radio ligand-binding assay
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous(ly)
screen
The act of determining if an individual meets minimum requirements to become part of a pool 
of potential candidates for participation in a clinical study. 
SD
standard deviation
SMBG
self-monitored blood glucose
SOC
system organ class
SUSAR
suspected unexpected serious adverse reaction
T1D
type 1 diabetes
T2D
type 2 diabetes
TBL
total bilirubin level

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TEAE
treatment-emergent adverse event:  An untoward medical occurrence that emerges during a 
defined treatment period, having been absent pretreatment, or worsens relative to the 
pretreatment state, which and does not necessarily have to have a causal relationship with this 
treatment.
ULN
upper limit of normal
URI
ultra-rapid insulin
VAS
visual analog scale
WPAI-GH
Work Productivity and Activity Impairment Questionnaire General Health

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Appendix 2.
Clinical Laboratory Tests
Clinical Laboratory Testsa
Hematology 
Clinical Chemistry(Serum Concentrations of):
Hemoglobin
Sodium
Hematocrit
Potassium
Erythrocyte count (RBC)
Total bilirubin
Mean cell volume 
Direct bilirubin
Mean cell hemoglobin concentration 
Alkaline phosphatase
Leukocytes (WBC)
Alanine aminotransferase (ALT)
Neutrophils, segmented
Aspartate aminotransferase (AST)
Lymphocytes
Blood urea nitrogen (BUN)
Monocytes
Creatinine
Eosinophils
Uric acid
Basophils
Calcium
Platelets
Chloride
Magnesium
Urinalysis 
Total protein
Specific gravity
Glucose
pH
Albumin
Protein
Creatine kinase (CK)
Glucose
Ketones
Serum glucose, fasting
Blood
1,5 Anhydroglucitol 
Urine leukocyte esterase
HbA1c
Bilirubin 
Nitrite
Lipid Panel 
LDLd
Serology
HDL
Anti-insulin lispro antibodies 
Total cholesterol
Triglycerides
Pregnancy Test (females only)b
Follicle-stimulating hormonec
Abbreviations:  HDL = high-density lipoproteins; IP = investigational product; LDL = low-density lipoproteins; 
RBC = red blood cells; WBC = white blood cells.
a
All laboratory tests will be assayed by a Lilly-designated central laboratory, unless otherwise noted.
b
Serum pregnancy test that is analyzed by central laboratory must be performed in women of childbearing 
potential at Visit 1 followed by a local urine or serum pregnancy test within 24 hours prior to IP exposure at 
randomization and at other times at the investigator’s discretion. When required per local regulations and/or 
institutional guidelines, local pregnancy testing will occur at mandatory times during the study treatment period.  
c
Follicle-stimulating hormone test must be performed at Visit 1 for a postmenopausal woman who is between 
50 and 54 years of age (inclusive) with an intact uterus, not on hormone therapy, and who has had at least 
6 months of spontaneous amenorrhea.
d
This value will be calculated. If triglycerides >400 mg/dL, then direct LDL will be assayed.

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Appendix 3.
Study Governance Considerations

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Appendix 3.1.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Appendix 3.1.1.
Informed Consent
The investigator is responsible for:

ensuring that the patient understands the potential risks and benefits of participating 
in the study, the potential risks and benefits of participating in the study, and that their 
participation is voluntary.

ensuring that informed consent is given by each patient or legal representative.  
This includes obtaining the appropriate signatures and dates on the informed 
consent form (ICF) prior to the performance of any protocol procedures and 
prior to the administration of investigational product (IP).

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 study.

ensuring that a copy of the ICF is provided to the participant or the 
participant’s legal representative and is kept on file.

ensuring that the medical record includes a statement that written informed 
consent was obtained before the participant was enrolled in the study and the 
date the written consent was obtained.  The authorized person obtaining the 
informed consent must also sign the ICF.
Appendix 3.1.2.
Ethical Review
The investigator or an appropriate local representative must give assurance that the ethical 
review board (ERB) was properly constituted and convened as required by International 
Conference on Harmonisation (ICH) guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Eli Lilly and 
Company (Lilly) before the study may begin at the investigative site(s).  Lilly or its 
representatives must approve the ICF, including any changes made by the ERBs, before it is used 
at the investigative site(s).  All ICFs must be compliant with the ICH guideline on good clinical 
practice (GCP).
The study site’s ERB(s) should be provided with the following:

the protocol and related amendments and addenda, current Investigator Brochure 
(IB) and updates during the course of the study

ICF

other relevant documents (for example, curricula vitae, advertisements)
Appendix 3.1.3.
Regulatory Considerations
This study will be conducted in accordance with:

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
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

applicable ICH GCP Guidelines

applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third party.
Appendix 3.1.4.
Investigator Information
Physicians with a specialty in endocrinology or primary care physicians specializing in 
endocrinology or internal medicine will participate as investigators in this clinical trial.
Appendix 3.1.5.
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.
Appendix 3.1.6.
Final Report Signature
The CSR coordinating investigator will sign the final clinical study report (CSR) for this study, 
indicating agreement that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.
An investigator will be selected by the Lilly study team to serve as the CSR coordinating 
investigator. The sponsor’s responsible medical officer and statistician will approve the final 
CSR for this study, confirming that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.
Appendix 3.2.
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

sponsor start-up 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 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 use standard computer edits to detect errors in 
data collection

conduct a quality review of the database.

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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 or its 
representatives, 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 original source 
documents.
Appendix 3.2.1.
Data Capture System
An electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
Some or all of a patient’s data will be directly entered into the electronic case report form 
(eCRF) at the time that the information is obtained. In instances where direct data entry is not 
used, the site will maintain source documentation in the trial files, and the patient’s data will be 
transcribed into the eCRF. Paper documentation provided by the patient will serve as the source 
document, including a study drug administration log and an event-medication diary, that will be 
identified and documented by each site in that site’s study file.
Case report form data will be encoded and stored in a clinical trial database.  Data managed by a 
central vendor, such as laboratory test data, will be stored electronically in the central vendor’s 
database system.  Data will subsequently be transferred from the central vendor to the Lilly data 
warehouse.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system..
Appendix 3.3.
Study and Site Closure
Appendix 3.3.1.
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.
Appendix 3.3.2.
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.
Appendix 3.4.
Publication Policy
The publication policy for Study  I8B-FH-ITSD is described in Clinical Trial Agreement.

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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 the 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
Direct 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 = aspirate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized
ratio; RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory (if test results are required urgently to manage patient care).
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.

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Appendix 5.
World Health Organization Classification 
for Diabetes
Type 1 Diabetes Mellitus:  Type 1 diabetes is judged to be present when the classical symptoms 
of diabetes (thirst, polyuria, wasting and stupor, or coma) are associated with readily detectable 
concentrations of glucose and ketone bodies in the blood and urine.  Insulin treatment is 
necessary not only to control hyperglycemia, but also to prevent spontaneous ketosis and death 
(Bennett 1991; Alberti and Zimmet 1998).
Type 2 Diabetes Mellitus:  Type 2 diabetes (T2D), although often asymptomatic, may also 
present with classical hyperglycemic symptoms (thirst, polyuria, and weight loss), but despite 
hyperglycemia, ketone bodies are present in only low concentrations in the blood and urine.  
Coma is rare in T2D, but may result from extreme hyperglycemia and hyperosmolarity; lactic 
acidosis or ketoacidosis can also occur in fulminating illness (for example, severe infection or 
mesenteric artery thrombosis) because of acute increase in insulin requirements, but spontaneous 
ketosis does not occur.  Some patients with T2D later progress to a state of absolute insulin 
deficiency (Bennett 1991; Alberti and Zimmet 1998).
References:
Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its 
complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a 
WHO consultation. Diabet Med. 1998;15(7):539-553.
Bennett P. Classification and diagnosis of diabetes mellitus and impaired glucose tolerance. In: 
Pickup JC, William G, editors. Textbook of diabetes. Vol. 1. 1st ed. Oxford: Blackwell 
Scientific Publications; 1991:p 37-44.

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Appendix 6.
New York Heart Association Cardiac 
Disease Classification
Functional Capacity
Class I
Patients with cardiac disease but without resulting limitation of physical activity.  Ordinary 
physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain.
Class II
Patients with cardiac disease resulting in slight limitation of physical activity.  They are 
comfortable at rest.  Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal 
pain.
Class III
Patients with cardiac disease resulting in marked limitation of physical activity.  They are 
comfortable at rest.  Less than ordinary activity causes fatigue, palpitation, dyspnea, or anginal 
pain.
Class IV
Patients with cardiac disease resulting in inability to carry on any physical activity without 
discomfort.  Symptoms of heart failure or the anginal syndrome may be present even at rest.  If 
any physical activity is undertaken, discomfort increases.
1994 Revisions to Classification of Functional Capacity and Objective Assessment of Patients 
with Diseases of the Heart
www.americanheart.org.  ©2011, American Heart Association, Inc.

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Appendix 7.
Classification of Contraceptive Methods
Women of child-bearing potential must use either 1 highly effective method of contraception or a 
combination of 2 effective methods of contraception.  The patient may choose to use a double-
barrier method of contraception (see chart below).  

Barrier protection methods without concomitant use of a spermicide are not an effective 
or acceptable method of contraception.  Thus, each barrier method must include use of a 
spermicide (that is, condom with spermicide, diaphragm with spermicide, female condom with 
spermicide).  It should be noted, however, that the use of male and female condoms as a 
double-barrier method is not considered acceptable due to the high failure rate when these 
barrier methods are combined.
Methods of Contraception
Highly Effective Methods of Contraception
Effective Methods of Contraception
(must use combination of 2 methods)

Combined oral contraceptive pill and mini-pill

NuvaRing®

Implantable contraceptives

Injectable contraceptives (such as Depo-Provera®)

Intrauterine device (such as Mirena® and ParaGard®)

Contraceptive patch – ONLY women <198 lb or 90 kg

Total abstinence

Vasectomy 

Male condom with spermicide

Female condom with spermicide

Diaphragm with spermicide

Cervical sponge

Cervical cap with spermicide

Leo Document ID = d4799142-03ae-4aa1-9ea7-b29f8a26fc8b
Approver:
Approval Date & Time: 13-Jul-2018 17:03:29 GMT
Signature meaning: Approved
Approver:
Approval Date & Time: 13-Jul-2018 17:03:29 GMT
Signature meaning: Approved
PPD
PPD