Conditions: Type 2 Diabetes Mellitus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 628
Healthy volunteers: no

Brief summary:
The purpose of this study is to see if LY900014 compared to insulin lispro (Humalog), both in combination with insulin glargine or insulin degludec, is safe and effective in participants with type 2 diabetes (T2D).

Detailed description:

Arms:
arm 1: Participants received 100 units per milliliter (U/mL) LY900014 subcutaneously (SC) 0-2 minutes before each meal with either basal insulin glargine or insulin degludec given SC once daily. arm 2: Participants received 100 U/mL insulin lispro (Humalog) given SC 0-2 minutes before each meal with either basal insulin glargine or insulin degludec given SC once daily.

Interventions: intervention 1: LY900014 intervention 2: Insulin Lispro intervention 3: Insulin Glargine intervention 4: Insulin Degludec
Intervention descriptions: intervention 1: Administered SC intervention 2: Administered SC intervention 3: Administered SC intervention 4: Administered SC

Protocol document:
Prot_000.pdf: 
Protocol I8B-FH-ITSE 
 
 
A Prospective, Randomized, Double-Blind Comparison of LY900014 to Insulin Lispro, Both 
in Combination with Insulin Glargine or Insulin Degludec in Adults with Type 2 Diabetes 
 
 
NCT03952143 
 
 
Approval Date: 27-Jun-2018 
 
 
 
 
 


I 8 B-F H -I TS E Cli ni c al Pr ot o c ol
P a g e 1
L Y 9 0 0 0 1 4
Pr ot o c ol I 8 B -F H -I T S E
A Pr o s p e cti v e, R a n d o mi z e d, D o u bl e -Bli n d C o m p ari s o n of 
L Y 9 0 0 0 1 4 t o I n s uli n Li s pr o, B ot h i n C o m bi n ati o n wit h I n s uli n 
Gl ar gi n e or I n s uli n D e gl u d e c i n A d ult s wit h T y p e 2 Di a b et e s
C o nfi d e nti al I nf or m ati o n
T h e i nf or m ati o n c o nt ai n e d i n t hi s d o c u m e nt i s c o nfi d e nti al a n d i s i nt e n d e d f or t h e u s e of 
cli ni c al i n v e sti g at or s.  It i s t h e pr o p ert y of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s a n d 
s h o ul d n ot b e c o pi e d b y or di stri b ut e d t o p er s o n s n ot i n v ol v e d i n t h e cli ni c al i n v e sti g ati o n of 
L Y 9 0 0 0 1 4 , u nl e s s s u c h p er s o n s ar e b o u n d b y a c o nfi d e nti alit y a gr e e m e nt wit h Eli Lill y a n d 
C o m p a n y or it s s u b si di ari e s.  
N ot e t o R e g ul at or y A ut h oriti e s :  T hi s d o c u m e nt m a y c o nt ai n pr ot e ct e d p er s o nal d at a 
a n d/ or c o m m er ci all y c o nfi d e nti al i nf or m ati o n e x e m pt fr o m p u bli c di s cl o s ur e.  Eli Lill y a n d 
C o m p a n y r e q u e st s c o n s ult ati o n r e g ar di n g r el e a s e/r e d a cti o n pri or t o a n y p u bli c r el e a s e.  I n 
t h e U nit e d St at e s, t hi s d o c u m e nt i s s u bj e ct t o Fr e e d o m of I nf or m ati o n A ct ( F OI A) 
E x e m pti o n 4 a n d m a y n ot b e r e pr o d u c e d or ot h er wi s e di s s e mi n at e d wit h o ut t h e writt e n 
a p pr o v al of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s .
L Y 9 0 0 0 1 4
Eli Lill y a n d C o m p a n y
I n di a n a p oli s, I n di a n a U S A 4 6 2 8 5
A p pr o v al D at e: 2 7- J u n- 2 0 1 8 G M T


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LY900014
Table of Contents
Section
Page
1.
Synopsis .............................................................................................................................8
2.
Schedule of Activities .......................................................................................................12
3.
Introduction ......................................................................................................................18
3.1.
Study Rationale............................................................................................................18
3.2.
Background..................................................................................................................18
3.3.
Benefit/Risk Assessment..............................................................................................20
4.
Objectives and Endpoints..................................................................................................21
5.
Study Design.....................................................................................................................23
5.1.
Overall Design .............................................................................................................23
5.2.
Number of Participants.................................................................................................24
5.3.
End of Study Definition ...............................................................................................24
5.3.1.
Safety Follow-Up Period......................................................................................25
5.4.
Scientific Rationale for Study Design...........................................................................25
5.5.
Justification for Dose ...................................................................................................25
6.
Study Population...............................................................................................................26
6.1.
Inclusion Criteria..........................................................................................................26
6.2.
Exclusion Criteria ........................................................................................................28
6.3.
Lifestyle Restrictions....................................................................................................31
6.4.
Screen Failures.............................................................................................................31
7.
Treatments........................................................................................................................32
7.1.
Treatments Administered .............................................................................................32
7.1.1.
Packaging and Labeling .......................................................................................32
7.1.2.
Medical Devices...................................................................................................32
7.2.
Method of Treatment Assignment ................................................................................33
7.2.1.
Selection and Timing of Doses.............................................................................33
7.2.1.1.
Target Glucose Values for Titration of Insulin Therapy ..................................33
7.2.1.2.
Basal Insulin Therapy.....................................................................................33
7.2.1.3.
Basal Insulin Titration ....................................................................................34
7.2.1.4.
Study Prandial Insulin Therapy.......................................................................35
7.2.1.5.
Transitioning off Study Prandial Insulin Therapy............................................38
7.3.
Blinding .......................................................................................................................38
7.4.
Dosage Modification....................................................................................................39
7.5.
Preparation/Handling/Storage/Accountability...............................................................39
7.6.
Treatment Compliance .................................................................................................39


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7.7.
Concomitant Therapy...................................................................................................40
7.7.1.
Management of Oral Antihyperglycemic Medications..........................................40
7.8.
Treatment after the End of the Study............................................................................41
7.8.1.
Continued Access.................................................................................................41
7.8.2.
Special Treatment Considerations ........................................................................41
8.
Discontinuation Criteria ....................................................................................................42
8.1.
Discontinuation from Study Treatment.........................................................................42
8.1.1.
Permanent Discontinuation from Study Treatment ...............................................42
8.1.2.
Temporary Discontinuation from Study Treatment...............................................43
8.1.3.
Discontinuation of Inadvertently Enrolled Patients...............................................43
8.2.
Discontinuation from the Study....................................................................................43
8.3.
Lost to Follow-Up........................................................................................................44
9.
Study Assessments and Procedures ...................................................................................45
9.1.
Efficacy Assessments...................................................................................................45
9.1.1.
Primary Efficacy Assessments .............................................................................45
9.1.2.
Secondary Efficacy Assessments..........................................................................45
9.1.3.
Appropriateness of Assessments ..........................................................................46
9.1.4.
Study Procedures .................................................................................................46
9.1.4.1.
Four-Point Self-Monitoring Blood Glucose ....................................................46
9.1.4.2.
Ten-Point Self-Monitoring Blood Glucose......................................................46
9.1.4.3.
Mixed-Meal Tolerance Test............................................................................46
9.1.4.4.
Diabetes Education and Nutritional Counseling ..............................................48
9.2.
Adverse Events ............................................................................................................48
9.2.1.
Serious Adverse Events........................................................................................49
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................50
9.2.2.
Complaint Handling.............................................................................................50
9.3.
Treatment of Overdose.................................................................................................51
9.4.
Safety...........................................................................................................................51
9.4.1.
Hypoglycemia......................................................................................................51
9.4.2.
Severe Hypoglycemia ..........................................................................................52
9.4.3.
Electrocardiograms ..............................................................................................52
9.4.4.
Vital Signs ...........................................................................................................53
9.4.5.
Laboratory Tests ..................................................................................................53
9.4.6.
Safety Monitoring ................................................................................................53
9.4.6.1.
Hepatic Safety Monitoring..............................................................................53
9.5.
Pharmacokinetics .........................................................................................................54
9.6.
Pharmacodynamics ......................................................................................................54
9.7.
Pharmacogenomics ......................................................................................................54


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LY900014
9.8.
Biomarkers and Predictive or Other Analyses...............................................................54
9.8.1.
Samples for Immunogenicity Testing ...................................................................54
9.9.
Health Economics ........................................................................................................54
9.9.1.
EQ-5D-5L............................................................................................................55
9.9.2.
Insulin Treatment Satisfaction Questionnaire .......................................................55
9.9.3.
Work Productivity and Activity Impairment Questionnaire 
General Health.....................................................................................................55
10.
Statistical Considerations ..................................................................................................57
10.1. Sample Size Determination ..........................................................................................57
10.2. Populations for Analyses..............................................................................................57
10.3. Statistical Analyses ......................................................................................................57
10.3.1.
General Statistical Considerations ........................................................................57
10.3.2.
Treatment Group Comparability...........................................................................59
10.3.2.1.
Patient Disposition..........................................................................................59
10.3.2.2.
Patient Characteristics ....................................................................................59
10.3.2.3.
Concomitant Therapy .....................................................................................60
10.3.3.
Efficacy Analyses ................................................................................................60
10.3.3.1.
Primary Analyses ...........................................................................................60
10.3.3.1.1.
Additional Analyses for the Primary Endpoint ..........................................60
10.3.3.2.
Secondary Analyses........................................................................................60
10.3.3.3.
Tertiary/Exploratory Analyses ........................................................................61
10.3.4.
Safety Analyses....................................................................................................61
10.3.5.
Other Analyses.....................................................................................................62
10.3.5.1.
Health Economics...........................................................................................62
10.3.6.
Interim Analyses..................................................................................................63
11.
References ........................................................................................................................64
12.
Appendices .......................................................................................................................66


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List of Tables
Table
Page
Table ITSE.1.
Objectives and Endpoints...............................................................................21
Table ITSE.2.
Treatment Regimens......................................................................................32
Table ITSE.3.
Target Glucose Values for Adjustment of Insulin Therapy.............................33
Table ITSE.4.
Basal Insulin Hypoglycemia Assessment .......................................................35
Table ITSE.5.
Summary of Basal Insulin Adjustments after Hypoglycemia 
Assessment....................................................................................................35
Table ITSE.6.
Prandial Insulin Doses and Corresponding Self Monitored Blood 
Glucose  Values Pattern Adjustment Plan ......................................................37
Table ITSE.7.
LY900014 or Insulin Lispro Adjustment Algorithm
Pattern Adjustment Plan ................................................................................37
Table ITSE.8.
Concomitant Medications ..............................................................................40
Table ITSE.9.
Insulin to Carbohydrate Ratio for the MMTT Prandial Insulin Dose ..............48


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List of Figures
Figure
Page
Figure ITSE.1.
Illustration of study design for Clinical Protocol I8B-FH-ITSE......................24


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LY900014
List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................67
Appendix 2.
Clinical Laboratory Tests...............................................................................71
Appendix 3.
Study Governance Considerations..................................................................72
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................76
Appendix 5.
World Health Organization Classification for Diabetes..................................77
Appendix 6.
New York Heart Association Cardiac Disease Classification .........................78
Appendix 7.
Classification of Contraceptive Methods........................................................79


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1.
Synopsis
Title of Study: 
A Prospective, Randomized, Double-Blind Comparison of LY900014 to Insulin Lispro, Both in Combination with 
Insulin Glargine or Insulin Degludec in Adults with Type 2 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, 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 non-inferior to 
insulin lispro on glycemic control as measured by change from baseline to Week 26 in hemoglobin A1c (HbA1c) in 
patients with T2D when administered in a double-blind manner as prandial insulin in combination with basal insulin 
glargine or degludec in accordance with local regulations.
Objectives/Endpoints:
Objectives
Endpoints
Primary Objective

To test the hypothesis that LY900014 is non-
inferior to insulin lispro on glycemic control 
(non-inferiority margin [NIM]=0.4% for 
HbA1c) in patients with T2D, 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 
postprandial glucose (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 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

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


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LY900014
Objectives
Endpoints

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 baseline 
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 at least 1 event) of documented 
symptomatic hypoglycemic events from 
baseline through Week 26

To compare LY900014 and insulin lispro with 
respect to 1,5-Anhydroglucitol (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 self-monitored blood glucose 
(SMBG) profiles

Change from baseline in 10-point SMBG values 
at week 26

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 ratio 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
Summary of Study Design:  
Study I8B-FH-ITSE is a Phase 3, prospective, randomized, double-blind, multinational, multicenter, 2-group, 
parallel, active-controlled study conducted in patients with T2D currently treated with basal insulin in combination 
with at least 1 prandial insulin injection OR premixed insulin with at least 2 injections daily.  
Treatment Groups and Duration:  
Patients will be randomized to 1 of the 2 treatment groups in 2:1 ratio  (LY900014:insulin lispro). 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 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.  
Number of Patients:


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LY900014
Approximately 705 patients will be screened to achieve 564 randomized patients and 480 patients completing 
26 weeks of treatment.  Approximately 450 Chinese patients will be randomized.  The other 114 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.
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).  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 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 including the follow-
up visit, regardless of IP use.  Analyses of hypoglycemia will use data collected prior to permanent discontinuation 
of IP, while analyses for post-treatment may be performed as needed.  Analyses of safety laboratory measurements 
will be performed on all data during the planned treatment period regardless of IP use.
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,
including data collected from all randomized patients prior to permanent discontinuation of IP through Week 26.  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 non-
inferior to insulin lispro.  The model for this analysis will include the fixed class effects of treatment, strata (country, 
type of basal insulin, and number of prandial doses at 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 [≤8.5%, 
>8.5%], and number of prandial doses at 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 


I8B-FH-ITSE Clinical Protocol
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LY900014
method.  For each of the other categories of hypoglycemia, the number of hypoglycemia events during a specific 
period (rate) after randomization (for example, 0 to 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 (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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LY900014
2. Schedule of Activities


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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
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 history and 
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
AEs 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 doses (as 
needed)k
X
X
X
X
X
X
X
X


I8B-FH-ITSE 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
Ancillary Supplies/Diaries/IP
Dispense blood glucose 
meter, monitoring and 
ancillary supplies and 
complete trainingl,m
X
X
X
X
X
X
X
X
X
Distribute 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-point 
and 10-point SMBG 
Profilen
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


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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
Laboratory Assessments
Patient fasts prior to visit
X
X
X
X
MMTTr
X
X
Urinalysis panel
X
Pregnancy tests
X
X
Follicle-stimulating 
hormone testt
X
Chemistry 
X
X
X
X
Fasting serum glucose
X
Hematology
X
X
X
X
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
ITSQ
X
X
X
X
EQ-5D-5L
X
X
X
X
WPAI-GH
X
X
X
X


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Abbreviations:  AE = adverse event; BP = blood pressure; ECG = electrocardiogram; eCRF = electronic case report form; ED = early discontinuation; EQ-5D-5L 
= European Quality of Life – 5 Dimensions 5 Level; FBG = fasting blood glucose; 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 IWRS.

Collect AEs and concomitant medications.

Review blood glucose readings and study drug doses.  Recommendations for basal or prandial insulin adjustments are provided, if necessary by the 
investigator or designee.

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 completing the 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.
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 BP 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 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.  
h
Only applies to patients treated with insulin glulisine, insulin aspart, regular human insulin, or premixed insulin.  
i
Patients will be transferred to insulin glargine U-100 once daily or to degludec U-100  once daily at Visit 2 if the patient enters the study on any other basal 
insulin regimen.  Investigators will determine the appropriate basal insulin regimen for each patient.  Basal insulin should be titrated during the 8-week lead-in 
period to the target FBG. 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 for safety reasons such as hypoglycemia or 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.  See also Sections 7.2.1.3
and 7.2.1.4.  


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k
During the initial 12 weeks after randomization, the prandial insulin dose (either fixed insulin dose or insulin to carbohydrate ratio) and correction factor (as 
applicable) should be adjusted as necessary in order to meet the target SMBG levels.  During the maintenance period (Weeks 12 to 26), it is expected that 
prandial insulin dose adjustments would be to maintain glycemic control or for safety reasons such as hypoglycemia or 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 in the one week before each visit.
p
Patients should be instructed to perform three 10-point SMBG profiles during a 2-week period.  The 10-point SMBG 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 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.  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 a 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 T2D when administered in a 
double-blind manner as prandial insulin in combination with basal insulin glargine or degludec
in accordance with local regulations.  The study will expand the evaluation of the efficacy and 
safety of LY900014 to a broader race/ethnic spectrum of patients with T2D.
3.2.
Background
Type 2 diabetes can remain asymptomatic for many years, and about 50% of people with T2D 
are undiagnosed (IDF [WWW]).  The global prevalence of diabetes in 2015 among adults was 
estimated to be 9.0% or 415 million people, with greater than 90% of these cases being T2D 
(IDF [WWW]).  
There have been many advances in the treatment of T2D 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 
were >7.5% in more than two thirds (70.8%) of people with T1D and in more than one third 


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LY900014
(34.3%) of those with T2D (NHS 2017) Currently available rapid-acting insulin analogs are
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 
lispro by local vasodilatation rather than an as an active pharmaceutical ingredient that elicits a 


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LY900014
systemic effect.  Treprostinil is a prostacyclin analog administered either by inhalation 
(Tyvaso®), intravenous (IV) infusion, or continuous subcutaneous 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.  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 ITSE.1 shows the objectives and endpoints of the study.
Table ITSE.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 T2D, 
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 baseline 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 at 
least 1 event) of documented symptomatic 
hypoglycemic events from baseline 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

To compare LY900014 and insulin lispro with 
respect to total, basal, and prandial insulin dose

Change from baseline in total, basal and prandial 
insulin dose and prandial/total insulin dose ratio at 
Week 26


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LY900014
Objectives and Endpoints
Objectives
Endpoints
Other Secondary Objectives (Continued)

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 relative to 
insulin lispro

Adverse events, vital signs, chemistry, and 
hematology laboratory measures

To compare the incidence of treatment-emergent 
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 from baseline to Week 26 in weight (kg)

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; T2D = type 2 diabetes; WPAI-GH = Work Productivity and Activity 
Impairment Questionnaire General Health.


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5.
Study Design
5.1.
Overall Design
Study I8B-FH-ITSE (ITSE) is a Phase 3, prospective, double-blind, randomized, multinational, 
multicenter, 2-group, parallel, active-controlled study conducted in patients with T2D currently 
treated with basal insulin in combination with at least 1 prandial insulin injection OR premixed 
insulin with at least 2 injections daily.  Patients will be randomized to 1 of the 2 treatment groups 
in 2:1 ratio  (LY900014: insulin lispro). Each of the treatment therapies, 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.
The purpose of the lead-in period (prior to randomization) will be to titrate basal insulin, obtain 
preliminary diagnostic laboratory tests, and determine baseline hypoglycemia rates.  Patients 
treated with either a) basal insulin (insulin glargine U-100, insulin degludec U-100, insulin 
detemir or neutral protamine Hagedorn [NPH] insulin) in combination with at least 1 prandial 
injection of bolus insulin or b) at least 2 injections of premixed insulin will be eligible for 
inclusion in the trial.  
Patients should use the same study basal insulin regimen throughout the trial, with allowed 
regimens as follows:  insulin glargine U-100 (Basaglar/Abasaglar or LANTUS) once daily or 
insulin degludec U-100 once daily in accordance with local regulation.  Patients using basal 
insulin regimens other than insulin glargine U-100 or degludec U-100 will be transferred at Visit 
2 to an allowed study basal insulin regimen, which will be chosen by the investigator.  Basal 
insulin will be titrated during the 8-week lead-in period using a titration algorithm to allow the 
patient to reach the target fasting blood glucose (FBG) by the end of this period.  
Patients treated with insulin aspart, insulin glulisine, regular human insulin, or premixed insulin
will be transferred to insulin lispro at Visit 2, so that all patients will be treated with insulin 
lispro throughout the lead-in period.  Patients treated with 1 to 2 prandial injections a day or 
premixed insulin prior to study entry will transition to 3 injections a day of prandial insulin lispro 
at the beginning of the lead-in period.  At Visit 8, patients will be randomized to either 
LY900014 or insulin lispro at each meal.  During the initial 12 weeks after randomization 
(intensive titration period), prandial insulin doses should be titrated 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 doses would be to maintain glycemic 
control or for safety reasons such as hypoglycemia or unacceptable hyperglycemia. 
Figure ITSE.1 illustrates the study design.


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LY900014
Abbreviations:  T = telephone visit; wk = week.
a At Visit 2, patients treated with insulin aspart, insulin glulisine, regular insulin, or 
premixed insulin will be transferred to insulin lispro.  At Visit 2, patients treated with a 
basal insulin regimen other than insulin glargine U-100 or insulin degludec will be 
transferred to insulin glargine U-100 once daily or insulin degludec U-100 once daily.  
At Visit 8, patients will be randomized to either insulin lispro or LY900014 and 
continue their basal insulin regimen.  
b Titrate basal insulin. 
c Titrate prandial insulin (insulin lispro or LY900014).
d Patients will discontinue study insulins at Week 26.
Figure ITSE.1.
Illustration of study design for Clinical Protocol I8B-FH-ITSE.
5.2.
Number of Participants
Approximately 705 patients will be screened to achieve 564 randomized patients and 480 
patients completing 26 weeks of treatment.  Approximately 450 Chinese patients will be 
randomized.  The other 114 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 study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last patient.


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LY900014
5.3.1. Safety Follow-Up Period
Safety follow-up visit guidelines are as follows (see Section 2):  

For patients who discontinue from the study early during the lead-in period (prior to 
randomization), only an early discontinuation visit should be completed.

For patients who discontinue from investigational product (IP) early but remain in the 
study, all remaining visits should be completed per the Schedule of Activities (Section 2).

For 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), an early discontinuation 
visit followed by the safety follow-up visit (Visit 801) should be completed as per the 
Schedule of Activities (Section 2).

For patients who finish Visit 18 without early discontinuation of IP, a safety follow-up 
visit should be completed 4 weeks after Visit 18.  
5.4.
Scientific Rationale for Study Design
Study ITSE is a Phase 3 study to evaluate LY900014 compared to insulin lispro each in 
combination with basal insulin glargine or degludec in patients with T2D.  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 2:1 randomization ratio is to meet the regulatory 
requirement of China SDA.
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 glycemic control over time and as the best marker for the 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 period to optimize prandial insulin dosing followed by a 14-week maintenance 
period to ensure that the primary endpoint HbA1c reflects glycemic control on the patient’s 
insulin regimen.  
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 T2D and are being treated with: 
basal insulin in combination with at least 1 prandial injection of bolus insulin or at least 
2 injections of premixed insulin for at least 90 days (Inclusion Criterion [3]), and have an HbA1c 
value of ≥7.0 and ≤11.0% at screening.  Prior to screening, patients may also be treated with up 
to 3 types of oral antihyperglycemic medications (OAMs) as specified in Inclusion Criterion [4].
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 T2D, based on the World Health 
Organization classification (Appendix 5) for at least 1 year prior to screening 
Patient Characteristics
[2]
Are at least 18 years of age 
[3]
Have been treated for at least 90 days prior to screening with one of insulin 
regimens:
(3a) Basal insulin (insulin glargine U-100, insulin detemir, insulin degludec U-
100, or NPH insulin) in combination with at least 1 prandial injection of bolus 
insulin (insulin lispro U-100 or U-200, insulin aspart, insulin glulisine, or 
regular human insulin) in accordance with local regulations
Or
(3b) Premixed analog or human insulin regimens with any basal and bolus insulin 
combination injected at least twice daily
[4]
Patients may be treated with up to 3 of the following OAMs in accordance with 
local regulations.:

Metformin  

Dipeptidyl peptidase-4 (DPP-4) inhibitor


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
Sodium glucose cotransporter 2 (SGLT2) inhibitor

Sulfonylurea

Meglitinide

Alpha-glucoside inhibitor
Combination medications (2 or more medications in 1 pill) should be counted as 
the number of individual components.
During the study lead-in and treatment periods, patients may continue the use of 
up to 2 of the following OAMs in accordance with local regulations:  
metformin, SGLT2 inhibitor.  Other prestudy OAMs will be discontinued at the 
beginning of the lead-in period.  Please also refer to management of OAMs in 
Section 7.7.1.  
[5]
Have an HbA1c value between ≥7.0 and ≤11.0%, according to the central 
laboratory at the time of screening (Visit 1).
[6]
Have a body mass index (BMI) of ≤35.0 kg/m2 at screening (Visit 1).
[7]
Male patients:
a) No male contraception required except in compliance with specific local 
government study requirements.
[8]
Female patients:  
a) Women not of childbearing potential may participate and include those who 
are:
i)
infertile due to surgical sterilization (hysterectomy, bilateral 
oophorectomy, or tubal ligation), congenital anomaly such as 
Mullerian agenesis; 
Or
ii) postmenopausal – defined as either
(1) a woman 50 to 54 years of age (inclusive) with an intact uterus, not 
on hormone therapy who has had either
(a) cessation of menses for at least 1 year; 
Or
(b) at least 6 months of spontaneous amenorrhea with a follicle-
stimulating hormone >40 mIU/mL; 
Or
(2) a woman 55 years of age or older not on hormone therapy, who has 
had at least 6 months of spontaneous amenorrhea; 
Or


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(3) a woman at least 55 years of age with a diagnosis of menopause 
prior to starting hormone replacement therapy.
b) Women of childbearing potential participating:
i)
Cannot be pregnant or intend to become pregnant,
ii) Cannot be breastfeeding (including the use of a breast pump), 
iii) 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),
iv) Test negative for pregnancy at the time of screening (Visit 1).  Note:  a 
local urine or serum pregnancy test is conducted at Visit 8.
[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:  
a) Inject insulin with the use of an insulin injection device (insulin pen) 
according to included directions 
b) Perform self-BG monitoring including 10-point SMBG on designated days 
c) Participate in two 4-hour mixed-meal tolerance tests (MMTTs) and consume 
a standardized meal for the tests
d) Follow a suggested algorithm for basal and prandial insulin dose adjustment 
as agreed upon with the investigator  
e) Comply with the use of the study insulin and scheduled visits  
f)
Complete patient diary and questionnaire
[12] Considered healthy (apart from T2D) 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:


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Medical Conditions
[14] Have any other condition (including known drug or alcohol abuse, psychiatric 
disorder including eating disorder) that precludes the patient from following and 
completing the protocol
[15] Have been diagnosed, at any time, with T1D or Latent Autoimmune Diabetes in 
Adults
[16] Have hypoglycemia unawareness as judged by the investigator  
[17] Have had any episode of severe hypoglycemia (defined as requiring assistance 
due to neurologically disabling hypoglycemia) within the 6 months prior to 
screening
[18] Have had 1 or more episodes of diabetic ketoacidosis or hyperglycemic 
hyperosmolar state within the 6 months prior to screening
[19] Have a known diagnosis of secondary diabetes (for example, diabetes caused by 
hemochromatosis, acromegaly, chronic pancreatitis, or pancreatectomy)
[20] Excessive insulin resistance defined as having received a total daily dose of 
insulin >2.0 U/kg at the time of screening
[21] Have a history of or are being evaluated for bariatric surgery including 
Roux-en-Y gastric bypass surgery, gastric banding, and/or gastric sleeve
[22] 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
[23] Renal:  
a) History of renal transplantation
b) Currently receiving renal dialysis
c) Serum creatinine >2.0 mg/dL (177 mol/L) at screening
[24] 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:
a) 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
b) Alanine aminotransferase (ALT) ≥3X ULN as defined by the central 
laboratory,
Or


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c) Aspartate aminotransferase (AST) ≥3X ULN as defined by the central 
laboratory
[25] 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
[26] Have any hypersensitivity or allergy to any of the insulins or excipients used in 
this trial
[27] Have hypersensitivity or allergy to the ingredients in the standardized test meal 
(for example, nut allergy)
[28]
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
[29] Have presence of clinically significant gastrointestinal disease (for example, 
clinically active gastroparesis associated with wide glucose fluctuations) in the 
investigator’s opinion 
Prior/Concomitant Therapy
[30] Have used thiazolidinediones, glucagon-like peptide 1 (GLP-1) receptor 
agonist, or pramlintide within 90 days prior to screening
[31] Have used insulin human inhalation powder (Afrezza®) within 90 days prior to 
screening
[32] Are currently taking traditional medicine (herbal medicine or patent medicine) 
with known/specified content of anti-hyperglycemic effects within 90 days prior 
to screening.
[33]
Have used CSII for more than 14 dayswithin 90 days prior to screening  
[34] 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 with the 
exception of replacement therapy for adrenal insufficiency
[35] Have used any weight loss drugs (for example: prescription drugs such as liraglutide, 
lorcaserin, orlistat, phentermine, phentermine/topiramate, naltrexone/bupropion; over-
the-counter weight loss medications; traditional/herbal medicine with known weight 
loss effects) within 90 days prior to screening
Prior/Concurrent Clinical Trial Experience
[36] 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


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[37] Have participated, within the last 30 days in a clinical trial involving an IP.  If 
the previous IP has a long half-life, 3 months or 5 half-lives (whichever is 
longer) should have passed
[38] Have previously completed or withdrawn from this study after having signed 
the informed consent form (ICF) or any other study investigating LY900014 
after receiving at least 1 dose of the IP
Other Exclusions
[39] 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
[40] Are Lilly employees or representatives (including employees, temporary 
contract workers, or designees responsible for the conduct of the study)
[41] 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 subcutaneously
0 to 2 minutes prior to the start of the meal for 26 weeks.  Table ITSE.2 shows the treatment 
regimens.
Table ITSE.2.
Treatment Regimens
Regimen
Dose
Strength
Dose
Administration
Route of
Administration
Timing of 
Dose 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 

explaining requirements for recording insulin doses 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.
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.


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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 2:1 ratio (double-blind LY900014 administered at meal time:double-
blind insulin lispro administered at meal time).  Stratification will be by country (China vs. 
Other), HbA1c stratum (≤8.5% vs. >8.5% at Visit 7), and type of basal insulin during the lead-in 
period (glargine U-100 vs. degludec U-100), and number of prandial doses at study entry (<3 vs.
≥3).  
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 study groups.  Site personnel will confirm that they 
have located the correct prefilled pens by entering a confirmation number found on the prefilled 
pen 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 ITSE.3.  
Table ITSE.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
Prebedtime
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.
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.  For patients treated with basal and 3 
or more prandial injections a day, 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 insulin.  


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At Visit 2, patients treated with 1 to 2 prandial insulin injections a day or 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 lead-in and treatment 
period 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
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.  Basal insulin 
should be titrated 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 during the study based upon the judgment of the 
investigator (for example, in response to hypoglycemia).  
Every effort should be made to reach the FBG target during the lead-in period to allow adequate 
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 minimum weekly intervals during the 
lead-in period and thereafter at each study visit and as clinically indicated. Additional discussion 
between 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.  
Hypoglycemia events can be assessed over the previous week, as shown in Table ITSE.4. After 
the hypoglycemia assessment, the median FBG value from the 3 previous corresponding FBG 
values can be used for basal insulin adjustment, as shown in Table ITSE.5.


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Table ITSE.4.
Basal Insulin Hypoglycemia Assessment
Hypoglycemic Events in the Previous Week
Basal Insulin Change 
2 or more nocturnal hypoglycemia events occur or 1 severe 
hypoglycemia event occurs at any time of the day 
Decrease the basal insulin dose to the previous lower  
dose (or by 10% if this is first dose)
1 nocturnal hypoglycemia event occurs 
Do not increase basal insulin dose.  Consider 
decrease in basal insulin dose if clinically indicated 
No nocturnal events occur
Titrate the basal insulin dose based upon 
Table ITSE.5
Table ITSE.5.
Summary of Basal Insulin Adjustments after Hypoglycemia 
Assessment
If Median FBG from the 3 Previous 
FBG Values is:
Adjust the Basal Insulin Dose by:
<80 mg/dL 
(<4.4 mmol/L)
Decreasing dose to previous lower dosea
80-100 mg/dL 
(4.4-5.6 mmol/L)
No adjustment
101-139 mg/dL 
(5.7-7.7 mmol/L)
Increasing by 0-2 units
140-179 mg/dL
(7.8-9.9mmol/L)
Increasing by 4units
≥180 mg/dL 
(≥10.0 mmol/L)
Increasing by 6 units
Abbreviation:  FBG = fasting blood glucose
a
If there is no previous dose because this was the first assigned dose, then the basal dose should be decreased by 
10% in consultation with the investigator.
Sources:  Adapted from Bartley et al. 2008; Bolli et al. 2009; Tinahones et al. 2014.
7.2.1.4.
Study Prandial Insulin Therapy
At Visit 2, insulin lispro will be dispensed to all patients for use throughout the lead-in period.  
Patients treated with 3 or more prandial injections a day of insulin aspart, insulin glulisine, or 
regular human insulin will be transferred to insulin lispro (unit for unit).  At Visit 2, patients 
treated with 1 to 2 prandial insulin injections a day or 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 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 during the lead-in as clinically indicated.  Modifications in the 
calculation of the prandial insulin dose may also be influenced by other clinical circumstances 
and safety considerations known to the investigator; thus, the prescribed prandial insulin dose 


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during the study lead-in and treatment period is determined by, and the responsibility of, the 
investigator.
At Visit 8, patients will be randomized to either LY900014 or insulin lispro, and will administer 
their first blinded study prandial insulin dose with the next meal following the randomization 
visit.  The total daily bolus insulin dose of LY900014 or insulin lispro may be initiated unit for 
unit.  Consideration can be made to reduce the initial total daily bolus insulin dose (including 
correction factor if applicable) by approximately 10% to 20%, such as for patients with fairly 
well-controlled HbA1c or SMBG levels.  Study prandial insulin will be administered 0-2 minutes 
prior to the start of each meal (pre morning meal, pre midday meal, and pre evening meal).  
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.  
This study will use 2 possible plans for determining prandial insulin dosing including:

Pattern adjustment:  The patient is prescribed a fixed dose or dose range of insulin for 
each meal.  The fixed dose or dose range of insulin may be individualized for each 
meal.

Carbohydrate counting:  If the patient performed carbohydrate counting for prandial 
insulin dosing (insulin to carbohydrate ratio plan) prior to study enrollment, this plan 
may be continued during the study.  The prandial insulin dose is based upon the 
patient 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 (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.  Decreases to the prandial 
insulin dose may be made at any time during the study based upon the judgment of the 
investigator (for example, in response to hypoglycemia).  
For patients who are carbohydrate counting, the insulin to carbohydrate ratio and correction 
factor should be assessed and adjusted as needed at minimum weekly in order to meet the study 
target SMBG levels during the initial 12 weeks after randomization (the intensive titration 
period).  The insulin to carbohydrate ratio 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 postprandial SMBG levels may be performed as clinically indicated.  
During the maintenance period (Weeks 12 to 26), it is expected that prandial insulin dose 
adjustments would be to maintain glycemic control or for safety reasons such as hypoglycemia 
or unacceptable hyperglycemia.  
For patients who are using the pattern adjustment plan, the prandial insulin dose and correction 
factor should be assessed and adjusted as needed, at least weekly, in order to meet the study 
target SMBG levels during the initial 12 weeks after randomization (the intensive titration 
period).  The prandial insulin dose may be adjusted every 3 to 4 days (twice per week) when 


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appropriate, based on the patient’s glycemic needs and SMBG levels. In addition to the 
minimum weekly investigator dose assessment, investigators may use discretion and provide 
direction for patients to adjust prandial insulin dosing per week.  Prandial insulin dose 
adjustments more than twice per week will not constitute a protocol violation.  Postprandial 
SMBG levels from 10-point SMBG profiles  should also be evaluated for optimization of 
prandial insulin dosing.  Additional postprandial SMBG levels may be performed as clinically 
indicated.  During the maintenance period (Weeks 12 to 26), it is expected that prandial insulin 
dose adjustments would be to maintain glycemic control or for safety reasons, such as 
hypoglycemia or unacceptable hyperglycemia. 
In the pattern adjustment plan, assessment of the prandial insulin dose includes review of the 
previous 3 days of SMBG levels for the corresponding meal or bedtime (Table ITSE.6).  For 
example, if assessing the need to adjust the fasting (pre morning meal) prandial insulin dose, 
review the preceding 3 pre midday meal SMBG levels. 
Table ITSE.6.
Prandial Insulin Doses and Corresponding Self Monitored Blood 
Glucose  Values Pattern Adjustment Plan 
Prandial Insulin Dose Assessed
Corresponding SMBG Value for Review
Fasting or morning premeal
3 previous midday premeal SMBG values
Midday premeal
3 previous evening premeal SMBG values
Evening premeal
3 previous bedtime SMBG values
Abbreviation:  SMBG = self-monitored blood glucose.
The median value from premeal glucose readings from the 3 previous days is chosen as the 
“adjustment value” and the change in dose (either increase or decrease) is based upon this value
Table ITSE.7.
Table ITSE.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 1-2 units
No change
Increase by 1-2 units
>20 units 
Decrease by 2-3 units
No change
Increase by 2-3 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.
For either prandial insulin dosing plan, the investigator may determine the appropriate correction 
factor for the patient to administer when premeal SMBG are above target based on clinical 


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judgment, taking into account the patient’s clinical history with previous/current insulin regimen 
and recent glucose profiles.  Alternatively, the correction factor may initially be calculated as 
follows:  
correction factor = 1800/total daily insulin dose = estimated decrease in SMBG (mg/dL) 
level per unit of prandial insulin administered or 
correction factor = 100/total daily insulin dose = estimated decrease in SMBG (mmol/L) 
level per unit of prandial insulin administered  
7.2.1.5.
Transitioning off Study Prandial Insulin Therapy
Patients will take their last prandial 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 who were using premixed insulins or premixed insulin analogs prior to study entry may 
choose to stay on basal bolus regimen at the discretion of the investigator.  However, patients 
who were not using insulin lispro prior to entry should NOT use insulin lispro during the safety
follow-up period.
7.3.
Blinding
This is a double-blind study.  The treatment groups, LY900014 and 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.  Patient safety must always be the first 
consideration in making such a determination.  If the investigator decides that unblinding is 


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warranted, the investigator should make every effort to contact the Lilly clinical research 
physician (CRP/CRS) prior to unblinding a patient’s treatment assignment unless this could 
delay emergency treatment of the patient.  If a patient’s treatment assignment is unblinded, Lilly 
must be notified immediately.
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.  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.  No specific study data will be collected for analysis of treatment compliance.


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7.7.
Concomitant Therapy
Guidance on restrictions for concomitant therapies is provided in Table ITSE.8.
Table ITSE.8.
Concomitant Medications
Drug Class
Acute 
Use
Chronic 
Use
Safety Follow-up Period
Conditions for Use
Sulfonylurea, meglitinide, DPP-4 
inhibitor, alpha-glucoside inhibitor
No
No
Yes
Thiazolidinedione, glucagon like 
peptide-1 receptor agonist
No
No
No
NPH insulin, insulin glargine U-300, 
insulin detemir,insuln degludec U-
200
No
No
Yes
May be used in 
emergencies for up to 14 
consecutive days
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
Insulin human inhalation powder 
(Afrezza®)
No
No
No
Weight loss drugs (for example:  
prescription drugs such as liraglutide, 
lorcaserin, orlistat, phentermine, 
phentermine/topiramate, 
naltrexone/bupropion; or over-the-
counter weight loss medications)
No
No
Yes
Systemic glucocorticosteroid 
(including IV, intramuscular, SC, or 
oral) but excluding non-systemic 
glucocorticosteroid (including 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 1-time use 
a total of ≤21 consecutive 
days.
Abbreviations:  DPP-4 = dipeptidyl peptidase-4; 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 lispro product prior to entry should NOT use lispro product during the 
follow-up period
7.7.1.Management of Oral Antihyperglycemic Medications
During the study lead-in and treatment periods, patients may continue the use of up to 2 of the 
following OAMs:  metformin, SGLT2 inhibitor in accordance with local regulations.  Please 
also refer to Exclusion Criterion [30] for criteria regarding thiazolidinediones, GLP-1 receptor 
agonists, and pramlintide (Section 6.2).  Other prestudy OAMs including sulfonylurea, 


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meglitinide, DPP-4 inhibitor, and alpha-glucosidase inhibitor agents will be discontinued at the 
beginning of the lead-in period (Visit 2).  
Oral antihyperglycemic medication dosing is to remain stable during study lead-in and treatment, 
except with the development of contraindications or for safety reasons.  During study lead-in and 
treatment, all glycemic management is to be conducted by adjustment of basal and prandial 
insulin doses.  In emergency situations, it may be necessary for patients to change their dose of 
OAM and/or be treated with a nonstudy insulin.  This will be allowed for up to 14 consecutive 
days (Section 8.1.2).
7.8.
Treatment after the End of the Study
7.8.1. Continued Access
LY900014 will not be made available after conclusion of the study to patients.  Rapid-acting 
insulin analogs and regular human insulin are available in all countries for use as prandial insulin.
7.8.2.Special Treatment Considerations
After discontinuation of IP at the end of the treatment period or earlier, randomized patients 
should restart the prandial insulin used prior to study entry or transition to a rapid-acting insulin 
analog other than insulin lispro if the patient was not treated with insulin lispro prestudy. 
Patients may continue treatment with the basal insulin used during the study or return to their 
prestudy basal insulin at investigator discretion.  
During this follow-up period, OAMs used during the study treatment period should be continued 
and other prestudy OAMs may be considered at investigator discretion as appropriate.  
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 ITSE.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 samples 
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 
primary treatment period (Week 26, 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.

Patients should not administer correction doses with insulin lispro or LY900014 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 a hypoglycemia episode requires more than approximately 20 
grams of carbohydrate within 8 hours of the start of the MMTT or the patient experiences a 
severe hypoglycemia episode (as defined in Sections 9.4.1 and 9.4.2), 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 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 
insulin to carbohydrate ratio 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 will be calculated based on the average total daily insulin dose for the 3 days 
prior to the MMTT per Table ITSE.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 ITSE.9.
Insulin to Carbohydrate Ratio for the MMTT Prandial Insulin Dose
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 
Abbreviation:  MMTT = mixed-meal tolerance test.
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), the patient should receive 15 grams of rapidly absorbable carbohydrate.  The 
patient’s BG should be retested in 15 minutes or as clinically indicated and, if it remains 
≤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 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 emergency 


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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.

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.  

Retain the IP under appropriate storage conditions, if available or when obtained, 
until instructed to return it to Lilly.  

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.

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 patient diaries.  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 patient diaries 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 


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hypoglycemia available. 
Documented Clinically Significant Hypoglycemia  with similar criterion as above except for 
threshold BG <54 mg/dL (3.0 mmol/L)

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).  


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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.  
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:  

elevation of serum ALT to ≥5X ULN on 2 or more consecutive blood tests

elevated serum TBL to ≥ 2X ULN (except for cases of known Gilbert’s 
syndrome)

elevation of serum ALP to ≥2X ULN on 2 or more consecutive blood tests


I 8 B-F H -I TS E Cli ni c al Pr ot o c ol
P a g e 5 4
L Y 9 0 0 0 1 4

pati e nt disc o nt i n ue d fr om treat me nt d ue t o a he patic e ve nt or a b n or malit y of li ver 
tests

he pat ic e ve nt c o nsi dere d t o be an S A E .
9. 5.
P h ar m a c o ki n eti c s
N ot a p plica ble.
9. 6.
P h ar m a c o d y n a mi c s 
N ot a p plica ble.
9. 7.
P h ar m a c o g e n o mi c s
N ot a p plica ble.
9. 8.
Bi o m ar k er s a n d Pr e di cti v e or Ot h er A n al y s e s
9. 8. 1.
S a m pl e s f or I m m u n o g e ni cit y T e sti n g
Bl o o d sa m pl es f or i m m u n o ge nicit y testi n g will be c ollecte d t o deter mi ne a nti b o d y pr o d uctio n 
a gai nst i ns uli n lis pr o as s pecifie d i n t he Sc he d ule of Act i vities ( Sectio n 2 ). 
9. 9.
H e alt h E c o n o mi c s 
T he self -re p orte d q uestio n nai res will be a d mi nistere d acc or di n g t o t he Sc he d ule o f Act i vities
( Sectio n 2 ) i n c o u ntries w here t he q uesti o n naires have bee n tra nslate d i nt o t he nati ve la n g ua ge o f 
t he re gi o n a n d li n g uist icall y vali date d.
C CI


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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 
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:
•
Inconvenience of Regimen (5 items)
•
Lifestyle Flexibility (3 items)
•
Glycemic Control (3 items)
•
Hypoglycemic Control (5 items)
•
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, 


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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 564 patients will be randomized in order that 480 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 T2D when administered in a double-blind manner as prandial insulin in 
combination with basal insulin glargine or insulin degludec and OAM.  
Patients will be randomized in a 2:1 ratio to LY900014 and insulin lispro, both 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%, 480 completers (320 in the LY900014 group and 
160 in the insulin lispro group) will provide 96% power to show noninferiority between 
LY900014 and insulin lispro using the upper limit of a 2-sided 95% confidence interval (CI; 
LY900014 – insulin lispro).  Assuming a 15% dropout rate for 26 weeks, approximately 564 
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.
The primary analysis is for the treatment period through Week 26.


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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 be performed, including data 
collected prior to permanent discontinuation of IP.  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 postbaseline 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 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 including the follow-up visit, regardless of IP use.  Analyses 
of hypoglycemia will use data collected prior to permanent discontinuation of IP; while analyses 
for post-treatment may be performed as needed.  Analyses of safety laboratory measurements 
will be performed on all data during the planned treatment period regardless of IP use.
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.  
A restricted maximum likelihood-based, mixed-effect model repeated measure (MMRM) 
analysis will be used to analyze continuous longitudinal variables.  All the longitudinal 
observations at each scheduled postbaseline visit will be included in the analysis.  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 number of prandial 
doses at 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.  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

Autoregressive

Compound symmetry without heterogeneous variances


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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) will also be used to analyze continuous variables. The 
model for the change from baseline to the Week 26 HbA1c endpoint will include treatment and
strata (country, type of basal insulin, and number of prandial doses at entry) as fixed effects and 
baseline as a covariate.  Unless otherwise stated, 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 
nominal 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 tests.  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. With no multiplicity control, nominal p-values from 
such comparisons should be interpreted as a descriptive measure. 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 descriptively summarized.
The use of OAMs during the treatment period will be summarized by treatment group.  In 
addition, the proportion of subjects on OAMs at baseline will be summarized. 
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 T2D, 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,
including data collected from all randomized patients prior to permanent discontinuation of IP 
through Week 26.  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.  
In addition to the primary objective, the superiority of LY900014 in controlling HbA1c 
compared to insulin lispro will also be assessed with the analysis approach described above.  If 
the p-value is less than the alpha level from the graphical approach allocated to the superiority 
hypothesis, LY900014 will be declared superior to insulin lispro.
10.3.3.1.1.Additional Analyses for the Primary Endpoint
The primary MMRM analysis model 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.  
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.  The graphical testing scheme will be described in the SAP.  


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An ANCOVA model with strata (country, type of basal insulin, number of prandial doses at 
entry, and baseline HbA1c [≤8.5%, >8.5%]), 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 SAP.
Superiority in change from baseline in HbA1c for LY900014 compared with insulin lispro will 
be determined from the analysis approaches outlined in Section 10.3.3.1.
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 or Pearson’s 
chi-square 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.  
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.


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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 1 sex, the denominator and computation 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 
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 (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 either 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.


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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.
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.
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in U.S. diabetes care, 1999-2010. N Engl J Med. 2013;368(17):1613-1624
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, 
Rodbard D, Tamborlane WV, Walsh J; American Association of Clinical Endocrinologists 
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consensus statement [published correction appears in Endocr Pract. 2016;22(4):516]. Endocr 
Pract. 2016;22(2):231-261. 
Barrett KE, Barman SM, Boitano S, Brooks HL. Ganong’s review of medical physiology. 25th 
ed. New York: McGraw-Hill Education; 2016. Chapter 24.
Bartley PC, Bogoev M, Larsen J, Philotheou A. Long-term efficacy and safety of insulin detemir 
compared to Neutral Protamine Hagedorn insulin in patients with Type 1 diabetes using a 
treat-to-target basal-bolus regimen with insulin aspart at meals: a 2-year, randomized, 
controlled trial. Diabet Med. 2008;25(4):442-449.
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.
Bergenstal RM, Johnson M, Powers MA, Wynne A, Vlajnic A, Hollander P, Rendell M. Adjust 
to target in type 2 diabetes: comparison of a simple algorithm with carbohydrate counting for 
adjustment of mealtime insulin glulisine. Diabetes Care. 2008;31(7):1305-1310.
Bolli GB, Kerr D, Thomas R, Torlone E, Sola-Gazagnes S, Vitacolonna E, Selam JL, Home PD. 
Comparison of a multiple daily insulin injection regime (basal once-daily glargine plus 
mealtime lispro) and continuous subcutaneous insulin infusion (lispro) in type 1 diabetes: a 
randomized open parallel multicenter study [published correction appears in Diabetes Care. 
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 
multiple comparison procedures using weighted Bonferroni, Simes, or parametric tests. 
Biometrical J. 2011;53(6):894-913.
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, 
Miller KM. Timing of meal insulin and its relation to adherence to therapy in Type 1 diabetes. 
J Diabetes Sci Technol. 2018;12(2):349-355.


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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.
Fineberg SE, Huang J, Brunelle R, Gulliya KS, Anderson JH Jr. Effect of long-term exposure to 
insulin lispro on the induction of antibody response in patients with type 1 or type 2 diabetes. 
Diabetes Care. 2003;26(1):89-96.
Humalog [package insert]. Indianapolis, IN: Eli Lilly and Company; 2015.
Humalog [summary of product characteristics]. The Netherlands. Eli Lilly Nederland B.V; 2016.
[IDF] International Diabetes Federation. IDF Diabetes Atlas 2015. 7th ed. Available at 
http://www.diabetesatlas.org. Accessed February 25, 2016.
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. 
[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.
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.
[PMR] Pharmaceutical and healthcare market in CEE and CIS. Remodulin approved in 
22 European countries, also Poland. PMR web site. Available at 
http://www.ceepharma.com/news/25318/remodulin-approved-in-22-european-countries-also-
poland. Published September 1, 2005. Accessed September 16, 2016.
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and 
activity impairment instrument. Pharmacoeconomics. 1993;4(5):353-365. 
Remodulin [package insert]. Research Triangle Park, NC: United Therapeutics Corp; 2014.
Scheiner G. Insulin-to-carb ratios made easy. Available at: 
http://integrateddiabetes.com/Articles/insu/carb%20ratio%20article%20for%20mendosa.pdf. 
Published November 2007.  Accessed September 23, 2016.
Tinahones FJ, Gross JL, Onaca A, Cleall S, Rodriguez A. Insulin lispro low mixture twice daily 
versus basal insulin glargine once daily and prandial insulin lispro once daily in patients with 
type 2 diabetes requiring insulin intensification: a randomized phase IV trial. Diabetes Obes 
Metab. 2014;16(10):963-970.
van Reenen M, Janssen B for the EuroQol Research Foundation. 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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12.
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
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
CSR
clinical study report
DPP-4
dipeptidyl peptidase-4


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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
GCP
good clinical practice
GD
glucodynamic(s)
GLP-1
glucagon-like peptide 1
GRAS
Generally Recognized As Safe
HbA1c
hemoglobin A1c
IB
Investigator’s Brochure
ICF
informed consent form
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
LOCF
last-observation-carried-forward
LS
least squares


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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
OAM
oral antihyperglycemic medication
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
SGLT2
sodium glucose cotransporter 2
SMBG
self-monitored blood glucose
SOC
system organ class
SUSARs
suspected unexpected serious adverse reactions
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 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 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-MC-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


L e o  D o c u m e n t  I D  =  3 4 6 5 9 e b 5 - 4 2 9 3 - 4 8 9 9 - b f 3 e - 2 a 5 3 e 9 0 3 0 a 7 b
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  2 7 - J u n - 2 0 1 8  0 1 : 3 6 : 0 6  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  2 7 - J u n - 2 0 1 8  0 1 : 3 6 : 0 6  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
P P D
P P D

SAP_001.pdf: 
 
Statistical Analysis Plan Version 2 I8B-FH-ITSE 
 
 
A Prospective, Randomized, Double-Blind Comparison of LY900014 to Insulin Lispro, Both 
in Combination with Insulin Glargine or Insulin Degludec in Adults with Type 2 Diabetes 
 
 
NCT03952143 
 
 
Approval Date: 10-Mar-2021 
 


I 8 B-F H -I TS E St ati sti c al A n al y si s Pl a n V er si o n 2
P a g e 1
L Y 9 0 0 0 0 1 4
1.
St ati sti c al A n al y si s Pl a n:
I 8 B-F H -I T S E:  A Pr o s p e cti v e, R a n d o mi z e d, D o u bl e -Bli n d 
C o m p ari s o n of L Y 9 0 0 0 1 4 t o I n s uli n Li s pr o, B ot h i n 
C o m bi n ati o n wit h I n s uli n Gl ar gi n e or I n s uli n D e gl u d e c i n 
A d ult s wit h T y p e 2 Di a b et e s
C o nfi d e nti al I nf or m ati o n
T h e i nf or m ati o n c o nt ai n e d i n t hi s d o c u m e nt i s c o nfi d e nti al a n d t h e i nf or m ati o n c o nt ai n e d 
wit hi n it m a y n ot b e r e pr o d u c e d or ot h er wi s e di s s e mi n at e d wit h o ut t h e a p pr o v al of Eli Lill y 
a n d C o m p a n y or it s s u b si di ari e s. 
N ot e t o R e g ul at or y A ut h oriti e s :  T hi s d o c u m e nt m a y c o nt ai n pr ot e ct e d p er s o n al d at a 
a n d/ or c o m m er ci all y c o nfi d e nti al i nf or m ati o n e x e m pt fr o m p u bli c di s cl o s ur e. Eli Lill y a n d 
C o m p a n y r e q u e st s c o n s ult ati o n r e g ar di n g r el e a s e/r e d a cti o n pri or t o a n y p u bli c r el e a s e.
I n 
t h e U nit e d St at e s, t hi s d o c u m e nt i s s u bj e ct t o Fr e e d o m of I nf or m ati o n A ct ( F OI A) 
E x e m pti o n 4 a n d m a y n ot b e r e pr o d u c e d or ot h er wi s e di s s e mi n at e d wit h o ut t h e writt e n 
a p pr o v al of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s.
L Y 9 0 0 0 1 4
St u d y I 8 B-F H -I T S E i s A Pr o s p e cti v e, R a n d o mi z e d, D o u bl e-Bli n d C o m p ari s o n of L Y 9 0 0 0 1 4 
t o I n s uli n Li s pr o, B ot h i n C o m bi n ati o n wit h I n s uli n Gl ar gi n e or I n s uli n D e gl u d e c i n A d ult s 
wit h T y p e 2 Di a b et e s .
Eli Lill y a n d C o m p a n y
I n di a n a p oli s, I n di a n a U S A 4 6 2 8 5
Pr ot o c ol I 8 B-F H -I T S E
P h a s e 3
St ati sti c al A n al y si s Pl a n V er si o n 2 el e ctr o ni c all y si g n e d a n d a p pr o v e d b y Lill y o n d at e 
pr o vi d e d b el o w.
A p pr o v al D at e: 1 0- M ar- 2 0 2 1 G M T


I8B-FH-ITSE Statistical Analysis Plan Version 2
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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan: I8B-FH-ITSE:  A Prospective, 
Randomized, Double-Blind Comparison of LY900014 to Insulin 
Lispro, Both in Combination with Insulin Glargine or Insulin 
Degludec in Adults with Type 2 Diabetes............................................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................7
4.
Study Objectives.................................................................................................................8
5.
Study Design.....................................................................................................................10
5.1.
Summary of Study Design............................................................................................10
5.2.
Determination of Sample Size ......................................................................................10
5.3.
Method of Assignment to Treatment ............................................................................10
6.
A Priori Statistical Methods ..............................................................................................12
6.1.
General Considerations ................................................................................................12
6.2.
Adjustments for Covariates ..........................................................................................15
6.3.
Handling of Dropouts or Missing Data.........................................................................16
6.4.
Multicenter Studies ......................................................................................................16
6.5.
Multiple Comparisons/Multiplicity...............................................................................16
6.6.
Patient Disposition .......................................................................................................16
6.7.
Patient Characteristics ..................................................................................................17
6.8.
Treatment Compliance .................................................................................................18
6.9.
Important Protocol Deviations......................................................................................18
6.10. Concomitant and Prior Therapy....................................................................................18
6.11. Efficacy Analyses ........................................................................................................19
6.11.1.
Primary Outcome and Methodology.....................................................................19
6.11.2.
Analyses of Multiplicity Adjusted Objectives.......................................................20
6.11.3.
Additional Analyses of the Primary Outcome.......................................................21
6.11.4.
Sensitivity Analyses for Missing Data..................................................................21
6.11.5.
Other Secondary Efficacy Analyses .....................................................................21
6.11.6.
Analyses of Exploratory Objectives .....................................................................22
6.12. Safety Analyses............................................................................................................24
6.12.1.
Extent of Exposure...............................................................................................25
6.12.2.
Adverse Events ....................................................................................................25
6.12.3.
Deaths..................................................................................................................27
6.12.4.
Hypoglycemic Events and Other Adverse Events.................................................27
6.12.4.1.
Hypoglycemic Events.....................................................................................27


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6.12.4.2.
Systemic Hypersensitivity Reaction................................................................29
6.12.4.3.
Injection Site Reaction....................................................................................29
6.12.4.4.
Hepatobiliary Events ......................................................................................30
6.12.4.4.1.
Treatment-Emergent Potential Hepatic Disorder.......................................30
6.12.4.4.2.
Liver Enzyme Lab Values.........................................................................30
6.12.4.4.3.
Treatment-Emergent Elevation of Liver Enzyme Lab 
Values ......................................................................................................30
6.12.5.
Clinical Laboratory Evaluation.............................................................................31
6.12.6.
Vital Signs and Other Physical Findings...............................................................32
6.12.7.
Immunogenicity...................................................................................................33
6.12.7.1.
Treatment Emergent Anti-Insulin Lispro Antibody.........................................33
6.12.8.
Patient Narratives.................................................................................................35
6.13. Subgroup Analyses.......................................................................................................35
6.13.1.
Subgroup Analyses for HbA1c.............................................................................35
6.13.2.
Subgroup Analyses for Hypoglycemic Events......................................................36
6.14. Interim Analyses and Data Monitoring.........................................................................36
6.15. Clinical Trial Registry Analyses...................................................................................37
7.
Novel Coronavirus (COVID-19) Impact............................................................................38
7.1.
Patients’ Study Visits Impacted by COVID-19.............................................................38
7.2.
Protocol Deviation .......................................................................................................38
7.3.
Patient Disposition .......................................................................................................38
7.4.
COVID-19 Infection ....................................................................................................38
7.5.
Some Mitigation Procedures.........................................................................................38
7.6.
Sensitivity Analysis for Efficacy ..................................................................................39
8.
Unblinding Plan................................................................................................................40
9.
References ........................................................................................................................41
10.
Appendices .......................................................................................................................42


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Table of Contents
Table
Page
Table 4.1.
Objectives and Endpoints.......................................................................................8
Table 6.1.
Patient Populations...............................................................................................12
Table 6.2.
Baseline and Post-Baseline Definitions and Patient Population by Study Period and 
Type of Analysis ...............................................................................................................14
Table 6.4
Additional Exploratory Efficacy Variables...........................................................24
Table 6.5.
Treatment-Emergent Adverse Event Analysis Periods..........................................26
Table 6.6.
Summary of Analyses for Endpoints Related to Hypoglycemia............................28
Table 6.7.
Categorical Criteria for Abnormal Treatment-Emergent Blood Pressure and Pulse 
Measurement, and Categorical Criteria for Weight for Adults............................................32


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Table of Contents
Figure
Page
Figure 5.1.
Illustration of study design. ..................................................................................11
Figure 6.1.
Testing scheme for primary and multiplicity adjusted objectives. .........................21


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Table of Contents
Appendix
Page
Appendix 1.
Empirical Estimation of Relative Event Rate ..................................................43


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3.
Revision History
Statistical analysis Plan (SAP) Version 1 was approved prior to the first patient visit. Version 1 
was based on the Protocol I8B-FH-ITSE (ITSE) approved on 27 June 2018.
The main changes of SAP Version 2 are listed below.

Analysis period of from randomization to Week 26 (including all data regardless 
of IP use) was added for some of the safety analysis.

Removed the baseline rate covariate from all hypoglycemia models as there were 
many critical outliers leading to inaccurate in the LSM and the biases were 
inconsistent.

For adjustments of covariates, HbA1c stratum at Visit 7 is changed to HbA1c 
stratum at baseline to be consistent with the global study ITRN..

COVID-19 related analyses are added.

Weights of the graphical testing scheme for the multiple testing of this study are 
updated by simulation and team decison.


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4.
Study Objectives
Table 4.1 shows the objectives and endpoints of the study. 
Table 4.1.
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 T2D, 
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 baseline 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 at 
least 1 event) of documented symptomatic 
hypoglycemic events from baseline 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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
To compare LY900014 and insulin lispro with 
respect to total, basal, and prandial insulin dose

Change from baseline in total, basal and prandial 
insulin dose and prandial/total insulin dose ratio 
at Week 26
Objectives and Endpoints
Objectives
Endpoints
Other Secondary Objectives (Continued)

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 relative to 
insulin lispro

Adverse events, vital signs, chemistry, and 
hematology laboratory measures

To compare the incidence of treatment-emergent 
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 from baseline to Week 26 in weight (kg)

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; T2D = type 2 diabetes; WPAI-GH = Work Productivity and Activity 
Impairment Questionnaire General Health.


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5.
Study Design
5.1.
Summary of Study Design
Study I8B-FH-ITSE (ITSE) is a Phase 3, prospective, double-blind, randomized, multinational, 
multicenter, 2-group, parallel, active-controlled study conducted in patients with type 2 diabetes 
mellitus (T2D) currently treated with basal insulin in combination with at least 1 prandial insulin 
injection OR premixed insulin with at least 2 injections daily.  Patients will be randomized to 1 
of the 2 treatment groups in 2:1 ratio  (LY900014: insulin lispro). Each of the treatment 
therapies, 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. Abbreviations:  T = telephone visit; wk = week.
a At Visit 2, patients treated with insulin aspart, insulin glulisine, regular insulin, or premixed 
insulin will be transferred to insulin lispro.  At Visit 2, patients treated with a basal insulin 
regimen other than insulin glargine U-100 or insulin degludec will be transferred to insulin 
glargine U-100 once daily or insulin degludec U-100 once daily.  At Visit 8, patients will be 
randomized to either insulin lispro or LY900014 and continue their basal insulin regimen.  
b Titrate basal insulin. 
c Titrate prandial insulin (insulin lispro or LY900014).
d Patients will discontinue study insulins at Week 26.
Figure 5.1 illustrates the study design.
5.2.
Determination of Sample Size
Patients will be randomized in a 2:1 ratio to LY900014 and insulin lispro, both administered 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%, 480 completers (320 in the LY900014 group and 
160 in the insulin lispro group) will provide 96% power to show noninferiority between 
LY900014 and insulin lispro using the upper limit of a 2-sided 95% confidence interval (CI; 
LY900014 – insulin lispro).  Assuming a 15% dropout rate for 26 weeks, approximately 564 
patients will need to be randomized. 
5.3.
Method of Assignment to Treatment
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 2:1 ratio (double-blind LY900014 administered at meal time:double-
blind insulin lispro administered at meal time).  Stratification will be by country (China vs. 
Other), HbA1c stratum at Visit 7 (≤8.5% vs. >8.5%), and type of basal insulin during the lead-in 
period (glargine U-100 vs. degludec U-100), and number of prandial doses at study entry (<3 vs. 
≥3).


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Abbreviations:  T = telephone visit; wk = week.
a At Visit 2, patients treated with insulin aspart, insulin glulisine, regular insulin, or premixed 
insulin will be transferred to insulin lispro.  At Visit 2, patients treated with a basal insulin 
regimen other than insulin glargine U-100 or insulin degludec will be transferred to insulin 
glargine U-100 once daily or insulin degludec U-100 once daily.  At Visit 8, patients will be 
randomized to either insulin lispro or LY900014 and continue their basal insulin regimen.  
b Titrate basal insulin. 
c Titrate prandial insulin (insulin lispro or LY900014).
d Patients will discontinue study insulins at Week 26.
Figure 5.1.
Illustration of study design.


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6.
A Priori Statistical Methods
6.1.
General Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly and Company (hereafter 
Lilly). 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 this SAP and/or in the clinical study report (CSR). Additional exploratory analyses 
will be conducted, as deemed appropriate.
For purposes of analysis, the following populations are defined in Table 6.1:
Table 6.1.
Patient Populations
Population
Description
Entered
All patients who give 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 
investigational product (IP). Treatment group will be defined on the basis of the 
treatment the patients are assigned.  
Completer
Patients included in the randomized population who have completed Week 26 of study 
treatment without permanent discontinuation of IP. Treatment group will be defined on 
the basis of the treatment the patients are assigned.  
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.
Unless otherwise stated, the efficacy analyses will be conducted on the Randomized Population, 
and the safety analyses will be conducted on the Safety Population.
The primary analysis is for the treatment period through Week 26. 
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. 


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The definitions of baseline and post-baseline for the efficacy and safety analyses depend on 
which analysis period is being used. The following analysis periods will be used:

Lead-in Period – Visits 2 to 8

26-Week Treatment Period – from randomization to Week 26 prior to 
discontinuation of investigational product (IP)


26-Week Treatment Period and Safety Follow-Up Visit – from randomization to 
Visit 801 (including all data regardless of IP use)
The data on IP is defined based on the following rules:

For data only measured at an office visit 
o
Mixed-meal tolerance test (MMTT) postbaseline data will be classified as 
on IP if the MMTT performance date is prior to or on the last IP dose date  
o
Other postbaseline data (for example, vital signs, safety laboratory tests,
and questionnaires) will be considered as on IP if the measurement was 
performed at or prior to the cutoff date defined as 14 days after the last IP 
dose date

For data collected as running records with an exact date stamp such as adverse 
events (AEs) and diary entries where the dates of the measures were not tied with 
the date of an office visit, postbaseline data with dates ≤(last study drug dose date 
+1) will be considered as data on IP.
Table 6.2 describes the rules for determining the patient population, baseline and postbaseline 
observations for the different analysis periods. 
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 (LS) means and standard errors derived from the analysis models will also be 
displayed. 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.
For laboratory values, Systeme International (SI) units will be presented.  Both % and mmol/mol 
will be presented for HbA1c and mmol/L will be presented for glucose measurements.  
All baseline measures will be analyzed using an analysis of variance (ANOVA) model that has 
treatment as the model term.


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Table 6.2.
Baseline and Post-Baseline Definitions and Patient Population by 
Study Period and Type of Analysis
Study Period/Analysis
Patient Population
Baseline Observations
Post-Baseline Observations
Lead-In Period
TEAEs
All Enrolled Patients
Prior to first dose of 
open-label insulin 
lispro (or Visit 2 date if 
the dose date is 
missing)
The entire lead-in period after first 
dose of open-label insulin lispro and 
prior to the first dose of IP (or Visit 
8 date if the dose date is missing).
Basal, prandial, and 
total insulin doses, and 
prandial/total insulin 
dose ratios continuous 
analysis
All Randomized 
Patients
Visit 2
Visits 3 to 8 prior to initiation of IP
Weight MMRM and 
ANCOVA
All Randomized 
Patients
Last of Visits 1-2
Visits 3–8
AND
Last of Visits 3-8
26-Week Treatment Period (including Safety Follow-Up Visit where applicable)
HbA1c MMRM and 
ANCOVA 
All Randomized 
Patients with a 
baseline and at least 
1 post-baseline 
observation while on 
IP
Last of Visits 7-8
Visits 11, 13, 15, and 18 prior to 
discontinuation of IP
AND
Last of Visits 9-18 prior to 
discontinuation of IP
HbA1c categorical 
analyses longitudinal 
logistic regression and 
LOCF logistic 
regression
All Randomized 
Patients with a 
baseline and at least 
one post-baseline 
observation while on 
IP
Last of Visits 7-8
Visits 11, 13, 15, and 18 prior to 
discontinuation of IP
AND
Last of Visits 9-18 prior to 
discontinuation of IP
1-hr and 2-hr PPG and 
other MMTT variables
All Randomized 
Patients with a post-
baseline observation
while on IP
Visit 8 prior to 
initiation of IP
Visit 18 prior to discontinuation of 
IP
10-point SMBG, basal, 
prandial insulin doses, 
prandial/total insulin 
dose ratios
All Randomized 
Patients with a 
baseline and at least 
one post-baseline 
observation 
Visit 8 prior to 
initiation of IP
Visits , 15, and 18 prior to 
discontinuation of IP
AND 
Last of Visits 9-18 prior to 
discontinuation of IP
Baseline and Post-Baseline Definitions and Patient Population by Study Period and Type of Analysis
Study Period/Analysis
Patient Population
Baseline Observations
Post-Baseline Observations
1,5-AG
All Randomized 
Patients with a 
baseline and at least 
one post-baseline 
observation
Visit 8 prior to 
initiation of IP
Visits 11, 15, and 18 prior to 
discontinuation of IP 
AND 
Last of Visits 9-18 prior to 
discontinuation of IP


I 8 B-F H -I TS E St ati sti c al A n al y si s Pl a n V er si o n 2
P a g e 1 5
L Y 9 0 0 0 0 1 4
Healt h o utc o me s:  
I T S Q, E Q - 5 D- 5 L, E Q -
V A S , W P AI -G H
All Ra n d o mize d 
Patie nts wit h a 
baseli ne a n d a p ost -
baseli ne o bser vati o n
Last of Visits 1 - 8
Last of Visits 9 - 1 8 pri or t o 
disc o nti n uati o n of I P
Safet y La b orat or y Tests 
(c he mistr y, 
he mat ol o g y, li pi ds) –
c o nti n u o us a na l ysis
All Patie nts i n t he 
Safet y P o p ulati o n 
wit h a baseli ne a n d a 
p ost -baseli ne 
o bser vati o n
Last of Visit 1 - 8
Visit 1 8 ( pla n ne d)
A N D 
last of Visits 9-1 8 ( pla n ne d 
i ncl u di n g earl y disc o nti n uati o n
visits ) re gar dless of I P use
Safet y La b orat or y Tests 
(c he mistr y, 
he mat ol o g y, li pi ds) –
cate g orical a na l ysis
All Patie nts i n t he 
Safet y P o p ulati o n 
wit h a n or mal 
baseli ne ( wit h 
res pect t o t he 
directi o n bei n g 
a nal yze d) a n d a p ost -
baseli ne o bser vati o n
Visits 1 -8 (i ncl u di n g 
u n pla n ne d tests)
Visits 9 -1 8 (i ncl u di n g u n pla n ne d 
tests) re gar dless of I P use
T E A Es
All Patie nts i n t he 
Safet y P o p ulati o n
Pri o r t o first d ose of 
ra n d o mize d I P ( or Visit 
8 date if t he d ose date 
is missi n g) b ut after t he 
first d ose of o pe n-la bel 
i ns uli n lis pr o i n t he 
Lea d -i n Peri o d
Fr o m first d ose of ra n d o mize d I P t o 
last d ose of ra n d o mize d I P
A N D
Fr o m first d ose of ra n d o mize d I P t o 
Visit 8 0 1 
H y p o gl yce mia e ve nts
Safet y P o p ulati o n
All V isits 2- 8
All Visits 9 -1 8 pri or t o 
disc o nti n uati o n of I P
Wei g ht a n d vital si g ns
All Patie nts i n t he 
Safet y P o p ulati o n 
wit h a baseli ne a n d a 
p ost -baseli ne 
o bser vati o n
Last of Visits 2 - 8
Visits 9 -1 8 pri or t o disc o nti n uati o n 
of I P
A N D
Visits 9 - 8 0 1 re gar dless of I P use
A nti- i ns uli n lis pr o 
a nti b o dies 
Safet y P o p ulati o n
Visit 2
Visits 3 - 8 0 1 re gar dless of I P use
A b bre viati o ns: 1, 5 -A G = 1, 5 -A n h y dr o gl ucit ol ; A N C O V A = a nal ysis of c o varia nce; E Q - 5 D-5 L = E ur o pea n Q ualit y 
of Life – 5 Di me nsi o ns 5 Le vel; E Q -V A S = E ur o Q ol vis ual a nal o g ue scale; H b A 1c = h e m o gl o bi n A 1c ; 
I P = i n vesti gati o nal pr o d uct; I T S Q = I ns uli n Treat me nt Satisfacti o n Q uesti o n naire ; I T T = i nte nti o n-t o-treat; 
L O C F – last-o bser vati o n -carrie d f or war d; M M T T = mi xe d meal t olera nce test ; M M R M = mi xe d -effect m o del 
re peate d meas ures; P P G = p ost pra n dial gl uc ose; S M B G = self-m o nit o re d bl o o d gl uc ose ; T E A E = treat me nt-
e mer ge nt a d verse e ve nt; W P AI -G H = W or k Pr o d ucti vit y a n d Acti vit y I m pair me nt Ge neral Healt h .
6. 2.
A dj u st m e nt s f or C o v ari at e s
Stratificat i on fact ors of t his st u d y incl u de c o u ntr y (C hi na vs. Ot her ), H b A 1c strat u m at baseli ne
(≤8. 5 % vs. > 8. 5 % ), t ype of basal i ns uli n d uri n g t he lea d -i n peri o d (gl ar gi ne U-1 0 0 vs. de gl u dec 
U- 1 0 0 ), a n d n u m ber of pra n dial d oses at st u d y  e ntr y (< 3 vs. ≥3 ).


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For the primary analysis of HbA1c, the stratification factor of HbA1c stratum (baseline) will not 
be included.  Instead, the continuous value of baseline (Visit 8) HbA1c will be included in the 
analysis models. 
Other efficacy analyses and safety analysis will include the stratification factors as noted in 
Sections 6.11 and 6.12.
6.3.
Handling of Dropouts or Missing Data
The analyses for the primary and multiplicity adjusted objectives will be performed with 
MMRM analysis including all data collected prior to permanent discontinuation of IP through 
Week 26. 
Missing data will be addressed by using a mixed-effect model repeated measures (MMRM) 
analysis for continuous longitudinal variables.  The MMRM model provides consistent estimator 
when data is missing at random. The model implicitly adjusts for missing data through a 
variance-covariance structure.  An ANCOVA model will also be used to analyze continuous
variables. Unless otherwise stated, missing endpoints will be imputed using the last-observation 
carried forward (LOCF) approach, using only postbaseline data, in the ANCOVA model.
6.4.
Multicenter Studies
I8B-FH-ITSE is a multi-country, multi-site study. Site will not be analysed as a fixed effect in
any of the models so pooling strategies will not be required.
China level reports of selected enrollment, baseline, efficacy and safety data may also be
produced, as applicable. 
Summary results for Argentina and Mexico may produced per country specific regulatory 
requirement.
6.5.
Multiple Comparisons/Multiplicity
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 
multiplicity adjusted objectives given in Section 4. See Section 6.11.2 for the details of 
graphical testing scheme.
No multiplicity test adjustment will be made for other objectives.
6.6.
Patient Disposition
Frequency counts and percentages of all randomized patients completing and discontinuing from 
the study will be presented for each treatment group. Reasons for discontinuation from the study 
and study treatment during the 26-week treatment period will be compared between treatment 
groups using Fisher’s exact test.  Reasons for discontinuation from the study at Visit 801 will be 
summarized by the randomized treatment groups. 
Frequency counts and percentages of all patients entered, enrolled, and discontinued from the 
study during the lead-in period will be summarized. Reasons for discontinuation during 


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screening will be summarized for all entered patients. Reasons for discontinuation from the 
study during the lead-in period will be summarized for all enrolled patients.
Time to all-cause discontinuation (discontinuation for any reason) from the study and from study 
treatment will be compared between treatment groups for the 26-week Treatment Period.  The 
Kaplan-Meier product limit method will be used to create survival curves and the log-rank test 
will be used for the treatment comparisons. Time to all-cause discontinuation is defined as the 
total number of days between the randomization date (Visit 8 date) and date of discontinuation 
plus 1.  Patients who complete the treatment period will be treated as censored using the total 
number of days between the randomization date and the Visit 18 date plus 1.  If sufficient 
numbers of patients discontinue the study because of AE, similar analysis will be performed for 
time to discontinuation due to AE. 
A listing of the primary reason for treatment discontinuation (if applicable) and study 
discontinuation will be generated for the Enrolled Population. 
Patient allocation by investigator, grouped by country, will be summarized indicating the number 
of patients who enter the study, the number of patients who participate in the lead-in period, the 
number of patients who are randomized to study treatment, and the number of patients who 
discontinue the study during the 26-Week treatment period.
A listing of the randomization treatment assignment will be generated for all randomized 
patients. 
A listing with all the entered subjects indicating entered, enrolled, randomized, safety, completer
of treatment, completer of study, per protocol will be provided. 
6.7.
Patient Characteristics
A summary table will be generated for patient characteristics at study entry using all randomized 
patients. The following variables will be included but not limited to: age, age groups (<40 and 
≥40 years, and <65 and ≥65 years), sex, country, race, height, weight, body mass index (BMI), 
BMI groups (<25, ≥25 to <30, ≥30 to <35, and ≥35 kg/m2). For continuous variables, the 
following statistics will be provided: mean, SD, minimum, maximum, and median, and 
treatment groups will be compared using an analysis of variance (ANOVA) model with a term of 
treatment. For categorical variables, summary statistics will include sample size, frequency and 
percentage, and treatment groups will be compared using Fisher’s exact test or Pearson’s chi-
square test. A listing of patient characteristics at study entry will be provided.
A similar summary of diabetes characteristics will also be generated. The following variables 
will be included but not limited to: duration of diabetes, the type of prandial insulin at study 
entry, the type of basal insulin therapy at study entry (including whether given once daily [QD]
or twice-daily [BID]) and randomization, the type of pre-mix insulin at study entry, number of 
prandial injections at study entry (<3, ≥3), oral antihyperglycemic medication (OAM) use at 
study entry and randomization, prandial insulin dosing plan, HbA1c at study entry and baseline, 
HbA1c stratum (based on measurement at baseline), and fasting serum glucose at Visit 2 and 
baseline (based on mixed-meal tolerance test [MMTT]). 


I 8 B-F H -I TS E St ati sti c al A n al y si s Pl a n V er si o n 2
P a g e 1 8
L Y 9 0 0 0 0 1 4
A listi n g of patie nts w h ose stratificati on fact or val ue e ntere d i nt o t he I WR S (f or treat me nt gr o u p 
assi g n me nt) is differe nt fr o m t he cli nical data base will als o be pr o vi de d.
F or all ra n d o mize d pat ient s, t he n u m ber a n d perce nta ge of patie nts wit h hist orical c o n dit i ons will 
be s u m marize d b y treat me nt gr o u p usi n g Me dical Di ct i onar y  f or Re g ulat or y Act i vities 
(Me d D R A ) P T ( wit h o ut re gar d t o S O C), a n d t he n u m ber a n d perce nta ge of patie nts wit h 
pree xist i n g c o n diti ons will als o be s u m marize d b y treat me nt gr o u p usi n g Me d D R A P T ( wit h o ut 
re gar d t o S O C).  Hist orical c o n diti ons are c o n di tio ns t hat e n d pri or t o i nf or m c o nse nt a n d 
pree xist i n g c o n diti ons are c o n di tio ns t hat are still o n g o i n g at i nf or m c o nse nt.  E ve nts will be 
or dere d b y  decreasi n g fre q ue nc y. N o stati stical c o m paris o ns bet wee n treat me nt gr o u ps will be 
perf or m e d.
6. 8.
Tr e at m e nt C o m pli a n c e
N o a nal ysis f or treat me nt c o m pli a n c e is pla n ne d f or t his st u d y.
6. 9.
I m p ort a nt Pr ot o c ol D e vi ati o n s
Pr ot oc ol  de viati ons will be i de nt ifie d t hr o u g h o ut t he st u d y. I m p orta nt pr ot oc ol de viati ons are
defi ne d as t h ose de viat i ons fr om t he pr ot oc ol li kel y t o ha ve a si g nifica nt i m pact o n t he
c o mplete ness, acc urac y , a n d/ or relia bilit y of t he st u d y data or t hat ma y si g nifica ntl y affect a
s u bject’s ri g hts, safet y, or well-bei n g.
 
T he list i n g of i m p orta nt pr ot oc ol de viati ons f or all r a n d o mize d patie nts d uri n g t he e ntire st u d y, 
wi t h t he i n dicati on of w het her t o be e xcl u de d fr o m t he P P p o p ulat i on, will als o be pr o vi de d .  
 
  
6. 1 0. C o n c o m it a nt a n d Pri or T h er a p y
C o nc o mita nt me dicat i on will be s u m marize d a n d c o mpare d bet wee n treat me nt gr o u ps usi n g 
Fis her’s e xact test f or t he Ra n d omize d P o p ulat i on d uri n g t he treat me nt peri o d . T he perce nta ges 
of  pati e nts recei vi n g eac h c o nc o mita nt me dicati o n will be s u m marize d b y  tr e at me nt usi n g P T
neste d wit hi n A nat o mical T hera pe ut ic C he mical ( A T C) Le vel 3 c o de .  Me dicati o ns will be 
or dere d b y  decreasi n g fre q ue nc y wit hi n A T C le vel.  C o nc o mita nt me dicati o n use d d uri n g t he 
lea d-i n peri o d will als o be s u m marize d f or t he E nr olle d P o p ulati on.
A s u m mar y  of pre vio us dia betes t hera pi es t hat were disc o nti n ue d pri or t o i nf or me d c o nse nt will 
be ge nerate d f or t he E nr olle d P o p ulat i on . 
T otal dail y  basal a n d t otal dail y  pra n dial  ins uli n d oses f or t he da y  prior t o Vi sit 2 will be e ntere d 
i nto t he e C R F.  T he dail y basal d oses a n d i n di vi d ual pra n dial i ns uli n d oses (t hat is, mor ni n g 
meal, mi d da y meal, e ve ni n g meal, be dt i me/s nac k/ ot her) will be e ntere d i nt o e C R F after Visit 2. 
At  a gi ve n visit, t ot al dail y basal i ns uli n d ose t o be use d f or a nal ysis will be calc ulate d as t he 
C CI
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mean of the total daily basal insulin doses on the 3 days prior to the visit date (or the days 
between the previous visit date and the current visit date if the number of days between the 2
visit dates is <3). Similarly, the dose for each meal will be calculated as the mean of the doses 
on the 3 days prior to the visit date (or the days between the previous visit date and the current 
visit date, whichever smaller).  Total daily prandial insulin dose to be used for analysis will be 
calculated as the sum of the individual meal insulin doses.  If either total daily basal insulin dose 
or total daily prandial insulin dose is missing, total daily insulin dose and prandial/total insulin 
dose ratio will be set as missing for analysis.
Total daily basal insulin dose, total daily prandial insulin dose, total insulin dose, and the ratio of 
prandial insulin dose to total insulin dose during the lead-in period will be summarized by visit
for the Randomized Population. The actual and change from Visit 2 values will be compared 
between treatment groups using an MMRM model including the corresponding dose at Visit 2,
treatment, strata (country, type of basal insulin during the lead-in period, the number of prandial 
doses at study entry and HbA1c stratum at baseline), visit, treatment-by-visit interaction in the 
model as fixed factors and patient as a random factor. The actual and change from Visit 2 at Visit 
8 (LOCF) will be compared using ANCOVA model including the corresponding dose at Visit 2, 
treatment, strata (country, type of basal insulin during the lead-in period, the number of prandial 
doses at study entry and HbA1c stratum at baseline). Doses will be summarized in U and U/kg.  
Basal insulin dose will be summarized independently for glargine and degludec as well as 
combined. 
Up to 3 OAMs (metformin, dipeptidyl peptidase-4 inhibitor [DPP-4] inhibitor, sodium-glucose 
co-transporter 2 [SGLT2] inhibitor, sulfonylurea, meglitinide and alpha-glucoside inhibitor) are 
allowed prior to the study, and up to 2 OAMs (metformin and SGLT2 inhibitor) are allowed 
during the lead-in and treatment periods. The proportion of patients who were treated with 
OAMs (by class of OAM) at each visit will be summarized and compared between treatment 
groups using Fisher’s exact test. The number of OAMs per patient will also be summarized by 
treatment and by period: lead-in period (Visit 2 to Visit 8) and treatment period (Visit 8 to 
Visit 18).
6.11. Efficacy Analyses
6.11.1. Primary Outcome and Methodology
The primary objective of this study (H1) is to test the hypothesis that LY900014 is noninferior to 
insulin lispro on glycemic control (NIM=0.4% for HbA1c) in patients with T2D, when 
administered as prandial insulin (0 to 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 
including data collected from all randomized patients prior to permanent discontinuation of IP 
through Week 26.  The model for the analysis of the primary efficacy endpoint of change from 


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baseline in HbA1c will include the fixed class effects of treatment, strata (country, type of basal 
insulin during the lead-in period, and number of prandial doses at study entry), visit, and 
treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline value. An 
unstructured covariance structure will be used to model the within-patient errors. Significance 
tests will be based on LS means and Type III tests. 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

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. 
For both primary analysis approaches, LY900014 will be declared noninferior to insulin lispro 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%. 
6.11.2. Analyses of Multiplicity Adjusted Objectives
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 the following multiplicity adjusted objectives: superiority of LY900014 
compared with insulin lispro for (H2) 1-hour postprandial plasma glucose (PPG) excursion at the 
study primary endpoint, (H3) 2-hour PPG excursion at the study primary endpoint, and (H4) 
change from baseline to the study primary endpoint in HbA1c.
The graphical testing scheme for this study is displayed in Figure 6.1. All the hypotheses are 
connected by lines with arrowheads indicating the directions of testing paths. The initial 
allocation of study total alpha for each hypothesis is located within the same node of the 
hypothesis. In this study, the study total alpha level (0.05) will be all used for the primary 
objective (H1) in the initial step. Then, the study total alpha level (0.05) will be allocated to 
other objectives according to the values of transition weights shown above the connecting lines 
in the figure once H1 is met. If 1 of the remaining objectives is successfully demonstrated with 
the given alpha level, its alpha will be allocated to the rest of objectives by the transition weights 
in the paths. The iterative test procedure continues until none of the remaining objectives can be 
demonstrated with their preserved alphas or all objectives are demonstrated successful.
An ANCOVA model with strata (country, type of basal insulin during the lead-in period, number 
of prandial doses at study entry, and HbA1c stratum) and treatment as fixed effects and baseline 
as a covariate will be used to analyze the 1-hour and 2-hour PPG excursions for all the 


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randomized subjects with data collected prior to discontinuation of IP. 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.
The superiority testing on change from baseline to the study primary endpoint in HbA1c will be 
assessed by the same analysis used for the primary objective. The analyses are described in 
Section 6.11.1. If the p-value is less than the alpha level allocated by the graphical approach, the 
superiority of LY900014 to insulin lispro will be achieved.
Figure 6.1.
Testing scheme for primary and multiplicity adjusted objectives.
6.11.3. Additional Analyses of the Primary Outcome
The primary MMRM analysis model will be repeated using the PP and Completer populations as 
a sensitivity analysis. If the conclusion differs from that of all randomized patients, the data and 
analyses will be further investigated.
A secondary analysis model for the change from baseline to study primary endpoint in HbA1c 
will be an ANCOVA with strata (country, type of basal insulin during the lead-in period, and 
number of prandial doses at study entry) and treatment as fixed effects and baseline as a 
covariate. Missing endpoints will be imputed using the LOCF approach using post-baseline data 
only.
6.11.4. Sensitivity Analyses for Missing Data
No sensitivity analysis for missing data will be executed.
6.11.5. Other Secondary Efficacy Analyses
The analyses described in Section 6.11.5 to Section 6.11.6 will include data collected from all 
randomized patients prior to permanent discontinuation of IP.  The longitudinal observations of 
actual and change from baseline in HbA1c up to Week 26 will be analyzed using the same 
MMRM model as for the analysis of the primary outcome. For the following secondary efficacy 
endpoints, an MMRM model similar to that for the primary outcome with an additional term of 
HbA1c stratum (≤8.5%, >8.5%) will be used:


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
actual and change from baseline 1,5-AG values

actual and change from baseline 10-point SMBG values (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)

actual and change from baseline in total, basal, and prandial insulin doses and 
prandial/total insulin dose ratios
Three 10-point SMBG profiles are expected to be collected during the 2 weeks prior to specified 
visits.  Valid SMBG profiles will be used for analysis, defined as having non-missing values at 
≥6 time points among the 10 pre-specified time points and being collected during 2 weeks prior 
to a given visit.  For each time point, the average of the corresponding SMBG values from the 
valid SMBG profiles will be used for analysis. The excursion of SMBG for each meal category 
(that is, morning meal, midday meal, and evening meal) calculated using the average values at 
the corresponding time points will be used for analysis.
The following endpoints, collected from the MMTT, will be analyzed using the ANCOVA 
model with strata (country, type of basal insulin during the lead-in period, number of prandial 
doses at study entry, and HbA1c stratum) and treatment as fixed effects and baseline as a 
covariate:

actual and change from baseline in fasting glucose (average of measurements at 
time -15 and 0), and PPG at 15, 30, 60, 120, 180, and 240 minutes after the meal 

PPG excursions at time 15, 30, 180, and 240 minutes after the meal (PPG minus 
fasting glucose)
Sensitivity analysis for PPG excursions may be performed to exclude patients whose PPG 
excursion could be affected by factors including MMTT consumption amount (for example, 
partial MMTT was consumed) and correction bolus insulin usage.  A summary of the MMTT 
consumption and bolus insulin dose at baseline and Week 26 will be provided.
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 with terms for treatment and baseline HbA1c value.
6.11.6. Analyses of Exploratory Objectives
For the Insulin Treatment Satisfaction Questionnaire (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 with strata (country, type of basal insulin during lead-in 


I 8 B-F H -I TS E St ati sti c al A n al y si s Pl a n V er si o n 2
P a g e 2 3
L Y 9 0 0 0 0 1 4
p eri o d , n u m ber of pra n dial d oses at st u d y e ntr y, a n d H b A 1c strat u m), a n d treat me nt as fi xe d 
effects a n d baseli ne as a c o variate.
S u m mar y  statistics, i ncl u di n g n u m ber of patient s a n d pr o p orti o n of cate g orical o utc o mes 
( 5 levels) f or t he 5 di me nsi o ns ( m o bilit y, self -care, us ual acti vity,  pai n/ disc o mf ort, a n d 
a n xiet y/ de pressi o n ) of t he E ur o pea n Q ualit y of  Life – 5 Di me nsi o ns 5 Le vel (E Q - 5 D- 5 L) will b e 
pr o vi de d b y visit a n d b y  tr e at me nt. T he c ha n ge fr o m baseli ne t o L O C F e n d p oi nt ( Wee k 2 6, 
Vi sit 1 8) i n t he E Q-5 D- 5 L U nite d Ki n g d o m (U K ) p o p ul at i on- base d healt h state i n de x sc ore a n d 
E ur o Q ol  vis ual a nal o g scale (E Q -V A S ) sc ore will be a nal yze d usi n g t he A N CO V A m o d el  
 
 
F or t he W o r k Pr o d ucti vity a n d Act i vity I m pair me nt Q uesti o n naire Ge neral Healt h (W P AI -G H ), 
t he c ha n ge fr o m baseli ne t o L O C F e n d p o i nt in eac h sc ore (a bse nteeis m, prese nteeis m, w or k 
pr o d ucti vit y l oss, a n d acti vity i m pair me nt) will be a nal yze d usi n g t he A N C O V A m o del si milar 
t o I T S Q.
Wit hi n -d a y  a n d bet wee n-da y gl yce mic varia bilit y meas ure d b y t he S D a n d t he c oefficie nt of 
variat i on ( C V) of 1 0 -p oi nt S M B G pr ofiles will als o be a nal yze d b y M M R M m o del s pecifie d i n 
Secti o n 6. 1 1. 5 .  At a gi ve n visit, t he C V a n d S D o n eac h da y with a vali d S M B G pr ofile will be 
calc ulate d usi n g all t he gl uc ose val ues wit hi n t hat da y, t he n t he a vera ge val ues of t hese C Vs a n d 
S Ds will be use d as t he wi t hi n-da y C V a n d S D at t hat visit i n a nal ysis.  At a gi ve n visit, t he C V 
a n d S D at eac h of t he 1 0 pre-s pecifie d S M B G ti me p oi nts will be calc ulate d usi n g t he 
c orres p o n di n g gl uc ose val ues o f t he vali d S M B G pr ofiles, t he n t he a vera ge val ues o f t hese C Vs 
a n d S Ds will be use d as t he bet wee n- d a y  C V a n d S D at t hat visit i n a nal ysis.  Ta ble 6. 3 lists 
a d ditio nal  v aria bles f or p ote ntial e x plor at or y  a nalyses.
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Table 6.3
Additional Exploratory Efficacy Variables
Variable Description
Derivation
Statistical Method
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 the meal in MMTT.
iAUC+:  the total area under the serum glucose 
curve but above the glucose level at time 0 when 
the meal starts for the MMTT within the specific 
time frame.  The area will be calculated by 
trapezoids rule. 
ANCOVA
Area under/above 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 the meal in MMTT.

AUC: Total area under the serum glucose 
curve calculated by trapezoids area within 
the specific time frame

AUC>180: Total area under the serum 
glucose curve but above the 180 mg/dL 
level within the specific time frame

AOC≤70: Total area above the serum 
glucose curve but below the 70 mg/dL 
level within the specific time frame.
ANCOVA
Glucose variability during MMTT

The CV of all serum glucose values 
collected during the MMTT

The SD of all serum glucose values 
collected during the MMTT.
ANCOVA
1-hour and 2-hour PPG excursions
by 10-point SMBG profile and 
daily average of the 10-point 
SMBG profile

The difference in means between 1-hour 
PPG and fasting PG at the same visit

The difference in means between 2-hour 
PPG and fasting PG at the same visit.

The average of daily mean of the 10-point 
SMBG profile at the same visit
MMRM
Incidence of HbA1c ≤6.5% and 
<7.0% without severe 
hypoglycemia

Binary indicator with 1 indicating HbA1c 
≤6.5% at Week 26 and no severe 
hypoglycemia during 0-26 weeks of 
treatment

Binary indicator with 1 indicating HbA1c 
<7% at Week 26 and no severe 
hypoglycemia during 0-26 weeks of 
treatment.
Logistic regression
Abbreviations: ANCOVA = analysis of covariance; AOC = area over the curve; AUC =  area under the curve; 
CV = coefficient of variation; iAUC = incremental area under the curve; HbA1c = hemoglobin A1c;
MMTT = mixed-meal tolerance test; MMRM = mixed-effect model repeated measures; PPG = postprandial 
glucose; SD = standard deviation; SMBG = self-monitored blood glucose.
6.12. Safety Analyses
Safety measures will include AEs, hypoglycemia, vital signs and weight, treatment exposure, 
laboratory measures, and antibodies to insulin lispro. Refer to Table 6.1 and Table 6.2 for the 
analysis population and the baseline definition used in the analysis of a safety measurement for a 
specific study period.


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6.12.1. Extent of Exposure
Duration of exposure to study drug will be summarized. The following summary statistics will 
be provided: n, mean, SD, median, minimum, maximum, and sum (that is, total patient-years of 
exposure). The number and proportion of patients falling into the following different exposure 
categories will also be summarized: <1 month (>0 and <30 days), ≥1 and <3 months (≥30 and 
<90 days), ≥3 and <6 months (≥90 days and <180 days) and ≥6 months (≥180 days). 
Patients who complete the study treatment period are required to complete a safety follow-up 
visit without study drug; and patients who discontinue the IP prematurely are encouraged to 
remain in the study without study drug. The days on study after discontinuing IP, and the days 
on study from date of first study drug to the last study visit date up to Visit 801 will also be 
summarized.
6.12.2. Adverse Events
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 including the follow-
up visit, regardless of IP use.
Events that are newly reported after the first dose of prandial insulin provided as study drug (that 
is, open-label insulin lispro used during the lead-in period or IP used during the treatment period)
or reported to worsen in severity from baseline (defined in Table 6.2 for a specific study period)
will be considered TEAEs.  The 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. For events occurring on the day of first dose of bolus insulin 
provided by this study, the case report form (CRF)-collected flag will be used to determine
whether the event started or worsened post-treatment. 
In an overview table, the number and percentage of patients who experienced a TEAE, 
experienced serious adverse event (SAE), died due to an AE, discontinued from study due to an
AE, discontinued IP due to an AE or TEAE related to study treatment will be summarized by 
treatment group .
The number and percentage of patients with TEAEs will be summarized by treatment using 
MedDRA PT nested within SOC. Events will be ordered by decreasing frequency within SOC.
As an additional table, the percentages of patients with TEAEs will be summarized by treatment 
using MedDRA PT (without regard to SOC). Events will be ordered by decreasing frequency.
Statistical comparisons will be applied at both the SOC and PT levels. Fisher’s exact test will be 
performed for treatment comparison.
The number and percentage of patients with TEAEs by maximum severity will be summarized
by treatment using MedDRA PT nested within SOC and data collected prior to permanent 
discontinuation of IP. For each patient and TEAE, the maximum severity for the MedDRA PT is 
the maximum postbaseline severity observed from all associated LLTs mapping to the MedDRA 
PT. No statistical comparison between treatment groups will be conducted.


I8B-FH-ITSE Statistical Analysis Plan Version 2
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LY9000014
The number and percentage of patients with common TEAEs (defined as ≥5% before rounding 
for LY900014-treated patients) will be summarized by treatment group using MedDRA PT 
(without regard to SOC). Events will be ordered by decreasing frequency. Treatment will be 
compared by Fisher’s exact test.
The number and percentage of patients who experienced an SAE including deaths and SAEs 
temporally associated or preceding deaths will be summarized by treatment group using 
MedDRA PT regardless of SOC. Events will be ordered by decreasing frequency. A listing of 
all SAEs will also be provided.
The number and percentage of patients who discontinued from study due to an AE will be 
summarized by treatment group using MedDRA (without regard to SOC) using all data 
regardless of IP use.  The number and percentage of patients who discontinued IP due to an AE 
will be also summarized by treatment group using MedDRA PT (without regard to SOC) using 
data prior to permanent discontinuation of IP.  Events will be ordered by decreasing frequency.  
A listing of all AEs as reason for study or IP discontinuation will also be provided.
The number and percentage of patients who experienced other notable TEAEs (potential 
systemic hypersensitivity reaction, injection site reaction, and hepatic disorder) will be 
summarized by treatment group using all TEAEs regardless of IP use.  For events that are 
gender-specific (as defined by MedDRA), the denominator and computation of the percentage 
will include only patients from the given gender.
Table 6.4 summarizes the planned analyses and the requirement of analysis data for different 
analysis periods. A ‘Yes’ in the IP USE column indicates that only data collected prior to 
permanent discontinuation of IP will be included. 
Table 6.4.
Treatment-Emergent Adverse Event Analysis Periods
Analysis Period
Analysis 
Population
Analysis
IP USE
Treatment
Lead-in Period
All enrolled 
patients
AE overview; TEAE by PT; 
SAE, discontinuation due to 
AE
N/A
Open-label insulin 
lispro
Treatment Period 
(0-26 Weeks)
All patients in 
safety population
AE overview; TEAE by 
SOC and by PT; common 
TEAE; TEAEs by maximum 
severity; SAE; IP 
discontinuation due to AE
Yes
LY900014, 
insulin lispro
Week 0 –
Visit 801
All patients in 
safety population
AE overview; TEAE by 
SOC; common TEAE; SAE; 
other notable AEs; study 
discontinuation due to AE
All data 
regardless of 
IP use
LY900014, 
insulin lispro
Abbreviations:  AE = adverse event; IP = investigational product; N/A = not applicable/available; PT = Preferred 
Term; SAE = serious adverse event; SOC = system organ class; TEAE = treatment-emergent adverse event.


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LY9000014
6.12.3. Deaths
The listing of all deaths by patient for all enrolled patients will be provided as part of the SAE 
listing, regardless of the investigator’s or the sponsor’s judgment about causality. Each listing 
will include study ID, investigator ID, patient ID, treatment group, baseline age, sex, associated 
AE, first and last dose date for open label insulin lispro and randomized IP, and the event date.
6.12.4. Hypoglycemic Events and Other Adverse Events
The analysis plans for the following AEs are discussed in Section 6.12.4.1 through 
Section 6.12.4.4:

hypoglycemic events

systemic hypersensitivity reaction

injection site reaction

hepatobiliary events
All these AE analyses will be similar to the TEAE analyses, refer to Table 6.4 for the 
requirement of analysis data for a specific analysis period. 
6.12.4.1. Hypoglycemic Events
Hypoglycemia events that occur during the study outside the MMTT will be captured using an 
paper diary starting from Visit 2 through Visit 801. Whenever hypoglycemia is suspected, the 
patient should record the blood glucose value, any associated symptoms, and the treatment 
administered in paper diary. A set of events is counted as 1 event in analysis if it consists of an 
originating event and subsequent continuing events as marked by the patient in paper diary, or 
the duration between adjacent events is ≤30 minutes.  The event with the highest severity will be 
selected for analysis with severity determined in the order of: 1) it is a severe hypoglycemia, 2) 
it has symptoms of hypoglycemia reported, and 3) it has the lowest blood glucose value.  If there 
are multiple events tied in all 3 aspects, the event with the largest number of non-missing 
responses to the questions of nocturnal hypoglycemia and postmeal time frame will be selected.  
If there are still multiple events tied, the latest event (based on data entry time) will be selected.
The following types of hypoglycemia events will be derived in the analysis data sets: 
documented hypoglycemia, severe hypoglycemia and nocturnal hypoglycemia. Only severe 
hypoglycemia will be collected as AEs and all episodes of severe hypoglycemia will be 
considered as SAEs.  Documented hypoglycemia (including documented symptomatic 
hypoglycemia, documented asymptomatic hypoglycemia and documented unspecified 
hypoglycemia) will be based on blood glucose (BG) ≤70 mg/dL.  In addition, documented 
clinically significant hypoglycemia with similar criterion as above documented hypoglycemia 
except for the threshold of BG <54 mg/dL will be summarized.
Table 6.5 provides detailed statistical methods for each endpoint related to hypoglycemia.  For 
these analyses, hypoglycemia events prior to the discontinuation of IP will be summarized.  
Additional analyses for other types of hypoglycemic events not mentioned in the table and for 
the post-treatment period may be conducted as needed.


I 8 B-F H -I TS E St ati sti c al A n al y si s Pl a n V er si o n 2
P a g e 2 8
L Y 9 0 0 0 0 1 4
T he i nci de nce a n d n u m ber of e pis o des of h y p o gl yce mia d uri n g t he M M T T will be s u m marize d 
b y treat me nt a n d ti me relati ve t o t he meal ( ≤0. 5, ≤1, ≤2, ≤4, > 1 t o ≤2 a n d > 2 t o ≤4 h o urs after 
start of t he me al) a n d a nal yze d b y Fis her’s e xact test.
A listi n g of patie nts wit h at least 1 se vere h y p o gl yce mia re p orte d (as S A E) after ra n d o mizati on 
will be pr o vi de d. S u m mar y of se vere h y p o gl yce mia treat me nt a n d o ut c o me fr o m t he patie nt 
di ar y will be pr ovi de d.
A list of Me d D R A P Ts will be use d f or t he narr o w searc h of p ote ntial se vere h y p o gl yce mia i n 
s p o nta ne o usl y re p orte d A Es. T he e ve nts i de ntifie d t hr o u g h t he searc h strate g y  t hat are als o 
re p orte d as S A Es will be s u m marize d a n d c o m pare d bet wee n treat ment s. Fi s her’s e xact test will 
be use d t o assess t he treat me nt differe nce i n t he pr o p orti o n of patie nts wit h p ote ntial se vere 
h y p o gl yce mia.
T a bl e 6 . 5.
S u m m ar y of A n al y s e s f or E n d p oi nt s R el at e d t o H y p o gl y c e mi a
E n d p o i n t
A n a l y s i s  P e r i o d
S t a t i s t i c a l  M e t h o d
E n d p o i n t
A n a l y s i s  P e r i o d
S t a t i s t i c a l  M e t h o d
Rate of h y p o gl yce mic e ve nts ( per 
patie nt per 3 0 da ys / year)

All D oc u me nte d a

N oct ur nal a

D oc u me nte d S y m pt o matic a

N o n -N oct ur nal ( D oc u me nte d
an d occ urre d bet wee n wa ki n g 
a n d be dti me)a
0 - 1 2, 0-2 6, 1 2 - 2 6 wee ks
Ne gati ve bi n o mial re gressi o n wit h 
treat me nt a n d l o g (e x p os ure/ 3 0 da ys ) or 
l o g (e x p os ure/3 6 5. 2 5 da ys) as t he offset
i n t he m o del.
I nci de nce of h y p o gl yce mic e ve nts

All D oc u me nte d a

N oct ur nal a

D oc u me nte d S y m pt o matic a

N o n -N oct ur nal ( D oc u me nte d
an d occ urre d bet wee n wa ki n g 
a n d be dti me)a
0 - 1 2, 0-2 6, 1 2 - 2 6 wee ks
L o gi stic re gressi o n wit h treat me nt as a n 
i n de pe n de nt varia ble.
Rate of p ost meal h y p o gl yce mic e ve nts 
( per patie nt per 3 0 da ys / year) f or all 
3 mai n meals 

D oc u me nte d S y m pt o matic a
≤0. 5, ≤1, ≤2, ≤4, > 1 t o ≤2 
a n d > 2 t o ≤4 h o urs after 
start of a meal wit hi n 
0 -1 2, 1 2 - 2 6, 0- 2 6 wee ks
Ne gati ve bi n o mial re gressi o n wit h 
treat me nt a n d l o g (e x p os ure/ 3 0 da ys) or 
l o g (e x p os ure/3 6 5. 2 5 da ys) as t he offset
i n t he m o del.
I nci de nce of p ost meal h y p o gl y ce mic 
e ve nts f or all 3 mai n meals

D oc u me nte d S y m pt o matic a
≤0. 5, ≤1, ≤2, ≤4, > 1 t o ≤2 
a n d > 2 t o ≤4 h o urs after 
start of a meal wit hi n 
0- 1 2, 1 2 - 2 6, 0-2 6 wee ks
L o gi stic re gressi o n wit h treat me nt as a n 
i n de pe n de nt varia ble.
S u m m ar y of A n al yses f or E n d p oi nts Rel ate d t o H y p o gl yce mi a
E n d p o i n t
A n a l y s i s  P e r i o d
S t a t i s t i c a l  M e t h o d
E n d p o i n t
A n a l y s i s  P e r i o d
S t a t i s t i c a l  M e t h o d
Rat e of se vere h y p o gl yce mic e ve nts 
( per patie nt per year / 1 0 0 years)
0 - 1 2, 0-2 6, 1 2 - 2 6 wee ks
E x p os u re a dj uste d rate per year / 1 0 0 
years (calc ulate d b y t otal n u m ber of
e ve nts di vi de d b y t otal e x p os ure f or
i n di vi d ual patie nts) will be pr o vi de d a n d
t he e m pirical met h o d (see A p pe n di x 1 f or 
details) will be use d f or treat me nt
c o m paris o n.


I 8 B-F H -I TS E St ati sti c al A n al y si s Pl a n V er si o n 2
P a g e 2 9
L Y 9 0 0 0 0 1 4
E n d p o i n t
A n a l y s i s  P e r i o d
S t a t i s t i c a l  M e t h o d
E n d p o i n t
A n a l y s i s  P e r i o d
S t a t i s t i c a l  M e t h o d
Inci de nce of se vere h y p o gl yce mic 
e ve nts
0 - 1 2, 0-2 6, 1 2 - 2 6 wee ks
Pr o p orti o n of patie nts wit h se vere 
h y p o gl yce mia will be re p orte d. T he
treat me nt c o m paris o n will be base d o n a
l o gistic re gressi o n m o del wit h treat me nt
as an i n de pe n de nt varia ble.
a
All d oc u me nte d h y p o gl yce mia a n d t he s u bcate g ories base d o n t he t hres h ol ds of bl o o d gl uc ose ≤7 0 m g/ d L a n d 
bl o o d gl uc ose < 5 4 m g/ d L will be a nal yze d , e xce pt f or p ost meal h y p o gl yce mia f or w hic h o nl y t he t hres h ol d of 
≤7 0 m g/ d L will be a p plie d . 
6. 1 2. 4. 2. S y st e mi c H y p er s e n siti vit y R e a c ti o n
T he n u m ber a n d pr o p orti o n of pat ient s e x perie nci n g treat me nt -e mer ge nt p ote ntial s yste mic 
h y perse nsit i vity react i ons will be s u m marize d a n d c o m pare d b y treat me nt gr o u p usi n g Fis her ’s
e xact test. T he f o ll owi n g Me d D R A S M Q will be use d t o i de ntif y p ote ntial s yste mic 
h y perse nsit i vity react i ons fr om all T E A Es:

A na p h ylactic reacti o n ( S M Q). Besi des usi n g t he narr o w a n d br oa d ter ms 
desi g nate d wit hi n t he S M Q, t he f oll owi n g searc h al g orit h m will als o be 
i m ple me nte d as a n ot her a p pr oac h t o deter mi ne if a patie nt ha d a n a na p h ylact ic 
reactio n:   if a patient  ( ha d at least 1 e ve nt i n Cate g or y A) or ( ha d at least 1 e ve nt 
t hat is i n cate g or y B a n d als o ha d at least 1 e ve nt t hat is i n cate g or y C) or ( ha d at 
least 1 e ve nt t hat is i n cate g or y D a n d [als o ha d at least 1 e ve nt  i n cate g or y B or at 
least 1 e ve nt i n cate g or y C])

A n gi oe de ma ( S M Q)

H y perse nsi tivi t y ( S M Q)
S pecificall y , nee d t o perf or m t h e fol l owi n g: ( 1) a n y narr o w or al g orit h mic ter m fr o m a n y 1 of
t he 3 S M Qs i n dicate d a b o ve (t hat is, c o m bi ne d searc h acr oss narr o w a n d al g orit h mic p orti o ns of
all 3 S M Qs); ( 2) a n y narr o w sc o pe ter m wit hi n eac h S M Q, se paratel y (t hat is, narr o w S M Q
searc h); ( 3) a n y t er m wit hi n eac h S M Q, se paratel y (t hat is, br oa d S M Q searc h); ( 4) narr o w sc o pe
t er m searc h wit hi n eac h S M Q, re p ort t he P T neste d wit hi n eac h S M Q.
A si milar s u m mar y will be pr o vi de d f or t he T E A E relate d t o st u d y  dr u g ju d ge d b y i n vest i gat or.
N ote t hat a n i n di vi d ual pat ient  ma y c o ntri b ute multi ple e ve nts. A ls o, a si n gle e ve nt ma y satisf y
m ult i ple S M Qs, i n w hic h case t he e ve nt co ntri b utes t o e ver y  a p plica ble S M Q.
6. 1 2. 4. 3. Inj e cti o n S it e R e a cti o n
T he i nject i on site react i ons will be searc he d b y Me d D R A P Ts fr om all T E A Es. T he n u m ber a n d 
perce nta ge of patie nts e x perie nci n g treat me nt -e mer ge nt i nject i on site react i on will be
s u m marize d a n d c o m pare d b y treat me nt gr o u p usi n g Fis her’s e xact test.
F or i nject i on site reacti o ns i de nt ifie d b y Me d D R A P Ts, t he prese nce a n d se verity of  er yt he ma, 
i n d urati o n, pai n , pr uri t us a n d e de ma (c ollecte d o n t he e C R F) will be s u m marize d f or eac h 
treat me nt. T here will be n o statistical c o m par is o n bet wee n treat me nts. 


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6.12.4.4. Hepatobiliary Events
6.12.4.4.1.
Treatment-Emergent Potential Hepatic Disorder
The percentages of patients with treatment-emergent drug-related hepatic disorder events will be 
summarized and compared by treatment group using MedDRA PT nested within each SMQ
ordered by decreasing frequency. The following SMQs based on MedDRA will be used to
identify potential hepatic disorders:

broad and narrow terms in the Liver related investigations, signs and symptoms 
SMQ (20000008)

broad and narrow terms in the Cholestasis and jaundice of hepatic origin SMQ 
(20000009)

broad and narrow terms in the Hepatitis non-infections SMQ (20000010)

broad and narrow terms in the Hepatic failure, fibrosis and cirrhosis and other
liver damage SMQ (20000013)

narrow terms in the Liver-related coagulation and bleeding disturbances SMQ
(20000015)
The percentage of patients with any 1 of the terms will be summarized in addition to the 
percentages for each MedDRA PT. The percentages of patients with potentially drug-related
hepatic disorders that led to permanent study treatment discontinuation will be summarized
similarly.
6.12.4.4.2.
Liver Enzyme Lab Values
The liver enzyme measures (alanine aminotransferase [ALT], aspartate aminotransferase [AST], 
alkaline phosphatase [ALP], direct bilirubin, total bilirubin) will be summarized by treatment
group. Post-baseline value and the change from baseline (last nonmissing value before 
randomization) to post-baseline value at Week 26 visit (planned test) will be summarized for 
patients who have both a baseline and at least 1 postbaseline result, and compared between 
treatment groups by using ANCOVA model with the term of treatment and baseline value of the 
response variable. All analyses will be provided in SI units.
The last nonmissing observation at or prior to Week 26 (including early discontinuation visits) 
will also be analyzed by an ANCOVA model with the term of treatment, baseline value of 
response variable. 
6.12.4.4.3.
Treatment-Emergent Elevation of Liver Enzyme Lab Values
The percentages of patients with the following elevations in hepatic laboratory tests at any time 
during the treatment period (0 to 26 weeks) will be summarized between treatment groups:

The percentages of patients with post-baseline ALT measurement ≥3 times (3X), 
5 times (5X), and 10 times (10X) the Covance upper limit of normal (ULN) will 
be summarized for all patients with a post-baseline value by the following 
baseline categories: ≤1X, >1X to <3X, ≥3X, missing.


I 8 B-F H -I TS E St ati sti c al A n al y si s Pl a n V er si o n 2
P a g e 3 1
L Y 9 0 0 0 0 1 4

T he perce nta ges of pat ient s wit h p ost -baseli ne A S T meas ure me nt greater t ha n or 
e q ual t o 3 X, 5 X, a n d 1 0 X t he C o va nce U L N will be s u m marize d f or all pat ient s 
wi t h a p ost-baseli ne val ue b y t he f o ll owi n g baseli ne cate g ories:
≤1 X, > 1 X t o 
< 3 X, ≥3 X , missi n g.

T he perce nta ges of pat ient s wit h p ost-baseli ne t otal bilir u bi n meas ure me nt
≥2 ti mes ( 2 X) t he C o va nce U L N will be s u m marize d f or all patient s wit h a p ost-
baseli ne val ue b y t he f o ll owi n g baseli ne cate g ories:
≤1 X, > 1 X t o < 2 X, ≥2 X, 
missi n g.
Baseli ne will be t he ma xi m u m o bser vat i on i n t he baseli ne peri o d i ncl u di n g t he lea d-i n p eri o d. 
T he m a xi m u m val ue will b e t h e ma xi m u m val ue fr o m t he treat me nt peri o d. Pl a n ne d a n d 
u n pla n ne d t ests will be i ncl u de d.
G ra p hical pr ofiles of A L T, A S T, t otal bilir u bi n, a n d A L P will be pr o vi de d f or patie nts wit h a n 
A L T or A S T ≥3 X U L N or t otal bilir u bi n ≥2 X U L N d uri n g t he treat me nt peri o d. A list i n g f or 
t hese patie nts will als o be pr o vi de d, i ncl u di n g t he act ual meas ure me nt of A L T, A S T, A L P, a n d 
t otal bilir u bi n, t he c orres p o n di n g refere nce hi g h li mits, de m o gra p hics, di s p ositio n, dr u g e x p os ure 
a n d A Es. T he re vie w f or t hese patie nts i ncl u des a n assess me nt of t he pr o xi mit y of a n y  A L T or 
A S T el e vat i on t o a n y  t ot al bilir u bi n ele vati on, A L P l e vels, ot her p ote ntial ca uses, a n d t he 
t e mp or al  ass ociatio n wi t h e ve nts s uc h as na usea, v o mit i n g, a n ore xia, a b d o mi nal pai n, or fat i g ue.
All p atie nt data, re gar dless of w het her o n I P, will be use d f or t he a b o ve a nal yses relate d t o 
he pat o biliar y  e v e nts.
6. 1 2. 5. Cli ni c al L a b or at or y E v al u ati o n
T he data fr o m safet y la b orat or y meas ures w ill be s u m marize d at Wee k 2 6 w here t he la b test is 
pl a n ne d t o be c ollecte d. P ost baseli ne a n d c ha n ge fr o m baseli ne t o p ost baseli ne f or la b orat or y  
tests will be s u m marize d f or patie nts w h o ha ve b ot h baseli ne a n d at least 1 p ost -baseli ne res ult 
a n d c o m pare d bet wee n treat me nt gr o u ps b y  usi n g A N C O V A m o del wit h t he ter m o f treat me nt 
a n d baseli ne val ue of t he res p o nse varia ble. A nal y ses will be pr o vi de d i n SI u nits.
T he l ast n o n missi n g o bser vati o n at or pri or t o Wee k 2 6 ( pla n ne d tests i ncl u di n g earl y 
ter mi nati o n) will als o be a nal yze d b y a n A N C O V A mo d el  wit h t he ter m of treat me nt, baseli ne 
val ue of t he res p o nse varia ble. 
T he perce nta ges of pat ient s wit h treat me nt -e mer ge nt a b n or mal, hi g h, or lo w l a b orat or y res ults at 
a n y ti me d ur i n g t he treat me nt peri o d ( 0 t o 2 6 wee ks) will be s u m marize d f or patie nts w h o ha ve 
b ot h baseli ne a n d at least 1 p ost- baseli ne res ult a n d c o m pare d bet wee n treat me nt gr o u ps usi n g 
Fis her’s e xact tests. A treat me nt -e mer ge nt a b n or mal res ult is defi ne d as a c ha n ge fr o m n or mal at 
all baseli ne vis its t o a b n or mal at a n y time d uri n g t he treat me nt peri o d. A treat me nt -e mer ge nt 
hi g h res ult is defi ne d as a c ha n ge fr o m a val ue less t ha n or e q ual t o t he hi g h li mit at all baseli ne 
visit s t o a val ue greater t ha n t he hi g h li mit at a n y time d uri n g t he treat me nt  perio d. A treat me nt -
e mer ge nt lo w res ul t is defi ne d as a c ha n ge fr o m a val ue greater t ha n or e q ual t o t he l o w li mit at 
all baseli ne visits t o a val ue less t ha n t he l o w li mit at a n y  ti me d uri n g t he treat me nt peri o d. 
Pl a n ne d a n d u n pla n ne d meas ure me nts will be i ncl u de d. 
 
C CI


I 8 B-F H -I TS E St ati sti c al A n al y si s Pl a n V er si o n 2
P a g e 3 2
L Y 9 0 0 0 0 1 4
be use d t o defi ne t he l o w a n d hi g h li mit s. O nl y patie nts w h o ha ve n or mal baseli ne val ues f or t he 
a nal ysis bei n g perf or me d will be i ncl u de d i n t he a nal ysis f or treat me nt -e mer ge nce.  
Li ver e nz y mes me as ures will n ot be i ncl u de d i n t he a b o ve a nal yses as differe nt a nal yses will be 
use d as descri be d i n Sect i on 6. 1 2. 4. 4. 2 a n d Secti o n 6. 1 2. 4. 4. 3 .
6. 1 2. 6. Vit al Si g n s a n d Ot h er P h y si c al Fi n di n g s
P os t-baseli ne meas ure me nts a n d c ha n ge fr o m baseli ne t o p o st-baseli ne f or vital si g ns a n d 
p h ysica l c haracteristics (s yst olic bl o o d press ure [ S B P], diast olic bl o o d press ure [ D B P], p ulse
rate, wei g ht, B MI) at t he sc he d ule d visits will be s u m marize d f or patie nts w h o ha ve b ot h
baseli ne a n d at least 1 p ost -baseli ne res ult. 
T he m eas ure me nts d uri n g t he trea t me nt perio d ( 0 t o 2 6 wee ks) will be a nal yze d b y a n M M R M 
m o d el  wi t h tr e at me nt, baseli ne val ue of t he res p o nse varia ble, visit, a n d visit b y  tr e at me nt 
i nteract i on as fi xe d fact ors a n d patie nt as t he ra n d o m fact or.
T he w ei g ht meas ure me nt d uri n g t he lea d -i n p eri o d will als o be a nal yze d b y  a n M M R M mo d el  
wi t h Visi t 2 val ue of t he re sp o nse varia ble , ra n d o mize d treat me nt, visit a n d tr e at me nt - b y-visit 
i nteract i on as fi xe d fact ors , a n d patie nt as t he ra n d o m fact or .  T he a nal ysis will be c o n d ucte d o n 
all ra n d o mize d pat ient s.
A n A N C O V A m o del will als o be use d f or t he a nal ysis o f t he last n o n missi n g o bser vat i on 
(incl u di n g earl y disc o nti n uati on visit ) d uri n g t he treat me nt peri o d a n d d uri n g t he e nt ire st u d y ( u p 
t o Visit 8 0 1). T he A N C O V A m o dels are t he sa me as t h ose use d f or cli nical la b orat or y meas ures. 
T he perce nta ges of pat ient s wit h treat me nt -e mer ge nt hig h or l o w vi t al si g ns a n d wei g ht at  a n y 
ti me d uri n g t he treat me nt peri o d ( 0 t o 2 6 wee ks) or d uri n g t he e nt ire st u d y incl u di n g safety 
f oll ow- u p peri o d will b e s u m marize d b y tr e at me nt gr o u p f or patie nts w h o ha ve b ot h baseli ne a n d 
at least 1 p ost baseli ne meas ure me nt. A treat me nt -e mer ge nt hig h res ul t is defi ne d as a c ha n ge 
fr om a valu e l ess t ha n or e q ual t o t he hi g h li mit at all baseli ne visits t o a val ue greater t ha n t he 
hi g h li mit at a n y  ti me t hat meets t he s pecifie d c ha n ge criteria d uri n g t he treat me nt peri o d or 
d uri n g t he e nt ire st u d y incl u di n g safet y  fol l ow- u p p eri o d. A treat me nt -e mer ge nt l o w res ult is 
defi ne d as a c ha n ge fr o m a val ue greater t ha n or e q ual t o t he l o w li mit at all baseli ne visi ts t o a 
val ue less t ha n t he l o w li mit at a n y  time t hat m eets t he s pecifie d c ha n ge criteria d uri n g t he 
treat me nt perio d or d uri n g t he e nt ire st u d y incl u di n g safety f oll ow- u p peri o d. Tr eat me nt 
c o mparis o n will  be base d o n Fis her’s e xact test .  Ta ble 6. 6 will be use d t o defi ne t he l o w a n d 
hi g h li mits a n d c ha n ge t hres h o l ds. 
T a bl e 6 . 6.
C at e g ori c al Crit eri a f or A b n or m al Tr e at m e nt -E m er g e nt Bl o o d 
Pr e s s ur e a n d P ul s e M e a s ur e m e nt, a n d C at e g ori c al Crit eri a f or
W ei g ht f or A d ult s
P a r a m e t e r
L o w
H i g h
P a r a m e t e r
L o w
H i g h
S yst olic B P ( m m H g)
(f ore ar m at he art le vel)
≤9 0 a n d decrease fr o m baseli ne ≥2 0 
≥1 4 0 a n d i ncrease fr o m baseli ne 
≥2 0
Di ast olic B P ( m m H g)
≤6 0 a n d decrease fr o m baseli ne ≥1 0 
≥9 0 a n d i ncrease fr o m baseli ne ≥1 0


I 8 B-F H -I TS E St ati sti c al A n al y si s Pl a n V er si o n 2
P a g e 3 3
L Y 9 0 0 0 0 1 4
(f ore ar m at he art le vel)
P ulse ( b p m)
( S u pi ne or sitti n g)
< 6 0 a n d decrease fr o m baseli ne ≥1 5
> 1 0 0 a n d i ncrease fr o m baseli ne 
≥1 5
Wei g ht ( k g)
( C o nsiste nt cl ot hi n g a n d
ti mi n g i n rel ati o ns hi p t o
me als a n d v oi di n g)
( L oss) decrease ≥7 %
( Gai n) i ncrease ≥7 %
A b bre viati o ns: B P = bl o o d press ure.
6. 1 2. 7. I m m u n o g e ni cit y
Bl o o d sa m pl es f or i m m u n o ge nicit y testi n g will be c ollecte d t o deter mi ne a nti b o d y pr o d uctio n 
a gai nst i ns uli n lis pr o f or all e nr olle d pat ient s si nce Visit 2 pri or t o t he first d ose of st u d y -
pr o vi de d pra n dial i ns uli n treat me nt. T heref ore, t he bl o o d sa m ple res ult at Visit 2 will be 
c o nsi dere d as t he a nt i-i ns uli n lis pr o le vel at baseli ne f or t his st u d y.
P ati e nts w h o c o mplete t he 4 -wee k safet y f oll ow- u p visit ( V isit 8 0 1) a n d ha ve treat me nt-
e mer ge nt a nti-i ns uli n lis pr o a nti b o dies t hat ha ve n ot ret ur ne d t o pres pecifie d baseli ne ra n ge 
( Visit 2) will be as ke d t o partici pate i n f oll o w -u p t o m o ni t or a nti b o d y le vels. T he assess me nt of 
i m m u n o ge nicity will  incl u de a nal ys es o f treat me nt -e mer ge nt a nti-i ns uli n lis pr o a nti b o d y u p t o 
Vi sit 8 0 1.
6. 1 2. 7. 1. Tr e at m e nt E m er g e nt A nti -I n s uli n Li s pr o A nti b o d y
T he treat me nt -e mer ge nt a nti-i ns uli n lis pr o a nti b o d y (de n ote d as treat me nt -e mer ge nt a ntidr u g 
a nt i b o d y [T E A D A] t hr o u g h o ut t his S A P) is base d o n t he c ha n ge fr o m baseli ne ( Visit 2) t o p ost -
baseli ne ( p ost -Visit 2) i n t he a nt i-i ns uli n lis pr o a nti b o d y le vel (perce nt bi n di n g ). T reat me nt -
e mer ge nt a ntidr u g a nt i b o d y ca n be s u b- classifie d as eit her treat me nt -i n d uce d ( n ot detecte d a nti-
i ns uli n lis pr o a nti b o d y at baseli ne) or treat me nt -b o oste d ( detecte d a nti -i ns uli n a nti b o d y at 
baseli ne):
T he T E A D A stat us d uri n g t he a nal ysis peri o d will be deter mi ne d usi n g all  data i n t he 
c orres p o n di n g a nal ysis peri o d re gar dless of I P use.  T he s u m mar y  for T E A D A stat us a n d t he 
a nt i-i ns uli n lis pr o a nti b o d y le vel will use t he sa me a nal ysis data.
T he n u m ber a n d perce nta ge of patie nts wit h p osit i ve T E A D A res p o nse d uri n g t he a nal ysis 
p eri o d of Visi t 2 t o Visit 8 0 1 will be s u m marize d b y tr e at me nt gr o u p. F or patie nts wit h p ositi ve 
T E A D A res p o nse a n y t i me d uri n g t he a nal ysis peri o d, t he n u m ber a n d perce nta ge of patient s 
wi t h p ositi ve i ns uli n cr oss-reacti vity a n ytime d uri n g t he a nal ysis peri o d, a n d t he n u m ber a n d 
perce nta ge of patie nts n ot meet i n g t he T E A D A criteria at Visit 8 0 1 will als o be s u m marize d b y 
treat me nt gr o u p. Treat me nt gr o u ps will be c o m par e d b y Fis her’s e xact test.
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Both actual and change from baseline (Visit 2) for the anti-insulin lispro antibody level in 
percent binding will be summarized by scheduled visit prespecified in the protocol for patients 
with positive TEADA response from Visit 2 to Visit 801. The repeated measurement from 
Visit 2 to Visit 801 will be analyzed by an MMRM model with treatment, baseline value of the 
response variable, visit, and visit by treatment interaction as fixed factors and patient as the 
random factor. The ANCOVA model using treatment and baseline value as covariates will be 
used for the analysis of last non-missing observation prior to or at Visit 801 and the analysis of 
maximum percent binding during the analysis period of Visit 2 to Visit 801. Plot of anti-insulin 
lispro antibody percent binding will be generated based on the MMRM and the ANCOVA 
models.
A listing of anti-insulin lispro antibody at each visit will be provided. The listing will include 
anti-insulin lispro antibody status (detected/not detected), anti-insulin lispro antibody percent 
binding, TEADA status (positive/negative), insulin cross-reactivity status, and insulin cross-
reactivity percent binding for the safety population.
Subgroup analysis for the following selected efficacy and safety variables will be performed by 
the TEADA status during the analysis period of Visit 2 to Visit 801:

Use data prior to discontinuation of IP:
o
HbA1c and change from baseline in HbA1c
o
1-hour and 2-hour PPG excursions
o
basal, prandial, and total insulin dose
o
event rate of overall hypoglycemic events

Use all data regardless of IP use:
o
treatment-emergent injection site reaction and hypersensitivity reaction 
The analyses for HbA1c and change from baseline in HbA1c will be performed using an 
MMRM model for the primary analysis and the HbA1c data prior to permanent discontinuation 
of IP. Besides treatment, the model will include additional fixed terms of subgroup, subgroup by 
treatment interaction, subgroup by visit interaction, and 3-way interaction of treatment, subgroup 
and visit. 
The PPG excursions will be analyzed by the ANCOVA model same as the model specified in 
Section 6.11.2 with data collected before permanent discontinuation of IP. The model will 
include additional terms of subgroup, subgroup by treatment interaction, subgroup by visit 
interaction, and 3-way interaction of treatment, subgroup and visit.
The subgroup analysis for insulin dose will use the MMRM model specified in Section 6.11.5
using data collected before permanent discontinuation of IP. The model will include additional 


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fixed terms of subgroup, subgroup by treatment interaction, subgroup by visit interaction, and 3-
way interaction of treatment, subgroup and visit.
The treatment-emergent injection site reaction and hypersensitivity reaction will be analyzed by 
a logistic regression model including terms of treatment, subgroup, treatment by subgroup 
interaction. All data regardless of IP use will be used for this analysis.
The negative binomial regression model specified in Table 6.5 with additional terms of 
subgroup, treatment by subgroup interaction will be used for the subgroup analysis of overall 
hypoglycemia event rate while on IP.
The interaction effects (3-way for MMRM and 2-way for ANCOVA/logistic regression 
model/negative binomial regression model) will be evaluated using a significance level of 0.10, 
unadjusted. If the interaction effect is significant (p<0.10), separate analysis without the terms 
related with the subgroup will be performed for each subpopulation.
6.12.8. Patient Narratives
Patient narratives will be provided for all patients in the study who experience any of the
following “notable” events prior to data cutoff for the submission:

deaths

serious adverse events

discontinuations from study (or study drug) due to AEs

pregnancy
A list of patients who meet the criteria for narratives will be provided.
6.13. Subgroup Analyses
6.13.1. Subgroup Analyses for HbA1c
The following subgroups will be analyzed for HbA1c if there are sufficient numbers of patients 
per group (for example, at least 10% in each group):

age (<65 versus ≥65 years and <75 vs. ≥75 years and <65, ≥65 to <75, ≥75 to 
<85, ≥85 years)

baseline hemoglobin A1c stratum (≤8.5% vs. >8.5%)

sex (male vs. female)

body mass index (<25 vs. ≥25, and <30 vs. ≥30 kg/m2 and <35 vs. ≥35 kg/m2)

duration of diabetes (using the median as the cut-off)

race

country

region


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
baseline 1-hour PPG excursion (≤ baseline median, > baseline median)

baseline 1-hour PPG (PPG ≤180 mg/dl, >180 mg/dl)

baseline 2-hour PPG excursion (≤ baseline median, > baseline median)

baseline 2-hour PPG (PPG ≤180 mg/dl, >180 mg/dl)

type of basal insulin during the lead-in period (glargine vs. degludec)

prandial insulin dosing plan (carbohydrate counting or pattern adjustment)

number of prandial doses at study entry (<3 vs. ≥3)

sodium-glucose co-transporter 2 inhibitor treatment
Analyses for HbA1c and change from baseline in HbA1c will be performed using an MMRM 
model that includes the same fixed effects given for the primary analysis model plus factors of 
subgroup, 2-way interaction of subgroup and treatment, 2-way interaction of subgroup and visit, 
and 3-way interaction of treatment, visit and subgroup. The interaction of subgroup and 
treatment at the primary endpoint will be evaluated to assess the treatment by subgroup 
interaction. When analyzing HbA1c stratum as a subgroup the baseline HbA1c will be not be 
included as a covariate to avoid confounding. The subgroup interaction effect will be evaluated 
using a significance level of 0.10, unadjusted.
Additional subgroup analyses may also be performed.
6.13.2. Subgroup Analyses for Hypoglycemic Events
For the documented symptomatic hypoglycemia based on the thresholds of blood glucose 
≤70 mg/dL, the following subgroups will be analyzed:

age (<65 vs. ≥65 years and <75 vs. ≥75 years and <65, ≥65 to <75, ≥75 to <85, 
≥85 years)

hemoglobin A1c stratum (≤8.5% vs. >8.5%)

type of basal insulin during the lead-in period (glargine U-100 vs. degludec 
U-100)

prandial insulin dosing plan (carbohydrate counting or pattern adjustment)
The event rate and incidence will be analyzed using the same model specified in Table 6.5 with 
the addition of factors for subgroup, and 2-way interaction of subgroup and treatment.  The 
2-way interaction will be used to evaluate treatment by subgroup interaction.
6.14. Interim Analyses and Data Monitoring 
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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6.15. Clinical Trial Registry Analyses
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.  
Analyses provided for the CTR requirements include the following:

Summary of AEs, provided as a dataset which will be converted to an XML file. Both 
Serious Adverse Events and ‘Other’ Non-Serious Adverse Events are summarized by 
treatment group and MedDRA PT.

An AE is considered ‘Serious’ whether or not it is a TEAE.

An AE is considered in the ‘Other’ category if it is both a TEAE and is not serious.  For 
each Serious AE and ‘Other’ AE, for each term and treatment group, the following are 
provided:
o
the number of participants at risk of an event
o
the number of participants who experienced each event term
o
the number of events experienced.
o
  

Consistent with www.ClinicalTrials.gov requirements, ‘Other’ AEs that occur in fewer 
than 5% of patients/subjects in every treatment group may be excluded if a 5% threshold 
is chosen.  Allowable thresholds include 0% (all events), 1%, 2%, 3%, 4%, and 5%.  

Adverse event reporting is consistent with other document disclosures for example, the 
CSR, manuscripts, and so forth. 


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7.
Novel Coronavirus (COVID-19) Impact
This section lists some of the potential statistical analyses may be performed at the final database 
lock due to the impact of COVID-19 pandemic, if data guarantee. 
7.1.
Patients’ Study Visits Impacted by COVID-19 
Percentage and count of randomized participants with study visits impacted by COVID-19 will 
be compared by treatment groups. These participants includes, but not limited to six kinds,
patients with any visit not performed, patients with any on-site visit changed to remote, patients 
with HbA1C missing, patients with 1,5 AG result missing, patients with MMTT result missing 
and patients with direct to patient drug supply. Listing of patients with study visits impacted by 
COVID-19 will also be provided.
For each of the six situations, a separate summary table and listing will be provided. 
7.2.
Protocol Deviation 
Percentage and count of randomized participants having protocol deviation related to COVID-19
pandemic will be summarized by treatment. No statistical comparison between treatment groups 
will be conducted.
A listing of all randomized participants having protocol deviation due to COVID-19 pandemic 
will be provided. 
A summary table and listing of all randomized participants having significant protocol deviation 
due to COVID-19 pandemic will also be provided.
7.3.
Patient Disposition
A summary table for dispositon reasons of all enrolled participants who discontinue study during
the lead-in period due to COVID-19 may be provided. For the treatment period, a summary table 
for dispositon reasons of all randomized participants who discontinue study or study treatment
due to COVID-19 may be provided. For the safety follow-up period, a summary table for 
dispositon reasons of all randomized participants in the safety follow-up period who discontinue 
study due to COVID-19 may be provided. 
7.4.
COVID-19 Infection
Percentage and count of randomized participants having COVID-19 infection, including death 
due to COVID-19 pandemic from lead-in period to safety follow-up period will be summarized 
by treatment.
A listing of randomized participants who had COVID-19 infection, including death due to 
COVID-19 infection, from lead-in period to safety follow-up period will be provided. 
7.5.
Some Mitigation Procedures  
Some mitigation procedures are conducted to reduce the impact of COVID-19 during the study, 
which include direct to patient drug supply, IP (bolus insulin) local purchase and Visit 7 and 
Visit 8 combined.


I 8 B-F H -I TS E St ati sti c al A n al y si s Pl a n V er si o n 2
P a g e 3 9
L Y 9 0 0 0 0 1 4
S u m mar y  a n d listi n g of I P lo c al  p ur c hase d ue t o t he C O VI D -1 9 pa n de mic will  be pr o vide d.
Ra n d o mize d partici pa nts wit h Visit 7 a n d Visit 8 c o m bi ne d d ue t o t he C O VI D -1 9 pa n de mic will 
be s u m marize d b y treat me nt.
7. 6.
S e n siti vit y A n al y si s f or Effi c a c y  
T he i m pact of C O VI D -1 9 o n t he efficac y of  I P o n t he patie nts ma y c o me fr om differe nt as pects 
s uc h as pr ol o n ge d treat me nt i nterr u pti o ns d ue t o C O VI D-1 9 ill ness or c o ntr ol meas ures, st u d y or
treat me nt disc o nt i n uati ons d ue t o C O VI D -1 9 ill ness or c o ntr ol meas ures, deat h d ue t o C O VI D -
1 9 a n d t he usa g e of pr ot oc ol pr o hi bit e d me dicatio ns t o treat C O VI D -1 9.
 
 
 
A se nse nti vity a nal ysis will be c o n d ucte d o n t he ra n d o mize d pat ient s wi t ho ut esse nt ial i m pact of 
C O VI D - 1 9, i.e., t he ra n d o mize d patie nts w h o ca n’t be classifie d i nt o t he a b o ve t w o gr o u ps. T he 
M M R M a n d A N C O V A m o dels as descri be d i n Secti o n 6. 1 1. 1 a n d Secti o n 6. 1 1. 3 res pecti vel y 
will be re peate d as t he mo d el s f or t he se nsiti vity a nal ysis. If t he c o nclusi o n  differs fr o m t hat of 
all ra n d o mize d pat ient s, t he data a n d a nal ysis will be furt her i n vesti gate d.
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8.
Unblinding Plan
The blinding and unblinding plan will be provided in a separate document stored in the Trial 
Master File. 


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9.
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.
Compuational Science Symposium Development of Standard Scripts and Programming Working 
Group. Analyses and Displays Associated with Measures of Central Tendency. Focus on vital 
Sign, Electrocardiogram, and Laboratory Analyte Measuremenets in Phase2-4 clinical Trials 
and Integrated Submission Documents. October 2013. Available at:  
http://www.phusewiki.org/docs/CSS%20White%20Papers%202016/CSS_WhitePaper_Central
Tendency_v1.0.pdf. Accessed March 21, 2018.
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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10. Appendices


I 8 B-F H -I TS E St ati sti c al A n al y si s Pl a n V er si o n 2
P a g e 4 3
L Y 9 0 0 0 0 1 4
A p p e n di x 1.
E m piri c al E sti m ati o n of R el ati v e E v e nt R at e
C CI


I 8 B-F H -I TS E St ati sti c al A n al y si s Pl a n V er si o n 2
P a g e 4 4
L Y 9 0 0 0 0 1 4
C CI


L e o  D o c u m e n t  I D  =  f d 5 c 6 4 a b - 6 f 2 9 - 4 2 d 1 - 9 2 4 3 - 2 5 c b 6 8 9 2 4 2 2 9
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  1 0 - M a r - 2 0 2 1  0 8 : 2 5 : 4 0  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
P P D