A Prospective, Randomized, Double-Blind, Crossover Comparison Evaluating Compatibility and Safety of LY900014 and Insulin Lispro With an External Continuous Subcutaneous Insulin Infusion System in Adult Patients With Type 1 Diabetes (PRONTO-Pump)
Phase: PHASE3
Conditions: Diabetes Type 1
Sponsor: Eli Lilly and Company

A Prospective, Randomized, Double-Blind, Crossover 
Comparison Evaluating Compatibility and Safety of 
LY900014 and Insulin Lispro with an External Continuous 
Subcutaneous Insulin Infusion System in Adult Patients 
with Type 1 Diabetes (PRONTO-Pump) 
 
NCT03433677 
 
Approval Date: 12Jan2018 

I8B-MC-ITSI (a) Clinical Protocol
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LY900014
Protocol I8B-MC-ITSI (a)
A Prospective, Randomized, Double-Blind, Crossover 
Comparison Evaluating Compatibility and Safety of 
LY900014 and Insulin Lispro with an External Continuous 
Subcutaneous Insulin Infusion System in Adult Patients 
with Type 1 Diabetes (PRONTO-Pump)
EuDRA CT #:  2017-002374-39
Confidential Information
The information contained in this document is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
LY900014, unless such persons are bound by a confidentiality agreement with Eli Lilly and 
Company or its subsidiaries.  
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure. Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
LY900014
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly: 23 October 2017
Amendment (a) Electronically Signed and Approved by Lilly
on approval date provided below.
Approval Date: 12-Jan-2018 GMT

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Table of Contents
Section
Page
Protocol I8B-MC-ITSI (a) A Prospective, Randomized, Double-Blind, 
Crossover Comparison Evaluating Compatibility and Safety of 
LY900014 and Insulin Lispro with an External Continuous 
Subcutaneous Insulin Infusion System in Adult Patients with Type 1 
Diabetes (PRONTO-Pump).................................................................................................1
Table of Contents........................................................................................................................2
1.
Synopsis .............................................................................................................................8
2.
Schedule of Activities .......................................................................................................12
3.
Introduction ......................................................................................................................18
3.1.
Study Rationale............................................................................................................18
3.2.
Background..................................................................................................................19
3.3.
Benefit/Risk Assessment..............................................................................................20
4.
Objectives and Endpoints..................................................................................................21
5.
Study Design.....................................................................................................................24
5.1.
Overall Design .............................................................................................................24
5.2.
Number of Participants.................................................................................................26
5.3.
End of Study Definition ...............................................................................................26
5.4.
Scientific Rationale for Study Design...........................................................................26
5.5.
Justification for Dose ...................................................................................................26
6.
Study Population...............................................................................................................28
6.1.
Inclusion Criteria..........................................................................................................28
6.2.
Exclusion Criteria ........................................................................................................30
6.3.
Lifestyle Restrictions....................................................................................................33
6.4.
Screen Failures.............................................................................................................33
7.
Treatments........................................................................................................................34
7.1.
Treatments Administered .............................................................................................34
7.1.1.
Packaging and Labelling ......................................................................................34
7.1.2.
Insulin Pumps ......................................................................................................35
7.1.3.
Method of Treatment Assignment ........................................................................35
7.1.4.
Selection and Timing of Doses.............................................................................35
7.1.4.1.
Target Glucose Values for Titration of Insulin Therapy ..................................35
7.1.4.2.
Insulin Titration..............................................................................................36
7.1.4.3.
Transitioning off Study Insulin Therapy .........................................................36
7.2.
Blinding .......................................................................................................................36
7.3.
Dosage Modification....................................................................................................37

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7.4.
Preparation/Handling/Storage/Accountability...............................................................37
7.5.
Treatment Compliance .................................................................................................37
7.6.
Concomitant Therapy...................................................................................................37
7.7.
Treatment after the End of the Study............................................................................38
7.7.1.
Continued Access.................................................................................................38
7.7.2.
Special Treatment Considerations ........................................................................38
8.
Discontinuation Criteria ....................................................................................................39
8.1.
Discontinuation from Study Treatment.........................................................................39
8.1.1.
Discontinuation of Inadvertently Enrolled Patients...............................................39
8.2.
Discontinuation from the Study....................................................................................39
8.3.
Lost to Follow-Up........................................................................................................40
9.
Study Assessments and Procedures ...................................................................................41
9.1.
Safety Assessments ......................................................................................................41
9.1.1.
Primary Assessments ...........................................................................................41
9.1.2.
Secondary Assessments........................................................................................41
9.1.3.
Appropriateness of Assessments ..........................................................................41
9.1.4.
Study Procedures .................................................................................................41
9.1.4.1.
Electronic Clinical Outcomes Assessment ......................................................41
9.1.4.1.1.
Correction Boluses....................................................................................42
9.1.4.1.2.
Infusion Set Changes ................................................................................42
9.1.4.1.3.
Hypoglycemia...........................................................................................42
9.1.4.1.4.
Self-Monitoring Blood Glucose ................................................................43
9.1.4.1.4.1.
Four-Point Self-Monitoring Blood Glucose.........................................43
9.1.4.2.
Troubleshooting Unexplained Hyperglycemia ................................................43
9.1.4.3.
Continuous Glucose Monitoring .....................................................................43
9.1.4.4.
Diabetes Education and Nutritional Counseling ..............................................44
9.2.
Adverse Events ............................................................................................................44
9.2.1.
Serious Adverse Events........................................................................................45
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................46
9.2.2.
Complaint Handling.............................................................................................46
9.2.2.1.
Device Complaint Handling............................................................................47
9.3.
Treatment of Overdose.................................................................................................47
9.4.
Safety...........................................................................................................................47
9.4.1.
Hypoglycemia......................................................................................................47
9.4.2.
Severe Hypoglycemia ..........................................................................................48
9.4.3.
Electrocardiograms ..............................................................................................48
9.4.4.
Vital Signs ...........................................................................................................48
9.4.5.
Laboratory Tests ..................................................................................................49

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9.4.6.
Immunogenicity Assessments ..............................................................................49
9.4.7.
Pump Occlusion Alarms and Suspected Pump Occlusions....................................49
9.4.8.
Safety Monitoring ................................................................................................49
9.4.8.1.
Hepatic Safety Monitoring..............................................................................49
9.5.
Pharmacokinetics .........................................................................................................50
9.6.
Pharmacodynamics ......................................................................................................50
9.7.
Pharmacogenomics ......................................................................................................50
9.8.
Biomarkers...................................................................................................................50
9.9.
Health Economics ........................................................................................................50
10.
Statistical Considerations ..................................................................................................51
10.1. Sample Size Determination ..........................................................................................51
10.2. Populations for Analyses..............................................................................................51
10.3. Statistical Analyses ......................................................................................................51
10.3.1.
General Statistical Considerations ........................................................................51
10.3.2.
Treatment Group Comparability...........................................................................53
10.3.2.1.
Patient Disposition..........................................................................................53
10.3.2.2.
Patient Characteristics ....................................................................................53
10.3.2.3.
Concomitant Therapy .....................................................................................53
10.3.2.4.
Treatment Compliance....................................................................................53
10.3.3.
Safety Analyses....................................................................................................54
10.3.3.1.
Primary Analyses ...........................................................................................54
10.3.3.2.
Secondary Analyses........................................................................................54
10.3.3.3.
Tertiary/Exploratory Analyses ........................................................................56
10.3.3.4.
Subgroup Analyses.........................................................................................56
10.3.4.
Efficacy Analyses ................................................................................................56
10.3.5.
Interim Analyses..................................................................................................57
11.
References ........................................................................................................................58
12.
Appendices .......................................................................................................................59

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List of Tables
Table
Page
Table ITSI.1.
Schedule of Activities....................................................................................13
Table ITSI.2.
Objectives and Endpoints...............................................................................21
Table ITSI.3.
Treatment Regimens......................................................................................34
Table ITSI.4.
Target Glucose Values for Adjustment of Insulin Therapy.............................36
Table ITSI.5.
Concomitant Medications ..............................................................................38

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

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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................60
Appendix 2.
Clinical Laboratory Tests...............................................................................63
Appendix 3.
Study Governance Considerations..................................................................64
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................69
Appendix 5.
World Health Organization Classification for Diabetes..................................70
Appendix 6.
Classification of Contraceptive Methods........................................................71
Appendix 7.
New York Heart Association Cardiac Disease Classification .........................72
Appendix 8.
Protocol Amendment I8B-MC-ITSI (a) Summary
A Prospective, Randomized, Double-Blind, Crossover Comparison 
Evaluating Compatibility and Safety of LY900014 and Insulin Lispro 
with an External Continuous Subcutaneous Insulin Infusion System in 
Adult Patients with Type 1 Diabetes (PRONTO-Pump).................................73

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1. Synopsis
Title of Study:
A Prospective, Randomized, Double-Blind, Crossover Comparison Evaluating Compatibility and 
Safety of LY900014 and Insulin Lispro with an External Continuous Subcutaneous Insulin 
Infusion System in Adult Patients with Type 1 Diabetes (PRONTO-Pump)
Rationale: 
Insulin pumps use only rapid-acting insulin for both basal and bolus insulin requirements.  Basal 
insulin is a continuous infusion of insulin that is delivered automatically 24 hours a day.  The 
purpose of basal insulin is to cover hepatic glucose production and maintain glucose stability 
during fasting states (between meals and during sleep).  Bolus insulin is delivered “on-demand,”
by the patient, for food intake and/or to correct glucose levels that are above the patient’s target 
range, delivered separately or together.  
Because insulin pump therapy uses only rapid-acting insulin, the onset of diabetic ketoacidosis 
(DKA) can occur quickly if insulin delivery is interrupted for a period of time. The most 
important DKA prevention strategies are:  1) adhering to a routine blood glucose (BG) 
monitoring/continuous glucose monitoring schedule and 2) never ignoring an unexplained high 
BG. A high BG level that is not responding to a correction bolus via insulin pump may indicate 
an infusion set occlusion or insulin pump malfunction.
The aim of this study is to compare LY900014 and insulin lispro with respect to the rate 
(events/patient/30 days) of infusion set failures that lead to premature infusion set changes, due 
to a pump occlusion alarm OR due to unexplained hyperglycemia with BG >250 mg/dL 
(13.9 mmol/L) that does not decrease within 1 hour following a correction bolus delivered via 
the pump.
Objective(s)/Endpoints:
Objectives
Endpoints
Primary Objective
1.
To compare LY900014 and insulin lispro with 
respect to the rate of infusion set failures that 
lead to premature infusion set changes, due to 
a pump occlusion alarm OR due to 
unexplained hyperglycemia with blood 
glucose >250 mg/dL (13.9 mmol/L) that does 
not decrease within 1 hour following a 
correction bolus delivered via the pump
1.
Rate (events/patient/30 days) of infusion set 
failures that lead to premature infusion set 
changes, due to a pump occlusion alarm OR due 
to unexplained hyperglycemia with blood 
glucose (SMBG) >250mg/dL (13.9 mmol/L) 
that does not decrease within 1 hour following a 
correction bolus delivered via the pump, during 
the 6-week treatment period

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Objectives
Endpoints
Secondary Objectives
2.
To compare LY900014 and insulin lispro with 
respect to the incidence of infusion set failures
that lead to premature infusion set changes, 
due to a pump occlusion alarm OR due to 
unexplained hyperglycemia with blood 
glucose >250 mg/dL (13.9 mmol/L) that does 
not decrease within 1 hour following a 
correction bolus delivered via the pump
2.
Incidence (percent of patients with at least 
1 event) of infusion set failures that lead to 
premature infusion set changes, due to a pump 
occlusion alarm OR due to unexplained 
hyperglycemia with blood glucose (SMBG)
>250 mg/dL (13.9 mmol/L) that does not 
decrease within 1 hour following a correction 
bolus delivered via the pump, during the 6-week 
treatment period
3.
To compare LY900014 and insulin lispro with 
respect to the rate and incidence of premature 
infusion set changes
3.
Rate (events/patient/30 days) and incidence of 
premature infusion set changes by reason 
(infusion set kinked, came out, or leaking; 
empty pump reservoir; infusion site pain or 
redness; pump occlusion alarm; suspected 
infusion set occlusion; other) during the 6-week 
treatment period
4.
To compare LY900014 and insulin lispro with 
respect to the time interval until infusion set 
change 
4.
Time interval until infusion set change during 
the 6-week treatment period
5.
To compare LY900014 and insulin lispro with 
respect to total, basal, and bolus insulin dose
5.
Bolus/total insulin dose ratio at the end of the 
6-week treatment period
6.
To compare LY900014 and insulin lispro with 
respect to the interstitial glucose reduction rate 
from hyperglycemia following a non-meal-
related correction bolus delivered via the pump
6.
Interstitial glucose reduction rate (glucose 
reduction [mg/dL and mmol/L] per minute) 
within 4 hours following a non-meal-related 
correction bolus via the pump, from 
hyperglycemia (interstitial glucose >180 mg/dL
[10 mmol/L]) to recovery (interstitial glucose 
≤180 mg/dL), from up to 6 weeks of CGM use
7.
To compare LY900014 and insulin lispro with 
respect to the rate of severe hypoglycemic 
events 
7.
Rate (events/patient/100 years) of severe 
hypoglycemic events during the 6-week 
treatment period
Abbreviations:  CGM = continuous glucose monitoring; SMBG = self-monitored blood glucose.

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Summary of Study Design:  
Study I8B-MC-ITSI is a Phase 3, prospective, randomized, double-blind, outpatient, 
multinational, multicenter, 2-treatment group, crossover, active-controlled study conducted in 
patients with type 1 diabetes currently using an external continuous subcutaneous insulin 
infusion pump.  In the two treatment groups, LY900014 and insulin lispro, meal bolus doses will 
be delivered immediately prior to each meal (0 to 2 minutes) in a double-blind manner.  
Treatment Arms and Duration:  
The study includes a 1-week screening period and a 2-week lead-in period followed by a 
2-period crossover and a 4-week post-treatment safety follow-up.  Each period of the crossover 
will consist of 6 weeks of treatment with no washout between periods.
Patients will be randomized to 1 of the 2 treatment sequences in a 1:1 ratio:
Sequence A: LY900014    insulin lispro
Sequence B: insulin lispro LY900014
Number of Participants:
Approximately 60 participants will be screened to achieve 48 randomized patients and 
approximately 42 patients completing 12 weeks of treatment.
Statistical Analysis:
Safety analyses will be conducted on the Safety Population. Analyses of AEs (including DKA)
will include all data collected during the course of the entire 6-week treatment period for each 
treatment group regardless of IP use.  Analyses of hypoglycemia will be conducted on data 
collected prior to permanent discontinuation (ie, last dose) of IP in each 6-week treatment period. 
Unless otherwise specified, pump-related safety analyses (infusion set failures, premature 
infusion set changes, time interval until infusion set change, and interstitial glucose reduction 
rate) will exclude data (if any) that are collected while patients temporarily are off pump or off 
IP.  Data collected during the safety follow-up period will not be used for comparisons between 
treatment groups.
Unless otherwise noted, all tests of treatment effects will be conducted at a 2-sided alpha level of 
0.05 and confidence intervals (CIs) will be calculated at 95%, 2-sided.
Baseline is defined as the last non-missing measurement at or before the randomization visit 
(Visit 3), unless otherwise specified.  
The primary objective of this study is to compare LY900014 and insulin lispro with respect to 
the rate (events/patient/30 days) of infusion set failures that lead to premature infusion set 
changes, due to a pump occlusion alarm OR due to unexplained hyperglycemia with blood 
glucose (SMBG) >250 mg/dL (13.9 mmol/L) that does not decrease within 1 hour following a 
correction bolus delivered via the pump, during the 6-week treatment period.

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To be considered as the primary endpoint, an infusion set failure must result in a premature 
infusion set change due to:
1. pump occlusion alarm(s), OR
2. unexplained hyperglycemia that meets the following conditions:

Associated with a non-meal-related correction bolus delivered via the pump at least 
1 hour before the infusion set change

Most recent self-monitored blood glucose (SMBG) within 1 hour before the 
correction bolus >250 mg/dL (13.9 mmol/L)  

At least 1 SMBG obtained following the correction bolus prior to the infusion set 
change

Within 1 hour (+10 minutes) following the correction bolus, the most recent SMBG
prior to the infusion set change does not indicate a decrease in blood glucose
If more than 1 non-meal-related correction bolus is given for an unexplained hyperglycemia, 
only the first correction bolus time will be used to determine the 1-hour (+10 minutes) timeframe 
following the correction bolus.
The analyses of the primary objective will be conducted on the Safety Population including data 
collected prior to permanent discontinuation of investigational product (ie, last dose) in each 
randomized treatment period (Period I and Period II) and excluding data (if any) that are 
collected while patients temporarily are off pump or off IP. Treatment group comparisons will 
be performed using Wilcoxon signed-rank test at the full significance level of 0.05, with patients 
who are dosed in both treatment periods.  No multiplicity adjustments will be made for the 
analysis of secondary and exploratory objectives.
The incidence (percent of patients with at least 1 event) of infusion set failure as defined in the 
primary objective, premature infusion set changes by reason, and severe hypoglycemia will be 
analyzed using Prescott’s exact test. 
The Wilcoxon signed-rank test will be used to analyze the rate of premature infusion set changes
by reason, and severe hypoglycemia, as described above for the primary endpoint.
For continuous measures, summary statistics will include sample size, mean, standard deviation, 
median, minimum, and maximum for both the actual and the change from baseline 
measurements.  Least square (LS) means and standard errors derived from the analysis models 
will also be displayed for the change from baseline measurements.  Treatment comparisons will 
be displayed showing the treatment difference LS means and the 95% CIs for the treatment 
differences, along with the p-values for the treatment comparisons.
For categorical measures (such as incidence of adverse events), summary statistics will include 
sample size, frequency, and percentages.  Prescott’s test will be used for treatment comparisons, 
unless otherwise specified.

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2. Schedule of Activities

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b
Randomization should occur after completion of all Visit 3 procedures.
c
The MiniMed Mio infusion set with 6-mm length cannula and 23” tubing length will be provided for all patients to use during the study. 
d
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.
e
Non-meal-related correction boluses are not associated with a meal or combined with a meal bolus.
f
Infusion set and reservoir changes must be at same time.
g
Patients should be advised to remove their shoes/coats and empty their pockets before the body weight is obtained.
h
Vital sign 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.
i
Patients must be supine for approximately 5 to 10 minutes before ECG collection and remain supine but awake during ECG collection.
j
Initial training at Visit 2 will include diabetes education, insulin pump education, and nutrition counseling. Training will include a review of correct pump 
use (frequency of reservoir and infusion set changes, infusion site rotation, carb counting, and adjusting pump basal rates and bolus calculator settings) and 
review patient’s ability to trouble shoot unexplained hyperglycemia and treat hypoglycemia.  Appropriate site personnel will administer training and 
education using locally approved diabetes education/training materials and programs or by using other materials that may be provided by the sponsor.  
Patients may be provided abbreviated training and education at visits following Visit 2 based upon patient needs.
k
Only for patients using insulin aspart or insulin glulisine. 
l
Complete all study procedures prior to reservoir and infusion set change at Visits 2, 3, 6, and 9.  Under the observation of site staff, patients will fill a new 
pump reservoir and infusion set, insert the infusion set cannula into an appropriate pump site, and begin infusion.
m At Visit 9 or ED, start non-study rapid-acting insulin.
n
Investigators, in discussion with patients, adjust basal rates and CRs, ISFs, and AIT for calculating bolus and correction doses to meet the target BG levels.
o
Complete all study procedures prior to initiating IP at Visits 2, 3, and 6.
p
Training may be repeated at other visits, as needed.
q
Patients should be instructed to perform a minimum of 4-point SMBG profiles daily starting at Visit 2.
r
Enter into Inform current pump basal rates, CRs, ISFs, and AIT from Device Settings Snapshot; total basal units and total bolus units for last 3 days prior to 
visit, and total number of Normal, Square Wave, and Dual Wave bolus doses given during the last 7 days prior to the visit from Daily Detail report.
s
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 (Visit 3) 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.
t
Follicle-stimulating hormone test must be performed at Visit 1 for a postmenopausal woman who is between 50 and 54 years of age (inclusive) with an intact 
uterus, not on hormone therapy, and has had at least 6 months of spontaneous amenorrhea.

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3. Introduction
3.1.
Study Rationale
Prandial insulin with faster onset and/or faster offset characteristics might reduce glycemic 
excursions, time to recovery from hyperglycemia, and the incidence of delayed postprandial 
hypoglycemia compared to currently available rapid-acting insulin analogs.  Rapid-acting 
insulins, such as Humalog®, have been shown to have a more rapid onset of action compared to 
human insulin; however, the general consensus is that they are not rapid enough to match 
carbohydrate absorption, whether delivered by pump or syringe/pen injector, limiting efficacy.  
An ultra-rapid-acting prandial insulin that would shift the pharmacokinetic and 
pharmacodynamic profiles of insulin to provide an even faster onset of action would better match 
carbohydrate absorption and allow for efficacious dosing immediately prior to meals.  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 (T1DM) and type 
2 diabetes mellitus (T2DM) when delivered by multiple daily injections (MDI), continuous 
subcutaneous insulin infusion (CSII), or in the development of closed loop insulin delivery 
systems.
Insulin pumps use only rapid-acting insulin for both basal and bolus insulin requirements.  Basal 
insulin is a continuous infusion of insulin that is delivered automatically 24 hours a day.  The 
purpose of basal insulin is to cover hepatic glucose production and maintain glucose stability 
during fasting states (between meals and during sleep).  Bolus insulin is delivered “on-demand,” 
by the patient, for food intake and/or to correct glucose levels that are above the patient’s target 
range, delivered separately or together.  
Because insulin pump therapy uses only rapid-acting insulin, the onset of diabetic ketoacidosis 
(DKA) can occur quickly if insulin delivery is interrupted for a period of time. DKA develops 
when insulin levels are insufficient to meet the body’s basic metabolic requirements. DKA 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.
The most important DKA prevention strategies are:  1) adhering to a routine blood glucose (BG) 
monitoring/continuous glucose monitoring (CGM) schedule and 2) never ignoring an 
unexplained high BG. A high BG that is not responding to a correction bolus via insulin pump 
may indicate an infusion set occlusion or insulin pump malfunction.
The aim of this study is to compare LY900014 and insulin lispro with respect to the rate
(events/patient/30 days) of infusion set failures that lead to premature infusion set changes, due 
to a pump occlusion alarm OR due to unexplained hyperglycemia >250 mg/dL (13.9 mmol/L) 
that does not decrease within 1 hour following a correction bolus delivered via the pump.

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3.2.
Background
There have been many advances in the treatment of T1DM in the last 20 years; however, 
reaching and maintaining glycemic goals remains challenging even under intensive insulin 
therapy regimens.  Only approximately 30% of insulin-requiring patients with diabetes are able 
to reach the goal hemoglobin A1c (HbA1c) target of <7% (Stark Casagrande et al. 2013).  
Currently available rapid-acting insulin analogs continue to be unable to match the kinetics of 
physiological post-meal insulin secretion, which is biphasic.  Thus, there remains a need to 
continue to develop formulations with a time-action profile that more closely approximates that 
of endogenous insulin section.
Ideally, currently available rapid-acting insulin analogs should be injected or bolused 
10 to 15 minutes prior to meal consumption to control postprandial glucose (PPG).  However, 
many people inject or bolus their rapid-acting insulin at the time of the meal or after the meal.  
According to survey data from the T1D Exchange on the timing of prandial insulin injection, 
16.3% of patients indicated they inject 15 minutes prior to meals, 33% inject 1 to 14 minutes 
prior to meals, 38.6% inject at the time of the meal, and 12.1% inject after meals.  Because 
patients often inject or bolus later than recommended, there is a greater mismatch between 
insulin action and postprandial BG elevations.
LY900014 is a formulation of insulin lispro developed as an ultra-rapid acting insulin with a 
faster onset of action and shorter duration of action compared to currently available rapid-acting 
insulin analogs.  LY900014 contains the prostacyclin analog (treprostinil), citrate, and other 
excipients.  This formulation involves the novel use of a microdose of treprostinil as an excipient
to enhance the absorption of insulin lispro by local vasodilatation rather than an as an active 
pharmaceutical ingredient that elicits a systemic effect.  Treprostinil is a prostacyclin analog for 
the treatment of symptomatic pulmonary arterial hypertension, and has been approved in the 
United States since 2002 (Remodulin package insert, 2014) and in Europe since 2005 (PMR 
[WWW]).  Sodium citrate, an excipient that speeds insulin absorption, is also included in the 
formulation to further enhance the absorption of insulin lispro.  Sodium citrate and the other 
excipients in the LY900014 formulation are listed in the Food and Drug Administration (FDA)
Generally Recognized As Safe food additives database and in the FDA Inactive Ingredients in 
Approved Drugs database.  Furthermore, the excipient concentration in LY900014 is within the 
limits identified for approved drug products in the FDA Inactive Ingredients in Approved Drugs 
database.  
Nine LY900014 Phase 1 clinical studies have been conducted to date in healthy subjects or 
patients with T1DM or T2DM.  Across these studies, LY900014 has consistently demonstrated a 
faster time-action profile than Humalog.  In patients with T1DM or T2DM treated with MDI 
insulin therapy, LY900014 significantly reduced PPG excursions compared to Humalog when 
both were dosed by syringe at the start of a test meal.  Two studies in patients with T1DM have 
been completed using CSII in an in-patient setting, both of which have demonstrated accelerated
time action.  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, 

I8B-MC-ITSI (a) Clinical Protocol
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LY900014
vasodilatation, rash, edema, and hypotension are described in the Remodulin package insert, 
2014).  All samples of treprostinil from LY900014 administration were below the lower limit of 
quantitation. The Investigator’s Brochure (IB) describes the clinical and nonclinical 
development of LY900014. 
3.3.
Benefit/Risk Assessment
In Phase 1 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 insulin lispro.
More detailed information about the known and expected benefits and risks of insulin lispro may 
be found in the country-specific product labeling (for example, Patient Information Leaflet, 
Package Insert, or Summary of Product Characteristics).
Safety evaluation in this study will include hypoglycemia, treatment-emergent adverse event 
(TEAEs), serious adverse events (SAEs), clinical laboratory assessments, anti-insulin lispro 
antibodies, CGM, frequent visits, ketone testing, 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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LY900014
4.
Objectives and Endpoints
Table ITSI.2 shows the objectives and endpoints of the study.
Table ITSI.2.
Objectives and Endpoints
Objectives
Endpoints
Primary Objective
1.
To compare LY900014 and insulin lispro with 
respect to the rate of infusion set failures that 
lead to premature infusion set changes, due to 
a pump occlusion alarm OR due to 
unexplained hyperglycemia with blood glucose 
>250 mg/dL (13.9 mmol/L) that does not 
decrease within 1 hour following a correction 
bolus delivered via the pump
1.
Rate (events/patient/30 days) of infusion set 
failures that lead to premature infusion set 
changes, due to a pump occlusion alarm OR due 
to unexplained hyperglycemia with blood 
glucose (SMBG) >250mg/dL (13.9 mmol/L) 
that does not decrease within 1 hour following a 
correction bolus delivered via the pump, during 
the 6-week treatment period
Secondary Objectives
2.
To compare LY900014 and insulin lispro with 
respect to the incidence of infusion set failures 
that lead to premature infusion set changes, 
due to a pump occlusion alarm OR due to 
unexplained hyperglycemia with blood glucose 
>250 mg/dL (13.9 mmol/L) that does not 
decrease within 1 hour following a correction 
bolus delivered via the pump
2.
Incidence (percent of patients with at least 
1 event) of infusion set failures that lead to 
premature infusion set changes, due to a pump 
occlusion alarm OR due to unexplained 
hyperglycemia with blood glucose (SMBG)
>250 mg/dL (13.9 mmol/L) that does not 
decrease within 1 hour following a correction 
bolus delivered via the pump, during the 6-week 
treatment period
3.
To compare LY900014 and insulin lispro with 
respect to the rate and incidence of premature 
infusion set changes
3.
Rate (events/patient/30 days) and incidence of 
premature infusion set changes by reason 
(infusion set kinked, came out, or leaking; 
empty pump reservoir; infusion site pain or 
redness; pump occlusion alarm; suspected 
infusion set occlusion; other) during the 6-week 
treatment period
4.
To compare LY900014 and insulin lispro with 
respect to the time interval until infusion set 
change 
4.
Time interval until infusion set change during 
the 6-week treatment period
5.
To compare LY900014 and insulin lispro with 
respect to total, basal, and bolus insulin dose
5.
Bolus/total insulin dose ratio at the end of the 6-
week treatment period
6.
To compare LY900014 and insulin lispro with 
respect to the interstitial glucose reduction rate 
from hyperglycemia following a non-meal-
related correction bolus delivered via the pump
6.
Interstitial glucose reduction rate (glucose 
reduction [mg/dL and mmol/L] per minute)
within 4 hours following a non-meal-related 
correction bolus via the pump, from 
hyperglycemia (interstitial glucose >180 mg/dL
(10.0 mmol/L) to recovery (interstitial glucose 
≤180 mg/dL), from up to 6 weeks of CGM use
7.
To compare LY900014 and insulin lispro with 
respect to the rate of severe hypoglycemic 
events 
7.
Rate (events/patient/100 years) of severe 
hypoglycemic events during the 6-week 
treatment period

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Objectives
Endpoints
Tertiary/Exploratory Objectives 
8.
To compare the safety of LY900014 and 
insulin lispro
8.
Adverse events and vital signs 
9.
To compare LY900014 and insulin lispro with 
respect to the rate and incidence of 
documented symptomatic post-meal 
hypoglycemia
9.
Rate (events/patient/year and/or 
events/patient/30 days) and incidence (percent 
of patients with at least 1 event) of documented 
symptomatic post-meal hypoglycemia within 
1 and 2 hours after the start of a meal during the 
last 2 weeks of the 6-week treatment period
10. To compare LY900014 and insulin lispro with 
respect to the rate and incidence of 
documented symptomatic hypoglycemia
10. Rate (events/patient/year and/or 
events/patient/30 days) and incidence (percent 
of patients with events) of documented 
symptomatic hypoglycemic events during the 
last 2 weeks of the 6-week treatment period
11. To compare LY900014 and insulin lispro with 
respect to the incremental AUCs after 
breakfast, obtained from CGM use
11. Incremental AUC0-1 hourafter breakfast during 
the last 2 weeks of up to 6 weeks of CGM use 
12. To compare LY900014 and insulin lispro with 
respect to the duration of time glucose values 
are within target range (71 and 180 mg/dL [3.9 
and 10.0 mmol/L]), obtained from CGM use
12. Duration (in minutes) and percentage of time 
with glucose values between 71 and 180 mg/dL 
(3.9 and 10.0 mmol/L), both inclusive, 
normalized to a 24-hour period, during the last 2 
weeks of up to 6 weeks of CGM use 
13. To compare LY900014 and insulin lispro with 
respect to the duration of time glucose values 
are within target range (71 and 140 mg/dL [3.9 
and 7.8 mmol/L]), obtained from CGM use
13. Duration (in minutes) and percentage of time 
with glucose values between 71 and 140 mg/dL 
(3.9 and 7.8 mmol/L), both inclusive, 
normalized to a 24-hour period, during the last 2 
weeks of up to 6 weeks of CGM use 
14. To compare LY900014 and insulin lispro with 
respect to the glucose profiles, obtained from 
CGM use
14. Average glucose for a 24-hour period during the 
last 2 weeks of up to 6 weeks of CGM use 
15. To compare LY900014 and insulin lispro with 
respect to the glucose variability, obtained 
from CGM use
15. Interquartile range, CV, LBGI, and HBGI
during the last 2 weeks of up to 6 weeks of 
CGM use 
16. To compare LY900014 and insulin lispro with 
respect to the factors affecting dosing in 
pumps 
16. Actual and change from baseline in factors 
affecting dosing in pump (breakfast CR, AIT, 
breakfast ISF, and frequency of use of 
non-normal bolus type [Square Wave or Dual 
Wave]), during the 6-week treatment period
17. To compare LY900014 and insulin lispro with 
respect to the duration of time spent in 
hypoglycemic glucose ranges, obtained from 
CGM use
17. Duration (in minutes) and percentage of time 
with glucose values <50, <60, and ≤70 mg/dL 
(0.8, 3.3, and 3.9 mmol/L), normalized to a 24-
hour period and number of episodes, defined as 
at least 10 consecutive minutes <50, <60, and 
≤70 mg/dL, during the last 2 weeks of up to 6 
weeks of CGM use 

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LY900014
Objectives
Endpoints
18. To compare LY900014 and insulin lispro with 
respect to the duration of time spent in 
hyperglycemic glucose ranges, obtained from 
CGM use 
18. Duration (in minutes) and percentage of time 
with glucose values >180, >250, and 
>300 mg/dL (10.0, 13.9, and 16.7 mmol/L), 
normalized to a 24-hour period and number of 
episodes, defined as at least 10 consecutive 
minutes >180, >250, and >300 mg/dL, during 
the last 2 weeks of up to 6 weeks of CGM use 
19. To separately evaluate the glycemic control of 
LY900014 and insulin lispro
19. Summary statistics of actual and change from 
baseline to Week 6 in HbA1c for each treatment 
20. To compare LY900014 and insulin lispro with 
respect to 1,5-AG
20. Actual and change from baseline to Week 6 in 
1,5-AG 
Abbreviations:  1,5-AG = 1,5-anhydroglucitol; AUC = area under the curve; CGM = continuous glucose 
monitoring; CV = coefficient of variation; HbA1c = hemoglobin A1c; HBGI = high blood glucose index; 
LBGI = low blood glucose index; SMBG = self-monitored blood glucose.

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5. Study Design
5.1.
Overall Design
Study I8B-MC-ITSI is a Phase 3, prospective, randomized, double-blind, outpatient, 
multinational, multicenter, 2-treatment group, crossover, active-controlled study conducted in 
patients with T1DM currently using CSII.  In the 2 treatment groups, LY900014 and insulin 
lispro, meal bolus doses will be delivered immediately prior to each meal (0 to 2 minutes) in a 
double-blind manner.  
The study is designed to compare LY900014 and insulin lispro with respect to the rate 
(events/patient/30 days) of infusion set failures that lead to premature infusion set changes due to 
a pump occlusion alarm OR due to unexplained hyperglycemia with blood glucose (SMBG) 
>250 mg/dL (13.9 mmol/L) that does not decrease within 1 hour following a correction bolus 
delivered via the pump.  The study includes a 1-week screening period and a 2-week lead-in 
period followed by a 2-period crossover and a 4-week post-treatment safety follow-up.  Each 
period of the crossover will consist of 6 weeks of treatment with no washout between periods.
Unexplained hyperglycemia is expected to be an uncommon event in this study and the use of 
real-time CGM, self-monitored blood glucose (SMBG), electronic clinical outcomes assessment
(eCOA), frequent study visits, and provision of standard of care hyperglycemia management 
guidelines and blood ketone testing meters and strips will all serve to maximize subject safety.  
Patients will be experienced pump users who have recent experience using CGM or flash glucose 
monitoring (FGM), and they will be guided to follow best standards of care in insulin pump 
management.  
Patients currently treated with a rapid-acting insulin analog via CSII will be eligible for inclusion 
in the trial.  All patients treated with insulin aspart or insulin glulisine at screening will be 
transferred to insulin lispro at Visit 2 so that all patients are using insulin lispro during the lead-
in period.  Patients must be using the MiniMed 530G, MiniMed 630G (US) or 640G (EU) insulin 
pump.  The bolus delivery speed for all pumps will be set to standard speed (1.5 U/minute) for 
the duration of the lead-in and treatment phases of the study.  The purpose of the lead-in period 
(prior to randomization) will be to obtain preliminary diagnostic tests, determine baseline 
hypoglycemia rate, and evaluate pump basal rates and bolus calculator settings (carb ratio [CR], 
insulin sensitivity factor [ISF], and active insulin time [AIT] for calculating mealtime and 
correction bolus doses) for appropriateness.  During the study, patients will be expected to use 
the pump’s bolus calculator to determine mealtime and correction bolus doses.  Patients will be 
required to suspend use of personal CGM or FGM and the SmartGuard/Threshold Suspend
feature of their pump, if applicable, during the lead-in and treatment phases of the study.  
Dexcom G5 will be used by all patients in real-time mode beginning at Visit 2 and continuing 
throughout the treatment phase of the study.  Dexcom G5 will allow patients to see real-time
continuous glucose readings every 5 minutes and can aid in the identification of trends and 
patterns in glucose levels and detection of hyperglycemia and hypoglycemia.  Patient 
interpretation of the Dexcom G5 data should be based on the glucose trends and several 

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LY900014
sequential readings over time. All patients will be required to have the alerts and alarm features 
of Dexcom G5 enabled throughout the study.
Patients will be required to perform SMBG using the study-provided glucometer a minimum of 4 
times/day, including pre-meal and bedtime, for calibration of the Dexcom G5 Mobile Continuous 
Glucose Monitoring System (Dexcom G5) every 12 hours, and to confirm episodes of 
hypoglycemia, unexplained hyperglycemia, and the SMBG response to a correction bolus.
At every office visit, the date and time of each device used in the study (insulin pump, eCOA 
diary, glucometer, ketone meter, and CGM receiver) should be synchronized and verified by site 
staff.
At Visit 3 (Randomization Visit), patients will be randomly assigned to 1 of the 2 treatment 
sequences of double-blind LY900014 and insulin lispro.  During Visit 3, under the observation 
of site staff, patients will insert a new CGM sensor and begin a new sensor session.  Also under 
the observation of site staff, patients will fill a new pump reservoir and infusion set with 
investigational product (IP), insert the infusion set cannula into an appropriate pump site, and 
begin infusion of IP.  
At Week 6 (Visit 6), patients will cross-over to the alternate treatment. Investigators will reset 
the patient’s pump to the bolus calculator settings (CR, ISF, and AIT) and basal rates that had 
been optimized during the lead-in period.  During the visit, under the observation of site staff, 
patients will insert a new CGM sensor and begin a new sensor session.  Also under the 
observation of site staff, patients will fill a new pump reservoir and infusion set with IP, insert 
the infusion set cannula into an appropriate pump site, and begin infusion of IP.  
During the treatment periods, patients and investigators will interact frequently and use SMBG 
and CGM data to optimize pump settings in order to maximize glycemic control.  
The overall glycemic control goals for all patients enrolled in the study are similar to those 
recommended by the American Association of Clinical Endocrinologists (Bailey et al. 2016).  
The glycemic targets for this study are for patients to achieve a pre-prandial glucose level of 
approximately 100 mg/dL (5.6 mmol/L), a 1- to 2-hour PPG level of <180 mg/dL 
(<10.0 mmol/L), and a bedtime glucose level of approximately 90-130 mg/dL (5.0-7.2 mmol/L) 
with no hypoglycemia (defined as BG ≤70 mg/dL [3.9 mmol/L]).
During the first 4 weeks of each treatment period, patients, in consultation with investigators, 
should use SMBG, CGM, and hypoglycemia data to adjust basal rates and bolus calculator 
settings (CR, ISF, and AIT) as necessary to meet the glycemic targets.  
During the last 2 weeks of each treatment period, it is expected that CR, ISF, AIT, and basal 
rates would remain fairly stable, with adjustments if needed for safety reasons, such as 
hypoglycemia or unacceptable hyperglycemia.  It is important to keep these as stable as possible, 
because CGM and hypoglycemia data from this period will be used for treatment comparisons.
Study governance considerations are described in detail in Appendix 3.
Figure ITSI.1 illustrates the study design.  

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LY900014
Figure ITSI.1.
Illustration of study design for Clinical Protocol I8B-MC-ITSI.
5.2.
Number of Participants
Approximately 60 participants will be screened to achieve 48 randomized patients for a total of 
approximately 42 patients to complete the study. 
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last patient.
5.4.
Scientific Rationale for Study Design
A crossover design was chosen for this study to reduce variability and increase the power as each 
patient serves as his or her own control.
At the crossover point, patients are required to change their reservoir and infusion set, insert a 
new CGM sensor, and begin a new sensor session, and investigator will reset the patient’s pump 
to the settings that had been optimized during the lead-in period. This avoids carryover effects 
on catheter occlusion-related treatment comparisons.  
In addition, patients are encouraged to reach stable dose during the last 2 weeks of each period. 
This also minimizes carryover effect on the exploratory safety and efficacy outcomes.
5.5.
Justification for Dose
Insulin lispro has been in the market for over 20 years with widespread use worldwide and has 
extensive efficacy and safety data. LY900014 will have the same insulin lispro concentration 

I8B-MC-ITSI (a) Clinical Protocol
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LY900014
(100 U/mL) as that of commercially available Humalog.  The addition of treprostinil to the 
insulin lispro formulation does not modify the physical, chemical, or biological integrity of 
insulin lispro.  The total serum insulin lispro exposure (area under the concentration curve from 0 
to 5 hour postdose) are similar between LY900014 and insulin lispro in T1DM CSII. In 
addition, the total glucodynamic activity as measured in euglycemic clamp studies was similar 
between LY900014 and Humalog.  In previous studies, these insulins were substituted unit for 
unit.  The basal rates and bolus doses of insulins used in this study should be determined based 
on the individual needs of each patient.  

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6.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.  Individuals who do not meet the criteria for 
participation in this study (screen failure) may not be rescreened.  Retests are also not allowed, 
except for cases when results are not available from the original sample.
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, based on the World Health 
Organization classification (Appendix 5) for at least 1 year prior to screening, 
and continuously using insulin for at least 1 year
Patient Characteristics
[2] Are at least 18 years of age 
[3] Male patients:
a) No male contraception required except in compliance with specific local 
government study requirements.
[4]
Female patients: 
a) Women not of childbearing potential may participate and include those who 
are:
i)
infertile due to surgical sterilization (hysterectomy, bilateral 
oophorectomy, or tubal ligation), congenital anomaly such as Mullerian
agenesis
Or
ii) postmenopausal – defined as either
(1) a woman 50 to 54 years of age (inclusive) with an intact uterus, not 
on hormone therapy who has had either
(a) cessation of menses for at least 1 year
Or
(b) at least 6 months of spontaneous amenorrhea with a 
follicle-stimulating hormone >40 mIU/mL
Or
(2) a woman aged 55 years or older not on hormone therapy, who has 
had at least 6 months of spontaneous amenorrhea

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Or
(3) a woman of at least 55 years of age with a diagnosis of menopause 
prior to starting hormone replacement therapy
b) Women of childbearing potential participating:
i)
cannot be pregnant or intend to become pregnant
ii) cannot be breastfeeding (including the use of a breast pump) 
iii) must remain abstinent or use 1 highly effective method of contraception 
or a combination of 2 effective methods of contraception for the entirety 
of the study (Appendix 6)
iv) test negative for pregnancy at the time of screening (Visit 1); note:  a 
urine pregnancy test is conducted at Visit 3
[5] Have been using CSII therapy for a minimum of 6 months prior to screening.  
Interruption of CSII is allowed once during the 6 months prior to screening for up 
to 14 consecutive days, such as during a hospitalization, a pump malfunction, or a 
“pump holiday”
[6] Are currently treated with the same rapid-acting analog insulin (insulin lispro 
U-100, insulin aspart, or insulin glulisine) via CSII (where approved) for at least 
the last 30 days prior to screening
[7] Have been using CGM or FGM (CGM preferred) for a total of at least 60 days 
during the 12 months prior to screening
[8] Have HbA1c values ≤8.5%, as determined by the central laboratory at screening 
(Visit 1)
[9] Have a body mass index (BMI) of ≤35 kg/m2 at screening (Visit 1)
[10] Are proficient, in the opinion of the investigator, in carbohydrate counting, and in 
adjusting basal rates and bolus calculator settings (CR, ISF, and AIT)
[11] Are willing to take at least 3 meal-time insulin boluses every day on a regular 
basis throughout the trial
[12] Are willing to use the pump’s bolus calculator (Bolus Wizard) to determine 
mealtime and correction bolus doses
[13] Are willing to adhere to an infusion set and reservoir change interval of every 72 
± 4 hours unless a change is required for failure of the infusion set
[14] Are willing to perform SMBG, using the study glucometer, at least 4 times daily
(including every 12 hours to calibrate the sensor), and to confirm hypoglycemia, 
unexplained hyperglycemia, and BG response following a correction bolus 
delivered via the pump
[15] Are willing to use the Dexcom G5 Mobile Continuous Glucose Monitor in real-
time mode throughout the study

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[16] Are willing to suspend use of personal CGM or FGM throughout the study
[17] Are willing to suspend use of SmartGuard/Threshold Suspend throughout the 
study
[18] Are willing to avoid use of all products containing acetaminophen or paracetamol
while using the Dexcom CGM system
[19] Must be using a MiniMed 530G or 630G (US) or 640G (EU) insulin pump for at 
least the last 30 days and willing to stay on the same pump throughout the study 
(pump must be approved for use in the country where the patient resides)
[20] Must use study-provided MiniMed insulin pump reservoirs and Mio infusion sets
[21] Are willing to keep records in eCOA devices as required by this protocol 
[22] Have access to a telephone, or alternative means for close monitoring and 
communications, and have access to a reliable cellular signal or wireless internet 
access for transmission of the eCOA data
[23] Have refrigeration in the home or have ready access to refrigeration for storage of 
insulin
Informed Consent
[24] 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
[25] Have hypoglycemia unawareness as judged by the investigator
[26] Have had more than 1 episode of severe hypoglycemia (defined as requiring 
assistance due to neurologically disabling hypoglycemia) within 6 months prior to 
screening
[27] Have had more than 1 emergency room visit or hospitalization due to poor 
glucose control (hyperglycemia or DKA) within 6 months prior to screening
[28] Have significant insulin resistance defined as having received a total daily dose of 
insulin >1.2 U/kg at the time of screening (Visit 1), as determined by the average 
total daily insulin dose over the 3 days prior to screening divided by weight in 
kilograms based on investigator review of the patient’s pump history
[29] Have significant lipohypertrophy, lipoatrophy, or scars within the subcutaneous 
tissue in areas of infusion, in the opinion of the investigator
[30] Have a history of abscess at an infusion site within the last 90 days prior to 
screening

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[31] Have a history within the past 6 months of changing their pump infusion set more 
frequently than every 3 days on a regular basis
[32] Have vision loss or hearing loss that does not allow recognition of pump screens, 
alerts, and alarms
[33] Have presence of clinically significant gastrointestinal disease (for example, 
clinically active gastroparesis associated with wide glucose fluctuations; in the 
investigator’s opinion) or gastric bypass.
[34] 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
[35] 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 
(Appendix 7), myocardial infarction, unstable angina pectoris, or coronary arterial 
bypass graft
[36] Renal: 
a.
History of renal transplantation
b. Currently receiving renal dialysis
c.
Serum creatinine >2.0 mg/dL (177 µmol/L) at screening (Visit 1) as 
measured by the central laboratory
[37] Hepatic:  
a.
Have obvious clinical signs or symptoms of liver disease (for example, 
acute or chronic hepatitis, or cirrhosis), or elevated liver enzyme 
measurements as indicated below at screening (Visit 1)
b. Total bilirubin level (TBL) ≥2X the upper limit of normal (ULN) (with the 
exception of Gilbert’s disease) as defined by the central laboratory Or 
c.
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3X 
ULN as defined by the central laboratory
[38] 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
[39] Have any hypersensitivity or allergy to any of the insulins or excipients used in 
this trial
[40] Hematologic:  have had a blood transfusion or severe blood loss within 90 days 
prior to screening or have known hemoglobinopathy, anemias, or any other traits 
known to interfere with measurement of HbA1c

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Prior/Concomitant Therapy
[41] Have used insulin human inhalation powder (Afrezza®) within 90 days prior to 
screening
[42] Are receiving any oral or injectable medication intended for the treatment of 
diabetes mellitus other than rapid-acting analog insulin via CSII in the 90 days 
prior to screening.  Occasional pen or syringe injection of insulin is allowed in the 
event of pump malfunction, unexplained hyperglycemia not responsive to pump 
correction bolus, etc.  
[43] Glucocorticoid therapy:  are receiving chronic (lasting longer than 7 consecutive 
days) systemic glucocorticoid therapy (including intravenous, IM, subcutaneous, 
and oral) or intra-articular, but excluding topical, intraocular, intranasal, and 
inhaled preparations), or have received such therapy within 8 weeks immediately 
prior to screening with the exception of replacement therapy for adrenal 
insufficiency
Prior/Concurrent Clinical Trial Experience
[44] Are currently enrolled in any other clinical study involving an IP or any other type 
of medical research judged not to be scientifically or medically compatible with 
this study
[45] Have participated, within the last 30 days in a clinical trial involving an IP.  If 
the previous IP has a long half-life, 3 months or 5 half-lives (whichever is 
longer) should have passed
[46] Have previously completed or withdrawn from this study after having signed the 
informed consent form (ICF) or any other study investigating LY900014 after 
receiving at least 1 dose of the IP
Other Exclusions
[47] Have an irregular sleep/wake cycle (for example, patients who sleep during the 
day and work during the night)
[48] 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
[49] Are Lilly employees or representative (including employees, temporary contract 
workers, or designees responsible for the conduct of the study)
[50] Are unable and/or unwilling to provide informed consent, to make themselves 
available for the duration of the study, or to abide by study procedures

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6.3.
Lifestyle Restrictions
Study participants 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 study.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened.  Retests are also not allowed, except for cases when results are not available from the 
original sample.

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LY900014
7. Treatments
7.1.
Treatments Administered
This study involves a comparison of LY900014 and insulin lispro with mealtime boluses 
administered 0 to 2 minutes prior to the start of the meal.  Patients will fill pump reservoirs from 
blinded vials with each infusion set change (that is, every 72 ± 4 hours). Table ITSI.3 shows the 
treatment regimens.  
Table ITSI.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; 
basal infusion rates 
throughout 24 hours a day; 
correction boluses as 
necessary
Insulin lispro
100 U/mL
Individualized dosing
CSII
Mealtime bolus 0-2 min 
prior to start of the meal; 
basal infusion rates 
throughout 24 hours a day; 
correction boluses as 
necessary
Abbreviation:  CSII = continuous subcutaneous insulin infusion.
The investigator or his/her designee is responsible for the following:

Explaining the correct use of IP to the patient

Explaining storage requirements for IP to the patient

Explaining requirements for recording date, time, and amount of correction 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 that all unused medications are 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 country’s 
regulatory requirements.  Study insulins (LY900014 and insulin lispro) will be supplied by Lilly 
or its representative, in accordance with current good manufacturing practices and will be 
supplied with lot numbers.
The blinded vials will contain a concentration of 100 U/mL in 10-mL vials of either LY900014
or insulin lispro.  

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During the lead-in period, insulin lispro 100 U/mL will be provided in open-label 10-mL vials.
7.1.2. Insulin Pumps
Patients will use their personal MiniMed 530G or 630G (US) or MiniMed 640G (EU) pump 
throughout the study, but will be required to use the reservoirs and infusion sets provided by the 
investigative site. MiniMed reservoirs and Mio infusion sets with 6-mm cannula and 23-inch 
tubing will be provided to all patients.  The Mio infusion set was chosen because of its all-in-one 
design that combines the infusion set with the inserter device. All patients’ pumps will be set to 
deliver boluses at standard speed (1.5 U/minute) for the duration of the lead-in and treatment 
phases of the study.  
7.1.3. Method of Treatment Assignment
Patients who meet all criteria for enrollment and complete the lead-in period will be randomized 
to double-blind treatment at Visit 3.  Assignment to treatment sequences will be determined by a 
computer-generated random sequence using an interactive web-response system (IWRS).  
Patients will be randomized to 1 of the 2 treatment sequences in a 1:1 ratio:
Sequence A:  LY900014 insulin lispro
Sequence B: insulin lispro    LY900014
Stratification will be by region (US, OUS), historical use of SmartGuard/Threshold Suspend
(Yes, No), and HbA1c stratum (≤7.3%, >7.3% at Visit 1).
Patients will fill a new pump reservoir and infusion set with IP, then insert a new pump infusion 
set cannula into an appropriate site, and begin infusion of IP prior to leaving the investigative site
at Visits 2, 3, and 6.  Patients will continue to fill reservoirs and infusion sets with IP and insert a 
new infusion set cannula into an appropriate site every 72 ± 4 hours as outpatients, unless a 
change is required for failure of the infusion set.
The IWRS will be used to assign all IP during the study, including insulin lispro during the 
lead-in period.  The IWRS will be used to assign vials containing double-blind IP to each patient
randomized to the sequence of treatment groups.  Site personnel will confirm that they have 
located the correct vials by entering a confirmation number found on the vials into the IWRS.
7.1.4. Selection and Timing of Doses
7.1.4.1.
Target Glucose Values for Titration of Insulin Therapy
All patients not currently using insulin lispro in their pumps will begin using insulin lispro 
at the beginning of the 2-week lead-in period.  Patients, in consultation with investigators, 
will be encouraged to adjust pump settings during the first 4 weeks of each treatment 
period with the goal of achieving glycemic targets so that these settings are fairly stable 
during the last 2 weeks of each period.  
The glycemic targets for patients in this study are listed in Table ITSI.4.

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7.3.
Dosage Modification
See section 7.1.4.
7.4.
Preparation/Handling/Storage/Accountability
The investigator or his/her designee is responsible for confirming that appropriate temperature 
conditions have been maintained during transit for all study treatment received and any 
discrepancies are reported and resolved before use of the study treatment.  
Only 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, 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).  
7.5.
Treatment Compliance
The investigator or designee will assess compliance of the patient at each visit, based on a review 
of the patient’s pump and CGM downloads, glycemic control, adherence to the visit and 
treatment schedule, and completion of the patient’s eCOA.  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 the study.  No 
specific study data will be collected to analyze treatment compliance.
7.6.
Concomitant Therapy
Guidance on restrictions for concomitant therapies is provided in Table ITSI.5.

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Table ITSI.5.
Concomitant Medications
Drug Class
Acute 
Use
Chronic 
Use 
Safety Follow-up 
Periods
Conditions for Use
Systemic 
glucocorticosteroid 
(including IM, IV, SC,
and oral) or 
intra-articulara except in 
the case of replacement 
therapy for adrenal 
insufficiency
No
No
No
Afrezza
(inhaled insulin)
No
No
No
Any oral or injectable 
medication intended for 
the treatment of diabetes 
mellitus other than 
rapid-acting analog 
insulin via CSII
Yes
No
Yes
In the event of interruption of CSII, such 
as for pump failure or hospitalization, 
injection of prandial and/or basal insulin 
will be allowed for up to 7 days during 
each of the 6-week treatment periods 
until CSII can be resumed
Acetaminophen- or 
paracetamol-containing 
medications
No
No
Yes
Abbreviations:  CSII = continuous subcutaneous insulin infusion; IM = intramuscular; IV = intravenous;
SC = subcutaneous.
Note:  According to country labeling.
a
Topical, inhaled, intraocular, or intranasal steroid preparations are allowed.
7.7.
Treatment after the End of the Study
7.7.1. Continued Access
LY900014 will not be made available to patients after conclusion of the study.  Rapid-acting 
insulin analogs are available in all countries for use as prandial/pump insulin.  
7.7.2. Special Treatment Considerations
After discontinuation of IP at the end of the treatment period or earlier, randomized patients 
should start a non-study rapid-acting analog insulin via CSII.
Investigators should provide patients with appropriate guidance for glucose monitoring and 
insulin dose adjustment throughout the follow-up period to maintain glycemic control.

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8.
Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
Patients who need to discontinue from study treatment will also be discontinued from the Study.  
Please refer to Section 8.2.
8.1.1. Discontinuation of Inadvertently Enrolled Patients
If the sponsor or investigator identifies a patient who did not meet enrollment criteria and was 
inadvertently enrolled, then the patient should be discontinued from study treatment unless there 
are extenuating circumstances that make it medically necessary for the patient to continue on 
study treatment.  If the investigator and the sponsor CRP/CRS agree it is medically appropriate 
to continue, the investigator must obtain documented approval from the sponsor CRP/CRS to 
allow the inadvertently enrolled patient to continue in the study with IP. Safety follow-up is as 
outlined in Section 2 (Schedule of Activities), Section 9.2 (Adverse Events), and Section 9.4
(Safety) of the protocol.
8.2.
Discontinuation from the Study
Patients will be discontinued 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 

The patient becomes pregnant

If an investigator, study site personnel performing assessments, or patient is 
unblinded, the patient must discontinue IP  

Frequent use of prohibited concomitant medication

Use of pump that is not allowed

Defiant continued use of SmartGuard/Threshold Suspend technology

The patient has not used IP for more than 7 consecutive days 

Enrollment in any other clinical study involving an IP or enrollment in any 
other type of medical research judged not to be scientifically or medically 
compatible with this study

Participation in the study needs to be stopped for medical, safety, regulatory, 
or other reasons consistent with applicable laws, regulations, and good clinical 
practice (GCP)

Investigator decision

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o
the investigator decides that the patient should be discontinued from the 
study
o
if the patient, for any reason, requires treatment with another therapeutic 
agent that has been demonstrated to be effective for treatment of the study 
indication, discontinuation from the study occurs prior to introduction of 
the new agent

Subject decision
o
the patient requests to be withdrawn from the study

Discontinuation due to a hepatic event or liver test abnormality: patients
who are discontinued due to a hepatic event or liver test abnormality should 
have additional hepatic safety data collected via electronic case report form
(eCRF).
Discontinuation 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:
o
ALT or AST >8X ULN
o
ALT or AST >5X ULN for more than 2 weeks
o
ALT or AST >3X ULN and TBL >2X ULN or international normalized 
ratio >1.5 
o
ALT or AST >3X ULN with the appearance of fatigue, nausea, vomiting, 
right upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(>5%)
o
alkaline phosphatase (ALP) >3X ULN
o
ALP >2.5X ULN and TBL >2X ULN
o
ALP >2.5X ULN with the appearance of fatigue, nausea, vomiting, right 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
Patients discontinuing from the study prematurely for any reason should complete AE and other 
safety follow-up per Section 2 (Schedule of Activities), Section 9.2 (Adverse Events), and 
Section 9.4 (Safety) of this protocol, with the exception of those who discontinue during the 
lead-in period will not need to have laboratory tests drawn.
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 eCRF.  
Lilly personnel will not be involved in any attempts to collect vital status information.

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9.
Study Assessments and Procedures
Section 2 lists the Schedule of Activities, with the study procedures and their timing (including 
tolerance limits for timing).
Appendix 2 lists the laboratory tests that will be performed for this study.
Unless otherwise stated in the subsections below, all samples collected for specified laboratory 
tests will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may 
be retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1.
Safety Assessments
9.1.1. Primary Assessments
The rate of infusion set failures that lead to premature infusion set changes, due to a pump 
occlusion alarm OR due to unexplained hyperglycemia with blood glucose (SMBG) >250 mg/dL 
(13.9 mmol/L) that does not decrease within 1 hour following a correction bolus delivered via 
the pump.
9.1.2. Secondary Assessments

The incidence of infusion set failures that lead to premature infusion set changes, due 
to a pump occlusion alarm OR due to unexplained hyperglycemia with blood glucose 
(SMBG) >250 mg/dL (13.9 mmol/L) that does not decrease within 1 hour following a 
correction bolus delivered via the pump

Rate and incidence of premature infusion set changes by reason (infusion set kinked, 
came out, or leaking; empty pump reservoir; infusion site pain or redness; pump 
occlusion alarm; suspected infusion set occlusion; other)

Time interval until infusion set change (overall and due to any suspected infusion set 
occlusion)

Bolus, basal, and total insulin dose (units and units/kg) and bolus/total insulin ratio 

Interstitial glucose reduction from hyperglycemia following a non-meal-related 
correction bolus delivered via the pump

Rate of severe hypoglycemia
9.1.3. Appropriateness of Assessments
All assessments included in this study are generally regarded as reliable and accurate with 
respect to diabetes mellitus.
9.1.4. Study Procedures
9.1.4.1.
Electronic Clinical Outcomes Assessment
The eCOA diary will wirelessly receive all glucose data directly from the study BG meter, 
thereby increasing the validity of measures reported by the patient and minimizing transcription 

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errors in recording the measures.  The use of e-diaries should also allow more complete and 
accurate capturing of infusion set change data, hypoglycemic events, suspected infusion set 
occlusion (unexplained hyperglycemia that leads to infusion set change), correction boluses, as 
well as more frequent and timely interactions between investigator and patients as the intensity 
of their individual diabetes management increases.  
Physicians and designated clinical staff will have access via the eCOA portal (secured web-based 
site) to BG readings, infusion set change data, hypoglycemic events, suspected infusion set 
occlusions, and correction boluses for each patient once transferred.  It is recommended that 
investigators review patient data via the eCOA portal at least once weekly for clinical decision 
making and safety monitoring.  More frequent reviews may be necessary for individual patient 
management.
An instruction manual will be provided to patients and investigative sites.  Additional instruction 
and training will be provided to the investigative sites regarding data collection, review, 
retention, and archival processes.  In the event of eCOA malfunction or loss, the patient will be 
instructed to immediately contact the investigative site for instructions regarding replacement of 
the equipment.
9.1.4.1.1. Correction Boluses
Patients will be instructed to enter the date, time, and dose for all non-meal-related correction 
bolus doses (those not associated with a meal or combined with a meal bolus) into the eCOA 
diary.  This information is critical data for evaluating the primary objective of the study.
9.1.4.1.2. Infusion Set Changes
The eCOA system will be used by patients to collect all infusion set changes, including date and 
time of change, designation of routine or premature change, primary reason for premature 
change (infusion set kinked, came out, or leaking; empty pump reservoir; infusion site pain or 
redness; pump occlusion alarm; suspected infusion set occlusion; other).
In the case of suspected infusion set occlusion, patients will choose or enter a new correction 
bolus from the eCOA diary that corresponds to the time of the suspected occlusion. They will 
then indicate if the correction bolus was given via pump or via syringe. If more than one 
correction bolus is given, patients should choose the first non-meal related correction bolus.  This 
information is also critical in order to evaluate the primary objective of the study.
Investigators will review pump occlusion alarms, suspected infusion set occlusions, and 
premature infusion set changes with patients at each visit.  
Any interruption of CSII will need to be documented in the eCRF.  When patients resume use of 
pump following the interruption, the infusion set insertion should be entered as “routine” 
infusion set change in eCOA.
9.1.4.1.3. Hypoglycemia
Hypoglycemic events will be captured throughout the clinical study in eCOA along with date 
and time of the BG level if measured and hypoglycemia treatment and outcome data.

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9.1.4.1.4. Self-Monitoring Blood Glucose
Patients will be instructed to perform SMBG according to the schedule of activities.  SMBG 
values are expected for mealtime bolus calculations and are required for calibrating Dexcom G5 
every 12 hours, and for confirming episodes of hypoglycemia, unexplained hyperglycemia, and 
the glucose response to a correction bolus.
9.1.4.1.4.1.
Four-Point Self-Monitoring Blood Glucose
Patients should be instructed to measure a minimum of 4 SMBG readings daily (consists of 
fasting [pre-morning meal], pre-midday meal, pre-evening meal, and pre-bedtime), with 
additional readings as needed for glucose self-management.
Site personnel may request additional SMBG from patients and/or assess SMBG values at other 
times for clinical decision-making.  Missing values in 4-point SMBG profiles will not be 
considered protocol deviations unless, in the opinion of the investigator, they are excessive and 
reflect noncompliance with the protocol.
9.1.4.2.
Troubleshooting Unexplained Hyperglycemia
Investigators will review unexplained hyperglycemia troubleshooting and management with
patients at Visit 2 and may repeat as necessary at subsequent visits.  Troubleshooting guidelines 
for unexplained hyperglycemia management will be provided as a tool for patient use.  A blood 
ketone meter and test strips will be provided to each patient to aid in hyperglycemia management.  
All episodes of unexplained hyperglycemia >250 mg/dL should be confirmed by SMBG using 
the study glucometer.  Patients should check to ensure the pump is in place, the prior bolus dose 
was delivered, and the infusion set is in place without any leaks or kinks in the system.  All non-
meal-related correction boluses including date, time, and dose should be entered into eCOA.  
Glucose response to the correction bolus should be confirmed by SMBG in approximately 1 hour.  
Blood ketones should be tested with the meter provided when unexplained hyperglycemia occurs
with blood glucose >250 mg/dL (13.9 mmol/L) or a pump occlusion alarm occurs with blood 
glucose >250 mg/dL (13.9 mmol/L).  If blood ketones are positive (>0.6 mmol/L) or nausea 
and/or vomiting is present, the patient should inject the correction dose by syringe, change the 
insulin, reservoir, and infusion set, and continue to monitor BG every 1 to 2 hours until within 
range.  If BG is not responding to correction and/or signs of DKA are present, the patient should 
go immediately to the nearest emergency room.
9.1.4.3.
Continuous Glucose Monitoring
The Dexcom G5 Mobile Continuous Glucose Monitoring System (Dexcom G5) will be used by 
all patients in real-time mode beginning at Visit 2 and continuing throughout the treatment phase 
of the study.  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 Mobile System 
including expectations for completion of the following daily requirements:

Strive to eat a similar breakfast each day to the extent possible and to avoid snacking for 
the 2-hour period after breakfast unless it is necessary to treat hypoglycemia.

Enter a Carbs Event marker at the start of the breakfast meal into the Dexcom receiver.

Enter an insulin Event marker at the time of the breakfast meal bolus into the Dexcom 
receiver.

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
Keep the Dexcom Receiver close to the body or within about 6 meters (about 20 feet) of 
the Dexcom Transmitter, without obstruction, to minimize the loss of transmitted data.

Calibrate the CGM sensor every 12 hours.
o
Use SMBG values taken only from finger-sticks for calibrations.  Do not use 
alternative BG site testing (forearm, palm, etc.) for sensor calibration.

Avoid products containing acetaminophen/paracetamol while using the Dexcom CGM 
System.
The CGM data will be downloaded at every site visit for clinical decision-making and 
transmitted to secure cloud storage for retrospective analysis.
9.1.4.4.
Diabetes Education and Nutritional Counseling
Initial training at Visit 2 will include diabetes education and nutrition counseling.  Training will 
include a review of correct pump use (frequency of reservoir and infusion set changes, priming 
of the infusion set, infusion site rotation) and review patient’s ability to carb count, use the 
pump’s bolus calculator to determine bolus and correction doses, use bolus types appropriately,
treat hypoglycemia, etc.  Appropriate site personnel will administer training and education using 
locally approved diabetes education/training materials and programs or by using other materials 
that may be provided by the sponsor.  Patients may be provided additional training and education 
at visits following Visit 2, based upon patient needs.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee of 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 following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the IP or the study, 
or that caused the patient to discontinue the IP before completing the study.  The patient should 
be followed up until the event resolves, stabilizes with appropriate diagnostic evaluation, or is 
reasonably explained.  The frequency of follow-up evaluations of the AE is left to the discretion 
of the investigator.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect.
After the ICF is signed, study site personnel will record via electronic data entry the occurrence 
and nature of each patient’s preexisting conditions, including clinically significant signs and 
symptoms of the disease under treatment in the study.  In addition, site personnel will record any
change in the condition(s) and any new conditions as AEs. Investigators should record their 
assessment of the potential relatedness of each AE to protocol procedure, 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

Severe hypoglycemic events:  episodes of severe hypoglycemia as determined by 
the investigator according to the definition provided in Section 9.4.2 must be 
reported as SAEs
All AEs occurring after signing the ICF are recorded in the case report form (CRF) and assessed 
for serious criteria.  The SAE reporting to the sponsor 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 as per SAE reporting requirements and timelines (see 
Section 9.2.1) if it is considered reasonably possibly related to study procedure.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms.  This 

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24-hour notification requirement refers to the initial SAE information and all follow-up SAE
information.  Patients with a serious hepatic adverse event should have additional data collected 
using the eCRF.
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 subjects once they have 
discontinued and/or completed the study (the patient disposition CRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly.
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 to 
ensure the safety of study participants, monitor quality, and 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.

Follow the instructions outlined in the Product Complaint Form for other reporting 
requirements.

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9.2.2.1.
Device Complaint Handling 
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with Dexcom G5 so that the situation can be assessed.  Any Dexcom G5 
complaint should be reported per the manufacturer’s label instructions.  Contact information will 
be provided to the investigative site personnel in the event that either personnel or patients have 
questions or complaints regarding Dexcom G5.
9.3.
Treatment of Overdose
Excess insulin administration may result in hypoglycemia.  Refer to the IB for LY900014 and 
product label for insulin lispro.
9.4.
Safety
9.4.1. Hypoglycemia
Patients are encouraged to perform SMBG whenever hypoglycemia may be suspected, either by 
symptoms experienced or perceived increased risk as related to dietary intake, physical activity,
or inadvertent or atypical insulin dosing.  All patients will be instructed to treat a BG level ≤70 
mg/dL (3.9 mmol/L) as hypoglycemia.
Hypoglycemic events will be collected in eCOA.  If a hypoglycemic event is suspected, the 
patient should record the BG value, any associated symptoms, and the treatment administered in 
eCOA.  The patient should contact the site as necessary.  Reports of hypoglycemia will be 
classified by the investigator as “severe” or “not severe” based upon data collected in eCOA and 
in consultation with the patient (see below and in Section 9.4.2). All episodes of severe 
hypoglycemia will be reported as AEs via electronic data entry and also as SAEs.  
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 
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 

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actively administer carbohydrate, glucagon, or other resuscitative actions.  BG
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
Relative Hypoglycemia (also referred to as Pseudohypoglycemia [Seaquist et 
al. 2013]):  an event during which typical symptoms of hypoglycemia occur that 
do not require the assistance of another person, are accompanied by BG 
>70 mg/dL (3.9 mmol/L).  Patients may report symptoms of hypoglycemia before 
their BG concentration falls below 70 mg/dL (3.9 mmol/L).  Events with BG ≤70 
mg/dL should not be categorized as relative hypoglycemia.  
o
Probable Symptomatic Hypoglycemia:  an event during which symptoms are 
present, but BG measurement was not reported. 
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, ECGs should be performed at Visit 1 according to the study-specific described 
in the Schedule of Activities (Section 2).
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.
9.4.4. Vital Signs
For each patient, vital sign measurements should be conducted according to the Schedule of 
Activities (Section 2) including the study-specific requirements.  

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9.4.5. Laboratory Tests
For each patient, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2). 
With the exception of laboratory test results that may unblind the study, Lilly or its designee will 
provide the investigator with the results of laboratory tests analyzed by a central vendor, if a 
central vendor is used for the clinical trial.  
Any clinically significant findings from laboratory tests that result in a diagnosis and that occur 
after the patient receives the first dose of IP should be reported to Lilly or its designee as an AE
via electronic data entry.
9.4.6. Immunogenicity Assessments 
Blood samples will be collected as specified in the Schedule of Activities (Section 2) for the
assessment of anti-insulin lispro antibodies; this assessment will be performed using a validated 
assay at a laboratory approved by the sponsor. 
Samples will be retained for a maximum of 15 years after the last patient visit, or for a shorter 
period if local regulations and ethical review boards (ERBs) allow, at a facility selected by the 
sponsor.  The duration allows the sponsor to respond to future regulatory requests related to 
LY900014.  Any samples remaining after 15 years will be destroyed.
9.4.7. Pump Occlusion Alarms and Suspected Pump Occlusions
Patients will document all pump infusion set changes in eCOA and designate if the change was 
routine or premature.  Patients will select whether the early infusion set change was due to an 
infusion set failure (kinked, came out, leaking), infusion site complication (pain or redness), 
empty pump reservoir, pump occlusion alarm, other, or if the early infusion set change was due 
to a suspected infusion set occlusion defined as unexplained hyperglycemia.  In the latter case, 
patients will choose or add a new correction bolus from the eCOA diary that corresponds to the 
timing of the suspected infusion set occlusion.  They will then indicate if the correction bolus 
was given via pump or via syringe. Investigators will review pump occlusion alarms and 
suspected pump occlusions with patients at each visit.  
9.4.8. Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.
9.4.8.1.
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 

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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.
9.7.
Pharmacogenomics
Not applicable.
9.8.
Biomarkers
Not applicable.
9.9.
Health Economics
Not applicable.

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10. Statistical Considerations
10.1. Sample Size Determination
Approximately 48 patients (24 patients in each treatment sequence) will be randomized in order 
that approximately 42 patients complete the study.
The primary objective of this study is to compare LY900014 and insulin lispro with respect to 
the rate (events/patient/30 days) of infusion set failures that lead to premature infusion set 
changes, due to a pump occlusion alarm OR due to unexplained hyperglycemia with blood 
glucose (SMBG) >250 mg/dL (13.9 mmol/L) that does not decrease within 1 hour following a 
correction bolus delivered via the pump during the 6-week treatment period. 
The study was designed following a regulatory interaction to assess the safety comparability of 
LY900014 and insulin lispro. It is not designed or powered to be a non-inferiority or superiority 
trial. 
Assuming a 12% dropout rate after randomization, approximately 48 patients (24 patients in each 
treatment sequence) will need to be randomized.
10.2. Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Entered
All patients who give informed consent.
Enrolled
All patients who receive at least 1 dose of open-label insulin lispro in the 2-week lead-in period.
Randomized
All patients who are randomly assigned to study treatment at Visit 3.  Treatment group will be 
defined on the basis of the treatment the patients are assigned to.
Safety
All randomized patients who receive at least 1 dose of the randomly assigned IP.
CGM 
All randomized patients who receive at least 1 dose of the randomly assigned IP and have CGM 
data from at least 1 collection period (lead-in, Period I and Period II).
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.  
Safety analyses will be conducted on the Safety Population. Analyses of AEs (including DKA)
will include all data collected during the course of the entire 6-week treatment period for each 
treatment group regardless of IP use. Analyses of hypoglycemia will be conducted on data 
collected prior to permanent discontinuation (i.e. last dose) of IP in each 6-week treatment
period. Unless otherwise specified, pump-related safety analyses (infusion set failures, 

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premature infusion set changes, time interval until infusion set change, and interstitial glucose 
reduction rate) will exclude data (if any) that are collected while patients temporarily are off 
pump or off IP.  Data collected during the safety follow-up period will not be used for 
comparisons between treatment groups.
Exploratory efficacy analyses (e.g., 1,5 AG and HbA1c) will be conducted on all randomized 
patients according to the treatment the patients are assigned to and CGM analyses will be 
conducted on the CGM Population.
Unless otherwise noted, all tests of treatment effects will be conducted at a 2-sided alpha level of 
0.05, and confidence intervals (CIs) will be calculated at 95%, 2-sided.  If conducted, all tests of 
interactions between treatment groups and other factors will be conducted at a 2-sided alpha 
level of 0.10.  
Treatment group comparisons will be performed for the primary objective (Section 10.3.3.1) at 
the full significance level of 0.05. No multiplicity adjustment will be made for secondary and 
exploratory objectives.
Baseline is defined as the last nonmissing measurement at or before the randomization visit
(Visit 3), unless otherwise specified.  
Unless otherwise specified, a restricted maximum likelihood based, mixed-effect model repeated
measure (MMRM) analysis will be used to analyze continuous longitudinal variables.  All the 
longitudinal observations at each scheduled postbaseline visit during the 6-week treatment period
for each treatment group will be included in the analysis. 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.  

MMRM Model 1: for analysis of variables that are measured at multiple designated visits 
within each randomized treatment period (e.g. weight and vital signs), the model will 
include the fixed class effects of treatment, period, sequence, strata (region, historical use 
of SmartGuard/Threshold Suspend, HbA1c), week (relative to the start of each 
randomized treatment period), and week-by-treatment interaction, and the continuous, 
fixed covariate of baseline value.  If the analysis fails to converge, the following 
covariance structures will be tested in order:
o
Compound symmetry with heterogeneous variances
o
Compound symmetry without heterogeneous variances

MMRM Model 2: for analysis of variables that are only measured once for each 
randomized treatment period (e.g., 1,5 AG), the model will include the fixed class effects 
of treatment, period, sequence, strata (region, historical use of SmartGuard/Threshold 
Suspend, HbA1c), and the continuous, fixed covariate of baseline value (Grizzle 1965).  
If the analysis fails to converge, a covariance structure of compound symmetry without 
heterogeneous variances will be used.
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom.  

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For continuous measures, summary statistics will include sample size, mean, standard deviation 
(SD), median, minimum, and maximum for both the actual and the change from baseline 
measurements.  LS means and standard errors derived from the analysis models will also be 
displayed for the change from baseline measurements.  Treatment comparisons will be displayed 
showing the treatment difference LS means and the 95% CIs for the treatment differences, along 
with the p-values for the treatment comparisons.
For categorical measures (such as incidence of AEs), summary statistics will include sample 
size, frequency, and percentages.  Prescott’s test will be used for treatment comparisons, unless 
otherwise specified.
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 overall and by treatment sequence and period. Reasons for discontinuation 
from the study during Period I and Period II will be summarized by treatment sequence and 
period.  
Reasons for discontinuation from the study during the lead-in and follow-up periods will be 
summarized for overall population.  
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 and by treatment sequence.  Summary statistics will 
include sample size, mean, SD, median, minimum, and maximum for continuous measures and 
sample size, frequency, and percent for categorical measures.  Baseline diabetes characteristics 
will be summarized in a similar manner.  
Medical history and AEs at baseline will be summarized by preferred term (PT) within system 
organ class (SOC).
10.3.2.3. Concomitant Therapy 
The type of rapid-insulin therapy at study entry will be summarized by treatment sequence.  The 
basal and bolus insulin doses during the lead-in period will be also be summarized by treatment 
sequence.  
Concomitant medications used during the treatment period will be summarized and compared 
between treatment groups using Prescott’s exact test.  
10.3.2.4. Treatment Compliance
No specific study data will be collected for analysis of treatment compliance (as defined in 
Section 7.5).  No analyses are planned to assess treatment compliance.

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10.3.3. Safety Analyses
10.3.3.1. Primary Analyses
The primary objective of this study is to compare LY900014 and insulin lispro with respect to 
the rate (events/patient/30 days) of infusion set failures that lead to premature infusion set 
changes, due to a pump occlusion alarm OR due to unexplained hyperglycemia with blood 
glucose (SMBG) >250 mg/dL (13.9 mmol/L) that does not decrease within 1 hour following a 
correction bolus delivered via the pump, during the 6-week treatment period.
To be considered as the primary endpoint, an infusion set failure must result in a premature 
infusion set change due to: 
1. pump occlusion alarm(s), OR
2. unexplained hyperglycemia that meets the following conditions:

Associated with a non-meal-related correction bolus delivered via the pump at least 
1 hour before the infusion set change

Most recent self-monitored blood glucose (SMBG) within 1 hour before the 
correction bolus >250 mg/dL (13.9 mmol/L)  

At least 1 SMBG obtained following the correction bolus prior to the infusion set 
change

Within 1 hour (+10 minutes) following the correction bolus, the most recent SMBG  
prior to the infusion set change does not indicate a decrease in blood glucose 
If more than 1 non-meal-related correction bolus is given for an unexplained hyperglycemia, 
only the first correction bolus time will be used to determine the 1 hour (+10 minutes) timeframe 
following the correction bolus as described in Section (9.1.4.1.1).
The infusion set failure rate (events/patient/30 days) will be derived for each patient for the lead-
in, Period I, and Period II, and summarized by treatment sequence.  
The analyses of the primary objective will be conducted on the Safety Population including data 
collected prior to permanent discontinuation of investigational product (i.e., last dose) in each 
randomized treatment period (Period I and Period II) and excluding data (if any) that are 
collected while patients temporarily are off pump or off IP. Treatment group comparisons will 
be performed using Wilcoxon signed-rank test at the full significance level of 0.05, with patients 
who are dosed in both treatment periods.  
10.3.3.2. Secondary Analyses
The incidence (percent of patients with at least 1 event) of infusion set failures, as defined in the 
primary objective, premature infusion set changes by reason, and severe hypoglycemia will be 
analyzed using Prescott’s exact test. 
Similarly, Wilcoxon signed-rank test will be used to analyze the rate of infusion set failures, 
premature infusion set changes by reason, and severe hypoglycemia, as described in Section 
10.3.3.1.

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As an additional analysis, the rate and incidence will be determined for infusion set failures 
leading to premature infusion set changes due to unexplained hyperglycemia with blood glucose 
>250 mg/dL that does not decrease by >50mg/dL within 1 hour following a correction bolus
delivered via the pump and analyzed in the same way as described for the primary endpoint.
For infusion set failures defined in the primary objective and premature infusion set changes, the 
number of events and the number of patients with events will be derived for each treatment 
group by infusion set catheter dwell time (≤24 hours, >24 and ≤48 hours, >48 and ≤72 hour, 
>72 hours), and overall (across over the course of approximately 72-hours of continuous 
infusion).  
Other safety measures will include AEs, hypoglycemia, vital signs and weight, treatment 
exposure, laboratory measures, and antibodies to insulin lispro. Analyses will be performed on 
data collected over the 6-week treatment period for each treatment group.
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.
Serious adverse events, AEs reported as reason for discontinuation from the IP or study, and 
TEAEs will be summarized in tables using the MedDRA PT, sorted by decreasing frequency 
within the LY900014 treatment group. 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 1 sex, the denominator and computation of the percentage will include only 
patients from the given sex. The number and proportion of patients with at least 1 event for each 
type of event will be summarized and compared between treatment groups using Prescott’s test.  
SAEs, AEs reported as reason for discontinuation from the study, and TEAEs will also be 
summarized for open-label insulin lispro during the lead-in period.  
If there are ≥10 patients with severe hypoglycemic event, the proportion of patients with at least 
1 severe hypoglycemic event (incidence) after randomization will be analyzed using a 
generalized linear mixed model with options of the binomial distribution and logit link function. 
The model will include treatment, period, and sequence. The within-patient error will be 
modeled as the compound symmetry variance-covariance matrix. Prescott’s exact test will be 
conducted as sensitivity analyses.
Both date and time of all infusion set changes will be captured and time interval until infusion set 
change will be derived through a minute-to-hour conversion.
The interstitial glucose reduction rate within 4 hours following a non-meal-related correction 
dose will be calculated by dividing the interstitial glucose reduction by the time it takes to 
recover (<180 mg/dL) from hyperglycemia after the correction dose. If within 4 hours a second 
correction bolus is given, only the first non-meal-related correction bolus time will be used. If 
the glucose never recovers to <180 mg/dL within 4 hours, the glucose rate will be calculated by 
dividing the greatest glucose reduction within 4 hours by the time it takes to reach this level.  

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The glucose reduction rate will be analyzed by a MMRM model. The MMRM model will 
include the fixed effects of treatment, period, and sequence as fixed effects and patient as a 
random effect.  The interstitial glucose reduction rate will also be analyzed by sub-intervals of 
interstitial glucose levels at the time of the non-meal-related correction bolus: 180 to 250, 250 to 
300, and >300 mg/dL (10 to 13.9, 13.9 to 16.7, and >16.7 mmol/L).
Actual and change from baseline in basal, bolus, and total dose, as well as the bolus/total insulin 
dose ratio, will be analyzed by a MMRM model as described in Section 10.3.1.
As described in Section 10.3.1, continuous safety variables (for example, time interval until 
infusion change), as well as the change from baseline for these variables (if applicable), will be 
analyzed by the MMRM models, and categorical variables will be analyzed using Prescott’s 
exact test for treatment comparisons unless otherwise specified.
Details for assessing immunogenicity data will be described in the SAP. No statistical 
comparisons between treatment groups will be conducted for immunogenicity data because 
patients will be exposed to both LY900014 and insulin lispro due to the crossover design.
10.3.3.3. Tertiary/Exploratory Analyses
Continuous variables and the change from baseline for these variables will be analyzed by the 
MMRM models as described in Section 10.3.1.  Categorical variables will be analyzed either by 
model (for example, a generalized linear mixed model) or nonparametric methods (for example, 
Wilcoxon signed-rank test or Prescott’s exact test).  
To assess the glucose control over the course of approximately 72-hours of continuous infusion, 
the duration and percentage of time in ranges (target, hypoglycemia or hyperglycemia) and 
incremental AUCs after breakfast, will be derived based upon the CGM raw data collected on  
Day 1, Day 2, and Day 3 of infusion set catheter wear and summarized by treatment group. 
Analysis details for the tertiary endpoints will be described in the SAP.
10.3.3.4. Subgroup Analyses 
The following subgroups will be explored to evaluate consistency of treatment effects on the 
primary safety measure:
•
Duration of CSII use (using the median as the cutoff)
•
Region (US, OUS)
•
Pump Model
Exploratory subgroup analyses or summaries of hypoglycemic event data on historical use of 
SmartGuard/Threshold Suspend (Yes, No) will also be conducted. 
Additional exploratory subgroup analyses may also be performed.
10.3.4. Efficacy Analyses
Efficacy data will be evaluated as exploratory objectives. Analysis details will be described in 
the SAP.

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

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11.
References
Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its 
complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a 
WHO consultation. Diabet Med. 1998;15(7):539-553.
Bailey TS, Grunberger G, Bode BW, Handelsman Y, Hirsch IB, Jovanovič L, Roberts VL, 
Rodbard D, Tamborlane WV, Walsh J; American Association of Clinical Endocrinologists 
(AACE); American College of Endocrinology (ACE). American Association of Clinical 
Endocrinologists and American College of Endocrinology 2016 outpatient glucose monitoring 
consensus statement. Endocr Pract. 2016;22(2):231-261. Erratum in: Endocr Pract. 
2016;22(4):516.
Bennett P. Classification and diagnosis of diabetes mellitus and impaired glucose tolerance. In: 
Pickup JC, William G, editors. Textbook of diabetes. Vol. 1. 1st ed. Oxford: Blackwell 
Scientific Publications; 1991:p 37-44.
Grizzle JE. The two-period change-over design and its use in clinical trials. Biometrics. 
1965;21:467-480.
[PMR] Pharmaceutical and healthcare market in CEE and CIS. Remodulin approved in 22 
European countries, also Poland. PMR web site. Available at 
http://www.ceepharma.com/news/25318/remodulin-approved-in-22-european-countries-also-
poland. Published September 1, 2005. Accessed September 16, 2016.
Remodulin [package insert]. Research Triangle Park, NC: United Therapeutics Corp; 2014.
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, Heller SR, Rodriguez H, 
Rosenzweig J, Vigersky R. Hypoglycemia and diabetes:  a report of a workgroup of the 
American Diabetes Association and the Endocrine Society. Diabetes Care. 2013;36(5):1384-
1395.
Stark Casagrande S, Fradkin JE, Saydah SH, Rust KF, Cowie CC. The prevalence of meeting 
A1C, blood pressure, and LDL goals among people with diabetes, 1988-2010. Diabetes Care. 
2013;36(8):2271-2279.
Thrasher J, Surks H, Nowotny I, Rotthaeuser B, Wernicke-Panten K, Garg S. Assessment of the 
safety of SAR342434 and Humalog when administered through insulin pump-pilot study
[poster]. In: American Diabetes Association 77th Scientific Sessions; Jun 9-13, 2017; San 
Diego (CA). Poster nr 1042-P.

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12.
Appendices

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Appendix 1.
Abbreviations and Definitions
Term
Definition
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 AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product.
AIT
active insulin time
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BG
blood glucose
blinding
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
CGM
continuous glucose monitoring
CI
confidence interval
confirmed pump 
occlusion
An interruption in continuous pump insulin flow that triggered an occlusion alarm that would 
not clear, after confirming that the pump and infusion set are in place without leaks or kinks 
in the system.
CR
carb ratio
CRF
case report form
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
DKA
diabetic ketoacidosis

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ECG
electrocardiogram
eCOA
electronic clinical outcomes assessment
eCRF
electronic case report form
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are those
who have been assigned to a treatment.
enter
Patients entered into a trial are those who sign the informed consent form directly or through 
their legally acceptable representatives.
ERB
ethical review board
FDA
Food and Drug Administration
FGM
flash glucose monitoring
GCP
good clinical practice
HbA1c
hemoglobin A1c
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
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 in 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
IWRS
interactive web-response system
LLT
lowest level term
LS
least squares
MDI
multiple daily injections
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed-effect model repeated measure
PPG
postprandial glucose
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 

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performance of a Lilly product after it is released for distribution.
PT
preferred term
SAE
serious adverse event
SAP
statistical analysis plan
screen
The act of determining if an individual meets minimum requirements to become part of a pool 
of potential candidates for participation in a clinical study. 
SD
standard deviation
SMBG
self-monitored blood glucose
SOC
system organ class
SUSARs
suspected unexpected serious adverse reactions
T1DM
type 1 diabetes mellitus
T2DM
type 2 diabetes mellitus
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 does not necessarily have to have a causal relationship with this 
treatment.
ULN
upper limit of normal
unexplained 
hyperglycemia
High blood glucose 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 (for example, kinked, came out, leaking), or an infusion site complication 
(for example, pain, redness).

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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
Creatinine kinase (CK)
Glucose
Ketones
Blood
1,5 Anhydroglucitol 
Urine leukocyte esterase
Hemoglobin A1c
Bilirubin 
Nitrite
Stored Samples
Anti-insulin lispro antibodies
Serology
Pregnancy test (females only)b
Follicle-stimulating hormonec
Abbreviations:  IP = investigational product; RBC = red blood cells; WBC = white blood cells.
a
All laboratory tests will be assayed by a Lilly-designated central laboratory, unless otherwise noted.
b Serum pregnancy test 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.  
c
Follicle-stimulating hormone test must be performed at Visit 1 for a postmenopausal woman who is between 
50 and 54 years of age (inclusive) with an intact uterus, not on hormone therapy, and who has had at least 
6 months of spontaneous amenorrhea.

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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 nature of the study, the potential 
risks and benefits of participating in the study, and that their participation is 
voluntary.

Ensuring that informed consent is given by each patient or legal 
representative.  This includes obtaining the appropriate signatures and dates 
on the ICF prior to the performance of any protocol procedures and prior to 
the administration of IP.

Answering any questions the patient may have throughout the study and 
sharing in a timely manner any new information that may be relevant to the 
patient’s willingness to continue his or her participation in the study.

Ensuring that a copy of the ICF is provided to the participant or the 
participant’s legal representative and is kept on file.

Ensuring that the medical record includes a statement that written informed 
consent was obtained before the participant was enrolled in the study and the 
date the written consent was obtained. The authorized person obtaining the 
informed consent must also sign the ICF.
Appendix 3.1.2.
Recruitment
Lilly or its designee is responsible for the central recruitment strategy for patients.  Individual 
investigators may have additional local requirements or processes.
Appendix 3.1.3.
Ethical Review
The investigator or an appropriate local representative must give assurance that the ERB was 
properly constituted and convened as required by International Council for Harmonisation (ICH) 
guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(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 GCP.
The study site’s ERB(s) should be provided with the following:

The protocol and related amendments and addenda, current IB, and updates 
during the course of the study, 

ICF

Other relevant documents (for example, curricula vitae, advertisements)

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Appendix 3.1.4.
Regulatory Considerations
This study will be conducted in accordance with the protocol and with the:

Consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International Organizations 
of Medical Sciences International Ethical Guidelines

Applicable ICH GCP Guidelines

Applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third party.
Appendix 3.1.5.
Investigator Information
Physicians with a specialty in endocrinology or primary care physicians specializing in 
endocrinology or internal medicine will participate as investigators in this clinical trial.
Appendix 3.1.6.
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 3.1.7.
Final Report Signature
The 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 CRF), 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.

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
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.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents.
Appendix 3.2.1.
Data Capture System
An electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
Electronic clinical outcomes assessment measures (for example, a rating scale) or other data 
reported directly by the patient (for example, daily dosing schedule, event diary) are entered into 
an eCOA instrument (for example, personal digital assistant, or by means of IWRS) at the time 
that the information is obtained.  In these instances where there is no prior written or electronic 
source data at the site, the eCOA instrument record will serve as the source.
If eCOA records are stored at a third-party site, investigator sites will have continuous access to 
the source documents during the study and will receive an archival copy at the end of the study 
for retention.
Case report form data will be encoded and stored in a clinical trial database.  Data managed by a 
central vendor, such as laboratory test data or ECG data, will be stored electronically in the 
central vendor’s database system.  Data will subsequently be transferred from the central vendor 
to the Lilly data warehouse.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
Appendix 3.3.
Study and Site Closure
Appendix 3.3.1.
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ERB of the study 
site judges it necessary for medical, safety, regulatory, or other reasons consistent with 
applicable laws, regulations, and GCP.

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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 normalized
ratio; RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory (if test results are required urgently to manage patient care).
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.

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Appendix 5.
World Health Organization Classification 
for Diabetes 
Type 1 Diabetes Mellitus:  T1DM is judged to be present when the classical symptoms of 
diabetes (thirst, polyuria, wasting and stupor, or coma) are associated with readily detectable 
concentrations of glucose and ketone bodies in the blood and urine.  Insulin treatment is 
necessary not only to control hyperglycemia, but also to prevent spontaneous ketosis and death 
(Bennett 1991; Alberti and Zimmet 1998).
Type 2 Diabetes Mellitus:  T2DM, although often asymptomatic, may also present with 
classical hyperglycemic symptoms (thirst, polyuria, and weight loss), but despite hyperglycemia, 
ketone bodies are present in only low concentrations in the blood and urine.  Coma is rare in 
T2D, but may result from extreme hyperglycemia and hyperosmolarity; lactic acidosis or 
ketoacidosis can also occur in fulminating illness (for example, severe infection or mesenteric 
artery thrombosis) because of acute increase in insulin requirements, but spontaneous ketosis 
does not occur.  Some patients with T2D later progress to a state of absolute insulin deficiency 
(Bennett 1991; Alberti and Zimmet 1998).

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Appendix 6.
Classification of Contraceptive Methods
Women of child-bearing potential must use either 1 highly effective method of contraception or a 
combination of 2 effective methods of contraception.  The patient may choose to use a 
double-barrier method of contraception (see chart below).  

Barrier protection methods without concomitant use of a spermicide are not an effective 
or acceptable method of contraception.  Thus, each barrier method must include use of a 
spermicide (that is, condom with spermicide, diaphragm with spermicide, female condom 
with spermicide).  It should be noted, however, that the use of male and female condoms 
as a double-barrier method is not considered acceptable due to the high failure rate when 
these barrier methods are combined.
Methods of Contraception
Highly Effective Methods of Contraception
Effective Methods of Contraception
(must use combination of 2 methods)

Combined oral contraceptive pill and mini-pill

NuvaRing®

Implantable contraceptives

Injectable contraceptives (such as Depo-Provera®)

Intrauterine device (such as Mirena® and ParaGard®)

Contraceptive patch – ONLY women <198 lb or 90 kg

Total abstinence

Vasectomy 

Male condom with spermicide

Female condom with spermicide

Diaphragm with spermicide

Cervical sponge

Cervical cap with spermicide

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Appendix 7.
New York Heart Association Cardiac 
Disease Classification
Functional Capacity
Class I
Patients with cardiac disease but without resulting limitation of physical activity.  Ordinary 
physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain.
Class II
Patients with cardiac disease resulting in slight limitation of physical activity.  They are 
comfortable at rest.  Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal 
pain.
Class III
Patients with cardiac disease resulting in marked limitation of physical activity.  They are 
comfortable at rest.  Less than ordinary activity causes fatigue, palpitation, dyspnea, or anginal 
pain.
Class IV
Patients with cardiac disease resulting in inability to carry on any physical activity without 
discomfort.  Symptoms of heart failure or the anginal syndrome may be present even at rest.  If 
any physical activity is undertaken, discomfort increases.
www.americanheart.org.  ©2011, American Heart Association, Inc. 1994 Revisions to 
Classification of Functional Capacity and Objective Assessment of Patients with Diseases of the 
Heart

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Appendix 8.
Protocol Amendment I8B-MC-ITSI (a)
Summary
A Prospective, Randomized, Double-Blind, Crossover 
Comparison Evaluating Compatibility and Safety of 
LY900014 and Insulin Lispro with an External 
Continuous Subcutaneous Insulin Infusion System in 
Adult Patients with Type 1 Diabetes (PRONTO-Pump)
Overview
Protocol I8B-MC-ITSI, A Prospective, Randomized, Double-Blind, Crossover Comparison 
Evaluating Compatibility and Safety of LY900014 and Insulin Lispro with an External 
Continuous Subcutaneous Insulin Infusion System in Adult Patients with Type 1 Diabetes 
(PRONTO-Pump) has been amended.  The new protocol is indicated by amendment (a) and will 
be used to conduct the study in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are described in the 
following table:

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Amendment Summary for Protocol I8B-MC-ITSI Amendment (a)
Section # and Name
Description of Change
Brief Rationale
Synopsis
Updated to match amended sections 
in main protocol
For consistency
Section 2 Schedule of Activities
Added line for collecting bolus 
types, updates to footnotes for bolus 
types
FDA request
Section 3.1 Study Rationale
Text updates to match Primary 
Objective
For consistency
Table ITSI.2 Objectives and 
Endpoints
Updated Objective and Endpoints 1, 
2 and 3. And added an Objective 16
to compare factors affecting insulin 
dosing in pumps
FDA request to change 
hyperglycemia threshold to > 250 
mg/dL, include a time frame (1 
hour) and assess infusion site 
changes due to pain
Section 5.1 Overall Design
Text updates to match objectives
For consistency
Section 6.1 Inclusion Criteria #13
Edit to make infusion set and 
reservoir change more clear
FDA specified language
Section 7.1.3 Method of Treatment 
Assignment
Edit to make more clear
For clarity
Section 9.1.1. Primary Assessments
Text updates to match primary 
objective
FDA Request
Section 9.1.2. Secondary 
Assessments
Text updates to match objectives
FDA Request
Section 9.1.4.1.1 Correction Boluses
Text updates for clarity
For clarity and emphasis
Section 9.1.4.1.2. Infusion Set 
Changes
Text updates to match objective 
changed ‘failure’ to ‘issue’
Category name in protocol changed 
from “failure” to “issue” to avoid 
confusion with primary objective 
“failure” term.
Section 9.1.4.2. Troubleshooting 
Unexplained Hyperglycemia
Added more procedural language for 
study subjects to check pump, 
infusion sets, and how to check 
blood ketones, 
Protocol language added to address 
FDA request for ketone testing 
Section 9.1.4.4. Diabetes Education 
and Nutritional Counseling
Added text ‘use bolus types 
appropriately’
Additional patient education point
Section 10.1. Sample Size 
Determination
Added text for infusion set failures 
and BG threshold to match primary 
objective;
Removed power analysis to detect a 
4.55-fold increase
FDA request
Section 10.2. Populations for 
Analyses
Added CGM population
For clarity

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Section # and Name
Description of Change
Brief Rationale
Section 10.3.1. General Statistical 
Considerations
Added more description for safety 
analyses and hypoglycemia 
analyses;
Added statement about multiplicity 
adjustment for treatment group 
comparisons
Added analysis for MMRM (1)-
variables measured at multiple visits 
and MMRM (2)- variables measured 
once for each randomization period
For clarity
Section 10.3.2.1. Patient Disposition
Replaced treatment period with 
Period I and Period II 
For clarity
Section 10.3.3.1. Primary Analyses
Text updates to match updates made 
to primary objective
For consistency
Section 10.3.3.2. Secondary 
Analyses
Text updates to match updates to 
secondary objectives;
Added additional analyses for the 
rate and incidence for a subset of 
infusion set failures defined in the 
primary objective
FDA request
Section 10.3.3.3. 
Tertiary/Exploratory Analyses
Added by-day analysis plan
FDA request for treprostinil 
exposure over 3 days

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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
Synopsis
Rationale:
A high BG level that is not responding to a correction bolus via insulin pump may indicate an 
infusion set occlusion or insulin pump problem malfunction.
The aim of this study is to compare LY900014 and insulin lispro with respect to the rate 
(events/patient/30 days) of suspected infusion set occlusions defined as failures that lead to 
premature infusion set changes, due to a pump occlusion alarm OR due to unexplained 
hyperglycemia with BG >300 BG >250 mg/dL (16.7 13.9 mmol/L) that does not decrease >50 
mg/dL (2.8 mmol/L)within 1 hour following a correction bolus delivered via the pump and that 
leads to an infusion set change.
Objective(s)/Endpoints:
Objectives
Endpoints
Primary Objective
1.
To compare LY900014 and insulin lispro with 
respect to the rate of suspected infusion set 
occlusions defined as failures that lead to 
premature infusion set changes, due to a pump 
occlusion alarm OR due to unexplained 
hyperglycemia with blood glucose 
>300250 mg/dL (16.7 13.9 mmol/L) that does 
not decrease by >50 mg/dL (2.8 
mmol/L)within 1 hour following a correction 
insulin bolus delivered via the pump and that 
leads to an infusion set change
1.
Rate (events/patient/30 days) of suspected
infusion set occlusions defined as failures that 
lead to premature infusion set changes, due to a 
pump occlusion alarm OR due to unexplained 
hyperglycemia with blood glucose (SMBG)
>300 mg250mg/dL (16.713.9 mmol/L) that does 
not decrease by >50 mg/dL (2.8 mmol/L)within 
1 hour following a correction bolus delivered via 
the pump and that leads to an infusion set 
change during the 6-week treatment period
Secondary Objectives
2.
To compare LY900014 and insulin lispro with 
respect to the incidence of suspected infusion 
set occlusions defined as failures that lead to 
premature infusion set changes, due to a pump 
occlusion alarm OR due to unexplained 
hyperglycemia with blood glucose >300
250 mg/dL (16.7 13.9 mmol/L) that does not 
decrease by >50 mg/dL (2.8 mmol/L)within 1 
hour following a correction insulin bolus 
delivered via the pump and that leads to an 
infusion set change
2.
Incidence (percent of patients with at least 
1 event) of suspected infusion set occlusions 
defined as failures that lead to premature 
infusion set changes, due to a pump occlusion 
alarm OR due to unexplained hyperglycemia 
with blood glucose (SMBG) >300mg250mg/dL 
(16.713.9 mmol/L) that does not decrease by 
>50 mg/dL (2.8 mmol/L)within 1 hour 
following a correction bolus delivered via the 
pump and that leads to an infusion set change 
during the 6-week treatment period

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Objectives
Endpoints
3.
To compare LY900014 and insulin lispro with 
respect to the rate and incidence of any 
suspected premature infusion set occlusions 
defined as unexplained hyperglycemia that 
leads to an infusion set change changes
3.
Rate (events/patient/30 days) and incidence of 
any premature infusion set changes by reason 
(infusion set kinked, came out or leaking; empty 
pump reservoir; infusion site pain or redness; 
pump occlusion alarm; suspected infusion set 
occlusions defined as unexplained 
hyperglycemia that leads to an infusion set 
change occlusion; other) during the 6-week 
treatment period
4.
To compare LY900014 and insulin lispro with 
respect to the rate and incidence of premature 
infusion set changes
4.
Rate (events/patient/30 days) and incidence of 
premature infusion set changes by reason during 
the 6 week treatment period
4.
5.To compare LY900014 and insulin lispro 
with respect to the days time interval until 
infusion set change 
4.
5.DaysTime interval until infusion set change 
during the 6-week treatment period
5.
6.To compare LY900014 and insulin lispro 
with respect to total, basal, and bolus insulin 
dose
5.
6.Bolus/total insulin dose ratio at the end of the 
6-week treatment period
6.
7.To compare LY900014 and insulin lispro 
with respect to the interstitial glucose 
reduction rate from hyperglycemia following a 
non-meal-related correction insulin bolus 
delivered via the pump
6.
7.Interstitial glucose reduction rate (glucose 
reduction [mg/dL and mmol/L] per minute) 
within 4 hours following a non-meal-related 
correction insulin bolus via the pump, from 
hyperglycemia (interstitial glucose >180 mg/dL
[10 mmol/L]), to recovery (interstitial glucose 
≤180 mg/dL), from up to 6 weeks of CGM use
7.
8.To compare LY900014 and insulin lispro 
with respect to the rate of severe 
hypoglycemic events 
7.
8.Rate (events/patient/100 years) of severe 
hypoglycemic events during the 6-week 
treatment period
Statistical Analysis:
Safety analyses will be conducted on the safety population and will only include data collected 
prior to permanent discontinuation Safety Population.  Analyses of AEs (including DKA) will 
include all data collected during the course of the entire 6-week treatment period for each 
treatment group regardless of IP use.  Analyses of hypoglycemia will be conducted on data 
collected prior to permanent discontinuation (i.e. last dose) of IP in each 6-week treatment 
period.  Unless otherwise specified, pump-related safety analyses (infusion set failures, 
premature infusion set changes, time interval until infusion set change, and interstitial glucose 
reduction rate) will exclude data (if any) that are collected while patients temporarily are off 
pump or off IP.  Data collected during the safety follow-up period will not be used for 
comparisons between treatment groups.
Unless otherwise noted, all tests of treatment effects will be conducted at a 2-sided alpha level of 
0.05, and confidence intervals (CIs) will be calculated at 95%, 2-sided.  All tests of interactions 
between treatment groups and other factors will be conducted at a 2 sided alpha level of 0.10.  

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Baseline is defined as the last nonmissing measurement at or before the randomization visit 
(Visit 3), unless otherwise specified.  
The primary objective of this study is to compare LY900014 and insulin lispro with respect to 
the rate (events/patient/30 days) of suspected infusion set occlusions defined as failures that lead 
to premature infusion set changes, due to a pump occlusion alarm or due to unexplained 
hyperglycemia with BG >300blood glucose (SMBG) >250 mg/dL (16.713.9 mmol/L) that does 
not decrease by >50 mg/dL (2.8 mmol/L)within 1 hour following a correction bolus delivered via 
the pump and that leads to an infusion set change, during the 6-week treatment period.  
To be considered as the primary endpoint, a suspected an infusion set failure must result in a 
premature infusion set change due to: 
1. pump occlusion must meet alarm(s), OR
2. unexplained hyperglycemia that meets the following conditions:

Led to an infusion set change

Associated with a non-meal related correction bolus delivered via the pump at least 1 
hour before the infusion set change

Most recent self-monitored blood glucose (SMBG) within 1 hour before the 
correction bolus >300250 mg/dL (16.713.9 mmol/L)  

At least 1 SMBG obtained following the correction bolus prior to the infusion set 
change

No SMBG measured Within 1 hour (+10 minutes) following the correction bolus (, 
the most recent SMBG prior to the infusion set change) indicates does not indicate a 
>50 mg/dL (2.8 mmol/L) decrease in blood glucose 
If more than 1 non-meal-related correction bolus is given via pump before the infusion set 
change for an unexplained hyperglycemia, only the first correction bolus time will be used to 
determine the 1 hour (+10 minutes) timeframe following the correction bolus.
The analyses of the primary objective will be conducted on the safety population Safety 
Population including data collected prior to permanent discontinuation of investigational 
product. (i.e. last dose) in each randomized treatment period (Period I and Period II) and 
excluding data (if any) that are collected while patients temporarily are off pump or off IP.
Treatment group comparisons will be performed using Wilcoxon signed-rank test at the full
significance level of 0.05, with patients who are dosed in both treatment periods.  No multiplicity 
adjustments will be made for the analysis of secondary and exploratory objectives.
The incidence (percent of patients with at least 1 event) of suspected infusion set occlusion
failure as defined in the primary objective, suspected infusion set occlusions, premature infusion 
set changes by reason, and severe hypoglycemia will be analyzed using Prescott’s exact test. 
Similarly,The Wilcoxon signed-rank test will be used to analyze the rate of suspected infusion 
set occlusions, premature infusion set changes by reason, and severe hypoglycemia, as described 
above for the primary endpoint.

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The aim of this study is to compare LY900014 and insulin lispro with respect to the rate 
(events/patient/30 days) of suspected infusion set occlusions defined as failures that lead to 
premature infusion set changes, due to a pump occlusion alarm OR due to unexplained 
hyperglycemia >300250 mg/dL (16.713.9 mmol/L) that does not decrease >50 mg/dL (2.8 
mmol/L)within 1 hour following a correction bolus delivered via the pump and that leads to an 
infusion set change.,
Table ITSI.2 Objectives and Endpoints
Objectives
Endpoints
Primary Objective
1.
To compare LY900014 and insulin lispro with 
respect to the rate of suspected infusion set 
occlusions defined as failures that lead to 
premature infusion set changes, due to a pump 
occlusion alarm OR due to unexplained 
hyperglycemia with blood glucose 
>300250 mg/dL (16.7 13.9 mmol/L) that does 
not decrease by >50 mg/dL (2.8 mmol/L)
within 1 hour following a correction insulin
bolus delivered via the pump and that leads to 
an infusion set change
1.
Rate (events/patient/30 days) of suspected
infusion set occlusions defined as failures that 
lead to premature infusion set changes, due to a 
pump occlusion alarm OR due to unexplained 
hyperglycemia with blood glucose (SMBG)
>300 mg250mg/dL (16.7 13.9 mmol/L) that 
does not decrease by >50 mg/dL (2.8
mmol/L)within 1 hour following a correction 
bolus delivered via the pump and that leads to 
an infusion set change during the 6-week 
treatment period
Secondary Objectives
2.
To compare LY900014 and insulin lispro with 
respect to the incidence of suspected infusion 
set occlusions defined as failures that lead to 
premature infusion set changes, due to a pump 
occlusion alarm OR due to unexplained 
hyperglycemia with blood glucose 
>300250 mg/dL (16.7 13.9 mmol/L) that does 
not decrease by >50 mg/dL (2.8 
mmol/L)within 1 hour following a correction 
insulin bolus delivered via the pump and that 
leads to an infusion set change
2.
Incidence (percent of patients with at least 
1 event) of suspected infusion set occlusions 
defined as failures that lead to premature 
infusion set changes, due to a pump occlusion 
alarm OR due to unexplained hyperglycemia 
with blood glucose (SMBG) >300 mg250mg/dL 
(16.713.9 mmol/L) that does not decrease by 
>50 mg/dL (2.8 mmol/L)within 1 hour
following a correction bolus delivered via the 
pump and that leads to an infusion set change
during the 6-week treatment period
3.
To compare LY900014 and insulin lispro with 
respect to the rate and incidence of any 
suspected premature infusion set occlusions 
defined as unexplained hyperglycemia that 
leads to an infusion set change changes
3.
Rate (events/patient/30 days) and incidence of 
any premature infusion set changes by reason 
(infusion set kinked, came out or leaking; empty 
pump reservoir; infusion site pain or redness; 
pump occlusion alarm; suspected infusion set 
occlusions defined as unexplained 
hyperglycemia that leads to an infusion set 
change occlusion; other) during the 6-week 
treatment period
4.
To compare LY900014 and insulin lispro with 
respect to the rate and incidence of premature 
infusion set changes
4.
Rate (events/patient/30 days) and incidence of 
premature infusion set changes by reason during 
the 6 week treatment period

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Objectives
Endpoints
4.
5.To compare LY900014 and insulin lispro 
with respect to the days time interval until 
infusion set change 
4.
5.DaysTime interval until infusion set change 
during the 6-week treatment period
5.
6.To compare LY900014 and insulin lispro 
with respect to total, basal, and bolus insulin 
dose
5.
6.Bolus/total insulin dose ratio at the end of the 
6-week treatment period
6.
7.To compare LY900014 and insulin lispro 
with respect to the interstitial glucose 
reduction rate from hyperglycemia following a 
non-meal-related correction insulin bolus 
delivered via the pump
6.
7.Interstitial glucose reduction rate (glucose 
reduction [mg/dL and mmol/L] per minute)
within 4 hours following a non-meal-related 
correction insulin bolus via the pump, from 
hyperglycemia (interstitial glucose >180 mg/dL
(10.0 mmol/L) to recovery (interstitial glucose 
≤180 mg/dL), from up to 6 weeks of CGM use
7.
8.To compare LY900014 and insulin lispro 
with respect to the rate of severe hypoglycemic 
events 
7.
8.Rate (events/patient/100 years) of severe 
hypoglycemic events during the 6-week 
treatment period
Tertiary/Exploratory Objectives 
8.
9.To compare the safety of LY900014 and 
insulin lispro
8.
9.Adverse events and vital signs 
9.
10.To compare LY900014 and insulin lispro 
with respect to the rate and incidence of 
documented symptomatic post-meal 
hypoglycemia
9.
10.Rate (events/patient/year and/or 
events/patient/30 days) and incidence (percent 
of patients with at least 1 event) of documented 
symptomatic post-meal hypoglycemia within 
1 and 2 hours after the start of a meal during the 
last 2 weeks of the 6-week treatment period
10. 11.To compare LY900014 and insulin lispro 
with respect to the rate and incidence of 
documented symptomatic hypoglycemia
10. 11.Rate (events/patient/year and/or 
events/patient/30 days) and incidence (percent 
of patients with events) of documented 
symptomatic hypoglycemic events during the 
last 2 weeks of the 6-week treatment period
11. 12.To compare LY900014 and insulin lispro 
with respect to the incremental AUCs after 
breakfast, obtained from CGM use
11. 12.Incremental AUC0-1 hourafter breakfast during 
the last 2 weeks of up to 6 weeks of CGM use 
12. 13.To compare LY900014 and insulin lispro 
with respect to the duration of time glucose 
values are within target range (71 and 
180 mg/dL [3.9 and 10.0 mmol/L]), obtained 
from CGM use
12. 13.Duration (in minutes) and percentage of time 
with glucose values between 71 and 180 mg/dL 
(3.9 and 10.0 mmol/L), both inclusive, 
normalized to a 24-hour period, during the last 2 
weeks of up to 6 weeks of CGM use 
13. 14.To compare LY900014 and insulin lispro 
with respect to the duration of time glucose 
values are within target range (71 and 
140 mg/dL [3.9 and 7.8 mmol/L]), obtained 
from CGM use
13. 14.Duration (in minutes) and percentage of time 
with glucose values between 71 and 140 mg/dL 
(3.9 and 7.8 mmol/L), both inclusive, 
normalized to a 24-hour period, during the last 2 
weeks of up to 6 weeks of CGM use 
14. 15.To compare LY900014 and insulin lispro 
with respect to the glucose profiles, obtained 
from CGM use
14. 15.Average glucose for a 24-hour period during 
the last 2 weeks of up to 6 weeks of CGM use 
15. 16.To compare LY900014 and insulin lispro 
with respect to the glucose variability, 
obtained from CGM use
15. 16.Interquartile range, CV, LBGI, and HBGI
during the last 2 weeks of up to 6 weeks of 

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Objectives
Endpoints
CGM use 
16. To compare LY900014 and insulin lispro with 
respect to the factors affecting dosing in 
pumps 
16. Actual and change from baseline in factors 
affecting dosing in pump (breakfast CR, AIT, 
breakfast ISF, and frequency of use of non-
normal bolus type [Square Wave or Dual 
Wave]), during the 6-week treatment period
Section 5.1 Overall Design
The study is designed to compare LY900014 and insulin lispro with respect to the rate 
(events/patient/30 days) of suspected infusion set occlusions defined as failures that lead to 
premature infusion set changes due to a pump occlusion alarm OR due to unexplained 
hyperglycemia >300with blood glucose (SMBG) >250 mg/dL (16.713.9 mmol/L) that does not 
decrease >50 mg/dL (2.8 mmol/L)within 1 hour following a correction bolus delivered via the 
pump and that leads to an infusion set change.  The study includes a 1-week screening period and 
a 2-week lead-in period followed by a 2-period crossover and a 4-week post-treatment safety 
follow-up.  Each period of the crossover will consist of 6 weeks of treatment with no washout 
between periods.
Unexplained hyperglycemia is expected to be an uncommon event in this study and the use of 
real-time CGM, self-monitored blood glucose (SMBG), electronic clinical outcomes assessment
(eCOA), frequent study visits, and provision of standard of care hyperglycemia troubleshooting
management guidelines and blood ketone testing meters and strips will all serve to maximize 
subject safety.  Patients will be experienced pump users who have recent experience using CGM 
or flash glucose monitoring (FGM), and they will be guided to follow best standards of care in 
insulin pump management.  
At every office visit, the date and time of each device used in the study (insulin pump, eCOA 
diary, glucometer, ketone meter, and CGM receiver) should be synchronized and verified by site 
staff.
Section 6.1 Inclusion Criteria
[13] Are willing to change both the pump reservoir and adhere to an infusion set 
and reservoir change interval of every 72 ± 4 hours unless necessary to maintain 
glycemic control in the event of a pump or change is required for failure of the 
infusion set/site malfunction
Section 7.1.3. Method of Treatment Assignment
Patients who meet all criteria for enrollment and complete the lead-in period will be randomized 
to double-blind treatment at Visit 3.  Assignment to treatment groups sequences will be 
determined by a computer-generated random sequence using an interactive web-response system 
(IWRS).  

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Patients will fill a new pump reservoir and infusion set with IP, then insert a new pump infusion 
set cannula into an appropriate site, and begin infusion of IP prior to leaving the investigative site
at Visits 2, 3, and 6.  Patients will continue to fill reservoirs and infusion sets with IP and insert a 
new infusion set cannula into an appropriate site every 72 ± 4 hours as outpatients, unless a 
change is required for failure of the infusion set
Section 8.2.
Discontinuation from the Study
•
Frequent use of prohibited concomitant medication.
Section 9.1.1. Primary Assessments
The rate of suspected infusion set occlusions is defined as failures that lead to premature infusion 
set changes, due to a pump occlusion alarm OR due to unexplained hyperglycemia >300with 
blood glucose (SMBG) >250 mg/dL (16.7 13.9 mmol/L) that does not decrease >50 mg/dL (2.8 
mmol/L)within 1 hour following a correction bolus delivered via the pump and that leads to an 
infusion set change.
Section 9.1.2. Secondary Assessments

The incidence of suspected infusion set occlusions defined as failures that lead to 
premature infusion set changes, due to a pump occlusion alarm OR due to
unexplained hyperglycemia >300 with blood glucose (SMBG) >250 mg/dL (16.7 
13.9 mmol/L) that does not decrease >50 mg/dL (2.8 mmol/L)within 1 hour
following a correction bolus delivered via the pump and that leads to an infusion set 
change

Rate and incidence of any suspected infusion set occlusions defined as unexplained 
hyperglycemia that leads to an infusion set change

Rate and incidence of premature infusion set changes by reason (non routine infusion 
set changes) by reason (infusion set kinked, came out or leaking; empty pump 
reservoir; infusion site pain or redness; pump occlusion alarm; suspected infusion set 
occlusion; other)  

DaysTime interval until infusion set change (overall and due to any suspected 
infusion set occlusion)

Interstitial glucose reduction from hyperglycemia following a non-meal-related 
correction insulin bolus delivered via the pump
Section 9.1.4.1.1 Correction Boluses
Patients will be instructed to enter the date, time, and dose for all non-meal-related correction 
bolus doses (those not associated with a meal or combined with a meal bolus) into the eCOA 
diary.  This information is critical data for evaluating the primary objective of the study.
Section 9.1.4.1.2. Infusion Set Changes
The eCOA system will be used by patients to collect all infusion set changes, including date and 
time of change, designation of routine or premature change, primary reason for premature 

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change (infusion set failure [infusion set kinked, came out, or leaking],; empty pump reservoir
infusion site complication [pain or redness], ; pump occlusion alarm; suspected infusion set 
occlusion;, or other).
In the case of suspected infusion set occlusion, patients will choose or enter a new correction 
bolus from the eCOA diary that corresponds to the time of the suspected occlusion. They will 
then indicate if the correction bolus was given via pump or via syringe.  If more than one 
correction bolus is given, patients should choose the first non-meal related correction bolus.  This 
information is also critical in order to evaluate the primary objective of the study.
Any interruption of CSII will need to be documented in the eCRF.  When patients resume use of 
pump following the interruption, the first infusion set insertion change that occurs should be 
entered as “routine” infusion set change in eCOA.
Section 9.1.4.2. Troubleshooting Unexplained Hyperglycemia
Investigators will review unexplained hyperglycemia troubleshooting and management with 
patients at Visit 2 and may repeat as necessary at subsequent visits.  Troubleshooting guidelines 
for unexplained hyperglycemia management will be provided as a tool for patient use.  A blood 
ketone meter and test strips will be provided to each patient to aid in hyperglycemia management.  
All episodes of unexplained hyperglycemia >250 to >300 mg/dL should be confirmed by SMBG 
using the study glucometer.  Patients should check to ensure the pump is in place, the prior bolus 
dose was delivered, and the infusion set is in place without any leaks or kinks in the system.  All 
non-meal-related correction boluses including date, time, and dose should be entered into eCOA.  
Glucose response to the correction bolus should be confirmed by SMBG withinin approximately 
1 hour.  Blood ketones should be tested when unexplained hyperglycemia occurs with blood 
glucose >250 mg/dL (13.9 mmol/L) or a pump occlusion alarm occurs with blood glucose >250 
mg/dL (13.9 mmol/L).  If blood ketones are positive (>0.6 mmol/L) or nausea and/or vomiting is 
present, the patient should inject the correction dose by syringe, change the insulin, reservoir, 
and infusion set, and continue to monitor BG every 1 to 2 hours until within range.  If BG is not 
responding to correction, and/or signs of DKA are present, the patient should go immediately to 
the nearest emergency room.
Section 9.1.4.4. Diabetes Education and Nutritional Counseling
Initial training at Visit 2 will include diabetes education and nutrition counseling.  Training will 
include a review of correct pump use (frequency of reservoir and infusion set changes, priming 
of the infusion set, infusion site rotation) and review patient’s ability to carb count, use the 
pump’s bolus calculator to determine bolus and correction doses, use bolus types appropriately, 
treat hypoglycemia, etc.  
Section 10.1. Sample Size Determination
Approximately 48 patients (24 completerspatients in each treatment sequence) will be 
randomized in order that approximately 42 patients complete the study.

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The primary objective of this study is to compare LY900014 and insulin lispro with respect to 
the rate (events/patient/30 days) of suspected infusion set occlusions defined asfailures that lead 
to premature infusion set changes, due to a pump occlusion alarm OR due to unexplained 
hyperglycemia with BG >300blood glucose (SMBG) >250 mg/dL (16.713.9 mmol/L) that does 
not decrease by >50 mg/dL (2.8 mmol/L)within 1 hour following a correction bolus delivered via 
the pump and that leads to an infusion set change during the 6-week treatment period. 
The study was designed following a regulatory interaction to assess the safety comparability of 
LY900014 and insulin lispro. It is not designed or powered to be a non-inferiority or superiority 
trial. 
Assuming the number of suspected infusion set occlusions defined in the primary objective 
follows a negative binomial distribution with a dispersion parameter of 0.29, and a rate of 0.44 
events/patient/30 days for insulin lispro (derived based upon Thrasher et al. 2017), 42 completers 
(21 completers in each treatment sequence) will provide at least 80% power to demonstrate a 
4.55 fold increase in the event rate (equal to a rate of 2 events/patient/30 days for LY900014), 
using Wilcoxon signed rank test with a 2 sided alpha level of 0.05.  The power was calculated 
based on the proportion of the trials showing statistical significance from 5000 simulated trials.  
Assuming a 12% dropout rate after randomization, approximately 48 patients (24 patients in each 
treatment sequence) will need to be randomized.
Section 10.2 Populations for Analyses
Population
Description
Entered
All patients who give informed consent.
Enrolled
All patients who receive at least 1 dose of open-label insulin lispro in the 2-week lead-in period.
Randomized
All patients who are randomly assigned to study treatment at Visit 3.  Treatment group will be 
defined on the basis of the treatment the patients are assigned to.
Safety
All randomized patients who receive at least 1 dose of the randomly assigned IP.
CGM 
All randomized patients who receive at least 1 dose of the randomly assigned IP, and have CGM 
data from at least 1 collection period (lead-in, Period I and Period II). 
Section 10.3.1. General Statistical Considerations
Safety analyses will be conducted on the safety population and Safety Population.  Analyses of 
AEs (including DKA) will only include all data collected during the course of the entire 6-week 
treatment period for each treatment group regardless of IP use.  Analyses of hypoglycemia will 
be conducted on data collected prior to permanent discontinuation of IP (Section 8.1). (i.e. last 
dose) of IP in each 6-week treatment period.  Unless otherwise specified, pump-related safety 
analyses (infusion set failures, premature infusion set changes, time interval until infusion set 
change, and interstitial glucose reduction rate) will exclude data (if any) that are collected while 
patients temporarily are off pump or off IP.  Data collected during the safety follow-up period 
will not be used for comparisons between treatment groups.

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Exploratory efficacy analyses (e.g., 1,5 AG and HbA1c) will be conducted on all randomized 
patients according to the treatment the patients are assigned to, using data collected prior to 
permanent discontinuation of IP.and CGM analyses will be conducted on the CGM Population. 
Unless otherwise noted, all tests of treatment effects will be conducted at a 2-sided alpha level of 
0.05, and confidence intervals (CIs) will be calculated at 95%, 2-sided.  AllIf conducted, all tests 
of interactions between treatment groups and other factors will be conducted at a 2-sided alpha 
level of 0.10.  
Treatment group comparisons will be performed for the primary objective (Section 10.3.3.1) at 
the full significance level of 0.05.  No multiplicity adjustment will be made for secondary and 
exploratory objectives.
Unless otherwise specified, a restricted maximum likelihood based, mixed-effect model repeated 
measure (MMRM) analysis will be used to analyze continuous longitudinal variables.  All the 
longitudinal observations at each scheduled postbaseline visit during the 6-week treatment period 
for each treatment group will be included in the analysis. 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.  The
MMRM Model 1: for analysis of variables that are measured at multiple designated visits 
within each randomized treatment period (e.g. weight and vital signs), the model will 
include the fixed class effects of treatment, period, sequence, strata (region, historical use 
of SmartGuard/Threshold Suspend, HbA1c), week (relative to the start of each 
randomized treatment period), and week-by-treatment interaction, and the continuous, 
fixed covariate of baseline value.  If the analysis fails to converge, the following 
covariance structures will be tested in order:
o
Compound symmetry with heterogeneous variances
o
Compound symmetry without heterogeneous variances 

MMRM Model 2: for analysis of variables that are only measured once for each 
randomized treatment period (e.g., 1,5 AG), the model will include the fixed class effects 
of treatment, period, sequence, strata (region, historical use of SmartGuard/Threshold 
Suspend, HbA1c), the random class effect of patient within sequence, and the 
continuous, fixed covariate of baseline value (Grizzle 1965).  If the If this analysis fails to 
converge, a covariance structure of compound symmetry without heterogeneous 
variances will be used.  
Section 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 overall and by treatment sequence and period. Reasons for discontinuation 
from the study during the treatment periodPeriod I and Period II will be summarized by 
treatment sequence and period.  

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Reasons for discontinuation from the study during the lead-in and follow-up periods will be 
summarized for overall population.  
Section 10.3.3.1. Primary Analyses
The primary objective of this study is to compare LY900014 and insulin lispro with respect to 
the rate (events/patient/30 days) of suspected infusion set occlusions defined as failures that lead 
to premature infusion set changes, due to a pump occlusion alarm or due to unexplained 
hyperglycemia with BG >300blood glucose (SMBG) >250 mg/dL (16.713.9 mmol/L) that does 
not decrease by >50 mg/dL (2.8 mmol/L) within 1 hour following a correction bolus delivered 
via the pump and that leads to an infusion set change , during the 6-week treatment period.  
To be considered as the primary endpoint, a suspectedan infusion set failure must result in a 
premature infusion set change due to: 
1. pump occlusion must meetalarm(s), OR
2. unexplained hyperglycemia that meets the following conditions:

Led to an infusion set change

Associated with a non-meal related correction bolus delivered via the pump at least 1 
hour before the infusion set change

Most recent SMBGself-monitored blood glucose (SMBG) within 1 hour before the 
correction bolus >300250 mg/dL (16.713.9 mmol/L)  

At least 1 SMBG obtained following the correction bolus prior to the infusion set 
change

No SMBG measuredWithin 1 hour (+10 minutes) following the correction bolus (, 
the most recent SMBG  prior to the infusion set change) indicates does not indicate a
>50 mg/dL (2.8 mmol/L) decrease in blood glucose 
If more than 1 non-meal-related correction bolus is given via pump before the infusion set 
changefor an unexplained hyperglycemia, only the first correction bolus time will be used. to 
determine the 1 hour (+10 minutes) timeframe following the correction bolus as described in 
Section 9.1.4.1.1.
The infusion set failure rate (events/patient/30 days) will be derived for each patient for the lead-
in, Period I and Period II, and summarized by treatment sequence for all patients in the Safety 
Population.  
The analyses of the primary objective will be conducted on the safety populationSafety 
Population including data collected prior to permanent discontinuation of IP. investigational 
product (i.e., last dose) in each randomized treatment period (Period I and Period II) and 
excluding data (if any) that are collected while patients temporarily are off pump or off IP.
Treatment group comparisons will be performed using Wilcoxon signed-rank test at the full 
significance level of 0.05, with patients who are dosed in both treatment periods.

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Section 10.3.3.2. Secondary Analyses
The incidence (percent of patients with at least 1 event) of suspected infusion set 
occlusionfailures, as defined in the primary objective, any suspected infusion set occlusions, 
premature infusion set changes by reason, and severe hypoglycemia will be analyzed using 
Prescott’s exact test. 
Similarly, Wilcoxon signed-rank test will be used to analyze the rate of suspected infusion set 
occlusionsfailures, premature infusion set changes by reason, and severe hypoglycemia., as 
described in Section 10.3.3.1.  
As an additional analysis, the rate and incidence will be determined for infusion set failures 
leading to premature infusion set changes due to unexplained hyperglycemia with blood glucose 
>250mg/dL that does not decrease by >50mg/dL within 1 hour following a correction bolus 
delivered via the pump, and analyzed in the same way as described for the primary endpoint.
For infusion set failures defined in the primary objective and premature infusion set changes, the 
number of events and the number of patients with events will be derived for each treatment 
group by infusion set catheter dwell time (≤24 hours, >24 and ≤48 hours, >48 and ≤72 hour, 
>72 hours), and overall (across over the course of approximately 72-hours of continuous 
infusion).  
Other safety measures will include AEs, hypoglycemia, vital signs and weight, treatment 
exposure, laboratory measures, and antibodies to insulin lispro. Analyses will be performed on 
data collected over the 126-week treatment period for each treatment group.  
Both date and time of all infusion set changes will be captured and daystime interval until 
infusion set change will be derived through an hoursa minute-to-dayshour conversion.  
Actual and change from baseline in basal, bolus, and total dose, as well as the bolus/total insulin 
dose ratio, will be analyzed by athe MMRM model as described in Section 10.3.1.
As described in Section 10.3.1, continuous safety variables (for example, time intervaldays until 
infusion change), as well as the change from baseline for these variables (if applicable), will be 
analyzed by the MMRM modelmodels, and categorical variables will be analyzed using 
Prescott’s exact test for treatment comparisons unless otherwise specified.
The analysesDetails for assessing immunogenicity data will be described in the SAP.  No 
statistical comparisons between treatment groups will be conducted for immunogenicity data 
because patients will be exposed to both LY900014 and insulin lispro due to the crossover 
design. 
Section 10.3.3.3. Tertiary/Exploratory Analyses
Continuous variables and the change from baseline for these variables will be analyzed by the 
MMRM modelmodels as described in Section 10.3.1.  Categorical variables will be analyzed 
either by model (for example, a generalized linear mixed model) or nonparametric methods (for 
example, Wilcoxon signed-rank test or Prescott’s exact test).  Analysis details for the tertiary 
endpoints will be described in the SAP.

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To assess the glucose control over the course of approximately 72-hours of continuous infusion, 
the duration and percentage of time in ranges (target, hypoglycemia or hyperglycemia) and 
incremental AUCs after breakfast, will be derived based upon the CGM raw data collected on  
Day 1, Day 2 and Day 3 of infusion set catheter wear and summarized by treatment group. 
Analysis details for the tertiary endpoints will be described in the SAP.