A Prospective, Randomized, Double-Blind Comparison of LY900014 to Humalog in Adults With Type 1 Diabetes Using Continuous Subcutaneous Insulin Infusion
Phase: PHASE3
Conditions: Type 1 Diabetes Mellitus
Sponsor: Eli Lilly and Company

Protocol I8B-MC-ITRO (c) 
 
 
A Prospective, Randomized, Double-Blind Comparison of LY900014 to Humalog in Adults with 
Type 1 Diabetes Using Continuous Subcutaneous Insulin Infusion PRONTO-Pump-2 
 
NCT03830281 
 
Approval Date: 8-Oct-2019 
 
 
 

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Protocol I8B-MC-ITRO (c)
A Prospective, Randomized, Double-Blind Comparison of 
LY900014 to Humalog in Adults with Type 1 Diabetes Using 
Continuous Subcutaneous Insulin Infusion
PRONTO-Pump-2
2015-005358-36 (EUDRA CTA)
Confidential Information
The information contained in this document is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
LY900014, unless such persons are bound by a confidentiality agreement with Eli Lilly and 
Company or its subsidiaries.  
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure. Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
LY900014
Study I8B-MC-ITRO is a Phase 3, prospective, randomized, double-blind, outpatient, 
multi-national, multi-center, 2-treatment group parallel, active-controlled study conducted in 
patients with type 1 diabetes currently using continuous subcutaneous insulin infusion.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly 17 October 2018
Amendment (b) Electronically Signed and Approved by Lilly 21 June 2019
Amendment (c) Electronically Signed and Approved by Lilly on approval date provided 
below
Approval Date: 08-Oct-2019 GMT

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Table of Contents
Section
Page
1.
Synopsis .............................................................................................................................8
2.
Schedule of Activities .......................................................................................................13
3.
Introduction ......................................................................................................................20
3.1.
Study Rationale............................................................................................................20
3.2.
Background..................................................................................................................20
3.3.
Benefit/Risk Assessment..............................................................................................20
4.
Objectives and Endpoints..................................................................................................22
5.
Study Design.....................................................................................................................25
5.1.
Overall Design .............................................................................................................25
5.2.
Number of Participants.................................................................................................26
5.3.
End of Study Definition ...............................................................................................26
5.3.1.
Safety Follow-up..................................................................................................26
5.4.
Scientific Rationale for Study Design...........................................................................27
5.5
Justification for Dose ...................................................................................................27
6.
Study Population...............................................................................................................29
6.1.
Inclusion Criteria..........................................................................................................29
6.2.
Exclusion Criteria ........................................................................................................32
6.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................34
6.3.
Lifestyle Restrictions....................................................................................................34
6.4.
Screen Failures.............................................................................................................34
7.
Treatments........................................................................................................................35
7.1.
Treatments Administered .............................................................................................35
7.1.1.
Packaging and Labelling ......................................................................................35
7.1.2.
Insulin Pumps ......................................................................................................35
7.1.2.1.
Personal Continuous Glucose Monitor Use in Study.......................................36
7.1.3.
Medical Devices...................................................................................................36
7.2.
Method of Treatment Assignment ................................................................................36
7.2.1.
Selection and Timing of Doses.............................................................................37
7.2.1.1.
Target Glucose Values for Titration of Insulin Therapy ..................................37
7.2.1.2.
Pump Settings.................................................................................................37
7.2.1.3.
Basal Rate Titration........................................................................................37
7.2.1.4.
Bolus Dose Titration.......................................................................................38
7.2.1.5.
Transitioning off Study Prandial Insulin Therapy............................................39
7.3.
Blinding .......................................................................................................................39

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7.4.
Dosage Modification....................................................................................................39
7.5.
Preparation/Handling/Storage/Accountability...............................................................39
7.6.
Treatment Compliance .................................................................................................40
7.7.
Concomitant Therapy...................................................................................................40
7.8.
Treatment after the End of the Study............................................................................41
7.8.1.
Treatment after Study Completion........................................................................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.
Use of Personal CGM or FGM .......................................................................46
9.1.4.2.
Collection of Glucose Profiles ........................................................................46
9.1.4.3.
Use of Study Provided Blood Glucose Meter..................................................47
9.1.4.4.
Infusion Set Changes......................................................................................47
9.1.4.5.
Urine Ketone Testing......................................................................................48
9.1.4.6.
Blinded Continuous Glucose Monitoring Sessions..........................................48
9.1.4.7.
Mixed Meal Tolerance Test ............................................................................49
9.1.4.8.
Diabetes Education and Nutritional Counseling ..............................................51
9.2.
Adverse Events ............................................................................................................51
9.2.1.
Serious Adverse Events........................................................................................52
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................53
9.2.2.
Complaint Handling.............................................................................................53
9.3.
Treatment of Overdose.................................................................................................54
9.4.
Safety...........................................................................................................................54
9.4.1.
Hypoglycemia......................................................................................................54
9.4.2.
Severe Hypoglycemia ..........................................................................................55
9.4.3.
Electrocardiograms ..............................................................................................55
9.4.4.
Vital Signs ...........................................................................................................56

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9.4.5.
Laboratory Tests ..................................................................................................56
9.4.6.
Safety Monitoring ................................................................................................56
9.4.6.1.
Hepatic Safety Monitoring..............................................................................56
9.5.
Pharmacokinetics .........................................................................................................56
9.6.
Pharmacodynamics ......................................................................................................56
9.7.
Pharmacogenomics ......................................................................................................57
9.8.
Immunogenicity Testing...............................................................................................57
9.9.
Health Economics ........................................................................................................57
9.9.1.
EQ-5D-5L............................................................................................................57
9.9.2.
Insulin Treatment Satisfaction Questionnaire .......................................................58
10.
Statistical Considerations ..................................................................................................59
10.1. Sample Size Determination ..........................................................................................59
10.2. Populations for Analyses..............................................................................................60
10.3. Statistical Analyses ......................................................................................................60
10.3.1.
General Statistical Considerations ........................................................................60
10.3.2.
Treatment Group Comparability...........................................................................62
10.3.2.1.
Patient Disposition..........................................................................................62
10.3.2.2.
Patient Characteristics ....................................................................................62
10.3.2.3.
Concomitant Therapy .....................................................................................62
10.3.3.
Efficacy Analyses ................................................................................................62
10.3.3.1.
Primary Analyses ...........................................................................................62
10.3.3.1.1.
Sensitivity Analyses for Missing Data.......................................................63
10.3.3.2.
Secondary Analyses........................................................................................64
10.3.3.3.
Tertiary/Exploratory Analyses ........................................................................64
10.3.4.
Safety Analyses....................................................................................................65
10.3.5.
Other Analyses.....................................................................................................66
10.3.5.1.
Health Economics...........................................................................................66
10.3.5.2.
Subgroup Analyses.........................................................................................66
10.3.6.
Interim Analyses..................................................................................................67
11.
References ........................................................................................................................68
12.
Appendices .......................................................................................................................69

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List of Tables
Table
Page
Table ITRO.1.
Schedule of Activities....................................................................................13
Table ITRO.2.
Objectives and Endpoints...............................................................................22
Table ITRO.3.
Treatment Regimens......................................................................................35
Table ITRO.4.
Target Glucose Values for Titration of Insulin Therapy .................................37
Table ITRO.5.
Collection Schedule for Glucose Profiles.......................................................47

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List of Figures
Figure
Page
Figure ITRO.1.
Illustration of study design for Clinical Protocol I8B-MC-ITRO....................26

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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................70
Appendix 2.
Clinical Laboratory Tests...............................................................................74
Appendix 3.
Study Governance Considerations..................................................................75
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................79
Appendix 5.
Classification of Contraceptive Methods........................................................80
Appendix 6.
Protocol Amendment I8B-MC-ITRO (c) Summary
A Prospective, Randomized, Double-Blind Comparison of LY900014 
to Humalog in Adults with Type 1 Diabetes Using Continuous 
Subcutaneous Insulin Infusion
PRONTO-Pump-2 .........................................................................................81

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1.
Synopsis
Title of Study:
A Prospective, Randomized, Double-Blind Comparison of LY900014 to Humalog in Adults with Type 1 Diabetes 
Using Continuous Subcutaneous Insulin Infusion:  PRONTO-Pump-2.
Rationale: 
Rapid-acting insulins have been shown to have a more rapid onset of action compared with human insulin; however, 
the 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 pharmacodynamic (PD) 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 would be useful in the treatment of type 1 diabetes (T1D) and type 2 diabetes (T2D) when 
delivered by multiple daily injections (MDIs), 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 
Humalog on glycemic control as measured by change from baseline to Week 16 in HbA1c in patients with T1D 
using CSII when bolus doses are delivered in a double-blind manner immediately prior to each meal via an insulin 
pump.  
Objective(s)/Endpoints:
Objectives
Endpoints
Primary Objective
1.
To test the hypothesis that LY900014 is 
noninferior to Humalog on glycemic 
control ([NIM = 0.4% for HbA1c) in 
patients with T1D using CSII for 16 weeks
1.
Difference between LY900014 and Humalog in 
change from baseline to Week 16 in HbA1c
Multiplicity Adjusted Objectives
2.
To test the hypothesis that LY900014 is 
superior to Humalog in controlling 1-hour 
postprandial glucose (PPG) 
2.
Difference between LY900014 and Humalog in 
the 1-hour PPG (serum glucose measured 1 
hour after the start of the meal) from a MMTT 
at Week 16
3.
To test the hypothesis that LY900014 is 
superior to Humalog in controlling 2-hour 
PPG 
3.
Difference between LY900014 and Humalog in 
the 2-hour PPG (serum glucose measured 2 
hours after the start of the meal) from a MMTT 
at Week 16
4.
To test the hypothesis that LY900014 is 
superior to Humalog on improving glycemic 
control (HbA1c) 
4.
Difference between LY900014 and Humalog in 
change from baseline to Week 16 in HbA1c

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5.
To test the hypothesis that LY900014 is 
superior to Humalog in the duration of time 
glucose values within target range 70 to 
180 mg/dL (3.9 to 10.0 mmol/L), obtained 
from CGM use during 24-hour period
5.
Duration (in minutes and percentage of time)
with glucose values between 70 and 180 mg/dL 
(3.9 and 10.0 mmol/L), both inclusive, 
normalized to a 24-hour period, from each 
14-day CGM session at Week 16
6.
To test the hypothesis that LY900014 is 
superior to Humalog in the duration of time 
glucose values within target range 70 to 
180 mg/dL (3.9 to 10.0 mmol/L), obtained 
from CGM use during daytime
6.
Duration (in minutes and percentage of time)
with glucose values between 70 and 180 mg/dL 
(3.9 and 10.0 mmol/L), both inclusive, 
normalized to daytime (0600 hours to 
midnight), from each 14-day CGM session at 
Week 16
Other Secondary Objectives
7.
To compare LY900014 and Humalog with 
respect to the rate of severe hypoglycemic 
events
7.
Rate (events/ patient/100 years) of severe 
hypoglycemic events from baseline through 
Week 16
8.
To compare LY900014 and Humalog with 
respect to the rate and incidence of 
documented postmeal hypoglycemia 
8.
Rate (events/patient/year) and incidence 
(percent of patients with at least 1 event) of 
documented postmeal hypoglycemia within 
1 and 2 hours after the start of the meal from 
baseline through Week 16
9.
To compare LY900014 and Humalog with 
respect to the rate and incidence of 
documented hypoglycemia
9.
Rate (events/patient/year) and incidence 
(percentage of patients with events) of 
documented hypoglycemic events from baseline 
through Week 16
10. To compare LY900014 and Humalog with 
respect to 1,5-AG
10. Change from baseline 1,5-AG values at 
Week 16
11. To compare LY900014 and Humalog with 
respect to 10-point SMBG profiles
11. Change from baseline 10-point SMBG values at 
Week 16
12. To compare LY900014 and Humalog with 
respect to total, basal, and bolus insulin dose
12. Change from baseline in bolus/total insulin dose 
ratio at Week 16
13. To compare LY900014 and Humalog with 
respect to the proportion of patients
achieving HbA1c targets
13. The proportion of patients with HbA1c <7% 
and ≤6.5% at Week 16
14. To compare LY900014 and Humalog with 
respect to the duration of time spent in 
hypoglycemic glucose ranges, obtained from 
CGM use
14. Duration (in minutes) and percentage of time 
with glucose values <54 and <70 mg/dL (3.0
and 3.9 mmol/L), normalized to a 24-hour 
period and number of episodes, defined as at 
least 10 consecutive minutes <54 and
<70 mg/dL, from each 14-day CGM session at 
Week 16
15. To compare LY900014 and Humalog with 
respect to the duration of time spent in 
hyperglycemic glucose ranges, obtained from 
CGM use
15. Duration (in minutes) and percentage of time 
with glucose values >180 and >250 mg/dL 
(10.0 and 13.9 mmol/L), normalized to a 
24-hour period and number of episodes, defined 
as at least 10 consecutive minutes >180 and
>250 mg/dL, from each 14-day CGM session at 
Week 16

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16. To compare LY900014 and Humalog with 
respect to the incidence and rate of pump 
occlusion alarms that lead to an unplanned 
infusion set change
16. Rate (events/patient/30 days) and incidence 
(percent of patients with at least 1 event) of 
pump occlusion alarms that lead to an 
unplanned infusion set change from baseline 
through Week 16
17. To compare LY900014 and Humalog with 
respect to the incidence and rate of 
episodes of unexplained hyperglycemia that 
lead to an unplanned infusion set change
17. Rate (events/patient/30 days) and incidence 
(percent of patients with at least 1 event of 
unexplained hyperglycemia > 300 mg/dL 
confirmed by SMBG that leads to an unplanned 
infusion set change from baseline through 
Week 16
Abbreviations:  1,5-AG = 1,5-Anhydroglucitol; AIT = active insulin time; AUC = area under the curve;
CGM = continuous glucose monitoring; CR = carbohydrate ratio; CSII = continuous subcutaneous insulin 
infusion; CV = coefficient of variation; EQ-5D-5L = EuroQol 5D-5L; EQ-VAS = EQ visual analog scale; 
HbA1c = hemoglobin A1c; HBGI = high blood glucose index; ISF = insulin sensitivity factor; ITSQ = Insulin 
Treatment Satisfaction Questionnaire; LBGI = low blood glucose index; MMTT = mixed meal tolerance test; 
NIM = noninferiority margin; SMBG = self-monitored blood glucose; T1D = type 1 diabetes; UK = United 
Kingdom.
Summary of Study Design:  
Study I8B-MC-ITRO (ITRO) is a Phase 3, prospective, randomized, outpatient, multinational, multicenter, 
2-treatment group, parallel, active-controlled, double-blind study conducted in adult patients with T1D currently 
using CSII therapy.
This study involves adult patients who have been diagnosed with T1D for at least one year, have been using CSII 
therapy without interruption for at least 6 months, and have an HbA1c value of ≥6.5% and ≤9.0% at screening.  
Patients must be using insulin lispro, insulin aspart, or insulin glulisine in their pumps.
Treatment Groups and Duration:  
The study includes a 1-week screening period and a 2-week lead-in period, followed by a 16-week treatment period, 
and a 4-week safety follow-up period.  In the 2 treatment groups, LY900014 and Humalog will be given as both 
bolus and basal insulin, bolus doses will be given immediately prior to each meal (0 to 2 minutes).  
Number of Patients:
Numbers are approximate:  526 participants will be screened to achieve 420 randomized patients and 368 patients
completing 16 weeks of treatment. 
Statistical Analysis:
The primary analysis is for the treatment period up through Week 16.  
Efficacy analyses will be conducted on all randomized patients according to the treatment the patients are assigned.  
The analyses for the primary and multiplicity adjusted objectives will be performed for the efficacy estimand 
including data collected prior to permanent discontinuation of investigational product (IP) and for the intention to 
treat (ITT) estimand including all data collected through Week 16 regardless of IP use.  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 one post-baseline measurement are available.  

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Safety analyses will be conducted on the Safety population.  Analyses of adverse events (AEs) will include 2 sets of 
analyses, unless otherwise specified.  The first set of analyses will include data collected prior to permanent 
discontinuation of IP.  The second set of analyses will include all data collected during the course of the entire study,
regardless of IP use.  Analyses of hypoglycemia will be conducted on data collected prior to permanent 
discontinuation of IP, while analyses for post-treatment may be conducted as needed.  Analyses of safety laboratory 
measurements will be performed on all data collected during the planned treatment period, regardless of IP use.  
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.  
For the US Food and Drug Administration (FDA) submission, the primary analysis method will use the copy 
reference approach to impute missing data based on multiple imputations with a pattern mixture model.  This 
analysis is for the ITT estimand (treatment regimen estimand) which will include all data collected regardless of IP 
use.  The reference for each treatment group will be from the retrieved dropout patients who discontinue IP but have 
the measurement at the primary endpoint in the same treatment group.  If there are only a limited number of patients 
in the reference group as described above that leads to a failure in performing the proposed multiple imputation 
analysis, the reference will be changed to include all observed data from all randomized patients in the same 
treatment arm who complete the study without missing data.  After imputation, the primary efficacy comparison will 
be based on the contrast between LY900014 and Humalog from the analysis of covariance (ANCOVA) analysis of 
change from baseline to Week 16 in HbA1c using all randomized patients. 
For non-FDA submissions and publications, the primary efficacy comparison will be based on the contrast between 
LY900014 and Humalog at Week 16 (Visit 13) from the mixed-effect model repeated measures (MMRM) analysis 
of change from baseline in HbA1c including data collected from all randomized patients prior to permanent 
discontinuation of IP through Week 16 (efficacy estimand).  
For both primary analysis approaches, LY900014 will be declared noninferior to Humalog if the upper limit of the 
2-sided 95% confidence interval (CI) for the least-squares mean difference in the change from baseline in HbA1c for 
LY900014 minus Humalog is below the noninferiority margin (NIM) of +0.4%.  In addition, the 95% CI for the 
treatment difference from the MMRM model will be compared with an alternative (NIM) of +0.3%.  Both estimands 
will be tested at the full significance level of 0.05.  
Hypoglycemia rates will be summarized for periods of 1 year and 100 years (severe hypoglycemia only).  The rate 
of severe hypoglycemia per 100 years will be compared between treatment groups using the empirical method.  For 
each of the other categories of hypoglycemia, the number of hypoglycemia events during a specific period (rate) 
after randomization (for example, 0- to 4 weeks of treatment period) will be analyzed by using a negative binomial 
regression model including treatment.  An offset defined as the log transformation of treatment exposure in the 
specific period (days)/365.25 days will be included in the model to estimate the rate of hypoglycemia per year.  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.  
Similarly, a negative binomial model and a logistic regression model including treatment will be used to analyze the 
rate of pump occlusion alarms leading to unplanned infusion set changes per 30 days, and the proportion of patients 
with at least 1 occlusion alarm (incidence) leading to unplanned infusion set changes, respectively.

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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 or Pearson’s chi-square test will be used to 
compare treatment groups unless otherwise specified.  
Change from baseline to last-observation-carried-forward endpoints for European Quality of Life – 5 Dimensions 5 
Level (EQ-5D-5L) and ITSQ will be analyzed using ANCOVA models.  

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Abbreviations:  AIT = active insulin time; CF = correction factor; CGM = continuous glucose monitoring; CR = carbohydrate ratio; ECG = electrocardiogram; 
eCRF = electronic case report form; ED = early discontinuation; eGFR = estimated glomerular filtration rate; EQ-5D-5L = European Quality of Life – 5 
Dimensions 5 Level; IP = investigational product; ISF = insulin sensitivity factor; ITSQ = Insulin Treatment Satisfaction Questionnaire; IWRS = interactive 
web-response system; MMTT = mixed meal tolerance test; SMBG = self-monitored blood glucose.
a
Telephone visits are indicated by shaded columns.
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 who are not already at the site will be asked to return for the 
ED in a nonfasting state and all activities should be completed except for laboratory tests and questionnaires.
c
Randomization should occur after all Visit 4 procedures including MMTT.  If MMTT is rescheduled post Visit 4, 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 Patients should be advised to remove their shoes/coats and empty their pockets before the body weight is obtained.
e
Vital sign measurements must be taken before obtaining an ECG tracing and before collection of blood samples for laboratory testing.  These measurements 
should be determined after patients have been seated quietly for at least 5 minutes in a chair with feet on the floor.  The arm used for blood pressure
measurement should be supported at heart level.  
f
Patients must be supine for approximately 5 to 10 minutes before ECG collection and remain supine but awake during ECG collection.
g Only for patients using insulin glulisine or insulin aspart.
h Low glucose suspend is referred to as “Threshold Suspend” (530G), “Low Glucose Suspend” (Paradigm Veo), or “Suspend on low” (630G and 640G).
i
Record infusion set model and cannula length if changed during the study.
j
Reservoir is filled with Humalog at lead-in (Visit 2), IP at randomization (Visit 4), and prestudy insulin at end of treatment (Visit 13).
k
During the lead-in period, basal rates and bolus settings should be evaluated and adjusted if needed.  During the treatment period, basal rates and bolus 
settings should be titrated in order to meet the target BG levels.
l
Training may be repeated at other visits, as needed. 
m Glucose profiles may be obtained from download of device software (CareLink, Dexcom, and Freestyle Libre).  Patient will be responsible for entering 
glucose values into pump for bolus calculation and to review with investigator.  Four- and 7-point profiles are needed for clinical management only.
n Patients should be instructed to perform two 7-point glucose profiles within the week prior to the 3 Visits.  The 7-point profile is completed over a 1-day 
period, preferably on 2 nonconsecutive days (weekdays and weekends).  
o Patients should be instructed to perform three 10-point SMBG profiles within the 2 weeks prior to the 3 visits.  The 10-point profile is completed over a 1-day 
period, preferably on 2 nonconsecutive days (weekdays and weekends) using the study blood glucose meter.  
p Sensors will need to be changed every 7 days during each CGM session.  One receiver will be used for all 3 sessions.  Two transmitters will be supplied; one 
for Sessions 1 and 2 and one for Session 3.  Transmitter and receiver will be stored at site between sessions.
q At Visits 4 and 13, remove sensor and transmitter following the completion of the MMTT.
r
Sites to check data acceptability reports following upload to confirm no major time gaps occurred during each data capture session.  Continuous glucose 
monitoring collection time gaps greater than 3 hours may require further investigation or re-training.
s
At Visits 4 and 6, provide an extra diary for the telephone Visits 5 and 7.

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t
Glucose monitoring supplies will be dispensed at other visits, as needed.
u Diary data should be discussed at telephone visits and transferred to the eCRF at subsequent office visits.
v
Review of 7- and 10-point SMBG profiles at the ED visit will take place only for patients randomized into the study.
w MMTT can occur 0 to 4 days prior to the visit and patient must be fasting prior to start of the MMTT.  The patient should change their infusion set the 
evening prior to the MMTT.
x Serum pregnancy test at Visit 1, urine pregnancy test at Visit 4 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.
y 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 has had at least 6 months of spontaneous amenorrhea.
z
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.

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3.
Introduction
3.1.
Study Rationale
Rapid-acting insulins have been shown to have a more rapid onset of action compared with 
human insulin; however, the 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 pharmacodynamic (PD) 
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 
would be useful in the treatment of type 1 diabetes mellitus (T1D) and type 2 diabetes mellitus 
(T2D) when delivered by multiple daily injections (MDIs), 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 Humalog on glycemic control as measured by change from baseline 
to Week 16 in HbA1c in patients with T1D using CSII when bolus doses are delivered in a 
double-blind manner immediately prior to each meal via an insulin pump.  
3.2.
Background
LY900014 is comprised of the active ingredient, insulin lispro, as well as 2 excipients 
(treprostinil and citrate) that facilitate rapid absorption of insulin lispro into the blood stream.  
This novel formulation results in earlier glucose lowering when compared with Humalog.  This 
faster glucose lowering response, as demonstrated by the PK and PD profiles of LY900014 when 
compared with Humalog, more closely mimics the time–action profile of normal endogenous 
insulin secretion.  This enhanced activity is expected to provide greater glycemic control as 
dosing relative to the start of a meal can be reduced when compared with the timing required for 
the currently available rapid-acting insulin analogs. Dosing closer to the start of a meal will 
allow patients to better match the needed insulin dose to the carbohydrate content of their meal.  
3.3.
Benefit/Risk Assessment
In Phase 1 clinical studies, the assessment of AEs, hypoglycemic events, local tolerability, vital 
signs, physical examination, electrocardiogram (ECG), anti-insulin lispro antibodies, and clinical 
laboratory assessments did not reveal any specific risks of LY900014 beyond those already 
known for Humalog. LY900014 has been well tolerated in both healthy subjects and patients 
with diabetes mellitus. Notably, there have been no clinically significant increases in adverse 
events (AEs) associated with systemic absorption of treprostinil (headache, diarrhea, nausea, jaw 
pain, vasodilatation, rash, edema, and hypotension are described in the Remodulin prescribing 
information, 2014). Plasma treprostinil concentrations were all below the lower limit of 
quantitation after subcutaneous (SC) administration of LY900014.  

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Because insulin pump therapy uses only rapid-acting insulin, the onset of diabetic ketoacidosis 
(DKA) can occur quickly if insulin delivery is interrupted.  Diabetic ketoacidosis develops when 
insulin levels are insufficient to meet the body’s basic metabolic requirements.  Diabetic 
ketoacidosis is an acute metabolic complication of diabetes characterized by hyperglycemia, 
hyperketonemia, and metabolic acidosis.  Signs and symptoms may include vomiting, abdominal 
pain, deep gasping breathing, increased urination, weakness, confusion, and occasionally loss of 
consciousness.  There has been one report of DKA in completed studies of LY900014. A high 
blood glucose (BG) that is not responding to a correction bolus via insulin pump may indicate an 
infusion set occlusion or insulin pump problem. Patients in the current study will be provided 
with guidance about the management of high BG, including provision of urine ketone strips, in 
the setting of possible infusion set occlusion or insulin pump malfunction.  Patients will also be
provided with insulin syringes as an alternate method of investigational product (IP) delivery in 
the event of pump malfunction and disruption.  
In Phase 1 clinical studies, LY900014 has consistently demonstrated a faster time–action profile 
than Humalog. In patients with T1D or T2D treated with MDI insulin therapy, LY900014 
significantly reduced postprandial glucose (PPG excursions compared with Humalog when both 
were dosed by syringe at the start of a test meal. Two studies in patients with T1D have been 
completed using CSII in an in-patient setting, both of which have demonstrated accelerated time 
action. 
More detailed information about the known and expected benefits and risks of Humalog may be 
found in the country-specific product labeling (for example, Patient Information Leaflet, Package 
Insert, or Summary of Product Characteristics). The Investigator’s Brochure (IB) describes the 
clinical and nonclinical development of LY900014.
Safety evaluation in this study will include hypoglycemia, treatment-emergent adverse events
(TEAEs), serious adverse events (SAEs), frequent glucose monitoring, frequent visits, provision 
of urine ketone test strips for hyperglycemia troubleshooting, blood pressure, and body weight.  
More information about the known and expected benefits, risks, SAEs, and reasonably 
anticipated AEs of LY900014 can be found in the IB.  

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4.
Objectives and Endpoints
Table ITRO.2 shows the objectives and endpoints of the study.
Table ITRO.2.
Objectives and Endpoints
Objectives
Endpoints
Primary Objective
1.
To test the hypothesis that LY900014 is 
noninferior to Humalog on glycemic 
control ([NIM = 0.4% for HbA1c) in 
patients with T1D using CSII for 16 weeks
1.
Difference between LY900014 and Humalog in 
change from baseline to Week 16 in HbA1c
Multiplicity Adjusted Objectives
2.
To test the hypothesis that LY900014 is 
superior to Humalog in controlling 1-hour 
postprandial glucose (PPG) 
2.
Difference between LY900014 and Humalog in 
the 1-hour PPG (serum glucose measured 1 
hour after the start of the meal) from a MMTT 
at Week 16
3.
To test the hypothesis that LY900014 is 
superior to Humalog in controlling 2-hour 
PPG 
3.
Difference between LY900014 and Humalog in 
the 2-hour PPG (serum glucose measured 2 
hours after the start of the meal) from a MMTT 
at Week 16
4.
To test the hypothesis that LY900014 is 
superior to Humalog on improving glycemic 
control (HbA1c) 
4.
Difference between LY900014 and Humalog in 
change from baseline to Week 16 in HbA1c
5.
To test the hypothesis that LY900014 is 
superior to Humalog in the duration of time 
glucose values within target range 70 to 
180 mg/dL (3.9 to 10.0 mmol/L), obtained 
from CGM use during 24-hour period
5.
Duration (in minutes and percentage of time)
with glucose values between 70 and 180 mg/dL 
(3.9 and 10.0 mmol/L), both inclusive, 
normalized to a 24-hour period, from each 
14-day CGM session at Week 16
6.
To test the hypothesis that LY900014 is 
superior to Humalog in the duration of time 
glucose values within target range 70 to 
180 mg/dL (3.9 to 10.0 mmol/L), obtained 
from CGM use during daytime
6.
Duration (in minutes and percentage of time)
with glucose values between 70 and 180 mg/dL 
(3.9 and 10.0 mmol/L), both inclusive, 
normalized to daytime  (0600 hours to 
midnight), from each 14-day CGM session at 
Week 16
Other Secondary Objectives
7.
To compare LY900014 and Humalog with 
respect to the rate of severe hypoglycemic 
events
7.
Rate (events/ patient/100 years) of severe 
hypoglycemic events from baseline through 
Week 16
8.
To compare LY900014 and Humalog with 
respect to the rate and incidence of 
documented postmeal hypoglycemia 
8.
Rate (events/patient/year) and incidence 
(percent of patients with at least 1 event) of 
documented postmeal hypoglycemia within 
1 and 2 hours after the start of the meal from 
baseline through Week 16
9.
To compare LY900014 and Humalog with 
respect to the rate and incidence of 
documented hypoglycemia
9.
Rate (events/patient/year) and incidence 
(percentage of patients with events) of 
documented hypoglycemic events from baseline 
through Week 16

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10. To compare LY900014 and Humalog with 
respect to 1,5-AG
10. Change from baseline 1,5-AG values at 
Week 16
11. To compare LY900014 and Humalog with 
respect to 10-point SMBG profiles
11. Change from baseline 10-point SMBG values at 
Week 16
12. To compare LY900014 and Humalog with 
respect to total, basal, and bolus insulin dose
12. Change from baseline in bolus/total insulin dose 
ratio at Week 16
13. To compare LY900014 and Humalog with 
respect to the proportion of patients 
achieving HbA1c targets
13. The proportion of patients with HbA1c <7% 
and ≤6.5% at Week 16
14. To compare LY900014 and Humalog with 
respect to the duration of time spent in 
hypoglycemic glucose ranges, obtained from 
CGM use
14. Duration (in minutes) and percentage of time 
with glucose values <54 and <70 mg/dL (3.0
and 3.9 mmol/L), normalized to a 24-hour 
period and number of episodes, defined as at 
least 10 consecutive minutes <54 and 
<70 mg/dL, from each 14-day CGM session at 
Week 16
15. To compare LY900014 and Humalog with 
respect to the duration of time spent in 
hyperglycemic glucose ranges, obtained from 
CGM use
15. Duration (in minutes) and percentage of time 
with glucose values >180 and >250 mg/dL 
(10.0 and 13.9 mmol/L), normalized to a 
24-hour period and number of episodes, defined 
as at least 10 consecutive minutes >180 and
>250 mg/dL, from each 14-day CGM session at 
Week 16
16. To compare LY900014 and Humalog with 
respect to the incidence and rate of pump 
occlusion alarms that lead to an unplanned
infusion set change
16. Rate (events/patient/30 days) and incidence 
(percent of patients with at least 1 event) of 
pump occlusion alarms that lead to an
unplanned infusion set change from baseline 
through Week 16
17. To compare LY900014 and Humalog with 
respect to the incidence and rate of 
episodes of unexplained hyperglycemia that 
lead to an unplanned infusion set change
17. Rate (events/patient/30 days) and incidence 
(percent of patients with at least 1 event of 
unexplained hyperglycemia > 300 mg/dL 
confirmed by SMBG that leads to an unplanned 
infusion set change from baseline through 
Week 16
Tertiary/Exploratory
18. To compare the safety of LY900014 and 
Humalog
18. Adverse events, vital signs, chemistry, and 
hematology laboratory measures
19. To compare the incidence of 
treatment-emergent positive anti-insulin 
lispro antibodies for LY900014 and 
Humalog
19. Incidence of treatment emergent anti-insulin 
lispro antibodies 
20. To compare LY900014 and Humalog with 
respect to quality of life as measured by the 
EQ-5D-5L
20. Change from baseline in EQ-5D-5L 
UK-population-based health state index score 
and EQ-VAS score at Week 16.
21. To compare LY900014 and Humalog with 
respect to diabetes treatment satisfaction as 
measured by the ITSQ
21. Change from baseline in ITSQ regimen 
inconvenience and lifestyle flexibility domain 
scores at Week 16

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22. To compare LY900014 and Humalog with 
respect to changes in body weight
22. Change in weight (kg) from baseline to 
Week 16
23. To compare LY900014 and Humalog with
respect to the time interval until infusion 
set change
23. Time interval until infusion set change during
the 16-week treatment period
24. To compare LY900014 and Humalog with
respect to the factors affecting dosing in 
pumps
24. Actual and change from baseline in factors
affecting dosing in pump (CR, ISF, AIT, and 
frequency of use of non-normal bolus type 
[Square Wave or Dual Wave]), during the 
16-week treatment period
25. To compare LY900014 and Humalog with 
respect to the proportion of patients
achieving improvement from baseline in 
HbA1c targets
25. The proportions of patients with shifts in 
HbA1c to <8% and ≤9%, from baseline to 
Week 16
26. To compare LY900014 and Humalog with 
respect to glycemic variability 
26. Within-day and between-day glycemic 
variability measured by the standard deviation 
and the coefficient of variation of 10-point 
SMBG profiles
27. To compare LY900014 and Humalog with 
respect to the incremental AUCs after all 
meals, obtained from CGM use
27. Incremental AUC0-1 hour and incremental AUC0-2
hour after all meals from each 14-day CGM 
session at Week 16
28. To compare LY900014 and Humalog with 
respect to the glucose profiles, obtained 
from CGM use
28. Average glucose for a 24-hour period from each 
14-day CGM session at Week 16
29. To compare LY900014 and Humalog with 
respect to the glucose variability, obtained 
from CGM use
29. Interquartile range, CV, LBGI, and HBGI from 
each 14-day CGM session at Week 16
Abbreviations:  1,5-AG = 1,5-Anhydroglucitol; AIT = active insulin time; AUC = area under the curve;
CGM = continuous glucose monitoring; CR = carbohydrate ratio; CSII = continuous subcutaneous insulin 
infusion; CV = coefficient of variation; EQ-5D-5L = EuroQol 5D-5L; EQ-VAS = EQ visual analog scale; 
HbA1c = hemoglobin A1c; HBGI = high blood glucose index; ISF = insulin sensitivity factor; ITSQ = Insulin 
Treatment Satisfaction Questionnaire; LBGI = low blood glucose index; MMTT = mixed meal tolerance test; 
NIM=noninferiority margin; SMBG = self-monitored blood glucose; T1D = type 1 diabetes; UK = United 
Kingdom.  

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5.
Study Design
5.1.
Overall Design
Study I8B-MC-ITRO (ITRO) is a Phase 3, prospective, randomized, outpatient, multinational, 
multicenter, 2-treatment group, parallel, active-controlled, double-blind study conducted in 
patients with T1D currently using CSII therapy. Patients will be randomized to receive 
LY900014 or Humalog as both basal and bolus insulin and will administer bolus doses 0 to 2 
minutes prior to meal (pre-meal).  The study is designed to demonstrate noninferiority of 
LY900014 when compared with Humalog in change in HbA1c from baseline to Week 16, when 
both are used via CSII and bolus doses are given prior to the start of the meal.  The study periods 
include 1-week screening, 2-week lead-in, 16-week treatment, and a 4-week safety follow-up.  
Patients treated with a rapid-acting insulin analoginsulin lispro, insulin aspart, or insulin 
glulisine via CSIIwill be eligible for inclusion in the trial.  All patients will use Humalog
during the lead-in period.  Those treated with either insulin aspart or insulin glulisine at 
screening will be transferred to Humalog at Visit 2. At Visit 4, patients will be randomized to 
either LY900014 or Humalog with bolus doses given immediately prior to each meal.  
Specific elements of this study design will include collection of 10-point self-monitored blood 
glucose (Section 9.1.4.2), blinded continuous glucose monitoring (CGM) sessions 
(Section 9.1.4.6), and Mixed Meal Tolerance Testing (Section 9.1.4.7.).  

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Study governance considerations are described in detail in Appendix 3.  Figure ITRO.1
illustrates the study design.
Abbreviation: T=Telephone Visits.
a
Pre-study rapid-acting insulins:  insulin lispro, insulin aspart, insulin glulisine 
via CSII.  At Visit 2, patients on insulin glulisine or insulin aspart will be transferred to 
Humalog.  At Visit 4, patients will be randomized to either LY900014 or Humalog.  
b
Patients will discontinue study insulins at Week 16.
Figure ITRO.1.
Illustration of study design for Clinical Protocol I8B-MC-ITRO.
5.2.
Number of Participants
Numbers are approximate:  526 participants will be screened to achieve 420 randomized and 368
patients completing 16 weeks of treatment.
5.3.
End of Study Definition
End of the study is the last scheduled procedure shown in the Schedule of Activities (Section 2, 
Table ITRO.1.) for the last patient.
5.3.1. Safety Follow-up
Safety follow-up visit guidelines are as follows (see Section 2, Table ITRO.1.): 

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Patients who discontinue from the study during the lead-in period (prior to 
randomization), only need to complete an early discontinuation visit.
Patients who discontinue from IP early will be encouraged to remain in the study
and complete all remaining visits per the Schedule of Activities, including Visit 
801.
Patients who discontinue from the study early (regardless of whether they 
discontinue IP at the same time or have discontinued IP at an earlier visit), should 
complete an early discontinuation visit followed by the safety follow-up visit as 
per the Schedule of Activities.
Patients who finish Visit 13 without early discontinuation of IP should complete a 
safety follow-up visit (Visit 801) 4 weeks after Visit 13.  
5.4.
Scientific Rationale for Study Design
Study ITRO is a Phase 3 study to evaluate LY900014 compared with Humalog when given by 
CSII in patients with T1D.  The study has 2 treatment groups, both of which are double-blind to 
allow comparison of LY900014 and Humalog when bolus doses are given immediately prior to 
the start of each meal.  
The primary endpoint of this study is designed to compare HbA1c lowering.  HbA1c is a 
validated measure of glycemic control over time and is the best marker for development and 
progression of diabetes complications.  HbA1c is widely accepted by health care providers 
(HCPs) and regulatory authorities.
During the 2-week lead-in period, the following will occur:

perform the first 14-day blinded CGM session, 

assess patient proficiency in carbohydrate counting and provide training, and

assess basal rates and bolus calculator settings and adjust if needed.
During the 16-week treatment period, the following should be titrated in order to meet the target 
BG levels:

pump basal rates

bolus calculator settings
o
carbohydrate ratios (CR), 
o
insulin sensitivity factors (ISF), and 
o
active insulin time (AIT)
5.5
Justification for Dose
The basal and bolus delivery of insulin will be determined based on the individual needs of each 
patient.  LY900014 has the same insulin lispro concentration (100 U/mL) as that of 
commercially available Humalog.  At the randomization visit, IP may be substituted for 
Humalog (used during lead-in) on a unit-for-unit basis.  The addition of treprostinil to the

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Humalog formulation does not modify the physical, chemical, or biological integrity of 
Humalog.  Furthermore, the total glucose-lowering effect during euglycemic clamp experiments 
is similar between LY900014 and Humalog.  Nevertheless, improved postprandial glucose 
values were observed with LY900014 after test meals, which may potentially increase the risk 
for early postprandial hypoglycemia with LY900014.  

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6.
Study Population
Patients must give written informed consent (approved by Eli Lilly and Company [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 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 
screening:
Type of Patient and Disease Characteristics
[1] Men or women diagnosed (clinically) with T1D for at least 1 year prior to 
screening, and continuously using insulin for at least 1 year
Patient Characteristics
[2] Are at least 18 years of age 
[3] Have HbA1c values of ≥6.5% and ≤9.0%, as determined by the central 
laboratory at screening (Visit 1)
[4] Have a body mass index (BMI) of ≤35.0 kg/m2 at screening (Visit 1). 
[5] Male patients:  
a. No male contraception required except in compliance with specific local 
government study requirements
[6] 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

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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
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 (See Appendix 5)
iv. Test negative for pregnancy at the time of screening (Visit 1).  
Note:  a urine pregnancy test is conducted at Visit 4.  
[7]
Have refrigeration in the home or have ready access to refrigeration for 
storage of insulin 
[8]
Are a patient for whom 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
Treatment Characteristics
[9] Currently treated with <100 Units of one of following rapid-acting analog 
insulin via CSII for at least the last 30 days prior to screening;
a. insulin lispro U-100, 
b. insulin aspart, 
c. fast-acting insulin aspart (where approved), or 

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d. insulin glulisine 
[10] Have been using CSII therapy for a minimum of 6 months prior to 
screening.  Interruption of CSII is allowed during the 6 months prior to 
screening for up to a total of 14 days, such as during a hospitalization, a 
pump malfunction, or a “pump holiday.”
[11] Must be using a MiniMed 530G (US), Paradigm Revel (US), MiniMed 
630G (US and Canada), MiniMed 640G or Paradigm Veo (in select 
countries outside the US), insulin pump for at least the last 90 days and are 
capable of and willing to 
a.
stay on the same pump throughout the study 
b. use study-provided MiniMed insulin pump reservoirs and infusion sets
c.
maintain their current bolus delivery speed (standard or quick) for the 
duration of the study
d. use carbohydrate counting for meal-related bolus dosing
e.
use the pump’s bolus calculator (Bolus Wizard®), including entry of the 
current glucose value, to determine mealtime and correction bolus doses
[12] May be wearing a Medtronic CGM using the “Threshold Suspend” (530G), 
“Low Glucose Suspend” (Paradigm Veo) “Suspend on low” (630G and 
640G), and/or “Suspend before low” (640G) pump feature.  Beginning with 
the lead-in period (Visit 2) patients must be willing to; 
a.
continue “Threshold Suspend” (530G), “Low Glucose Suspend” (Paradigm 
Veo) or “Suspend on low” (630G or 640G) for the duration of the lead-in 
and treatment periods
b. stop “Suspend before low” (640G) for the duration of the lead-in and 
treatment periods.
[13] May be using personal CGM or FGM to self-monitor glucose at study entry.  
a.
If chooses to continue, must be willing to maintain its use for the 
duration of the study.  
b. May not begin use of personal CGM or FGM during the study.
[14]
Are capable of, and willing, to do the following: 
a.
Perform 10-point self-monitored blood glucose (SMBG), prior to 
designated visits (patients using a personal CGM or flash glucose 
monitoring (FGM) device must perform 10-point SMBG with study 
provided glucose meter)

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b. Perform 4- and 7-point glucose profiles prior to designated visits 
c.
Adhere to a routine infusion set and reservoir change interval of every 3 
days 
d. Avoid use of all products containing acetaminophen or paracetamol 
while using the study-provided Dexcom CGM
e.
Keep records in patient study diaries required by this protocol 
f.
Receive diabetes education 
g. Comply with required study treatment and study visits
Informed Consent
[15] Have given written informed consent to participate in this study in 
accordance with local regulations
6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at 
screening:
Medical Conditions
[16] Have any other condition (including known drug or alcohol abuse or 
psychiatric disorder including eating disorder) that precludes the patient
from following and completing the protocol
[17] Have hypoglycemia unawareness as judged by the investigator
[18] Have had more than 1 episode of severe hypoglycemia (defined as requiring
assistance due to neurologically disabling hypoglycemia) within 6 months 
prior to screening
[19] Have had more than 1 emergency room visit or hospitalization due to poor 
glucose control (hyperglycemia or DKA) within 6 months prior to screening
[20] Have cardiovascular disease, within the last 6 months prior to screening, 
defined as stroke, decompensated heart failure New York Heart Association 
class III or IV (CCNYHA 1994), myocardial infarction, unstable angina 
pectoris, percutaneous transluminal coronary angioplasty or coronary 
arterial bypass graft
[21] Renal:
a. History of renal transplantation
b. Currently receiving renal dialysis
c. Serum creatinine >2.0 mg/dL (177 µmol/L) at screening, or
d. An estimated glomerular filtration rate of <30 mL/min/1.73 m2.

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[22] 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 Gilberts Disease) as defined by the central laboratory,
Or
b. Alanine aminotransferase (ALT) ≥3X ULN as defined by the central 
laboratory, 
Or
c. Aspartate aminotransferase (AST) ≥3X ULN as defined by the central 
laboratory
[23] 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
[24] Have any hypersensitivity or allergy to any of the insulins or excipients used 
in this trial
[25] Hematologic:  have had a blood transfusion or severe blood loss within 
90 days prior to screening or have known hemoglobinopathy, anemia that is 
clinically significant based on investigator judgement, or any other traits of 
known to interfere with measurement of HbA1c
[26] Have presence of clinically significant gastrointestinal disease (for example,
clinically active gastroparesis associated with wide glucose fluctuations; 
includes those with gastric bypass) in the opinion of investigator
[27] Have significant lipohypertrophy, lipoatrophy, or scars within the SC tissue 
in areas of infusion, in the opinion of the investigator
[28] Have a history of abscess at an infusion site within the last 90 days prior to 
screening
[29] Have vision loss or hearing loss that does not allow recognition of pump 
screens, alerts and alarms
Prior/Concomitant Therapy
[30] Have used insulin human inhalation powder (Afrezza®) within 30 days prior 
to screening
[31] Are receiving any oral or injectable medication intended for the treatment of 
diabetes other than rapid-acting analog insulin via CSII in the 90 days prior 
to screening.  In the event of interruption of CSII ≤14 days during the 6 
months prior to screening, injection of bolus and basal insulin is allowed. 

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[32] Glucocorticoid therapy:  are receiving chronic (lasting longer than 14 
consecutive days) systemic glucocorticoid therapy (including intravenous
(IV), intramuscular (IM), SC, and oral), but excluding topical, intraocular, 
intranasal, intra-articular, and inhaled preparations), or have received such 
therapy within 4 weeks immediately prior to screening with the exception of 
replacement therapy for adrenal insufficiency
Prior/Concurrent Clinical Trial Experience
[33] 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
[34] Have participated, within the last 30 days in a clinical trial involving an IP
[35] Have previously completed or withdrawn from this study or any other study 
investigating LY900014 after receiving at least 1 dose of the IP  
Other Exclusions
[36] Have an irregular sleep/wake cycle (for example, patients who sleep during 
the day and work during the night)
[37] 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
[38] Are Lilly employees (including employees, temporary contract workers, or 
designees responsible for the conduct of the study)
6.2.1. Rationale for Exclusion of Certain Study Candidates
The use of LY900014 in pediatric patients (<18 years of age) will be studied separately.  This 
study will specifically examine comparison of LY900014 to Humalog in adult patients using 
CSII.  Criterion [2] defines the population age for the purpose of this study.  Therefore, pediatric 
patients are excluded.
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 diet or exercise during the study.  Patients should 
be instructed to avoid all medications that contain acetaminophen/paracetamol during the blinded 
CGM study sessions.  Patients should be instructed to avoid major changes in dietary intake or 
physical activity during the 3 days prior to mixed meal tolerance test (MMTT).  
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened, with the exception of individuals from select countries who initially screen failed 
because they use a Paradigm Revel or Paradigm Veo pump.  Retests are also not allowed, except 
for cases when results are unavailable from the original sample.

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7. Treatments
7.1.
Treatments Administered
This study involves a double-blind comparison of LY900014 and Humalog, in patients with T1D
using CSII.  Table ITRO.3 shows the treatment regimens.
Table ITRO.3.
Treatment Regimens
Regimen
Dose Strength
Dose 
Administration
Route of 
Administration
Timing of Dose
LY900014
100 U/mL
Individualized
Dosing
CSII 
Mealtime bolus 0-2 min prior 
to start of the meal; continuous 
basal infusion; correction 
boluses as necessary
Humalog
100 U/mL
Individualized
Dosing
CSII
Mealtime bolus 0-2 min prior 
to start of the meal; continuous 
basal infusion; correction 
boluses as necessary
Abbreviation:  CSII = continuous subcutaneous insulin infusion.
The investigator or his or her designee is responsible for the following:

explaining the correct use of IP to the patient

explaining storage requirements for IP

explaining requirements for recording time and amount of bolus doses to the 
patient

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 Labelling
Clinical trial materials will be labeled as IP as appropriate, and according to the regulatory 
requirements of the country.  Study insulins (LY900014 and Humalog) will be supplied by Lilly 
or its representative, in accordance with current good manufacturing practices and will be 
supplied with lot numbers.
The blinded vials will contain a concentration of 100 U/mL in 10-mL vials of either LY900014
or Humalog.  
During the lead-in period, Humalog 100 U/mL will be provided in open-label 10-mL vials.
7.1.2. Insulin Pumps
Patients will use their personal insulin pumps for the duration of the study but will be required to 
use reservoirs and infusion sets provided by the investigative site.  Pump reservoirs will be filled 

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with IP and infusion sets will be primed according to the manual of use provided by the pump 
manufacturer.  Patients will be required to change the insulin, reservoir, and infusion set every 3 
days, routinely throughout the study, in accordance with the label of the infusion sets.  Sites 
should assist patients with setting a reminder in their pump to prompt for a reservoir and infusion 
set change every 3 days.
If a pump malfunction requires a patient to change to a new insulin pump during the study, it will 
be allowed as long as the new pump

is approved in the country where the patient resides 

is allowed by the study (MiniMed 530G, Paradigm Revel, 630G, Paradigm Veo or 640G)

Training has been provided to the patient by a qualified HCP, and

is compatible with a Contour Link blood glucose meter that
o
is approved in the country where the patient resides and
o
can be sourced by the Sponsor for the Study.
7.1.2.1.
Personal Continuous Glucose Monitor Use in Study
Patients may continue to use their personal CGM or FGM during the study. 
Patients will not be allowed to start using personal CGM or FGM during the study.  In order to 
account for potential differences between patients who wear a CGM or FGM and those who do 
not, stratification by patients’ personal CGM or FGM use will ensure balance of this factor 
across treatments.  Patients may use their personal CGM or FGM for the required glucose value
entries into the pump bolus calculator for meal and correction boluses, if approved in their 
country for making treatment decisions (i.e., nonadjunctive use).  Patients will be required to 
perform SMBG with the study provided blood glucose meter for the study procedures described 
in Section 9.1.4.3.
7.1.3. Medical Devices
Study patients will be provided with an approved, compatible blood glucose meter.  The patient’s 
meter must be wirelessly connected to their insulin pump.  Instructions for connecting are found 
in the pump and meter user guides and also provided as a site tool.  Once connected, the pump 
automatically controls the date and time of the meter.  It will also send all BG results directly to 
the pump when the “Always” meter send option is selected (recommended). The BG meters
used in this study will be have received clearance from the Food and Drug Administration (FDA)
and meet the following standard for blood glucose meters:  ISO 15197:2013.  At every site visit 
beginning with Visit 2, site staff should verify synchronization of the dates and times of the 
pump and BG meter. 
7.2.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will be randomized to double-blind treatment at 
Visit 4.  Assignment to treatment groups will be determined by a computer-generated random 
sequence using an interactive web-response system (IWRS).  The IWRS will be used to assign 
all vials containing double-blind IP during the study and open-label Humalog during the lead-in 

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period.  Site personnel will confirm that they have located the correct vials by entering a 
confirmation number found on the vials into the IWRS.
Patients will be randomized to 1 of 2 treatment groups in 1:1 ratio.  Stratification will be by 
country, HbA1c stratum (≤7.5%, >7.5% at Visit 1), and patient’s personal CGM or FGM use 
during the study (yes/no).  
Patients will begin using double-blind IP in their pumps immediately following successful 
completion of the Visit 4 MMTT.  Patients will fill a new pump reservoir and infusion set with 
IP, then insert a new pump infusion set cannula and begin infusion of IP prior to leaving the 
investigative site.  
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 (AACE) (Bailey 
et al. 2016).  Fasting, prandial, bedtime, and peak PPG target values used to reach the 
glucose targets and for determination of titration in insulin therapy are listed in Table 
ITRO.4
Table ITRO.4.
Target Glucose Values for Titration of Insulin Therapy
Time of Measurement 
Target (Range)
Fasting or pre-morning meal
Target:  100 mg/dL or 5.6 mmol/L
Range: 80 to <100 mg/dL or 4.4 to 6.1 mmol/L
Pre-midday meal
Target:  100 mg/dL or 5.6 mmol/L
Range:  80 to <110 mg/dL or 4.4 to 6.1 mmol/L
Pre-evening meal
Target:100 mg/dL or 5.6 mmol/L 
Range:  80 to <110 mg/dL or 4.4 to 6.1 mmol/L
Pre-bedtime and 03:00 AM
Range:  90 to 130 mg/dL or 5.0 to 7.2 mmol/L
1-2-hour postprandial 
Target:  <180 mg/dL or 10.0 mmol/L 
7.2.1.2.
Pump Settings
Evaluating and titrating pump settings is at the discretion of the investigator and should be done 
with a methodical approach by reviewing relevant glucose data, insulin delivery settings and 
carbohydrate intake.  During titration of pump settings, patients should eat meals that have 
known carbohydrate content and can be accurately counted and avoid snacking between meals 
(unless treating hypoglycemia).  Patients will be allowed to use low glucose suspend for the 
lead-in and duration of the treatment period. Patients will not be allowed to use “SmartGuard 
Suspend before low” (Refer Section 6.1 Inclusion Criteria [12]). 
7.2.1.3.
Basal Rate Titration
At all clinic and telephone visits during the 16-week treatment period following randomization, 
titration of basal rates should be based on glucose values, hypoglycemia data and determined by 
the investigator in discussion with the patient.  Additional discussion between visits may be 

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required to enable the patient to reach the fasting blood glucose target of 100 mg/dL (5.6 
mmol/L) and to optimize 24-hour basal rates.  Titration of basal rates may be influenced by other 
clinical circumstances and safety considerations known to the investigator; thus, the prescribed 
basal rates during the study are determined by, and the responsibility of, the investigator.  
Overnight basal rates should be assessed by observing patterns across time segments (bedtime to 
mid-sleep; mid-sleep to awakening) and titrated to match diurnal variations.  When basal rates 
are set correctly, patients should be able to sleep late, eat late, or skip a meal without 
experiencing glucose excursions.  
Daytime basal rates can be titrated using either the fasting method or nonfasting method. 
If using the fasting method, evaluate glucose levels across skipped-meal time segments
(pre-morning to pre-midday, pre-midday to pre-evening, or pre-evening to bedtime) and
titrate/add basal rate(s) based on the patterns observed across skipped-meal times.  
If using the nonfasting method, evaluate basal rates by comparing the 2-hour postmeal glucose to 
the next premeal glucose.  Postmeal glucose should steadily decline and return to premeal target 
range by next meal. 
7.2.1.4.
Bolus Dose Titration
Postprandial glucose levels from 10-point SMBG profiles and 7-point glucose profiles should be 
evaluated by the investigator for titration of bolus dosing.  Additional glucose testing should be 
considered during the days following transition to study insulin.  Titration of bolus calculator 
settings (CR, ISF, and AIT) during the study are determined by, and the responsibility of, the 
investigator.  
Patients should use the pump Bolus Wizard® calculator for calculating bolus and correction 
doses to ensure that the carbohydrate content of each meal is covered and the preprandial glucose 
level is accounted for in the preprandial bolus dose.  
In order to meet the target glucose levels during the 16-week treatment period, the investigator in 
discussion with the patient should; 

Weekly assess and titrate the CR, ISF, and AIT 
o
The CR is used to calculate food bolus amounts.  Evaluate CRs by 
comparing the pre-meal glucose to its corresponding 2-hour post-meal 
glucose. The CR may be titrated every 3-4 days (twice per week) 
when appropriate, based on the patient’s glycemic needs and glucose 
levels.  
o
The ISF is used to calculate correction bolus amounts that is needed to 
bring the glucose into target range.  

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
Weekly discuss and determine optimal bolus types (normal, square or dual 
wave) for meals of different macronutrient composition.  For meals that tend 
to be larger in size and of higher protein and fat content (often the dinner 
meal), a higher bolus dose or a dual or square wave bolus may be appropriate
to prevent late postmeal hyperglycemia.  
7.2.1.5.
Transitioning off Study Prandial Insulin Therapy
Patients will give their last bolus dose of study insulin (LY900014 or Humalog) at Visit 13 with 
the MMTT or at early discontinuation.  No special instructions are necessary for patients who 
were randomized to either LY900014 or Humalog.  After completion of study treatment, patients 
will restart the rapid-acting insulin analog used prior to study entry via CSII and their pumps 
settings will be reset to those used at randomization.
7.3.
Blinding
This is a double-blind study.  LY900014 and Humalog treatment groups will have premeal bolus 
doses given via CSII.  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.  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 
warranted, the investigator should make every effort to contact the Lilly clinical research 
physician/clinical research scientist (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 or 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.  

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Only participants 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.
Vials of insulin not currently in-use should be refrigerated until ready to use.  In-use insulins 
should be maintained at room temperature (between 20°C and 25°C) when possible and 
refrigerated material should be warmed to near room temperature before infusion.  In-use insulin 
must not be used after 28 days.
The investigator is responsible for study treatment accountability, reconciliation, and record 
maintenance (such as receipt, reconciliation, and final disposition records).  
7.6.
Treatment Compliance
The investigator or designee will assess compliance of the patient at each visit, based on a review 
of the patient’s glycemic control, adherence to the visit and treatment schedule, and completion 
of the patient’s study diary.  Patients who are deemed noncompliant will receive additional 
diabetes education and training, as required, and the importance of compliance with the protocol 
will be reinforced.  Patients who, in the opinion of the investigator, are deemed consistently 
noncompliant may be discontinued from IP.  
7.7.
Concomitant Therapy
The following concomitant medications 

are NOT allowed at any time during the study; 
o
Any noninsulin diabetes treatment therapy
o
Afrezza® (inhaled insulin) 

Are NOT allowed during the blinded CGM sessions; 
o
Medicines containing Acetaminophen/paracetamol

ARE allowed for up to a total of 7 days during the lead-in period and 14 days 
during the treatment period;  
o
Systemic glucocorticosteroids

IV, IM, SC, oral 

except in the case of replacement therapy for adrenal 
insufficiency

ARE allowed for 14 days or less during the study
o
Basal insulin

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o
Regular human insulin or a nonstudy rapid-acting analog insulin

ARE allowed at any time
o
Topical, inhaled, intraocular, intra-articular, or intranasal steroid 
preparations
7.8.
Treatment after the End of the Study
7.8.1. Treatment after Study Completion
LY900014 will not be made available to patients after conclusion of the study.  Rapid-acting 
insulin analogs and regular human insulin are available in all countries for use as prandial/pump
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 rapid-acting analog insulin used prior to study entry.  
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.  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 (HbA1c) and safety data will be collected at 
scheduled visits.  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 immediately.

The patient may decide to stop 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 (Guidance on restrictions for 
concomitant therapies is provided in Section 7.7).

Use of pump that is not allowed.

If the patient has not used IP for more than 14 days total. 

If the patient experiences a second episode of severe hypoglycemia
Discontinuation due to a hepatic event or liver test abnormality.  Patients who are 
discontinued from IP due to a hepatic event or liver test abnormality should have additional 
hepatic safety data collected via case report form (CRF).

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Discontinuation of the IP 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.  

ALT or AST >8X ULN

ALT or AST >5X ULN for more than 2 weeks

ALT or AST >3X ULN and TBL >2X ULN or prothrombin time >1.5X ULN

ALT or AST >3X ULN with the appearance of fatigue, nausea, vomiting, 
right upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

alkaline phosphatase (ALP) >3X ULN

ALP >2.5X ULN and TBL >2X ULN

ALP >2.5 ULN with the appearance of fatigue, nausea, vomiting, right 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
Patients discontinuing from the IP prematurely for any reason should complete AE and other 
follow-up procedures per Section 2 (Schedule of Activities Table ITRO.1.), Section 9.2 (Adverse 
Events), and Section 9.4 (Safety) of this protocol.
8.1.2. Temporary Discontinuation from Study Treatment
Patients can have temporary discontinuation of IP for up to a total of 14 days (consecutive or 
nonconsecutive).  
In the event of a pump failure, MDI therapy is allowed for ≤14 days.  Bolus and basal insulin 
will be determined by the investigator or other HCP.  When possible, continuing on IP is 
preferred.  Investigational product may be withdrawn from the vial and injected as needed to 
cover meals and correct hyperglycemia using the insulin syringes provided.  
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 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 IP. Safety 
follow-up is as outlined in Section 2 (Schedule of Activities Table ITRO.1.), 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 the following:

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

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
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 to discontinue the patient from the study

The patient requests to be discontinued from the study

The patient discontinues Humalog regimen for >3 consecutive days in the 
lead-in period
Patients discontinuing from the study prematurely for any reason should complete AE and other 
safety follow-up per Section 2 (Schedule of Activities Table ITRO.1.), Section 9.2 (Adverse 
Events), and Section 9.4 (Safety) of this protocol.  Patients who discontinue during the lead-in 
period will not need to fast, have laboratory tests drawn, or complete questionnaires, but will 
have all other early discontinuation procedures performed.  Site should document details 
regarding the reason for discontinuation when available.  
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.  Due diligence efforts should be documented in electronic 
case report form (eCRF).  

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9.
Study Assessments and Procedures
Section 2 lists the Schedule of Activities (Table ITRO.1.), 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 16 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:  serum glucose measured 1 hour and 2 hours 
after the start of the meal 
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:
o
1-hour and 2-hour PPG and PPG excursions by meal and across all 
meals
o
Within- and between-day glucose variability measured by the 
coefficient of variation and SD

CGM
o
Duration and percentage of time in range (70-180 mg/dL [3.9-
10.0 mmol/L]) during the daytime (0600 hours to midnight) and 24-
hour period obtained by study-provided Dexcom blinded CGM
o
Duration and percentage of time with glucose values <54 and 
<70 mg/dL (3.0 and 3.9 mmol/L)

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o
Duration and percentage of time with glucose values >180 and
>250 mg/dL (10.0 and 13.9 mmol/L)

Proportion of patients with HbA1c ≤6.5% and <7.0% 

Bolus, basal and total insulin dose (units and units/kg) and bolus/total insulin 
ratio 
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.
Use of Personal CGM or FGM
Patients may continue to use their personal CGM or FGM throughout the study (Section 7.1.2.1).  
Patients will be allowed to use their personal CGM/FGM for the 4- and 7-point glucose profiles
(as consistent with local regulations and standard of care), and then enter the sensor glucose 
values into their pump.  If patients do not have a personal CGM/FGM, they will be required to 
perform the 4- and 7-point glucose profiles using the study provided BG meter and these glucose 
values will be automatically transferred to the pump. The 4-and 7-point values are required at 
the times described in Table ITRO.5.
9.1.4.2.
Collection of Glucose Profiles
Patients will be asked to collect 4-, 7-, and 10-point glucose profiles according to Table ITRO.5.  
The 4- and 7-point profiles are needed for clinical management.  The 10-point profile will be 
required for a study endpoint.  The 10-point must be collected using the study BG meter.  Site 
personnel may request additional glucose values at other times to make clinical management 
decisions.  Missing values in any glucose or SMBG profile will not be considered protocol 
deviations unless, in the opinion of the investigator, they are excessive and reflect 
noncompliance with the protocol.  
During the 10-point SMBG profiles, patients should be encouraged to eat meals in the morning, 
midday, and evening (and eat a snack if that is their usual practice).

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9.1.4.5.
Urine Ketone Testing
Patients will be provided urine ketone testing strips for use in hyperglycemia management.  It is 
recommended that patients test for urine ketones and record in Patient Diary when; 

SMBG is >300 mg/dL, 

nausea, vomiting, or abdominal pain is present,

an illness occurs.
If moderate or large amounts of urine ketones are present, patients should notify the investigator 
immediately and go to the Emergency Room.
9.1.4.6.
Blinded Continuous Glucose Monitoring Sessions
The Dexcom G5 Mobile Continuous Glucose Monitoring System (Dexcom G5) will be used by 
all patients in blinded mode 14 days prior to Visits 4, 10, and 13.  The Dexcom G5 is an 
FDA-approved and European Union European Conformity (CE) labelled device, developed for 
continuous monitoring of interstitial glucose levels in persons with diabetes mellitus.  Prior to 
each blinded CGM session, site staff should verify the date and time of the Dexcom G5 Receiver 
and adjust if needed.  Patients will be instructed to change the Dexcom G5 sensor every 7 days 
according to the product label. Patients will receive training on the use of the Dexcom G5 and 
will be expected to complete daily requirements.  
Patients will need to consider the second 7-day end time of the baseline and endpoint sensor 
sessions so that they are able to continue to wear the blinded CGM during both MMTTs.  If the 
second sensor is scheduled to end on the day of the MMTT, the patient should end the sensor 
session and insert a new sensor the evening prior to the scheduled time of the MMTT.
Daily Requirements for Patients during each Blinded Dexcom G5 Session

Eat a similar breakfast each day and avoid snacking for the 2-hour period after 
breakfast unless it is necessary to treat hypoglycemia.

Enter date and start time of all meals into the Patient Diary 

Enter date and start time of bedtime snack, if consumed, into the Patient Diary 

Keep the Dexcom G5 Receiver close to the body
o
within about 6 meters (about 20 feet) of the Dexcom G5 Transmitter, 
o
without obstruction, to minimize the loss of transmitted data.

Calibrate the Dexcom G5 Sensor every 12 hours.
o
Use SMBG values taken only from finger-sticks for calibrations.  
o
Do not use alternative BG site testing (forearm, palm, etc.) for sensor 
calibration.

Avoid products containing acetaminophen/paracetamol while using the 
Dexcom G5.

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9.1.4.7.
Mixed Meal Tolerance Test
A 4-hour MMTT will be performed in all patients at 

baseline (Week 0, Visit 4) and 

the end of the treatment period (Week 16, Visit 13).
The MMTT can

occur 0 to 4 days prior to Visit 4 or Visit 13, but as close to the Visit date as 
possible. 

be rescheduled up to 2 times within the visit window, ideally at 24-hour 
intervals, if the patient does not meet the target FBG. 

occur after a non-severe hypoglycemic episode is recorded within the 8-hour 
fasting period and up to 2 hours prior to the test meal if it is treated and 
resolved with 20 grams or less of carbohydrate
The MMTT cannot occur

if a correction bolus dose was given less than 4 hours before the start of the 
test meal.

if non-severe hypoglycemic episode during the 8-hour fasting period and up to 
2 hours prior to the start of test meal requires more than 20 grams of 
carbohydrate, or

if patient has an episode of severe hypoglycemia within the past 24 hrs.
The day prior to the MMTT, patients will be instructed to 

follow normal eating and exercise routines 

refrain from intake of alcohol
The evening prior to the MMTT, patients will be instructed to

fast for at least 8 hours prior to scheduled testing

fill a new pump reservoir and infusion set 
o
with open-label Humalog - Visit 4
o
with IP - Visit 13

insert a new infusion set into an appropriate site
The morning of scheduled MMTT, patients will be instructed to 

measure SMBG at 4 AM
o
This SMBG value should be used by patients to evaluate the need for a 
correction bolus or the intake of no more than 20 grams of 
carbohydrate to arrive at the investigator site with a BG between 
71 and 180 mg/dL prior to the MMTT. 

keep programmed basal rates 

continue to wear the CGM device until the end of the MMTT

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9.1.4.8.
Diabetes Education and Nutritional Counseling
Initial training at Visit 2 will include diabetes education and nutrition counseling.  Patients may 
be provided additional training and education at visits following Visit 2, based on individual
needs.  Appropriate site personnel will provide training and education using locally approved 
diabetes education/training materials and programs or by using other materials that may be 
provided by the sponsor.  
Training will include reviews of: 

correct pump use 
o
3-day frequency of routine reservoir and infusion set changes, 
o
priming of the infusion set, 
o
infusion site rotation, 
o
use of temporary basal rates and alternate bolus types

carbohydrate counting, 

calculating bolus and correction doses, and

treating hypoglycemia. 

managing hyperglycemia
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.
The investigator remains responsible for all AEs through an appropriate health care option.  All 
AEs will be followed until restoration or until a stable condition has been achieved. The 
follow-up should not be interrupted, even if there is a reasonable explanation for the event.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect.
After the informed consent form (ICF) is signed, study site personnel will record via electronic 
data entry the occurrence and nature of each patient’s preexisting conditions, including clinically 
significant signs and symptoms of the disease under treatment in the study.  In addition, site 
personnel will record any change in the condition(s) and any new conditions as AEs. 
Investigators should record their assessment of the potential relatedness of each AE to protocol 
procedure, IP, via electronic data entry.  

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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 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 pump 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 Section 9.4.1 and Section 9.4.2 must 
be reported as SAEs
All AEs occurring after signing the ICF are recorded in the CRF. The 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, the SAE should be reported to the sponsor according to 
SAE-reporting requirements and timelines if it is considered reasonably possibly related to study 
procedure.

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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 AE 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 he or she considers the event reasonably possibly related to 
the study treatment or study participation, the investigator 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.  Patients will be instructed to contact the investigator as soon as possible 
if he or she has a complaint or problem with the IP or their insulin pump so that the situation can 
be assessed.  Any insulin pump issue will be assessed at the investigative site and if not resolved,
the investigator should report the complaint directly to the pump manufacturer in accordance 
with the product labeling. Investigators should report these complaints as they would for 
products in the marketplace. 

Complaints on IP must be reported to Lilly by site staff within 24 hours of 
notification, or within 24 hours of study/site personnel becoming aware of a 
product issue, regardless of the availability of the complaint sample.

Investigative sites must 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 and 
insulin pumps) that do not have a Lilly Product Batch or Control number are 
reported directly to the manufacturer per product label.

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
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 Humalog.
9.4.
Safety
9.4.1. Hypoglycemia
Patients will be required to perform SMBG when hypoglycemia is suspected through

symptoms experienced, 

personal CGM or FGM readings, or

a perceived increased risk as related to 
o
dietary intake, 
o
physical activity, or
o
inadvertent or atypical insulin dosing.  
All patients will be instructed to treat a BG ≤70 mg/dL (3.9 mmol/L) as hypoglycemia.
If a hypoglycemia event is suspected, the patient should record the BG value, any associated 
symptoms, and the treatment administered in the study diary.  The patient should contact the site 
as necessary.  All hypoglycemia events (severe and nonsevere) must be reported on the 
hypoglycemia eCRF.  All episodes of severe hypoglycemia must be confirmed by the 
investigator and then reported as SAEs on the AE eCRF page and on the SAE eCRF page.  
Episodes of hypoglycemia not meeting the criteria for severe hypoglycemia should not be 
reported as an AE.  
Hypoglycemia will be described using the following definitions:

Documented Glucose Alert; BG ≤70 mg/dL (3.9 mmol/L):  
o
Documented symptomatic hypoglycemia:  an event with typical 
symptoms of hypoglycemia. 
o
Documented asymptomatic hypoglycemia:  an event without typical 
symptoms of hypoglycemia. 
o
Documented unspecified hypoglycemia:  with no information about 
symptoms of hypoglycemia available (this has also been called 
unclassifiable hypoglycemia).

Documented Clinically Significant Hypoglycemia with similar criterion as 
above except for threshold BG <54 mg/dL (3.0 mmol/L)
o
Documented symptomatic hypoglycemia 

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o
Documented asymptomatic hypoglycemia
o
Documented unspecified hypoglycemia

Probable Symptomatic Hypoglycemia:  an event during which symptoms 
are present, but BG measurement was not reported. 

Severe Hypoglycemia:  during these episodes, patients have an altered mental 
status and cannot assist in their own care, may be semiconscious or 
unconscious, or experience coma with or without seizures, and the event 
requiring assistance of another person to actively administer carbohydrate, 
glucagon, or other resuscitative actions.  Blood 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
o
Nocturnal Hypoglycemia:  any documented hypoglycemic event 
(including severe hypoglycemia) that occurs between bedtime and 
waking.  
o
Overall (or Total) Hypoglycemia:  this category combines all cases 
of hypoglycemia (documented hypoglycemia and probable
symptomatic hypoglycemia, including severe hypoglycemia)
excluding the events of relative hypoglycemia.  Nocturnal and severe 
hypoglycemia are special cases of documented or probable 
hypoglycemia. If an event of hypoglycemia falls into multiple 
subcategories, the event is only counted once in this category.
9.4.2. Severe Hypoglycemia
The determination of a hypoglycemic event as an episode of severe hypoglycemia, as defined 
above, 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, an ECGs should be performed at Visit 1 according to the study-specific 
requirements described in the Schedule of Activities (Section 2, Table ITRO.1.).  
ECGs will be interpreted by a qualified physician (the investigator or qualified designee) at the 
site as soon after the time of ECG collection as possible, and ideally while the patient is still 
present, to determine whether the patient meets entry criteria and for immediate patient 
management, should any clinically relevant findings be identified. 
ECGs may be obtained at additional times, when deemed clinically necessary.

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9.4.4. Vital Signs
For each patient, vital sign measurements should be conducted according to the Schedule of 
Activities (Section 2, Table ITRO.1.) 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, Table ITRO.1.). 
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 eCRF if 1 or more of the following conditions 
occur: 

Elevation of serum ALT to ≥5X ULN on 2 or more consecutive blood tests

Elevation of serum TBL to ≥2X ULN (except for cases of known Gilbert’s 
syndrome)

Elevation of serum ALP to ≥2X ULN on 2 or more consecutive blood tests

Patient discontinued from treatment due to a hepatic event or abnormality of 
liver tests

Hepatic event considered to be a SAE
9.5.
Pharmacokinetics
Not applicable
9.6.
Pharmacodynamics
Not applicable

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9.7.
Pharmacogenomics
Not applicable
9.8.
Immunogenicity Testing
Blood samples for immunogenicity testing will be collected to determine antibody production 
against insulin lispro as specified in the Schedule of Activities (Section 2, Table ITRO.1).  
Immunogenicity will be assessed by a validated radio ligand-binding assay (RBA) to detect 
anti-insulin lispro antibodies in the presence of lispro.  Instead of quantitating the level of 
anti-insulin lispro antibodies by titer, the RBA reports a semiquantitative percent-binding for 
each positive sample.  Additionally, positive samples will be characterized for cross-reactive 
binding to native insulin.  
Clinical and reliable on-market data indicate that the immunogenic potential of insulin lispro is 
comparable to other marketed insulins such as regular human insulin (Fineberg et al.  1996) and, 
when present, anti-insulin antibodies do not appear to be clinically consequential (Fineberg et al. 
2003).  Therefore, rather than relying on an in vitro neutralization assay, well established in vivo 
measures of insulin lispro efficacy (that is, insulin dose, HbA1c) will be utilized to directly 
monitor for any potential neutralizing effect of anti-lispro antibodies.
Samples will be retained for a maximum of 15 years after the last patient visit for the study, or 
for a shorter period if regulations and ERBs impose shorter time limits, at a facility selected by 
Lilly or its designee.  The duration allows the sponsor to respond to future regulatory requests 
related to LY900014.
9.9.
Health Economics
The self-reported questionnaires will be administered according to the Schedule of Activities
(Section 2, Table ITRO.1.) in countries where the questionnaires have been translated into the 
native language of the region and linguistically validated.
9.9.1. EQ-5D-5L
The European Quality of Life – 5 Dimensions 5 Level (EQ-5D-5L) (van Reenen and Janssen 
[WWW]) is a patient-rated questionnaire used to evaluate health status.  The questionnaire 
consists of 2 parts.  The first part assesses 5 dimensions (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression) that have 5 possible levels of response (no problems, 
slight problems, moderate problems, severe problems, extreme problems).  This part of the 
EQ-5D can be used to generate a health state index score, which is often used to compute 
quality-adjusted life years for utilization in health economic analyses.  The health state index 
score is 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).

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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 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 0-100 (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.

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10. Statistical Considerations
10.1. Sample Size Determination
Approximately 420 patients will be randomized in order that approximately 368 patients 
complete the study through the primary endpoint at Week 16.
The primary objective of this study is to test the hypothesis that LY900014 is noninferior to 
Humalog on glycemic control as measured by change from baseline to Week 16 in HbA1c in 
patients with T1D when administered in a double-blind manner using CSII with bolus doses 
delivered 0 to 2 minutes prior to the meal.  
Patients will be randomized in a 1:1 ratio to double-blind LY900014 with bolus dose delivered 0 
to 2 minutes before meals or double-blind Humalog with bolus doses delivered 0 to 2 minutes 
before meals.  Assuming an NIM of 0.4%, no true difference between treatment groups, and an 
SD of 0.88%, 368 completers (184 in each treatment group) will provide at least 99% power to 
show noninferiority between LY900014 and Humalog in change from baseline to Week 16 in 
HbA1c using the upper limit of a two-sided 95% confidence interval (CI) (LY900014 –
Humalog).  Assuming a 12% dropout rate for 16 weeks, approximately 420 patients will need to 
be randomized.  This sample size also has 90% power to show noninferiority between LY900014
and Humalog using a 0.3% NIM at Week 16.  

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10.2. Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Entered
All patients who give informed consent
Enrolled
All patients who receive at least 1 dose of open-label Humalog in the 2-week lead-in period
Randomized
All patients who are randomly assigned to study treatment at Visit 4.
Treatment group will be defined based on the treatment the patients were assigned.
Safety
All randomized patients who receive at least 1 dose of the randomly assigned IP.  
Treatment group will be defined based on the treatment the patients were assigned.
Abbreviation:  IP = investigational product.
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 
statistical analysis plan (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 up through Week 16.  
Efficacy analyses will be conducted on all randomized patients according to the treatment the 
patients are assigned. The analyses for the primary and multiplicity-adjusted objectives will be 
performed for the efficacy estimand including data collected prior to permanent discontinuation 
of IP and for the ITT estimand including all data collected through Week 16 regardless of IP use 
(Section 10.3.3.1).  Unless otherwise specified, the efficacy analyses for other secondary 
objectives and exploratory objectives will be performed for the efficacy estimand.  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 a postbaseline measurement are available.  
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 be conducted on data collected prior to permanent discontinuation of IP, 
while analyses for post-treatment may be conducted as needed.  Analyses of safety laboratory 
measurements will be performed on all data collected during the planned treatment period 
regardless of IP use.  
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.  Countries in similar 
geographic regions with fewer than 10 patients, based on the all-randomized population, will be 

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pooled to achieve a pooled country of at least 10 patients.  All analyses using country in the 
model will use a pooled country, unless otherwise specified.  The final pooling by country and 
geographic region will be finalized prior to data lock.
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 4) unless otherwise specified.  
A restricted-maximum-likelihood-based, mixed model repeated measures (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 (pooled country and patient’s personal CGM use during the study), 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 (≤7.5%, >7.5%) will be included in
the model.  An unstructured covariance structure will be used to model the within-patient errors.  
Significance tests will be based on least-squares (LS) means and Type III tests.  SAS PROC 
MIXED will be used to perform the analysis.  If this analysis fails to converge, the following 
covariance structures will be tested in order:

Toeplitz with heterogeneity

Autoregressive with heterogeneity

Compound symmetry with heterogeneous variances

Toeplitz

Autoregressive

Compound symmetry without heterogeneous variances.
The first covariance structure that converges will be used.  The Kenward-Roger approximation 
will be used to estimate denominator degrees of freedom.  
An analysis of covariance (ANCOVA) will also be used to analyze continuous variables
collected only at baseline and endpoint.  The model will include treatment and strata (pooled 
country, HbA1c stratum (≤7.5%, >7.5%), and patient’s personal CGM use during the study) 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 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-square 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 

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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 or Pearson’s chi-square 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 or Pearson’s chi-square test for categorical data and an analysis of 
variance (ANOVA) with treatment in the model for continuous data.  Baseline diabetes 
characteristics (including pump brand/model) will be summarized in a similar manner.  
Medical history and AEs at baseline will be summarized by preferred term (PT) within system 
organ class, and comparison between treatment groups will be performed using Fisher’s exact 
test.  
10.3.2.3. Concomitant Therapy 
The type of rapid-acting insulin therapy, and the total, basal and bolus insulin doses at study 
entry and at baseline will be compared between treatment groups using Fisher’s exact tests and 
ANOVA with treatment in the model.  
Concomitant medications used during the treatment period will be summarized and compared 
between treatment groups using Fisher’s exact test.  
10.3.3. Efficacy Analyses
10.3.3.1. Primary Analyses
The primary objective of this study is to test the hypothesis that LY900014 is noninferior to 
Humalog on glycemic control (NIM = 0.4% for HbA1c) in patients with T1D using CSII with 
bolus doses delivered 0 to 2 minutes prior to the meal for 16 weeks.  There will be 2 primary 
analysis methods, each tested at the full significance level of 0.05.  

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For the US FDA submission, the primary analysis will use the copy reference approach to impute 
missing data based on multiple imputations with a pattern mixture model.  This analysis is for 
the ITT estimand (treatment regimen estimand) which will include all data collected regardless 
of IP use.  The reference for each treatment group will be from the retrieved dropout patients 
who discontinue IP but have the measurement at the primary endpoint in the same treatment 
group.  If there are only a limited number of patients in the reference group as described above 
that leads to a failure in performing the proposed multiple imputation analysis, the reference will 
be changed to include all observed data from all randomized patients in the same treatment arm 
who complete the study without missing data.  After imputation, the primary efficacy 
comparison will be based on the contrast between LY900014 and Humalog from the ANCOVA 
analysis of change from baseline to Week 16 in HbA1c using all randomized patients as 
described in Section 10.3.1.
For non-FDA submissions and publications, the primary efficacy comparison will be based on 
the contrast between LY900014 and Humalog at Week 16 (Visit 13) 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 16 (efficacy estimand). The analysis model and
selection of covariance structure is described in Section 10.3.1.  
For both primary analysis approaches, LY900014 will be declared noninferior to Humalog 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 Humalog is below +0.4%.  In addition, the 95% CI for the 
treatment difference will be compared to an alternative NIM of +0.3%.  Both estimands will be 
tested at the full significance level of 0.05.  
In addition to the primary objective, the superiority of LY900014 in controlling HbA1c 
compared with Humalog will also be assessed for each 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 Humalog.
10.3.3.1.1.Sensitivity Analyses for Missing Data
A missing-not-at-random-based analysis will be performed for both the efficacy and ITT 
estimands to assess sensitivity to departures from the missing-at-random (MAR) assumption. 
The tipping-point approach that will be used is similar to a progressive stress test (Ratitch et al.
2013).  The basic idea is to impute the missing values and add a value (delta) to the imputed 
values of the experimental treatment group and perform an analysis for the primary endpoint on 
the delta-adjusted data set to see whether the conclusion of the primary analysis is overturned.  If
not, a larger delta is chosen, and the process repeated until the primary result is overturned.  If 
the delta required to overturn the primary result is not a plausible departure from MAR, then the 
primary result is robust to plausible departures from MAR.  The initial delta is set to 0.1 with an
increment of 0.1.  Imputation under the noninferiority null method (where delta equals the NIM)
will be included as a special case of the progressive stress test.
For the ITT estimand, the reference group will be as described for the FDA primary analysis, and 
ANCOVA on the change from baseline to Week 16 in HbA1c will be used.  

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For the efficacy estimand, the reference group will be the Humalog treatment group.  Imputation 
will be for all longitudinal visits. 
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 Humalog
for 1-hour PPG during MMTT at Week 16, 2-hour PPG during MMTT at Week 16, change from 
baseline to Week 16 in HbA1c, the duration of time glucose values are within target range during 
a 24-hour period at Week 16, and the duration of time glucose values are within target range 
during daytime (0600 hours to midnight) at Week 16. The glucose target range is defined as 70
to 180 mg/dL (3.9 to 10.0 mmol/L), both inclusive, obtained from CGM..  Analyses will be 
performed for both the efficacy estimand and ITT estimand as described in Section 10.3.3.1
using the same graphical testing scheme.
The graphical testing scheme will be described in the SAP.  The study total alpha level (or 
study-wise type I error) is preset to be 5% for each estimand. The study total alpha level will be 
used for the primary objective in the initial step. The alpha level will be allocated to other key 
endpoints based on the weights in testing paths once the primary endpoint is successfully 
demonstrated. If 1 of the remaining hypotheses is successfully demonstrated with the preserved 
alpha level, its preserved alpha will be allocated to the remainder of the hypotheses by the 
weights in the paths. The iterative test procedure continues until none of the remaining 
hypotheses can be demonstrated with their preserved alphas or all hypotheses are demonstrated 
successful.  
An ANCOVA model as described in Section 10.3.1 will be used to analyze the 1-hour and 
2-hour PPG. 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.  Analysis details will be documented in the SAP.
For continuous longitudinal secondary endpoints, the MMRM model similar to that for the
primary analysis will be used with HbA1c stratum (≤7.5%, >7.5%) added as a fixed effect.  
Duration and percent time in range, time in hypoglycemia and time in hyperglycemia derived 
from CGM data will also be analyzed using MMRM model with HbA1c stratum (≤7.5%, >7.5%) 
as a fixed effect.  Continuous nonlongitudinal secondary endpoints will be analyzed using the 
ANCOVA model with treatment and strata as fixed effects and baseline as a covariate.  
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.  Actual and 
change from baseline in basal, bolus, and total dose, as well as the bolus/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 by either 

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MMRM or ANCOVA models described in Section 10.3.1. Categorical variables will be 
analyzed either by models (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, unplanned infusion set changes and reasons, 
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 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.
SAEs, 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.  TEAEs will also be summarized by PT sorted by decreasing 
frequency within SOC for all TEAEs and by maximum severity.  For events that are specific to 
only one 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 study, and TEAEs will be 
summarized for open-label Humalog during the lead-in period.  
Hypoglycemia rates will be summarized for periods of 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 to 4 weeks of treatment period) will be analyzed by 
using a negative binomial regression model including treatment.  An offset defined as the log 
transformation of treatment exposure in the specific period (days)/365.25 days will be included 
in the model to estimate the rate of hypoglycemia per year.  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.  
Similarly, a negative binomial model and a logistic regression model including treatment will be 
used to analyze the rate of pump occlusion alarms leading to unplanned infusion set changes per 
30 days, and the proportion of patients with at least 1 occlusion alarm (incidence) leading to 
unplanned infusion set changes, respectively.
Continuous safety variables, as well as the change from baseline for these variables, will be 
analyzed by either MMRM or ANCOVA models.  For categorical variables, Fisher’s exact test 
or Pearson’s chi-square test will be used to compare treatment groups unless otherwise specified.  
The analyses for assessing immunogenicity data will be described in the SAP after being agreed 
with the FDA on the threshold for determining treatment-emergent antibodies to insulin lispro.

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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 16, Visit 13) in the EQ-5D-5L UK population-based 
health state index score and EQ-VAS score will be analyzed using the ANCOVA model 
described in the 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, and 
delivery system) and overall transformed score will be analyzed using the ANCOVA model 
described the Section 10.3.1.
10.3.5.2. Subgroup Analyses
The following subgroups will be analyzed using the efficacy estimand to evaluate consistency of 
treatment effects on the primary efficacy measure if there are sufficient numbers of patients in 
each treatment by subgroup (for example, 10%):

Age (40 years, 40 years)

HbA1c stratum (≤7.5%, >7.5%)

Patient’s personal CGM use during the study (yes/no)

Patient’s use of low glucose suspends during the study (yes/no)

Sex (Male or Female)

BMI (<25, ≥25 kg/m2 )

Bolus delivery speed at study entry

Duration of Diabetes (using the median as the cutoff)

Race

Ethnicity

Country

Region
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 (Week 16) will be evaluated to assess the treatment by 
subgroup interaction.  When analyzing HbA1c stratum (≤7.5%, >7.5%) as a subgroup the 
baseline HbA1c will be not be included as a covariate to avoid confounding.  

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

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11.
References
Anderson RT, Skovlund SE, Marrero D, Levine DW, Meadows K, Brod M, Balkrishnan R. 
Development and validation of the insulin treatment satisfaction questionnaire. Clin Ther. 
2004;26(4):565-578.
Battelino T, Bergenstal RM, Amiel SA, Beck R, Biester T, Bosi E, Buckingham BA, Cefalu WT, 
Close KL, Cobelli C, Dassau E, DeVries JH,, Donaghue KC, Dovc K, Doyle FJ rd, Garg S, 
Grunberger G, Heller S, Heinemann L, Hirsch IB, Hovorka R, Jia W, Kordonouri O, 
Kovatchev B, Kowalski A, Laffel L, Levine B, Mayorov A, Mathieu C, Murphy HR, Nimri R, 
Nørgaard K, Parkin CG, Renard E, Rodbard D, Saboo B, Schatz D, Stoner K, Urakami T, 
Weinzimer SA, Phillip M. Clinical targets for continuous glucose monitoring data 
interpretation: Recommendations from the International Consensus on Time in Range
[published online June 8, 2019]. Diabetes Care. doi: 10.2337/dci19-0028.
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.
[CCNYHA] The Criteria Committee of the New York Heart Association. Nomenclature and 
criteria for diagnosis of diseases of the heart and great vessels. 9th ed. Boston (MA): Little, 
Brown & Company; 1994: 253-256.
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
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? Statist Med. 
2009;28(2):2509-2530.
Lu K. On efficiency of constrained longitudinal data analysis versus longitudinal analysis of 
covariance. Biometrics. 2010;66(3):891-896.
Ratitch B, O’Kelly M, Tosiello R. Missing data in clinical trials: from clinical assumptions to 
statistical analysis using pattern mixture models. Pharm Stat. 2013;12(6):337-347.
Remodulin [prescribing information]. Research Triangle Park, NC: United Therapeutics Corp; 
2014.
Van Reenen M, Janssen B. EuroQol Research Foundation. EQ-5D-5L Users Guide.EuroQol.org. 
Available at:
http://www.euroqol.org/fileadmin/user_upload/Documenten/PDF/Folders_Flyers/EQ-5D-5L_
UserGuide_2015.pdf. Accessed December 9, 2015.

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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 
patient administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An adverse event 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.
AIT
active insulin time
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANOVA
analysis of variance
AST
aspartate aminotransferase
BG
blood glucose
blinding/masking
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the patient is not, or vice versa, or when the sponsor is aware of the treatment,
but the investigator and/his staff and the patient are not.
A double-blind study is one in which neither the patient nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the patients are 
aware of the treatment received.
BMI
body mass index
CF
correction factor
CGM
continuous glucose monitoring
CI
confidence interval
CRF
case report form
Product complaint
Product complaints are a customer’s written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a Lilly product after it is released for distribution.
CR
Carbohydrate ratio

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CRP/CRS
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
ECG
electrocardiogram
EDC
electronic data-capture
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
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
Food and Drug Administration
FGM
flash glucose monitoring
GCP
good clinical practice
GD
glucodynamic(s)
GRAS
Generally Recognized As Safe
HbA1c
hemoglobin A1c
HCP
health care provider
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use

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IM
intramuscular
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.
ISF
Insulin sensitivity factor
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
MAR
missing at random
MDI
multiple daily injections
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed-effect model repeated measure
MMTT
Mixed-meal tolerance test
NIM
noninferiority margin
NPH
neutral protamine Hagedorn
PD
Pharmacodynamic(s)
PK
pharmacokinetic(s)
PPG
postprandial glucose
PT
preferred term

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RBA
radio ligand-binding assay
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
screen
The act of determining if an individual meets minimum requirements to become part of a pool 
of potential candidates for participation in a clinical study. 
SD
standard deviation
SMBG
self-monitored blood glucose
SUSARs
suspected unexpected serious adverse reactions
T1D
type 1 diabetes
T2D
type 2 diabetes
TBL
total bilirubin level
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
Unexplained
Hyperglycemia
High blood glucose (≥300 mg/dL) that cannot be explained by a missed prior bolus, dietary 
indiscretion, rebound or treatment of hypoglycemia, a pump failure, an empty pump 
reservoir, an infusion
set complication (e.g.; kinked, came out, leaking), or an infusion site complication
(e.g.; pain, redness).
VAS
visual analog scale

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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
eGFR (calculated by MDRD equation)b
Ketones
Blood
1,5 Anhydroglucitol 
Urine leukocyte esterase
HbA1c
Bilirubin 
Nitrite
Serology
Anti-insulin lispro antibodies 
Pregnancy test (females only)c
Follicle-stimulating hormoned
Abbreviations:  eGFR = estimated glomerular filtration rate; HbA1c = glycated hemoglobin A1c IP = investigational 
product; MDRD = Modification of Diet in Renal Disease Study; 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
MDRD:  175 [SCr] 1.154 [age] – 0.203 [0.742 if female] [1.212 if black]; SCr = serum creatinine 
(mg/dL), final value will be expressed as mL/min/1.73 m2.
c
Serum pregnancy test must be performed in women of childbearing potential at Visit 1 followed by a urine 
pregnancy test within 24 hours prior to IP exposure at randomization and at other times at the investigator’s 
discretion.  When required per local regulations and/or institutional guidelines, local pregnancy testing will occur 
at mandatory times during the study treatment period.  
d
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.

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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

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 trial.
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 Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) 
guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the informed consent form (ICF) must be 
provided to 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 current Investigator’s Brochure (IB) and updates during the course of the 
study

ICF

relevant curricula vitae.
Appendix 3.1.3.
Regulatory Considerations
This study will be conducted in accordance with:

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

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Some of the obligations of the sponsor will be assigned to a third-party.
Appendix 3.1.4.
Investigator Information
A physician with expertise treating patients with type 1 diabetes (T1D) and experience in clinical 
trials.
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 clinical study report (CSR) coordinating investigator will sign the final 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 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
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.

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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
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.
An electronic data-capture (EDC) system will be used in this study for the collection of CRF 
data.  The investigator maintains a separate source for the data entered by the investigator or 
designee into the sponsor-provided EDC system.  The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF.
Additionally, clinical outcome assessment data (questionnaires and self-reported diary data) will 
be collected by the subject, via a paper source document and will be transcribed by the 
investigator-site personnel into the EDC system.
Data collected via the sponsor-provided data capture system will be stored with a third party.  
The investigator will have continuous access to the data during the study and until 
decommissioning of the data-capture system.  Prior to decommissioning, the investigator will 
receive an archival copy of pertinent data for retention.
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and reports will be provided to the investigator for review 
and retention.  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.

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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
Alkaline Phosphatase Isoenzymesa
CPK
Anti-smooth muscle antibody (or anti-actin antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspirate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalised 
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.
Classification of Contraceptive Methods
Women of childbearing 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.  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

Bilateral tubal occlusion

Total abstinencea

Vasectomy 

Male condom with spermicide

Female condom with spermicide

Diaphragm with spermicide

Cervical sponge with spermicide

Cervical cap with spermicide
a
Total abstinence (as patient’s preferred and usual lifestyle) or in a same-sex relationship (as part of patient’s 
preferred and usual lifestyle). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods), declaration of abstinence just for the duration of a trial, and withdrawal are not acceptable methods of 
contraception.

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Appendix 6.
Protocol Amendment I8B-MC-ITRO (c) 
Summary
A Prospective, Randomized, Double-Blind Comparison 
of LY900014 to Humalog in Adults with Type 1 Diabetes 
Using Continuous Subcutaneous Insulin Infusion
PRONTO-Pump-2
Overview
Protocol I8B-MC-ITRO A Prospective, Randomized, Double-Blind Comparison of 
LY900014 to Humalog in Adults with Type 1 Diabetes Using Continuous Subcutaneous 
Insulin Infusion PRONTO-Pump-2 has been amended.  The new protocol is indicated by 
amendment (c) and will be used to conduct the study in place of any preceding version of the 
protocol.
The overall changes and rationale for the changes made to this protocol are described in the 
following table:
Amendment Summary for Protocol I8B-MC-ITRO Amendment (c)
Section # and Name
Description of Change
Brief Rationale
Section 1, Synopsis
Section 4, 
Objectives and 
Endpoints
The secondary objectives of 1- and 2-hour 
postprandial glucose excursions were
changed to 1- and 2-hour postprandial 
glucose. 
The secondary objective that compared 
glucose time in range (70-180 mg/dL)  
during the 24-hour period for LY900014 and 
Humalog is now controlled for Type I error 
and included with the multiplicity adjusted 
objectives. 
The glucose time in range (70-180 mg/dL) 
during the daytime period (6 am to midnight) 
for LY900014 and Humalog was added and 
is controlled for Type I error and included 
with the multiplicity adjusted objectives. 
PPG excursion endpoints were changed 
to actual PPG measurements based on 
improvements in both fasting and 
postprandial glucose observed in Study 
I8B-MC-ITSI and predicted in PK/PD 
models with administration of 
LY900014 by CSII.  The use of absolute 
1- and 2-hour PPG values, rather than 
PPG excursions, will provide a more 
complete evaluation of the glycemic 
benefit offered by LY900014 during 
CSII, and it is expected that this change 
will result in greater power to detect 
differences between treatment groups in 
this study. 
Section 9.1.2, 
Secondary Efficacy 
Assessments
‘Excursions’ and ‘minus fastings serum 
glucose’ were removed from the secondary 
efficacy measure of ‘Fasting and PPG 
collected during the MMTT’ to reflect the 
change in objectives. 
Section 10.3.3.2, 
Secondary Analyses
‘Excursion’ was removed from the 1 and 2-
hour PPG secondary objective to reflect the 
change in objectives. 

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Also, the duration of time glucose values was
within the target range of 70 and 180 mg/dL
during the daytime (6 am to midnight) and 
24-hour period was added  the secondary 
analyses. 
Time in range endpoints were added as 
this measure is becoming of increasing 
importance to patients and prescribers, 
as evidenced in recent consensus 
statements from ADA (Battelino et al., 
2019).  All patients in the study will 
undergo several blinded CGM 
evaluation periods; these data will form 
the basis for the TIR analyses.  
Measurements were added to evaluate 
time in range over a 24-hour time period 
and also over the daytime period (6 am 
to midnight).  Including these measures 
in the graphical approach allows us to 
control the type I error and correct for 
multiplicity, meaning that these 
endpoints, if positive, may be suitable 
for inclusion in product labeling.  

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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
Section 1 Synopsis and Section 4 Objectives and Endpoints
Objective(s)/Endpoints:
Objectives
Endpoints
Primary Objective
1.
To test the hypothesis that LY900014 is 
noninferior to Humalog on glycemic 
control ([NIM = 0.4% for HbA1c) in 
patients with T1D using CSII for 16 weeks
1.
Difference between LY900014 and Humalog in 
change from baseline to Week 16 in HbA1c
Multiplicity Adjusted Objectives
2.
To test the hypothesis that LY900014 is 
superior to Humalog in controlling 1-hour 
postprandial glucose (PPG) excursions
2.
Difference between LY900014 and Humalog in
change from baseline to Week 16 in the 1-hour 
PPG excursion (serum glucose measured 1 hour 
after the start of the meal minus fasting serum 
glucose) from a MMTT at Week 16 and change 
from baseline to Week 16
3.
To test the hypothesis that LY900014 is 
superior to Humalog in controlling 2-hour 
PPG excursions 
3.
Difference between LY900014 and Humalog in 
change from baseline to Week 16 in the 2-hour 
PPG excursion (serum glucose measured 2 
hours after the start of the meal minus fasting 
serum glucose) from a MMTT at Week 16 and 
change from baseline to Week 16
4.
To test the hypothesis that LY900014 is 
superior to Humalog on improving glycemic 
control (HbA1c) 
4.
Difference between LY900014 and Humalog in 
change from baseline to Week 16 in HbA1c
5.
To test the hypothesis that LY900014 is 
superior to Humalog in the duration of time 
glucose values within target range 70 to
180 mg/dL (3.9 to 10.0 mmol/L), obtained 
from CGM use during 24-hour period
5.
Duration (in minutes and percentage of time)
with glucose values between 70 and 180 mg/dL 
(3.9 and 10.0 mmol/L), both inclusive, 
normalized to a 24-hour period, from each 
14-day CGM session at Week 16 
6.
To test the hypothesis that LY900014 is 
superior to Humalog in the duration of time 
glucose values within target range 70 to
180 mg/dL (3.9 to10.0 mmol/L), obtained 
from CGM use during daytime
6.
Duration (in minutes and percentage of time)
with glucose values between 70 and 180 mg/dL 
(3.9 and 10.0 mmol/L), both inclusive, 
normalized to daytime  (0600 hours to 
midnight), from each 14-day CGM session at 
Week 16 
Other Secondary Objectives
7.
To compare LY900014 and Humalog with 
respect to the rate of severe hypoglycemic 
events
7.
Rate (events/ patient/100 years) of severe 
hypoglycemic events from baseline through 
Week 16

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8.
To compare LY900014 and Humalog with 
respect to the rate and incidence of 
documented postmeal hypoglycemia 
8.
Rate (events/patient/year) and incidence 
(percent of patients with at least 1 event) of 
documented postmeal hypoglycemia within 
1 and 2 hours after the start of the meal from 
baseline through Week 16
9.
To compare LY900014 and Humalog with 
respect to the rate and incidence of 
documented hypoglycemia
9.
Rate (events/patient/year) and incidence 
(percentage of patients with events) of 
documented hypoglycemic events from baseline 
through Week 16
10. To compare LY900014 and Humalog with 
respect to 1,5-AG
10. Change from baseline 1,5-AG values at 
Week 16
11. To compare LY900014 and Humalog with 
respect to 10-point SMBG profiles
11. Change from baseline 10-point SMBG values at 
Week 16
12. To compare LY900014 and Humalog with 
respect to total, basal, and bolus insulin dose
12. Change from baseline in bolus/total insulin dose 
ratio at Week 16
13. To compare LY900014 and Humalog with 
respect to the proportion of patients 
achieving HbA1c targets
13. The proportion of patients with HbA1c <7% 
and ≤6.5% at Week 16
To compare LY900014 and Humalog with
respect to the duration of time glucose values 
are within target range (70 and 180 mg/dL 
[3.9 and 10.0 mmol/L]), obtained from CGM 
use
Duration (in minutes) and percentage of time 
with glucose values between 70 and 180 mg/dL 
(3.9 and 10.0 mmol/L), both inclusive, 
normalized to a 24 hour period, from each 
14 day CGM session at Week 16
14. To compare LY900014 and Humalog with 
respect to the duration of time spent in 
hypoglycemic glucose ranges, obtained from 
CGM use
14. Duration (in minutes) and percentage of time 
with glucose values <54 and <70 mg/dL (3.0 
and 3.9 mmol/L), normalized to a 24-hour 
period and number of episodes, defined as at 
least 10 consecutive minutes <54 and
<70 mg/dL, from each 14-day CGM session at 
Week 16
15. To compare LY900014 and Humalog with 
respect to the duration of time spent in 
hyperglycemic glucose ranges, obtained from 
CGM use
15. Duration (in minutes) and percentage of time 
with glucose values >180 and >250 mg/dL 
(10.0 and 13.9 mmol/L), normalized to a 
24-hour period and number of episodes, defined 
as at least 10 consecutive minutes >180 and
>250 mg/dL, from each 14-day CGM session at 
Week 16
16. To compare LY900014 and Humalog with 
respect to the incidence and rate of pump 
occlusion alarms that lead to an unplanned 
infusion set change
16. Rate (events/patient/30 days) and incidence 
(percent of patients with at least 1 event) of 
pump occlusion alarms that lead to an 
unplanned infusion set change from baseline 
through Week 16
17. To compare LY900014 and Humalog with 
respect to the incidence and rate of 
episodes of unexplained hyperglycemia that 
lead to an unplanned infusion set change
17. Rate (events/patient/30 days) and incidence 
(percent of patients with at least 1 event of 
unexplained hyperglycemia > 300 mg/dL 
confirmed by SMBG that leads to an unplanned 
infusion set change from baseline through 
Week 16

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Abbreviations:  1,5-AG = 1,5-Anhydroglucitol; AIT = active insulin time; AUC = area under the curve;
CGM = continuous glucose monitoring; CR = carbohydrate ratio; CSII = continuous subcutaneous insulin 
infusion; CV = coefficient of variation; EQ-5D-5L = EuroQol 5D-5L; EQ-VAS = EQ visual analog scale; 
HbA1c = hemoglobin A1c; HBGI = high blood glucose index; ISF = insulin sensitivity factor; ITSQ = Insulin 
Treatment Satisfaction Questionnaire; LBGI = low blood glucose index; MMTT = mixed meal tolerance test; 
NIM = noninferiority margin; SMBG = self-monitored blood glucose; T1D = type 1 diabetes; UK = United 
Kingdom.
Section 9.1.2 Secondary Efficacy Assessments

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 the 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:
o
1-hour and 2-hour PPG and PPG excursions by meal and across all 
meals
o
Within- and between-day glucose variability measured by the 
coefficient of variation and SD

CGM
o
Duration and percentage of time in range (70-180 mg/dL [3.9-
10.0 mmol/L]) during the daytime (0600 hours to midnight) and 24-
hour period obtained by study-provided Dexcom blinded CGM
o
Duration and percentage of time with glucose values <54 and 
<70 mg/dL (3.0 and 3.9 mmol/L)
Section 10.3.3.2 Secondary Analyses
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 Humalog
for 1-hour PPG excursion during MMTT at Week 16, 2-hour PPG excursion during MMTT at 
Week 16, and change from baseline to Week 16 in HbA1c, the duration of time glucose values 
are within target range during daytime (0600 hours to midnight) at Week 16. The glucose target 
range is desfined as 70 to 180 mg/dL (3.9 to 10.0 mmol/L), both inclusive, obtained from CGM . 

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Analyses will be performed for both the efficacy estimand and ITT estimand as described in 
Section 10.3.3.1 using the same graphical testing scheme.
The graphical testing scheme will be described in the SAP.  The study total alpha level (or 
study-wise type I error) is preset to be 5% for each estimand. The study total alpha level will be 
used for the primary objective in the initial step. The alpha level will be allocated to other key 
endpoints based on the weights in testing paths once the primary endpoint is successfully 
demonstrated. If 1 of the remaining hypotheses is successfully demonstrated with the preserved 
alpha level, its preserved alpha will be allocated to the remainder of the hypotheses by the 
weights in the paths. The iterative test procedure continues until none of the remaining 
hypotheses can be demonstrated with their preserved alphas or all hypotheses are demonstrated 
successful.  
An ANCOVA model as described in Section 10.3.1 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.  Analysis details will be documented in the SAP.
For continuous longitudinal secondary endpoints, the MMRM model similar to that for the
primary analysis will be used with HbA1c stratum (≤7.5%, >7.5%) added as a fixed effect.
Duration and percent time in range, time in hypoglycemia and time in hyperglycemia derived 
from CGM data will also be analyzed using MMRM model with HbA1c stratum (≤7.5%, >7.5%) 
as a fixed effect.  Continuous nonlongitudinal secondary endpoints will be analyzed using the 
ANCOVA model with treatment and strata as fixed effects and baseline as a covariate.  
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.  Actual and 
change from baseline in basal, bolus, and total dose, as well as the bolus/total insulin dose ratio 
will be analyzed by the MMRM models described in Section 10.3.1.

Leo Document ID = 162755db-eda4-4fa1-93bd-33cd456572f7
Approver: 
Approval Date & Time: 08-Oct-2019 14:38:18 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 08-Oct-2019 16:36:20 GMT
Signature meaning: Approved
PPD
PPD