Conditions: Diabetes Type 1
Keywords: insulin pump
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 49
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the compatibility and safety of LY900014 and insulin lispro with an external continuous subcutaneous insulin infusion system in adult participants with type 1 diabetes.

Detailed description:

Arms:
arm 1: 100 units per milliliter (U/mL) LY900014 administered by individualized, continuous, subcutaneous insulin infusion (CSII) arm 2: 100 U/mL insulin lispro (Humalog®) administered by individualized CSII

Interventions: intervention 1: LY900014 intervention 2: Insulin lispro
Intervention descriptions: intervention 1: Administered by CSII intervention 2: Administered by CSII

Protocol document:
Prot_000.pdf: 
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.


I8B-MC-ITSI (a) Clinical Protocol
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LY900014
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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LY900014
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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LY900014
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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LY900014
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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LY900014
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


I8B-MC-ITSI (a) Clinical Protocol
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LY900014
[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


I8B-MC-ITSI (a) Clinical Protocol
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LY900014
[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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LY900014
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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LY900014
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.

SAP_001.pdf: 
Statistical Analysis Plan 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: 29Aug2018 


I8B-MC-ITSI Statistical Analysis Plan Version 3
Page 1
LY900014
1.
Statistical Analysis Plan:
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)
Confidential Information
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of Eli Lilly 
and Company or its subsidiaries.  
Note to Regulatory Authorities: this document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure. Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries..
LY900014
Study I8B-MC-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 continuous subcutaneous insulin infusion.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol I8B-MC-ITSI
Phase 3
Statistical Analysis Plan electronically signed and approved by Lilly:  20 February 2018
Statistical Analysis Plan version 2 electronically signed and approved by Lilly:  26 April 
2018
Statistical Analysis Plan version 3 electronically signed and approved by Lilly on date 
provided below.
Approval Date: 29-Aug-2018 GMT


I8B-MC-ITSI Statistical Analysis Plan Version 3
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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan: 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
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................6
4.
Study Objectives.................................................................................................................7
5.
Study Design.....................................................................................................................10
5.1.
Summary of Study Design............................................................................................10
5.2.
Determination of Sample Size ......................................................................................11
5.3.
Method of Assignment to Treatment ............................................................................12
6.
A Priori Statistical Methods ..............................................................................................13
6.1.
General Considerations ................................................................................................13
6.2.
Adjustments for Covariates ..........................................................................................18
6.3.
Handling of Dropouts or Missing Data.........................................................................18
6.4.
Multicenter Studies ......................................................................................................18
6.5.
Multiple Comparisons/Multiplicity...............................................................................18
6.6.
Patient Disposition .......................................................................................................18
6.7.
Patient Characteristics ..................................................................................................19
6.8.
Treatment Compliance .................................................................................................20
6.9.
Important Protocol Deviations......................................................................................20
6.10. Concomitant and Prior Therapy....................................................................................24
6.11. Safety Analyses............................................................................................................25
6.11.1.
Primary Outcome and Methodology.....................................................................25
6.11.2.
Other Secondary Safety Analyses.........................................................................25
6.11.3.
Pump Factors .......................................................................................................28
6.11.4.
Extent of Exposure...............................................................................................28
6.11.5.
Adverse Events ....................................................................................................28
6.11.6.
Deaths..................................................................................................................30
6.11.7.
Hypoglycemic Events and Other Adverse Events.................................................30
6.11.7.1.
Hypoglycemic Events.....................................................................................30
6.11.7.2.
Systemic Hypersensitivity Reaction................................................................32
6.11.7.3.
Infusion Site Reaction.....................................................................................33
6.11.7.4.
Hepatobiliary Events ......................................................................................33


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6.11.7.4.1.
Treatment-Emergent Potential Hepatic Disorder.......................................33
6.11.7.5.
Malignant Neoplasm Events...........................................................................34
6.11.8.
Blood Ketones .....................................................................................................34
6.11.9.
Clinical Laboratory Evaluation.............................................................................34
6.11.10. Vital Signs and Other Physical Findings...............................................................34
6.11.11. Immunogenicity...................................................................................................35
6.11.11.1. Treatment-Emergent Anti-Insulin Lispro Antibody.........................................35
6.11.12. Patient Narratives.................................................................................................36
6.12. CGM Analyses.............................................................................................................36
6.13. Efficacy Analyses ........................................................................................................41
6.14. Subgroup Analyses for Primary Endpoint.....................................................................42
6.15. Interim Analyses and Data Monitoring.........................................................................42
6.16. Clinical Trial Registry Analyses...................................................................................42
7.
Unblinding Plan................................................................................................................44
8.
References ........................................................................................................................45
9.
Appendix 1 .......................................................................................................................46
9.1.
Derivation of CGM Variables.......................................................................................46
9.2.
General Derivation Specifications ................................................................................46
9.3.
Interstitial Glucose Reduction Rate following a Correction Bolus 
via the Pump ................................................................................................................46
9.4.
Incremental Area under the Glucose Curve (iAUC)......................................................47
9.5.
Average Glucose Excursions........................................................................................47
9.6.
Glucose in Target Ranges, Hypoglycemia- or Hyperglycemia......................................48
9.7.
Hypoglycemic/Hyperglycemic Episodes ......................................................................48
9.8.
Glucose Variability ......................................................................................................48
9.8.1.
Within-Day Variability ........................................................................................49
9.8.2.
Between-Day Variability......................................................................................50
9.8.3.
Overall Variability ...............................................................................................50
9.8.4.
Risk for Hypo/Hyperglycemia..............................................................................50
9.9.
Daily CGM Data Summary..........................................................................................51
9.10. AUC ............................................................................................................................52
9.11. Highest Postprandial Glucose.......................................................................................52
9.11.1.
Time to the highest postprandial glucose within 3 hours after 
Meals ...................................................................................................................52
9.11.2.
Highest Postprandial Glucose Level within 3 hours after 
Meals ...................................................................................................................52
9.12. Other............................................................................................................................52


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Table of Contents
Table
Page
Table ITSI.4.1.
Objectives and Endpoints............................................................................7
Table ITSI.6.1.
Patient Populations ...................................................................................13
Table ITSI.6.2.
Baseline and Post-Baseline Definitions and Patient Population by Study 
Period and Type of Analysis..............................................................................................15
Table ITSI.6.3.
Description of Important Protocol Deviations ...........................................21
Table ITSI.6.4.
Source Data for Infusion Set Changes.......................................................27
Table ITSI.6.5.
Adverse Event Analysis Periods ...............................................................30
Table ITSI.6.6.
Summary of Analyses for Endpoints Related to Hypoglycemia.................31
Table ITSI.6.7.
Categorical Criteria for Abnormal Treatment-Emergent Blood Pressure and 
Pulse Measurement, and Categorical Criteria for Weight Changes for Adults ....................35
Table ITSI.6.8.
Outcome Measures of CGM DATA..........................................................37


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Table of Contents
Figure
Page
Figure ITSI.5.1.
Illustration of study design for Clinical Protocol I8B-MC-ITSI.................10
Figure ITSI.5.2.
Flow chart for reporting infusion set changes............................................11


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3.
Revision History
Statistical Analysis Plan (SAP) Version 1 was approved prior to the first patient visit.  Version 1
is based on the Protocol I8B-MC-ITSI approved on 23 October 2017 and amended on Jan 12, 
2018.
SAP Version 2 was approved on 26 April 2018. The main changes from Version 1 are listed 
below:

adding analysis details (for example, analysis of time until infusion set changes) and rules 
(for example, to define unique hypoglycemia events). 

deleting the following analyses:
o
hypoglycemia summaries for postmeal all documented and documented 
unspecified hypoglycemia because the information of time relative to meal is 
missing for documented unspecified hypoglycemia events
This SAP is the third version approved prior to the first unblinding.  The main changes from 
Version 2 are listed below:

modifying the baseline definition for treatment-emergent adverse event (TEAE) analyses 
for the two 6-week randomized treatment periods: use observations prior to first dose of 
randomized investigational product (IP) (or Visit 3 date if the dose date is missing) but 
after the first dose of open-label lispro in the lead-in period.

adding treatment-emergent potential hepatic disorder analyses.

adjusting the hypoglycemia rate analysis methods to Wilcoxon signed-rank test only and 
removing the basal rate from hypoglycemia incidence analysis model, to address the 
model convergence issue due to the relatively small sample size of the study.

adding more details as to how to identify a non-meal related correction bolus in electronic 
clinical outcomes assessment (eCOA) captured data.


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4.
Study Objectives
Table ITSI.4.1 shows the objectives and endpoints of the study.
Table ITSI.4.1.
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) >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
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


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Objectives
Endpoints
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
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


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Objectives
Endpoints
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 
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.
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 (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 includes a 1-week screening period and a 2-week lead-in period followed by a 2-
period (Period I and Period II) 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.
Figure ITSI.5.1 illustrates the study design.  
Figure ITSI.5.1.
Illustration of study design for Clinical Protocol I8B-MC-ITSI.
Patients who need to discontinue from study treatment will also be discontinued from the study.  
Please refer to Protocol Sections 8.1 and 8.2.  In this document, discontinuation of IP refers to 
the last dose of IP in a study period (lead-in, Period I, or Period II). 
The eCOA diary will be used by patients to document 4-point SMBGs (consists of fasting [pre-
morning meal], pre-midday meal, pre-evening meal, and pre-bedtime), hypoglycemia, and 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 


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pump reservoir; infusion site pain or redness; pump occlusion alarm; suspected infusion set 
occlusion; other) as depicted in Protocol 9.1.4.1.  Additional data on infusion site complications 
will be collected by investigators. 
Patients will enter all non-meal-related correction boluses into the eCOA diary.  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.
Pump interruption is defined as patient is off pump due to pump malfunction and is temporarily 
using injection therapy. It does not include the condition where patient uses a syringe to inject a 
correction bolus dose while still on pump.  Any interruption of CSII will need to be documented 
in the electronic case report form (eCRF).  When patients resume use of pump following the 
interruption, the infusion set insertion should be entered as “routine” infusion set change in 
eCOA.
Figure ITSI.5.2.
Flow chart for reporting infusion set changes.
5.2.
Determination of Sample Size
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 


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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.
5.3.
Method of Assignment to Treatment
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).


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6.
A Priori Statistical Methods
6.1.
General Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly and Company (hereafter 
Lilly).  Any change to the data analysis methods described in the protocol will require an 
amendment ONLY if it changes a principal feature of the protocol.  Any other change to the data 
analysis methods described in the protocol, and the justification for making the change, will be 
described in this SAP and/or in the clinical study report (CSR). Additional exploratory analyses 
will be conducted, as deemed appropriate.
For purposes of analysis, the following populations are defined in Table ITSI.6.1:
Table ITSI.6.1.
Patient Populations
Population
Description
Entered
All patients who give informed consent.
Enrolled
All patients who receive at least 1 dose of open-label insulin lispro in the 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.
Treatment group will be defined on the basis of the treatment the patients are assigned 
to.
CGM Population
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).
Treatment group will be defined on the basis of the treatment the patients are assigned
to.
Safety analyses will be conducted on the Safety Population.  Analyses of adverse events (AEs)
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 (e.g., infusion set failures, 
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 specified, exploratory efficacy analyses will be conducted on the Randomized 
Population. CGM outcome 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.


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The definitions of baseline and post-baseline for the safety and efficacy analyses depend on 
which analysis period is being used.  The following analysis periods will be used:

Lead-in Period – Visits 2-3

12-Week Treatment Period while on IP – from first dose to last dose of IP in each 6-week 
randomized treatment period (Period I and Period II)

12-Week Treatment Period Regardless of IP use – from randomization to Week 6 of 
each randomized treatment period (including all data regardless of IP use)

Safety Follow-up Period – Visit 801
Table ITSI.6.2 describes the rules for determining the patient population, baseline and 
postbaseline observations for the different analysis periods. The data in the lead-in and the 
safety follow-up visit, if summarized, will be for overall, not by treatment group.
The data on IP is defined based on the following rules:

for data only measured at an office visit (for example, HbA1c), if the office visit date (or 
laboratory sample collection date) is within 14 days of the date of last study drug dose of 
the randomized treatment period (Period I or Period II), then postbaseline data measured 
at or prior to that office visit will be considered as data on IP.

for data collected as running records with an exact date and/or time stamp such as diary 
entries where the date and time of the measures was not tied with the date of an office 
visit, postbaseline data with date and time ≤ (last study drug dose date and time) will be 
considered as data on IP.
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.  Least squares (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.
Unless otherwise specified, a restricted maximum likelihood based, mixed-effect model repeated 
measures (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 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:


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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 this 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.  
For either of the two models, if the model fails to converge for any covariance structure, strata 
may be deleted from the model.
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.
For laboratory values, both conventional (CN) and Systeme International (SI) units will be 
presented.  Therefore, both % and mmol/mol will be presented for HbA1c and both mg/dL and 
mmol/L will be presented for glucose measurements.  
Table ITSI.6.2.
Baseline and Post-Baseline Definitions and Patient Population by 
Study Period and Type of Analysis
Study Period/Analysis
Patient Population
Baseline Observations
Post-Baseline Observations
Lead-In Period (Overall1 only)
TEAEs
All Enrolled Patients
Prior to first dose of open-
label insulin lispro (or Visit 
2 date if the dose date is 
missing)
The entire lead-in period after 
first dose of open-label 
insulin lispro and prior to first 
dose of IP (or Visit 3 date if 
the dose date is missing)
Basal, bolus, and total 
insulin doses, and 
bolus/total insulin dose 
ratios continuous 
analysis
All Randomized Patients
Visit 2
Visit 3 prior to first dose of 
IP
Weight and vital signs 
All Randomized Patients
Last of Visits 1-2
Visit 3
Pump factors - breakfast 
CR, AIT, breakfast ISF)
All Randomized Patients
Visits 2
Visit 3 prior to first dose of 
IP, excluding data (if any) 
that are collected while 
patients temporarily are off 
pump or off open-label 
insulin lispro
Pump factor - frequency 
of use of non-normal 
bolus type [Square 
Wave or Dual Wave] 3
Population with a 
baseline and at least one 
post-baseline observation
Visit 2
Visit 3


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Study Period/Analysis
Patient Population
Baseline Observations
Post-Baseline Observations
12-Week Treatment Period While on IP 
(from first to last dose of IP in each  6-week randomized treatment period)
Infusion set failures 
All Patients in the Safety 
Population 
From first to last dose of 
open-label insulin lispro, 
excluding data (if any) that 
are collected while patients 
temporarily are off pump or 
off open-label insulin lispro
From first to last dose of IP in 
each randomized treatment 
period (Period I and Period 
II), excluding data (if any) 
that are collected while 
patients temporarily are off 
pump or off IP
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)
All Patients in the Safety 
Population 
From first to last dose of 
open-label insulin lispro, 
excluding data (if any) that 
are collected while patients 
temporarily are off pump or 
off open-label insulin lispro
From first to last dose of IP in 
each randomized treatment 
period (Period I and Period 
II), excluding data (if any) 
that are collected while 
patients temporarily are off 
pump or off IP
Time interval until 
infusion set change
All Patients in the Safety 
Population with a 
baseline and a post-
baseline observation
From first to last dose of 
open-label insulin lispro, 
excluding data (if any) that 
are collected while patients 
temporarily are off pump or 
off open-label insulin lispro
From first to last dose of IP in 
each randomized treatment 
period (Period I and Period 
II), excluding data (if any) 
that are collected while 
patients temporarily are off 
pump or off IP
Basal, bolus, and total
insulin doses, 
bolus/total insulin dose 
ratios
All Patients in the 
Randomized Population 
with a baseline and a 
post-baseline observation
Visit 3 prior to first dose of 
IP
Visits 4, 6, 7, and 9 prior to 
last dose of IP in each 
randomized treatment period 
(Period I and Period II)
CGM outcome variables
(including interstitial 
glucose reduction rate)
All Patients in the CGM
Population (with a 
baseline and a post-
baseline observation for 
continuous variables, 
unless otherwise2)
From first to last dose of 
open-label insulin lispro, 
excluding data (if any) that 
are collected while patients 
temporarily are off pump or 
off open-label insulin lispro
From first to last dose of IP in 
each randomized treatment 
period (Period I and Period 
II), excluding data (if any) 
that are collected while 
patients temporarily are off 
pump or off IP
Hypoglycemia events
All Patients in the Safety 
Population
From first to last dose of 
open-label insulin lispro 
Visits 4, 5, 6, 7, 8 and 9 after 
first dose of IP and prior to 
last dose of IP in each 
randomized treatment period 
(Period I and Period II)
HbA1c summary 
statistics
All Randomized Patients 
with a baseline and at 
least one post-baseline 
observation while on IP
Last of Visit 1-3 prior to 
the first dose of IP
Visits 6 and 9 


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Study Period/Analysis 
Patient Population 
Baseline Observations 
Post-Baseline Observations 
1,5 AG 
All Randomized Patients 
with a baseline and at 
least one post-baseline 
observation while on IP 
Last of Visit 1-3 prior to 
the first dose of IP  
Visits 6 and 9  
Pump factors - breakfast 
CR, AIT, breakfast ISF) 
All Patients in the Safety 
Population with a 
baseline and at least one 
post-baseline observation 
Visit 3 prior to the first 
dose of IP excluding data 
(if any) that are collected 
while patients temporarily 
are off pump or off open-
label insulin lispro 
 
Visits 4, 6, 7, and 9 prior to 
last dose in IP of each 
randomized treatment period 
(Period I and Period II) 
excluding data (if any) that 
are collected while patients 
temporarily are off pump or 
off IP 
Pump factor - frequency 
of use of non-normal 
bolus type [Square 
Wave or Dual Wave]3 
Population with a 
baseline and at least one 
post-baseline observation 
Visit 3 
Visit 4, 6, 7, 9  
12-Week Treatment Period Regardless of IP use 
(from randomization to Week 6 of each randomized treatment period regardless of IP use) 
TEAEs  
All Patients in the Safety 
Population 
Prior to first dose of 
randomized IP (or Visit 3 if 
the dose date is missing) 
but after the first dose of 
open-label insulin lispro in 
the lead-in period 
From randomization to Week 
6 of each randomized 
treatment period regardless of 
IP use 
Weight and vital signs 
All Patients in the Safety 
Population with a 
baseline and a post-
baseline observation 
Last of Visits 2-3  
Visits 4, 6, 7, and 9 
regardless of IP use 
Safety Follow-Up Visit (Overall1 Only) 
TEAEs  
All Patients in the Safety 
Population who enter the 
safety follow-up period 
After first dose of IP and 
prior to last dose of IP in 
the 12-Week Treatment 
Period 
From the date of the last visit 
of the 12-Week treatment 
period to the end of study 
Weight and vital signs  
All Patients in the Safety 
Population who enter the 
safety follow-up period 
Last of Visits 2-3 
Visits 801  
Abbreviations:  1,5-AG = 1,5-Anhydroglucitol; CGM = Continuously Glucose Monitoring; CR = carb ratio; HbA1c 
= hemoglobin A1c; IP = investigational product; MMRM = mixed-effect model repeated measures; SMBG = 
self-monitored blood glucose; TEAE = treatment-emergent adverse event 
Note: 
1 
Overall means that data will be summarized in total and no by-treatment group summary or statistical analysis 
will be included. 
2    Not required for the interstitial glucose reduction rate and duration of each individual hypoglycemic episode 
because it is possible that some patients may not have any non-meal related correction bolus or hypoglycemic 
event to baseline values. 
3     Per protocol, pump factor - frequency of use of non-normal bolus type [Square Wave or Dual Wave] were 
collected over the 7 days prior to designated visits, when patients were on pump and on IP. 
 


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6.2.
Adjustments for Covariates
Stratification factors of this study include region (US, OUS), historical use of 
SmartGuard/Threshold Suspend (Yes, No) and HbA1c stratum (≤7.3%, >7.3%).  Stratification 
factors will be entered into the IWRS for randomization and also collected in the database by 
eCRF or central laboratory.  The analysis models will use the stratification factors as collected in 
the database.
Other analyses will include the stratification factors as noted in Sections 6.11 to 6.14.
6.3.
Handling of Dropouts or Missing Data
For continuous variables, missing data will be addressed by using a MMRM analysis for 
continuous longitudinal variables.  The MMRM model provides consistent estimator when data 
is missing at random.  The model implicitly adjusts for missing data through a variance-
covariance structure.  
Otherwise, handling of dropouts or missing data is described for each individual primary or 
secondary endpoint in Sections 6.11 to 6.13.
6.4.
Multicenter Studies
This study is conducted at multiple investigators sites in U.S and Spain.  All analyses using 
region in the model will use region (US, OUS), unless otherwise specified.  
6.5.
Multiple Comparisons/Multiplicity
Treatment group comparisons will be performed for the primary objective (Section 6.11.1) at the 
full significance level of 0.05. No multiplicity adjustments will be made for secondary and 
exploratory objectives.
6.6.
Patient Disposition
Patient disposition will be displayed in a flowchart showing the number of patients entered, 
enrolled, randomized, and discontinued across all study periods.
Frequency counts and percentages of all randomized patients completing and discontinuing from 
the study will be presented for overall and by each treatment sequence and period.  Reasons for 
discontinuation from the study will be summarized for overall and by treatment sequence and 
period.  Reasons for discontinuation from the study at Visit 801 will be summarized by the 
randomized treatment sequences.
Frequency counts and percentages of all patients entered, enrolled, and discontinued from the 
study during the lead-in period will be summarized.  Reasons for discontinuation during 
screening will be summarized for the Entered Population.  Reasons for discontinuation from the 
study during the lead-in period will be summarized for the Enrolled Population.
A listing of the primary reason for study discontinuation will be generated for the Enrolled 
Population.


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Patient allocation by investigator, grouped by country, will be summarized indicating the number 
of patients who enter the study, the number of patients who participate in the lead-in period, the 
number of patients who are randomized to treatment sequences and the number of patients who 
discontinue the study.
A listing will be generated for the Randomized Population, including the following variables but 
not limited to: investigator ID, patient ID, date of signature of informed consent form, 
randomization treatment sequence assignment, randomization date, first and last dose date in 
each treatment period (lead-in, Period I and Period II). 
6.7.
Patient Characteristics
A summary table for overall and by treatment sequence will be generated for patient 
characteristics at study entry using all randomized patients.  The following variables will be 
included but not limited to:  age, age groups (<40 and ≥40 years, and <65, ≥65 to <75, ≥75 to 
<85, ≥85 years), sex, country, region, ethnicity, race, height, weight, body mass index (BMI), 
BMI groups (<25, ≥25 to <30, ≥30 to <35, and ≥35 kg/m2).  No statistical comparisons between 
treatment sequences will be performed. For continuous variables, the following statistics will be 
provided:  mean, SD, minimum, maximum, and median.  For categorical variables, summary 
statistics will include sample size, frequency and percentage.  A listing of patient characteristics 
at baseline will be provided.
A similar summary of diabetes characteristics will also be generated.  The following variables 
will be included but not limited to:  duration of diabetes, duration of CSII use, pump model, the 
type of rapid-insulin at study entry, total daily dose at study entry, historical use of 
SmartGuard/Threshold Suspend at study entry, HbA1c at study entry and baseline, HbA1c 
stratum at baseline.
A listing of patients whose stratification factor value entered into the IWRS (for treatment group 
assignment) is different from the clinical database will also be provided.
The total daily insulin dose for the last 3 days prior to screening will be entered into the eCRF.  
The dose at study entry will be calculated as the mean of the doses for the last 3 days prior to the 
visit.  Doses will be summarized in U and U/kg. Total daily insulin dose will also be presented 
by the definitions in protocol exclusion criterion #28 (≤1.2 U/kg, >1.2 U/kg).  
For all randomized patients, the number and percentage of patients with historical conditions will 
be summarized using Medical Dictionary for Regulatory Activities (MedDRA) Preferred Term 
(PT) (without regard to System Organ Class (SOC)), and the number and percentage of patients 
with preexisting conditions will also be summarized using MedDRA PT (without regard to 
SOC).  Historical conditions are conditions that end prior to informed consent and preexisting 
conditions are conditions that are still ongoing at informed consent.  Events will be ordered by 
decreasing frequency. 
All baseline measures will be summarized for overall and by treatment sequence.  No statistical 
comparison between treatment sequences will be performed given the small sample size of this 
study.


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6.8.
Treatment Compliance
No analysis for treatment compliance is planned for this study.
6.9.
Important Protocol Deviations
Important protocol deviations that potentially compromise data integrity or patients’ safety will 
be summarized by treatment group for all randomized patients.  Table ITSI.6.3 lists the 
categories/subcategories of important protocol deviations, source of identification, and the 
method to identify each deviation. 


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Table ITSI.6.3.
Description of Important Protocol Deviations
Category
Sub-categories
Trial Specific
Source
Methods of Identification
Informed 
Consent
Informed Consent 
Not Obtained
N/A
Mixed 
(monitoring and 
clinical database)
Compare all assessment 
dates to ICD date (except 
those assessments that may 
occur before ICD, e.g.,
disease assessments).
Informed 
Consent
Improper Consent
N/A
Mixed 
(monitoring and 
clinical database)
Failure to reconsent after an 
ICD amendment at first 
possible visit.
Unauthorized personnel 
administered ICD.
Patient signed incorrect 
version of ICD.  
ICD was not dated. 
ICD was lost.
Informed 
Consent
Revoke Consent
N/A
Mixed 
(Monitoring and 
clinical database)
Patient revoked ICD.
If patient revokes consent, 
data are excluded from the 
study.
Eligibility
Inclusion/Exclusion
Type of Patient 
and Disease 
Characteristics
Mixed 
(monitoring and 
clinical database)
CRF (Medical History: 
Diabetes Duration panel) 
data indicate diagnosis date 
of T1D <1 year prior to 
screening date (#1). 
CRF (Prior Diabetes 
Therapies/Concomitant 
panel) data to indicate start 
date for continuously using 
insulin < 1 year prior to 
screening date (#1). 
Also identified by CRA as 
captured in sCTMS.


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Category
Sub-categories
Trial Specific
Source
Methods of Identification
Eligibility
Inclusion/Exclusion
Age not in 
compliance with
entry criteria
Mixed 
(monitoring and 
clinical database)
CRF data indicate the age 
<18 yrs at Visit 1 (#2).
Also identified by CRA as 
captured in sCTMS.
Eligibility
Inclusion/Exclusion
Previous non-
insulin 
antihyperglycemic 
medications
Mixed 
(monitoring and 
clinical database)
CRF Prior Diabetes 
Therapies / Concomitant 
Therapy panel data to 
indicate not compliant with 
entry criteria #42.
Also identified by CRA as 
captured in sCTMS. 
Eligibility
Inclusion/Exclusion
Previous insulin 
therapy
Mixed 
(monitoring and 
clinical database)
CRF Prior Diabetes 
Therapies / Concomitant 
Therapy panel data to 
indicate not compliant with 
entry criteria #5 [basal 
insulin was used for >14 
consecutive days during the 
6 months prior to screening], 
#6, or #41 
Also identified by CRA as 
captured in sCTMS.  
Eligibility
Inclusion/Exclusion
Other Inadvertent 
Enrollment
Non 
Programmable 
(monitoring)
Identified by CRA as 
captured in sCTMS.
Eligibility
Inclusion/Exclusion
Use of non-study 
device or materials
Non 
Programmable 
(monitoring)
Use of non-study pumps, 
infusion sets, and use of 
Enlite sensor (enables Smart-
Guard)
Investigational 
Product
Treatment 
Assignment/ 
Randomization Error
N/A
Non 
Programmable 
(monitoring)
IWRS data entry errors that 
impact patient stratification, 
for example, lab data 
indicated different strata 
from IWRS stratification 
report.
Dispensing error: Patient is 
assigned to a treatment, but 
site gave a different 
treatment to the patient.
Investigational 
Product
Unblinding
N/A
Non 
Programmable 
(monitoring)
Any inadvertent unblinding 
affecting, patients, 
investigator or sponsor.
Investigational 
Product
Patient Took 
Medication Not Fit 
for Use
N/A
Non 
Programmable 
(monitoring)
Study Drug not fit for use 
administered to patient.


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Category
Sub-categories
Trial Specific
Source
Methods of Identification
Investigational 
Product
Other
Use of expired CT 
material
Non 
Programmable 
(monitoring)
Also identified by CRA as 
captured in sCTMS.
Study 
Procedures
Other
Infusion set 
change frequency
Programmable 
(clinical database)
eCOA data indicate that 
≥75% of routine infusion set 
changes are not in the range 
of 72 ± 4 hours during the 
two 6-week treatment 
periods (#13).
Study 
Procedures
Violation of 
Discontinuation 
Criteria
N/A
Mixed 
(monitoring and 
clinical database)
Patients not discontinued 
from study despite having 
met protocol specified 
discontinuation criteria.
Also identified by CRA as 
captured in sCTMS. 
Protocol Section 8 (e.g.,
patient(s) become pregnant 
according to central/local lab 
or CRF AE page).
Study 
Procedures
Excluded Conmeds
N/A
Mixed 
(monitoring and 
clinical database)
CRF Prior Diabetes 
Therapies / Concomitant 
Therapy panel data to 
indicate not compliant with 
entry criteria #43 and study-
specific restriction on 
concomitant therapies Table 
ITSI.5 in the study protocol.
Also identified by CRA as 
captured in sCTMS.
Study 
Procedures
Visit Schedule 
Criteria
N/A
Programmable 
(clinical database)
CRF data indicate that two 
consecutive office visits are 
completely missing.
Study 
Procedures
Other
Electronic Clinical 
Outcomes 
Assessment 
(eCOA)
Mixed 
(monitoring and 
clinical database)
Patients did not use eCOA 
system during the entire 
study.
Comparison of patient data 
from CRF and eCOA to 
identify randomized patients 
who have no eCOA data 
entered.
Administrative/
Oversight
Suspected 
Misconduct
N/A
Non 
Programmable 
(monitoring)
Site staff sharing account 
details for systems (e.g.,
IWRS, EDC, eConsent or 
ePresentOnline).
Suspected falsification of 
data.


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Category
Sub-categories
Trial Specific
Source
Methods of Identification
Administrative/
Oversight
PI oversight
N/A
Non 
Programmable 
(monitoring)
Identified by CRA as 
captured in sCTMS.
Safety
Safety Mailings
N/A
Non 
Programmable 
(monitoring)
Lack of, significant delay in 
safety mailing review 
(significant delay defined as 
a delay of 1 month).
Safety
SAEs
Failure to report 
SAE in 24 hours
Non 
Programmable 
(monitoring)
Failure to report an SAE 
within 24 hours of the 
investigator being made 
aware of the SAE.
Failure to respond to SAE 
queries.
Safety
Other
Failure to report 
product complaint 
within 24 hours
Non 
Programmable 
(monitoring)
Identified by CRA as 
captured in sCTMS.
Abbreviations:  CRA = clinical research associate; CRF = clinical (case) report form; CT = clinical trial; ICD = 
informed consent document; EDC = Electronic Data Capture; ITSI = Study I8B-MC-ITSI; IWRS = interactive 
Web Response System; OAM = oral antihyperglycemic medication; MedDRA = Medical Dictionary for 
Regulatory Activities; NA = not applicable; SAE = serious adverse event; sCTMS = Simplicity Clinical Trial 
Management System; T1D = type 1 diabetes; yrs = years.
#: number of inclusion/exclusion criteria in the protocol.
The listing of important protocol deviations for all randomized patients during the entire study,
will be provided in the CSR. 
6.10. Concomitant and Prior Therapy
Concomitant medications will be summarized and compared between treatment groups using 
Prescott’s exact test for the Randomized Population during the 2 randomized treatment periods
(Period I and Period II). The percentages of patients receiving each concomitant medication will 
be summarized by treatment using preferred term nested within Anatomical Therapeutic 
Chemical (ATC) Level 3 code.  Medications will be ordered by decreasing frequency within 
ATC level.  Concomitant medication used during the lead-in period will also be summarized for 
the Enrolled Population.  
A summary of previous diabetes therapies that were discontinued prior to informed consent will 
be generated for the Enrolled Population. 
The daily basal dose, daily bolus dose, total insulin dose, and the ratio of bolus dose to total 
insulin dose during the lead-in period will be summarized by visit for overall and by treatment 
sequence. The doses and bolus/total insulin dose ratios for each visit will be calculated as the 
mean of the doses for the last 3 days prior to the visit date that are entered in the eCRF.  Doses 
will be summarized in U and U/kg.  


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6.11. Safety Analyses
6.11.1. Primary Outcome and Methodology
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 9.1.4.1.2 of the protocol.
For each treatment period (lead-in, Period I and Period II), the infusion set failure rate
(events/patient/30 days) will be calculated for each patient as the total number of events while 
the patient is on pump and on study treatment divided by the days of exposure [last dose date and 
time – first dose date and time – duration of pump or treatment interruption] times 30. 
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.  
6.11.2. Other Secondary Safety Analyses
The analyses described in Section 6.11.2 will include data collected for the Safety Population
including data collected prior to permanent discontinuation (i.e., last dose) of IP in each 6-week 
treatment period.  In addition, other than severe hypoglycemia events, all secondary safety 
endpoints are pump-related, and therefore the corresponding analyses will also exclude data (if 
any) that are collected while patients temporarily are off pump or off IP.  


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For the following secondary safety endpoints, the incidence (percent of patients with at least 1 
event) and rate will be analyzed using Prescott’s exact test and Wilcoxon signed-rank test, 
respectively, as described above for the primary endpoint.

suspected infusion set occlusions defined as unexplained hyperglycemia with blood 
glucose (SMBG) >250 mg/dL (13.9 mmol/L) that does not decrease within 1 hour (+10 
minutes) following a correction bolus delivered via the pump and that leads to an infusion 
set change

infusion set failures leading to premature infusion set changes due to unexplained 
hyperglycemia with blood glucose >250 mg/dL that does not decrease by >50 mg/dL 
within 1 hour (+10 minutes) following a correction bolus delivered via the pump

premature infusion set changes for any reason and for each individual reason (infusion set 
kinked, came out or leaking; empty pump reservoir; infusion site pain or redness; pump 
occlusion alarm; suspected infusion set occlusion; other)

severe hypoglycemic events
For the infusion set failures 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).  
A listing of premature infusion set changes due to unexplained hyperglycemia will be generated.  
For each premature infusion set change due to unexplained hyperglycemia, the following 
information will be provided: 

whether it is an infusion set failure that meets the primary endpoint definition

whether it is an infusion set failure that meets the secondary endpoint definition ( i.e. 
leads 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 by >50 mg/dL within 1 hour [+10 minutes] following a correction 
bolus delivered via the pump)

the most recent SMBG within 1 hour before the correction bolus

the 3 most recent CGM values within 20 minutes before the correction bolus

the most recent SMBG within 1 hour (+10 minutes) following the correction bolus that 
was collected prior to the infusion set change

the most recent SMBG within 2 hours (+10 minutes) following the correction bolus that 
was collected prior to the infusion set change

the 3 CGM measures within the time interval of [1 hour-10 minutes, 1 hour+10 minutes] 
following the correction bolus that were collected prior to the infusion set change

the 3 CGM measures within the time interval of [2 hour-10 minutes, 2 hour+10 minutes] 
following the correction bolus that were collected prior to the infusion set change

the highest ketone testing value within ±2 hours of the correction bolus

the highest ketone test value within ±2 hours of the infusion set change
Similarly, a listing of premature infusion set changes due to pump alarms and a listing of all 
premature infusion set changes will also be provided. The SMBG values, CGM values, and 
ketone test values relative to the infusion set change time will be provided. Both date and time 


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of all infusion set changes will be collected in the database by either eCRF or eCOA (Table 
ITSI.6.4).
Table ITSI.6.4.
Source Data for Infusion Set Changes
Study Period
Infusion Set Changes
Data Source
Lead-in period
First infusion set change
eCRF: First Dose Open Label Lead-in 
Treatment
Other infusion set changes- outside of the office visit
eCOA
Last infusion set change
eCRF: Last Dose Open Label Lead-in 
Treatmenta
Period I
First infusion set change
eCRF: First Dose Study Treatment 
Period I
Other infusion set changes – outside of the office visit
eCOA
Last infusion set change
eCRF: Last Dose Study Treatment 
Period Ia
Period II
First infusion set change
eCRF: First Dose Study Treatment 
Period II
Other infusion set changes – outside of the office visit
eCOA
Last infusion set change
eCRF: Last Dose Study Treatment 
Period IIa
Safety Follow-
up 
NA
NA
a
In extremely rare cases where patients stopped treatment on pump but continued to use treatment through syringe
until they discontinue from the study, the last dose form will capture the timing of the last dose of treatment in 
CRF, which will not be the last infusion set change.
The last infusion set change in each treatment period (lead-in, Period I or Period II) occurs only 
when a patient comes to an office visit or early discontinuation of study treatment.  This change 
is not reflective of patients’ behavior regarding infusion set changes, and thus it will not be 
included in the derivation of time until infusion set changes.  Patient-reported premature infusion 
set changes due to the reason “Other” or patient-reported routine infusion set changes that occur 
within 1 hour of a previous infusion set change (captured in the case report form [CRF]), will be
treated as a redundant entry in eCOA and excluded from all analyses.  In addition, any patient-
reported routine infusion set change that occurred within 24 hours of a previous infusion set 
change could have been misreported as routine or are redundant entries in eCOA, and thus will 
be excluded from all analyses.


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Time interval until infusion set change for each infusion set can be derived through a minute-to-
day conversion by dividing the time difference between the infusion set change and its previous 
infusion set change by 1440 minutes.  The protocol requires that patients change infusion set 
every 72 ± 4 hours unless a change is required for failure of the infusion set.  To handle potential 
missing input in eCOA for the infusion set change, time interval until infusion set change greater 
than 7 days (168 hours) will be excluded.  For each treatment period, time interval until infusion 
set change will be derived by averaging all infusion set changes within the period.  The analyses 
will be conducted by an MMRM model (Model 2) as specified in Section 6.1.  
Derivation and analysis of interstitial glucose reduction rate are described in Section 6.12.  
Actual and change from baseline in total, basal, and bolus insulin doses and bolus/total insulin 
dose ratios will be compared between LY900014 and insulin lispro using an MMRM model 
(Model 1) as specified in Section 6.1.  The doses and bolus/total insulin dose ratios for each visit 
will be calculated as the mean of the doses for the last 3 days prior to the visit.  A listing of 
insulin doses will also be provided, including data collected at Visit 801.
6.11.3. Pump Factors
Actual and change from baseline in pump factors affecting insulin dosing, including breakfast 
CR, AIT, breakfast ISF, and frequency of use of non-normal bolus type (Square wave or Dual 
Wave), will be summarized and compared between LY900014 and insulin lispro using an 
MMRM models as specified in Section 6.1.  
For each patient, frequency of use of non-normal bolus type at a visit will be calculated as the 
total number of meal-related bolus doses given as Square Wave or Dual Wave during the 7 days 
prior to the visit date divided by the total number of meal-related bolus doses during the 7 days 
prior to the visit date.
A listing of these pump factors will also be provided, including data collected at Visit 801.
6.11.4. Extent of Exposure
Duration of exposure to study drug will be summarized.  The following summary statistics will 
be provided:  n, mean, SD, median, minimum, maximum, and sum (that is, total patient-years of 
exposure).  The number and proportion of patients falling into the following different exposure 
categories will also be summarized:  <7 days (>0 and <7 days), ≥7 and <14 days , ≥14 and <28 
days, ≥28 days and < 42 days) and ≥42 days. 
Patients who complete the study treatment period are required to complete a safety follow-up 
visit without study drug; and patients who discontinue the IP prematurely are required to 
discontinue from the study (ITSI Protocol 8.1-8.2).  
6.11.5. Adverse Events
Events that are newly reported after the first dose of rapid-acting insulin provided as study drug 
(i.e., open-label insulin lispro used during the lead-in period or IP used during each of the two 6-
week randomized treatment periods) or are reported to worsen in severity from baseline (defined 


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in Table ITSI.6.6 for each specific study period) will be considered TEAEs.  Events that continue
during more than 1 study period (lead-in, Period I, Period II) with the same severity will only be 
counted once for the first study period.
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.  For events occurring on the day of first dose of 
blinded bolus insulin provided in this study during each treatment period (lead-in, Period I and 
Period II), the CRF-collected flag will be used to determine whether the event started or 
worsened post-treatment, and/or the treatment of which period the AE should be assigned. 
In an overview table, the number and percentage of patients who experienced a TEAE, 
experienced serious adverse event (SAE), died due to an AE, and discontinued from study due to 
an AE will be summarized.
The number and percentage of patients with SAEs and who discontinued from the study due to 
an AE will be summarized using MedDRA Preferred Term (PT) nested within System Organ 
Class (SOC). Prescott’s exact test will be performed for treatment comparison.
The number and percentage of patients with TEAEs (overall and by possible relatedness: related 
to study disease, study drug, study procedure or study device) will be summarized by treatment 
using MedDRA PT nested within SOC.  Events will be ordered by decreasing frequency within 
SOC.  As an additional table, the percentages of patients with TEAEs will be summarized by 
treatment using MedDRA PT (without regard to SOC).  Events will be ordered by decreasing 
frequency in total group.  Statistical comparisons will be applied at both the SOC and PT levels.  
Prescott’s exact test will be performed for treatment comparison.  
The number and percentage of patients with TEAEs by maximum severity will be summarized 
by treatment using MedDRA PT (without regard to SOC).  For each patient and TEAE on each 
treatment, the maximum severity for the MedDRA PT is the maximum postbaseline severity 
observed from all associated LLTs mapping to the MedDRA PT during the corresponding 
randomized treatment period for the specified treatment.  No statistical comparison between 
treatment groups will be conducted.
The number and percentage of patients who experienced a SAE including deaths and SAEs 
temporally associated or preceding deaths will be summarized by treatment group using 
MedDRA PT (without regard to SOC).  Events will be ordered by decreasing frequency within 
SOC.  A listing of all SAEs (including data collected during the safety follow-up period) will 
also be provided.
The number and percentage of patients who discontinued from study in Period I and Period II 
due to an AE will be summarized by treatment group using MedDRA PT (without regard to 
SOC).  Events will be ordered by decreasing frequency.  A listing of all AEs as reason for study 
discontinuation will also be provided. 
For events that are gender-specific (as defined by MedDRA), the denominator and computation 
of the percentage will include only patients from the given gender.


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Table ITSI.6.5 summarizes the planned analyses and the requirement of analysis data for 
different analysis periods. 
Table ITSI.6.5.
Adverse Event Analysis Periods
Analysis Period
Analysis Population
Analysis
IP USE
Treatment
Lead-in Period
All Enrolled Patients
AE overview; TEAE by 
PT; SAE, 
discontinuation due to 
AE
N/A
Open-label 
insulin lispro
Treatment Period 
(0-12 Weeks)
Safety Population
AE overview; TEAE by 
SOC and by PT; TEAEs 
by maximum severity; 
SAE; discontinuation 
due to AE; other notable 
AEs
All data regardless 
of IP use
LY900014, 
insulin lispro
Safety Follow-up 
Period
All Patients in the 
Safety Population
who enter follow-up 
period
TEAE by PT
All data 
Overalla
Abbreviations:  AE = adverse event; IP = investigational product; N/A = not applicable/available; PT = preferred 
term; SAE = serious adverse event; SOC = system organ class; TEAE = treatment-emergent adverse event
Note:
a overall means that data will be summarized in total and no by-treatment group summary or statistical 
analysis will be included.
6.11.6. Deaths
The listing of all deaths by patient for all enrolled patients will be provided as part of the SAE 
listing, regardless of the investigator’s or the sponsor's judgment about causality. Each listing 
will include study ID, investigator ID, patient ID, treatment sequence, treatment group, baseline 
age, sex, associated AE, first and last dose date for open label insulin lispro and randomized IP, 
and the event date.
6.11.7. Hypoglycemic Events and Other Adverse Events
The analysis plans for the following adverse events are discussed in Section 6.11.7.1 through 
Section 6.11.8:

hypoglycemic events

systemic hypersensitivity reaction

infusion site reaction

malignant neoplasm events
These AE analyses will be similar to the TEAE analyses, refer to Table ITSI.6.5 for the 
requirement of analysis data for a specific analysis period. 
6.11.7.1. Hypoglycemic Events
Hypoglycemia events that occur during the study will be captured using an eCOA diary starting 
from Visit 2 through Visit 801.  Whenever hypoglycemia is suspected, the patient should record 
the blood glucose value, any associated symptoms, and the treatment administered in eCOA. A 


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set of events is counted as 1 event in analysis if it consists of an originating event and subsequent 
continuing events as marked by the patient in eCOA, or the duration between adjacent events is 
≤30 minutes. The event with the highest severity will be selected for analysis with severity 
determined in the order of: 1) it is a severe hypoglycemia, 2) it has symptoms of hypoglycemia 
reported, and 3) it has the lowest blood glucose value. If there are multiple events tied in all 3 
aspects, the event with the largest number of non-missing responses to the questions of nocturnal 
hypoglycemia and postmeal time frame will be selected. If there are still multiple events tied, 
the latest event (based on data entry time) will be selected.
The following types of hypoglycemia events will be derived in the analysis data sets:  
documented hypoglycemia, severe hypoglycemia, nocturnal hypoglycemia, probable 
symptomatic hypoglycemia, and overall hypoglycemia.  Only severe hypoglycemia will be 
collected as AEs and all episodes of severe hypoglycemia will be considered as SAEs.  
Documented hypoglycemia (including documented symptomatic hypoglycemia, documented 
asymptomatic hypoglycemia and documented unspecified hypoglycemia) will be based on blood 
glucose (BG) ≤70 mg/dL.  In addition, documented clinically significant hypoglycemia with 
similar criterion as above documented hypoglycemia except for the threshold of BG <54 mg/dL 
will be summarized. 
Table ITSI.6.6 provides detailed statistical methods for each endpoint related to hypoglycemia.  
For these analyses, hypoglycemia events prior to the discontinuation (i.e., last dose) of IP will be 
summarized.  Additional analyses for other types of hypoglycemic events not mentioned in the 
table may be conducted as needed.
A listing of patients with at least 1 severe hypoglycemia reported (as SAE) after randomization
(including Visit 801) will be provided.
A list of MedDRA PTs will be used for the narrow search of potential severe hypoglycemia in 
spontaneously reported AEs.  The events identified through the search strategy that are also 
reported as SAEs will be summarized and compared between treatments.  Prescott’s exact test 
will be used to assess the treatment difference in the proportion of patients with potential severe 
hypoglycemia.
Table ITSI.6.6.
Summary of Analyses for Endpoints Related to Hypoglycemia
Endpoint
Analysis Period
Statistical Method
Rate of hypoglycemic events (per patient 
per 30 days / year)

All Documenteda

Nocturnala

Documented Symptomatica

Overall

Non-Nocturnal (or Daytime)
(Documented and between 
waking and bedtime)a

Probable Symptomatic
0-4, 0-6, 4-6 weeks
Wilcoxon signed-rank test will be conducted.


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Endpoint
Analysis Period
Statistical Method
Incidence of hypoglycemic events

All Documenteda

Nocturnala

Documented Symptomatica

Overall

Non-Nocturnal (or 
Daytime)(Documented and 
between waking and bedtime)a

Probable Symptomatic
0-4, 0-6, 4-6 weeks
If there are ≥5 patients with at least one event 
within the specified time period, a generalized 
linear mixed model with options of the binomial
distribution and logit link function with 
treatment, period, sequence. The within-patient 
error will be modeled as a compound symmetry
without heterogeneous variance-covariance 
matrix.
If the model does not converge, Prescott’s exact 
test will be conducted.
Rate of post-meal hypoglycemic events 
(per patient per 30 days / year) 

Documented Symptomatica

Documented Asymptomatica
≤0.5, ≤1, ≤2, ≤4, >1 
to ≤2 and >2 to ≤4 
hours after start of a 
meal within 0-4, 0-
6, and 4-6 weeks
Wilcoxon signed-rank test will be conducted.
Incidence of post-meal hypoglycemic 
events 

Documented Symptomatica

Documented Asymptomatica
≤0.5, ≤1, ≤2, ≤4, >1 
to ≤2 and >2 to ≤4 
hours after start of a 
meal within 0-4, 0-
6, and 4-6 weeks
If there are ≥5 patients with at least one event
within the specified time period, a generalized 
linear mixed model with options of the binomial 
distribution and logit link function with 
treatment, period, sequence. The within-patient 
error will be modeled as a compound symmetry 
without heterogeneous variance-covariance 
matrix.
If the model does not converge, Prescott’s exact 
test will be conducted.
Rate of severe hypoglycemic events (per 
patient per year / 100 years)
0-4, 0-6, 4-6 weeks
Exposure adjusted rate per year / 100 years 
(calculated for each patient by total number of
events divided by total exposure) will be 
provided and Wilcoxon signed-rank test will be 
used for treatment comparison.
Incidence of severe hypoglycemic events
0-4, 0-6, 4-6 weeks
Proportion of patients with severe hypoglycemia 
will be reported.  The treatment comparison will 
be based on Prescott’s exact test.
a All documented hypoglycemia and the subcategories based on the thresholds of blood glucose ≤70 mg/dL and 
blood glucose <54 mg/dL will be analyzed, except for post-meal hypoglycemia for which only the threshold of 
≤70 mg/dL will be applied.
6.11.7.2. Systemic Hypersensitivity Reaction
The number and proportion of patients experiencing treatment-emergent potential systemic 
hypersensitivity reactions will be summarized and compared by treatment group using Prescott’s
exact test.  The following Standardised MedDRA Query (SMQ) will be used to identify potential 
systemic hypersensitivity reactions from all TEAEs:

Anaphylactic reaction (SMQ).  Besides using the narrow and broad terms designated 
within the SMQ, the following search algorithm will also be implemented as another 
approach to determine if a patient had an anaphylactic reaction:  if a patient (had at least 
1 event in Category A) or (had at least 1 event that is in category B and also had at least 1 


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event that is in category C) or (had at least 1 event that is in category D and [also had at 
least 1 event in category B or at least 1 event in category C])

Angioedema (SMQ)

Hypersensitivity (SMQ)
Specifically, the following need to be performed: (1) any narrow or algorithmic term from any 1 
of the 3 SMQs indicated above (that is, combined search across narrow and algorithmic portions 
of all 3 SMQs); (2) any narrow scope term within each SMQ, separately (that is, narrow SMQ
search); (3) any term within each SMQ, separately (that is, broad SMQ search); (4) narrow scope
term search within each SMQ, report the PT nested within each SMQ.
A similar summary will be provided for the TEAE reported by the investigator as possibly 
related to study drug.
Note that an individual patient may contribute multiple events. Also, a single event may satisfy
multiple SMQs, in which case the event contributes to every applicable SMQ.
6.11.7.3. Infusion Site Reaction
The infusion site reactions will be searched by MedDRA PTs from all TEAEs.  The number and 
percentage of patients experiencing at least one treatment-emergent infusion site reaction will be 
summarized and compared by treatment group using Prescott’s exact test.  
For infusion site reactions identified by MedDRA PTs, the presence and severity of erythema, 
induration, pain, pruritus and edema are collected on the eCRF, and will be summarized for each 
treatment.  There will be no statistical comparison between treatments. 
6.11.7.4. Hepatobiliary Events
6.11.7.4.1.
Treatment-Emergent Potential Hepatic Disorder
The percentages of patients with treatment-emergent drug-related hepatic disorder events will be 
summarized and compared by treatment group using MedDRA PT nested within each SMQ, and 
ordered by decreasing frequency. The following SMQs based on MedDRA will be used to
identify potential hepatic disorders:

Broad and narrow terms in the Liver related investigations, signs and symptoms SMQ 
(20000008)

Broad and narrow terms in the Cholestasis and jaundice of hepatic origin SMQ 
(20000009)

Broad and narrow terms in the Hepatitis non-infections SMQ (20000010)

Broad and narrow terms in the Hepatic failure, fibrosis and cirrhosis and other liver 
damage SMQ (20000013)

Narrow terms in the Liver-related coagulation and bleeding disturbances SMQ
(20000015)
The percentage of patients with any 1 of the terms will be summarized, in addition to the 
percentages for each MedDRA PT. The percentages of patients with potentially drug-related
hepatic disorders that lead to permanent study discontinuation will be summarized similarly.


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6.11.7.5. Malignant Neoplasm Events
The Malignant tumors SMQ will be used to identify treatment-emergent malignant neoplasm 
event. 
6.11.8. Blood Ketones
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 a test is performed, ketone values should be documented 
in the eCRF and will be presented by (≤0.6 mmol/L, >0.6 mmol/L) for each treatment group.
There will be no statistical comparison between treatments.
6.11.9. Clinical Laboratory Evaluation
The data from safety laboratory measures will be only collected at Visit 1 and Visit 2 for patient 
safety. Therefore no by-treatment group summary or statistical analysis will be provided. 
6.11.10.
Vital Signs and Other Physical Findings
Post-baseline measurements and change from baseline to post-baseline for vital signs (systolic 
blood pressure [SBP], diastolic blood pressure [DBP], pulse rate) and physical characteristics 
(weight, BMI) at the scheduled visits will be summarized by week (relative to the start of each 
randomized treatment period) for patients who have both baseline and at least 1 post-baseline 
result. 
The measurements during the treatment period (0-12 weeks) will be analyzed by MMRM model 
with treatment, baseline value of the response variable, sequence, period, week (defined from the 
start of each randomized treatment period), and week by treatment interaction as fixed factors 
and patient as the random factor.  
Change from the minimum value during the baseline period to the minimum value during the 2 
randomized treatment periods for vital signs and physical characteristics will be summarized by 
treatment group for patients who have both baseline and at least 1 post-baseline result.  Baseline 
will be the minimum of nonmissing observations in the baseline period.  The minimum value in 
the treatment period will be analyzed.  Similarly, change from the maximum value during the 
baseline period to the maximum value during each of the 2 randomized treatment periods (Period 
I and Period II) for vital signs and physical characteristics will be summarized by treatment 
group for patients who have both baseline and at least 1 post-baseline result.  Baseline will be the 
maximum of nonmissing observations in the baseline period.  The maximum value in the 
treatment period will be analyzed.  Planned and unplanned measurements will be included in the 
analysis.
The percentages of patients with treatment-emergent high or low vital signs and weight at any 
time after randomization during each of the 2 randomized treatment periods (Period I and Period 
II) will be summarized and compared between treatment groups using Prescott’s exact test for 
patients who have both baseline and at least 1 postbaseline measurement.  A treatment-emergent 
high result is defined as a change from a value less than or equal to the high limit at all baseline 


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visits to a value greater than the high limit at any time that meets the specified change criteria 
during the 2 randomized treatment periods.  A treatment-emergent low result is defined as a 
change from a value greater than or equal to the low limit at all baseline visits to a value less than 
the low limit at any time that meets the specified change criteria during the 2 randomized 
treatment periods.  Table ITSI.6.7 will be used to define the low and high limits and change 
thresholds. 
Table ITSI.6.7.
Categorical Criteria for Abnormal Treatment-Emergent Blood 
Pressure and Pulse Measurement, and Categorical Criteria for 
Weight Changes for Adults
Parameter
Low
High
Systolic BP (mm Hg)
(Supine or sitting – forearm at 
heart level)
≤90 and decrease from baseline ≥20
≥140 and increase from baseline ≥20
Diastolic BP (mm Hg)
(Supine or sitting – forearm at 
heart level)
≤50 and decrease from baseline ≥10
≥90 and increase from baseline ≥10
Pulse (bpm)
(Supine or sitting)
<50 and decrease from baseline ≥15
>100 and increase from baseline ≥15
Weight (kg)
(Consistent clothing and timing 
in relationship to meals and 
voiding)
(Loss) decrease ≥7%
(Gain) increase ≥7%
Abbreviations:  BP = blood pressure.
6.11.11.
Immunogenicity
Blood samples for immunogenicity testing will be collected to determine antibody production 
against insulin lispro for all enrolled patients since Visit 2 prior to the first dose of study-
provided insulin treatment.  Therefore, the blood sample result at Visit 2 will be considered as 
the anti-insulin lispro level at baseline for this study.
6.11.11.1.
Treatment-Emergent Anti-Insulin Lispro Antibody
The treatment-emergent anti-insulin lispro antibody (denoted as treatment-emergent antidrug 
antibody [TEADA] throughout this SAP) is based on the change from baseline (Visit 2) to post-
baseline (post-Visit 2) in the anti-insulin lispro antibody level (percent binding).  Treatment-
emergent antidrug antibody can be sub-classified as either treatment-induced (not detected anti-
insulin lispro antibody at baseline) or treatment-boosted (detected anti-insulin antibody at 
baseline):

treatment-induced response:  change from not detected anti-insulin lispro at baseline
(Visit 2) to post-baseline detected anti-insulin lispro;

treatment-boosted response:  change from detected anti-insulin lispro at baseline (Visit 2) 
to post-baseline detected anti-insulin lispro antibody level (percent binding) at least 157% 
of the baseline value.  


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The TEADA status during a specific analysis period will be determined using all data in the 
corresponding analysis period regardless of IP use.  The summary for TEADA status and the 
anti-insulin lispro antibody level will use the same analysis data.
The number and percentage of patients with positive TEADA response during the study (from 
Visit 2 to Visit 801) will be summarized for the Safety Population overall.  For patients with 
positive TEADA response any time during the study, the number and percentage of patients with 
positive insulin cross-reactivity anytime during the study, and the number and percentage of 
patients not meeting the TEADA criteria at Visit 801 will also be summarized for overall.  No 
statistical comparisons between treatment groups will be conducted because patients were 
exposed to both LY900014 and Humalog due to the crossover design.
The anti-insulin lispro antibody level in percent binding will be summarized by scheduled visit 
prespecified in the protocol for patients with positive TEADA response from Visit 2 to Visit 801.  
A listing of anti-insulin lispro antibody at each visit will be provided.  The listing will include 
anti-insulin lispro antibody status (detected/not detected), anti-insulin lispro antibody percent 
binding, TEADA status (positive/negative), insulin cross-reactivity status, and insulin cross-
reactivity percent binding for the Safety Population.
6.11.12.
Patient Narratives
Patient narratives will be provided for all patients in the study who experience any of the 
following “notable” events prior to data cutoff for the submission:

deaths

SAEs

discontinuations from study (or study drug) due to AEs

pregnancy
A list of patients who meet the criteria for narratives will be provided.
6.12. CGM Analyses
The analyses described in Section 6.12 will include data collected from first dose to last dose of 
study drug (i.e., open-label insulin lispro used during the lead-in period or IP used during each of 
the randomized treatment periods [Period I and Period II]) , excluding data (if any) that are 
collected while patients temporarily are off pump or off study treatment.
All of the variables will be derived for the lead-in period, Period I and Period II.  For the lead-in 
period, the variables will be derived based upon the data collected during the 2-week open-label 
lispro treatment period.  For Period I and Period II, the variables will be derived for 0-4, 0-6, and 
4-6 weeks relative to the start of each randomized treatment period, respectively. For the 
interstitial glucose reduction rate, treatment comparisons will be based upon the derived outcome 
variables for 0-6 weeks. For other variables, treatment comparisons will be based upon the 
derived outcome variables for 4-6 weeks. 


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Table ITSI.6.8 lists all numerical measures for CGM data, including all secondary and 
exploratory CGM outcome variables.  
To ensure that the CGM outcome variables are only calculated from CGM session days with 
sufficient data within the 24-hour, daytime (0600 hours to midnight), or nighttime (midnight to 
0600 hours) periods, the following criteria will be used to determine a valid CGM session day to 
be counted into the calculation for a visit:  1) minimum number of measures per day – at least 
70% of the total measures that are supposed to be obtained (for example, 70% of the 288 
measures for the 24-hour period or 70% of 72 measures for the nighttime period); 2) maximum 
allowable missing interval – no interval greater than 3 hours between non-missing measures.
Similarly, for the by-meal outcome variables, the following criteria will be used to determine a 
valid CGM session day for a visit: 1) minimum number of measures per day – at least 70% of 
the total measures that are supposed to be obtained.  For example, 70% of the 24 measures for 
the iAUC0-2hr after breakfast; 2) maximum allowable missing interval – no interval greater than 
20 minutes between non-missing measures for the outcome variables using ≤ 2-hour of CGM 
data (including iAUC0-1hr, iAUC0-2hr, average glucose excursions 0-1 or 0-2 hours and time in 
ranges 0-1 or 0- 2 hours after breakfast), and 25 minutes for other by-meal outcome variables. 
The definition and derivation of these variables are described in detail in 9.1.
Table ITSI.6.8.
Outcome Measures of CGM DATA
Category
Endpoints
24-Hour
Daytime1
Nighttime2
Breakfast3
Interstitial Glucose Reduction Rate following a Correction Bolus via the Pump (mg/dl/min and mg/dl/)4
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) 
across all non-meal-related correction doses via the 
pump
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] and ≤250 mg/dL [13.9 
mmol/L]) to recovery (interstitial 
glucose ≤180 mg/dL)
across all non-meal-related correction doses via the 
pump


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Category
Endpoints
24-Hour
Daytime1
Nighttime2
Breakfast3
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 >250 mg/dL [13.9 
mmol/L] and ≤300 mg/dL [16.7 
mmol/L]) to recovery (interstitial 
glucose ≤180 mg/dL)
across all non-meal-related correction doses via the 
pump
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 >300 mg/dL (16.7 
mmol/L) to recovery (interstitial glucose 
≤180 mg/dL)
across all non-meal-related correction doses via the 
pump
Incremental AUCs (iAUCs) after Meals
iAUC0-1hr
x
iAUC0-2hr
x
Average Glucose Excursions
average glucose excursion 0 to 1 hours
x
average glucose excursion 0 to 2 hours
x
Glucose in the Target Ranges
Duration (in minutes) and percentage of 
time with glucose values within target 
range 71 to 180 mg/dL [3.9 and 
10.0 mmol/L], both inclusive
x
x
x
x5
Duration (in minutes) and percentage of 
time with glucose values within target 
range 71 to 140 mg/dL [3.9 and 
7.8 mmol/L], both inclusive
x
x
x
x5
Duration (in minutes) and percentage of 
time with glucose values 180 mg/dL 
[10.0 mmol/L]
x
x
x
x5
Hypoglycemic Episodes
Duration (in minutes) and percentage of 
time with glucose values <50, <60, and 
≤70 mg/dL of hypoglycemic episodes,
defined as at least 10 consecutive 
minutes <50, <60, and 70 mg/dL [2.8, 
3.3, and 3.9 mmol/L]
x
x
x
x5


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Category
Endpoints
24-Hour
Daytime1
Nighttime2
Breakfast3
Rate (events/patient/year and/or 
events/patient/30 days) and incidence 
(percent of patients with at least 1 event) 
of hypoglycemic episodes, defined as at 
least 10 consecutive minutes <50, <60, 
and 70 mg/dL [2.8, 3.3, and 3.9 
mmol/L]
x
x
x
Hyperglycemic Episodes
Duration (in minutes) and percentage of 
time with glucose values >180, >250, 
and >300 mg/dL [10.0, 13.9, and 16.6 
mmol/L] and hyperglycemic episodes, 
defined as at least 10 consecutive 
minutes >180, >250, and >300 mg/dL 
[10.0, 13.9, and 16.6 mmol/L]
x
x
x
x5
Rate (events/patient/year and/or 
events/patient/30 days) and incidence 
(percent of patients with at least 1 event) 
of hyperglycemic episodes, defined as at 
least 10 consecutive minutes >180, 
>250, and >300 mg/dL [10.0, 13.9, and 
16.6 mmol/L]
x
x
x
Daily CGM Data Summary
Average glucose level
x
x
x
Median glucose level
x
x
x
Glucose Variability and Risk Assessment
Within-Day
CV
x
x
x
SD
x
x
x
IQR
x
x
x
MAGE
x
x
x
LBGI: frequency and extent of low BG 
readings
x
x
x
HBGI: frequency and extent of high BG 
readings
x
x
x
BGRI = LBGI + HBGI: a measure of 
overall variability and risks of hypo- and 
hyperglycemia
x
x
x


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Category
Endpoints
24-Hour
Daytime1
Nighttime2
Breakfast3
Between-day
CV
x
x
x
SD
x
x
x
MODD
x
x
x
Overall6
CV
x
x
x
SD
x
x
x
IQR
x
x
x
LBGI
x
x
x
HBGI
x
x
x
BGRI 
x
x
x
Highest Postprandial Glucose
Time from start of meal to the highest 
postprandial glucose level (minutes)
within 3 hours after breakfast
x
Highest postprandial glucose level 
within 3 hours after breakfast
x
Other
Duration (in minutes) of each individual 
hypoglycemic episode (defined as at 
least 10 consecutive minutes <50, <60, 
and ≤70 mg/dL [2.8, 3.3, and 3.9 
mmol/L])
across all hypoglycemic episodes with duration at 
least 10 consecutive minutes
Abbreviations:  AUC = area under curve; BGRI = blood glucose risk index; CGM = continuous glucose monitoring; 
CV = coefficient of variation; HBGI = high blood glucose index; IQR = interquartile range; LBGI = low blood 
glucose index; MAGE = mean amplitude of glycemic excursions; MODD = mean of daily differences; 
SD = Standard deviation.
Note: 
1
Daytime:  0600 hours to midnight (06:00:00-23:59:59 on the 24-hour clock).
2
Nighttime:  midnight to 0600 hours (00:00:00-05:59:59 on the 24-hour clock).
3
Breakfast is defined as the first “Carbs” event between 4 AM and 11 AM that is associated with an “Insulin” 
event within ±30 minutes.
4
All eCOA non-meal related correction doses excluding those confirmed as delivered via syringe for an 
unexplained hyperglycemia that leads to infusion set change, will be those delivered via the pump.
5
Time in ranges within 0-1 hour and 0-2 hours after breakfast
6
Overall variability refers to the variability calculated based upon all the CGM measurements collected across 
all valid days for each derivation period (e.g. 4-6 weeks relative to the start of each of the randomized 
treatment period).
To assess the glucose control over the course of approximately 72-hours of continuous insulin 
infusion, the duration and percentage of time in ranges (target, hypoglycemia or hyperglycemia) 


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and incremental AUCs after breakfast, will be derived based upon the CGM raw data collected 
on each of the infusion set catheter dwell days, including Day 1 (<0 and ≥24 hours), Day 2 (<24 
and ≥48 hours) and Day 3 (<48 and ≥72 hours), and summarized by treatment group. 
The glucose reduction rate and duration of each individual hypoglycemia episode will be 
analyzed by an 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 glucose reduction rate and duration of each hypoglycemia episode will be analyzed by an 
MMRM model. The MMRM model will include the fixed effects of treatment, period, and 
sequence as fixed effects and patient as a random effect. 
Hypoglycemia/hyperglycemia rates as measured by CGM data will be summarized for 30 days 
and 1 year / 100 years (hypoglycemia <50 mg/dl and hyperglycemia >300 mg/dl only).  The rate 
of hypoglycemia and hyperglycemia will be compared between treatment groups using
Wilcoxon signed-rank test.
The proportion of patients with at least 1 hypoglycemia/hyperglycemia event as measured by 
CGM data in each category (incidence) during a specific period after randomization will be 
analyzed using a generalized linear mixed model with options of the binomial distribution and 
logit link function with treatment, period, and sequence. The within-patient error will be 
modeled as an unstructured variance-covariance matrix. Prescott’s exact test will be conducted 
as sensitivity analyses.
Other than that, all continuous variables (actual and change from baseline, if applicable) will be 
compared between LY900014 and insulin lispro at Week 6 using the MMRMs (Model 2) defined 
in Section 6.1.
In addition, the following standardized glucose summary reports from AGP will be generated, 
based upon the observed CGM measures during Weeks 4 to 6 of each randomized treatment 
period:

24-hour period at individual patient level

0-1 hours and 0-2 hours relative to breakfast starting time, excluding patients who have 
had the next Carb or Insulin event (if any is captured) at the treatment group level
6.13. Efficacy Analyses
The analyses described in Section 6.13 will include data collected prior to permanent 
discontinuation (i.e., last dose) of IP in each 6-week treatment period, for all randomized 
patients.
The longitudinal observations of actual and change from baseline in HbA1c during the 12-week 
treatment period will be summarized by period and by treatment sequence.  HbA1c reflects 
patients’ blood glucose control over the past 2-3 months and therefore there may be potential 
carryover effect from Period I to Period II. For this reason, no treatment comparison will be 
conducted.


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Actual and change from baseline 1,5-AG values will be compared between LY900014 and 
insulin lispro using MMRM defined in Section 6.1.
6.14. Subgroup Analyses for Primary Endpoint
The following subgroups will be explored to evaluate consistency of treatment effects on the 
primary safety measure using data collected from the Safety Population excluding data that are 
collected while patients temporarily are off pump or off IP:
•
Duration of CSII use (using the median as the cutoff)
•
Region (US, OUS)
•
Pump Model 
In addition, the primary endpoint will be assessed in the subset of patients with HbA1c ≤8% 
level at entry.
Exploratory subgroup analyses or summaries of hypoglycemic event data on historical use of 
SmartGuard/Threshold Suspend (Yes, No) will also be conducted on the Safety Population.  
Additional exploratory subgroup analyses may also be performed.
6.15. Interim Analyses and Data Monitoring 
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the appropriate Lilly medical director, or designee, will be consulted to determine 
whether it is necessary to amend the protocol.
6.16. Clinical Trial Registry Analyses
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.  
Analyses provided for the CTR requirements include the following:
Summary of AEs, provided as a dataset which will be converted to an XML file.  Both SAEs
and ‘Other’ Non-SAEs are summarized: by treatment group, by MedDRA preferred term.

An AE is considered ‘Serious’ whether or not it is a TEAE.

An AE is considered in the ‘Other’ category if it is both a TEAE and is not serious.  For 
each Serious AE and ‘Other’ AE, for each term and treatment group, the following are 
provided:
o
the number of participants at risk of an event
o
the number of participants who experienced each event term
o
the number of events experienced.

For each SAE, these additional terms are provided for EudraCT:
o
the total number of occurrences causally related to treatment


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o
the total number of deaths
o
the total number of deaths causally related to treatment.  

Consistent with www.ClinicalTrials.gov requirements, ‘Other’ AEs that occur in fewer 
than 5% of patients/subjects in every treatment group may be excluded if a 5% threshold 
is chosen.  Allowable thresholds include 0% (all events), 1%, 2%, 3%, 4%, and 5%.  

AE reporting is consistent with other document disclosures for example, the CSR, 
manuscripts, and so forth. 


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7.
Unblinding Plan 
The purpose of this unblinding plan is to maintain the scientific integrity of the study.  The 
following actions/procedures will be put in place prior to any unblinding of the study data.
This is a double-blind study where investigators and patients are not aware of their assigned 
treatment.  Study treatment codes will be scrambled in the analysis data sets until the primary 
database lock and therefore, there will be no other unblinding for this study.


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8.
References
Baghurst PA. Calculating the mean amplitude of glycemic excursion from continuous glucose 
monitoring data: an automated algorithm. Diabetes Technol Ther. 2011;13(3):296-302.
Clarke W, Kovatchev B. Statistical tools to analyze continuous glucose monitor data. Diabetes 
Technol Ther
Hirsch IB. Glycemic variability: It’s not just about A1c anymore! Diabetes Technol Ther. 
2005;7(5):780-783.
Kovatchev BP, Clarke WL, Breton M, Brayman K, McCall A. Quantifying temporal glucose 
variability in diabetes via continuous glucose monitoring: mathematical methods and clinical 
application. Diabetes Technol Ther. 2005;7(6):849–862.
Mazze RS, Strock E, Wesley D, Borgman S, Morgan B, Bergenstal R, Cuddihy R. 
Characterizing glucose exposure for individuals with normal glucose tolerance using 
continuous glucose monitoring and ambulatory glucose profile analysis. Diabetes Technol 
Ther. 2008;10(3):149-159.
Rodbard D. Interpretation of continuous glucose monitoring data: glycemic variability and 
quality of glycemic control. Diabetes Technol Ther. 2009;11(Suppl 1):S55-S67.
Service FJ, Molnar GD, Rosevear JW, Ackerman E, Gatewood LC, Taylor WF. Mean amplitude 
of glycemic excursions, a measure of diabetic instability. Diabetes. 1970;19(9):644–655.
Service FJ, O’Brien PC, Rizza RA. Measurements of glucose control. Diabetes Care. 
1987;10(2):225–237.


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9.
Appendix 1
9.1.
Derivation of CGM Variables
9.2.
General Derivation Specifications
All CGM variables will be derived for each patient, for each time interval of each study period
(lead-in, Period I and Period II), based upon the data from valid CGM session days (Section
6.12).  For Period I and Period II, the variables will be derived for 0-4, 2-6 (interstitial glucose 
reduction rates only), 0-6, and 4-6 weeks relative to the start of each randomized treatment
period, respectively. 
If any concentration below lower limit of quantification (LOQ) or above upper LOQ are 
identified, they will be treated as LOQ for calculation of the CGM parameters.  No missing 
CGM values will be imputed.
Since the CGM values may not be measured at the exact same time for each day for a specific 
individual patient, due to device changes or gaps in usage, non-overlapping intervals (‘buckets’) 
of 5 minutes over 00:00:00 to 23:59:59 (00:00:00 to 00:04:59, 00:05:00 to 00:09:59, etc.) will be 
used for any derivations requiring time-matched measurements across days within a visit 
(e.g., mean of daily difference [MODD]). 
All CGM parameters will be estimated to precision of 1 decimal place, unless stated otherwise.  
All CGM glucose derivations will be conducted in units of mg/dL and mmol/L. 
Only readings collected from valid CGM days while patients are on pump and on IP, will be 
included in the derived.
9.3.
Interstitial Glucose Reduction Rate following a Correction Bolus 
via the Pump
The interstitial glucose reduction rate (mg/dl per minute and mg/dl per minute per unit of insulin 
dose) within 4 hours following a non-meal-related correction dose via the pump will be 
calculated by dividing the interstitial glucose reduction by the time it takes to first recover (≤180 
mg/dL) from hyperglycemia after the correction dose. 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). The interstitial glucose levels at the time of the non-meal-related correction bolus, is 
defined as the most recent interstitial glucose within 1 hour prior to the correction bolus.
The non-meal related correction boluses delivered by pump will be derived through the 
following steps:

Step 1: pull all correction boluses captured in eCOA;

Step 2: exclude those correction boluses delivered through syringe;


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 Step 3:  exclude those associated with the last prior SMBG within 1 hour ≤180 mg/dl and 
the last post SMBG within 2 hours increases from prior SMBG. These correction boluses 
should not have been reported as non-meal related;  
 Step 4:  remove duplicate correction boluses. If 2 correction boluses are reported for the 
exact same time, only 1 correction bolus will be included; 
 Step 5:  if within 4 hours a second correction bolus is given before recovery 
(≤180 mg/dl), only the first non-meal-related correction bolus time will be used and the 
data after the second correction bolus will be censored.  If the glucose never recovered to 
≤180 mg/dL within 4 hours before any other correction boluses are given, the glucose 
reduction rate will be calculated by dividing the greatest glucose reduction within 4 hours 
before any other correction bolus, by the time it took to reach this level.  
9.4. Incremental Area under the Glucose Curve (iAUC) 
iAUC0-T will be calculated as the average value of iAUC on all valid CGM days during that visit 
with sufficient data to calculate the iAUC0-T (Section 6.12).  For each day, iAUC0-T will be 
calculated as the sum of areas of all individual trapezoids within the time frame according to the 
formula: 
݅AUC଴ି୘ൌ ෍ܣ݅
௞
௜ୀଵ
ൌ෍ሺܩ௜െܩ଴ሻ൅ሺܩ௜ିଵെܩ଴ሻ
2
∆࢚࢏
௞
௜ୀଵ
 
where Ai is area of the respective trapezoid, Gi is glucose concentration at a particular time, G0 is 
the starting glucose concentration before the start of the meal, ∆࢚࢏ is the time interval between 
consecutive ISIG glucose measures, which should be always 5 minutes unless missing data 
occur, and k is the total number of intervals within the time frame 0-T.  If the intermediate time 
points are missing, the next available time point will be used in calculating the trapezoid area.  
Also since it is possible that Gi < G0 or Gi-1 < G0, Ai  could also be negative.  G0, the starting 
glucose concentration, will be calculated as the average of the CGM values in the time window 
[-19, 0] mins relative to the start of the meal (at most 3 ISIG glucose measures); Gk, the last 
glucose concentration, is defined as the average of the CGM values in the window [0, +14] 
minutes relative to the last time point of the time frame (at most 2 ISIG glucose measures).  For 
example, to calculate iAUC0-2hr, Gk will be the average of the CGM values in the window 
[0, +14] minutes relative to the 2 hours after the start of breakfast.  The derivation of each 
iAUC0-T will require that G0 and Gk values are both available. 
9.5. Average Glucose Excursions 
Average glucose excursions 0 to 1 hours and 0 to 2 hours will be calculated by averaging all 
excursion values within 1 or 2 hours.  Excursions will be derived by subtracting glucose values 
by the starting glucose concentration, which is the average of the CGM values in the time 
window [-19, 0] mins relative to the start of the meal (at most 3 ISIG glucose measures). 


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9.6. Glucose in Target Ranges, Hypoglycemia- or Hyperglycemia 
The percentage of time within a glucose range (target, hypo- or hyperglycemia ranges) will be 
calculated as the number of observations within the specified range divided by the number of 
observations in the time interval (e.g., 24-hour period).  The duration (in minutes) within the 
glucose range will then be calculated as the percentage of time within the glucose range times the 
length of the period (24 hour, 18 hour, and 6 hour, for the periods of 24-hour, daytime or 
nighttime, respectively).  
For example, if a patient had a total of 135 observations with glucose values ≤70 mg/dL 
(3.9 mmol/L) out of a total of 3078 observations recorded during the 24-hour period across days 
for Visit 8, the percentage of time spent in hypoglycemia during the 24-hour period for this 
patient at Visit 8 will be calculated as 135/3078 = 4.4%.  The duration (in minutes) with 
hypoglycemia (glucose value ≤70 mg/dL [3.9 mmol/L]) during the 24-hour period for this 
patient at Visit 8 will be calculated as the percentage times 1440, i.e., 135/3078*1440 = 
63.2 minutes.  
The percentage and duration in ranges within 0-1 hour, 0-2 hours and 0-3 hours after breakfast 
will also be derived. 
9.7. Hypoglycemic/Hyperglycemic Episodes 
Hypoglycemic/hyperglycemic episodes as measured by CGM data are defined as at least 10 
consecutive minutes below/above the specified threshold, and determined by 3 or more 
consecutive CGM values meeting the criterion.  
The number of distinct hypoglycemic episodes that start will be derived along with days of CGM 
use (Section 6.12) to calculate the rate of hypoglycemic episodes during a 24-hour period.  For 
example, the rate of postprandial hypoglycemic episodes (70 mg/dL [3.9 mmol/L]), during the 
24-hour period, will be calculated with the following steps: 
 Step 1:  identify all events as runs of 3 or more consecutive CGM values meeting the 
criterion, where the pre-marker glucose value (70 mg/dL[3.9 mmol/L]).  Consecutive 
implies no gaps in time more than 6 minutes between measurements.  Events will be 
identified without regard for the CGM level prior to the start of the Carb event.  
 Step 2:  Count the number of distinct events over the 24-hour period.  
 Step 3:  Calculate rate per month by multiplying count by 30/days of CGM use.  Days of 
CGM use will be calculated as the number of observations during the 24-hour period 
divided by the observation supposed to be measured during the period (288 observations 
for the 24-hour period). 
9.8. Glucose Variability  
Glycemic variability will be evaluated using the notation below: 


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i represents a time point within a time period (a 24-hour period, daytime or nighttime) 
n represents the number of time points within the time period  
k represents a day within a visit 
m represents number of days CGM is performed at a visit  
i
k,
BG
 represents the glucose value at time point i on day k unless otherwise specified under 
MAGE definition. 
9.8.1. Within-Day Variability 
For variables assessing within-day variability, first determine the variability within each day, 
then average across days within a visit.  
Within-day glucose standard deviation (SD) [Hirsch 2005; Rodbard 2009]: 
 
 
 
 
 
Within-day glucose coefficient of variation (CV) [Clarke 2009]:  
 
 
 
 
Inter-quartile range (IQR) [Mazze et al. 2008]: 
 
                  






m
k
m
k
k
m
IQR
m
IQR
1
1
 
k)
day 
on 
 
BG values
 
all
 
of
 
percentile
25th 
  -
(75th 
1
1
 
 
Mean amplitude of glycemic excursions (MAGE) [Service et al. 1970 and 1987; Baghurst 2011]:  
MAGE is the mean of the excursions between consecutive peaks and nadirs in BG that meet 
qualifying criteria, 
 
 
where,  
BGk,l = the low point in consecutive BG time points for the kth day (nadir) 
BGk,l-h  = the high point in consecutive BG time points for the kth day (peak) 
p
BG
BG
MAGE
p
1
l
h
l,
l,





k
k
k
























m
k
i
k
i
k
m
k
k
n
m
m
SD
1
2
n
1
i
,
n
1
i
,
1
1
)
n
BG
(BG
1
SD
1









m
k
i
k
k
m
k
k
SD
m
CV
m
CV
1
n
1
i
,
1
100
)
n
BG
(
1
1


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p = the number of qualifying excursions:  (BGk,l – BGk,l-h) ≥ 1 SDk and that follow the direction 
of the first qualifying difference within the BG time points for the kth day. 
MAGE- and MAGE+ will also be calculated for both negative and positive excursions, in 
addition to MAGE+/- for all positive and negative excursions combined [Baghurst 2011].  The 
peaks and nadirs will be algorithmically [Baghurst 2011; Approach 1], using a variant that 
removes the proposed and unnecessary first step of using a smoothing function. 
9.8.2. Between-Day Variability 
For variables assessing between-day variability, first determine the variability for each time 
points across days within a visit then average across all time points.  
Between-day glucose standard deviation (SD) [Rodbard 2009]: 
 
 
 
 
 
 
Between-day glucose coefficient of variation (CV) [Kovatchev 2009]: 
 
  
 
 
 
Mean of daily differences (MODD):  this parameter is calculated as the mean of absolute 
differences between glucose values at corresponding time points of consecutive days. 
 
 
 
 
9.8.3. Overall Variability 
The CV, SD, IQR, LBGI, HBGI and BGRI will be calculated using the standard formulas across 
collected across all valid days for time interval in each randomized treatment period.  
9.8.4. Risk for Hypo/Hyperglycemia 
The low blood glucose index (LBGI) has been developed to quantitate both frequency and 
severity of hypoglycemia.  The LBGI has been validated as a predictor of severe hypoglycemia, 





















n
i
m
k
k
i
m
n
CV
n
CV
1
1
i,
n
1
i
i
100
BG
SD
1
1








1
1
n
1
i
,
1,
n
BG
BG
1
1
MODD
m
k
i
k
i
k
m
























n
i
m
SD
1
2
m
1
k
i
k,
m
1
k
i
k,
n
1
i
i
1
m
)
BG
(BG
n
1
n
1
SD


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which is a SAE and could result in coma or death if unrecognized and untreated.  The high blood 
glucose index (HBGI) quantifies both frequency and severity of hyperglycemia and has been 
related to HbA1c and risk for hyperglycemia (Kovatchev et al. 2005).  Additionally, both the 
LBGI and HBGI have a high sensitivity to changes in glycemic profiles and control (Kovatchev 
et al. 2005).  Low blood glucose index is a non-negative number that increases as the number of 
low readings increases.  High blood glucose index is a non-negative number that increases as the 
number of high readings increases. 
The LBGI, HBGI, and blood glucose risk index (BGRI) will be derived for each day of a visit 
and for overall in the following steps: 
Step 1:  For each blood glucose (BG [mg/dL]) at the ith time point, compute the following: 
f(BGi) = 1.509×[(ln(BGi))1.084-5.381] 
This transforms the BG data using a nonlinear transformation that maps the BG range of 20 to 
600 mg/dL to a symmetric interval of

10
,
10

  
The center of the BG scale is 112.5 mg/dL and is mapped to 0 
Step 2:  Compute BG risk for each reading 




2
i
i
BG
f
10
BG
rl


 if f(BG) < 0; otherwise rl(BGi) = 0 




2
i
i
BG
f
10
BG
rh


 if f(BG) > 0; otherwise rh(BGi) = 0 
Assign the risk of each BG value by applying the above quadratic risk function 
Value range from 0 (achieved when BG = 112.5, the center) to 100 
Left side of the parabola is risk of hypoglycemia, and the right side is risk of hyperglycemia 
Step 3:  Compute LBGI and HBGI 



n
1
i
i)
rl(BG
n
1
LBGI
 



n
1
i
i)
rh(BG
n
1
HBGI
 
Step 4:  Compute BGRI  
BGRI = LBGI + HBGI  
9.9. Daily CGM Data Summary 
For daily CGM summary variables, first determine the values within each day, then average 
across days within a visit.  


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9.10. AUC
Area under the curve (AUC) during a period (24-hour, daytime, or nighttime) will be calculated 
using the standard linear trapezoidal method as defined previously in Section 9.4, by multiplying 
the sum of trapezoids by (the length of the period)/(the length of the period - total length of gaps 
that are not counted into the calculation of the AUC).
9.11. Highest Postprandial Glucose
9.11.1. Time to the highest postprandial glucose within 3 hours after 
Meals
Time from start of meal to the highest postprandial glucose level will be calculated as the time 
from start of meal to the maximum glucose value within 3 hours after meals, excluding the data 
from patients who have had the next Carb or Insulin event.
9.11.2. Highest Postprandial Glucose Level within 3 hours after Meals
Highest postprandial glucose level excursions within 3 hours after meals, will be calculated as 
the maximum glucose value during 0-3 hours after start of meal, excluding the data from patients 
who have had the next Carb or Insulin event.
9.12. Other
The duration of each episode of hypoglycemia will be calculated as stop time – start time.