Evaluation of LY900014 in a Medtronic Pump
Phase: PHASE2
Conditions: Type1 Diabetes Mellitus
Sponsor: Eli Lilly and Company

Protocol I8B-MC-ITSM (b)
Evaluation of LY900014 in a Medtronic Pump  
NCT03760640
Approval Date: 13-Apr-2019

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Protocol I8B-MC-ITSM(b)
Evaluationof LY900014 in a Medtronic Pump
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.
Approval Date: 13-Apr-2019 GMT
LY900014
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly on 24 October 2018.
Amendment (a) Electronically Signed and Approved by Lilly on 24 January 2019.
Amendment (b) Electronically Signed and Approved by Lilly on date provided below.

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Table of Contents
Section
Page
Protocol I8B-MC-ITSM (b) Evaluation of LY900014 in a Medtronic 
Pump ..................................................................................................................................1
Table of Contents........................................................................................................................2
1.
Synopsis .............................................................................................................................6
2.
Schedule of Activities .........................................................................................................9
3.
Introduction ......................................................................................................................14
3.1.
Study Rationale............................................................................................................14
3.2.
Background..................................................................................................................14
3.3.
Benefit/Risk Assessment..............................................................................................16
4.
Objectives and Endpoints..................................................................................................18
5.
Study Design.....................................................................................................................20
5.1.
Overall Design .............................................................................................................20
5.2.
Number of Participants.................................................................................................22
5.3.
End of Study Definition ...............................................................................................22
5.4.
Scientific Rationale for Study Design...........................................................................22
5.5.
Justification for Dose ...................................................................................................22
6.
Study Population...............................................................................................................23
6.1.
Inclusion Criteria..........................................................................................................23
6.2.
Exclusion Criteria ........................................................................................................25
6.3.
Lifestyle Restrictions....................................................................................................28
6.4.
Screen Failures.............................................................................................................28
7.
Treatments........................................................................................................................29
7.1.
Treatments Administered .............................................................................................29
7.1.1.
Packaging and Labeling .......................................................................................29
7.1.2.
Insulin Pumps ......................................................................................................30
7.1.2.1.
Pump Bolus Delivery Speed ...........................................................................30
7.1.2.2.
Pump Bolus Delivery Time.............................................................................30
7.1.2.3.
Pump Alerts....................................................................................................30
7.2.
Method of Treatment Assignment ................................................................................30
7.3.
Blinding .......................................................................................................................31
7.4.
Dosage Modification....................................................................................................31
7.5.
Preparation/Handling/Storage/Accountability...............................................................31
7.6.
Treatment Compliance .................................................................................................32
7.7.
Concomitant Therapy...................................................................................................32

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CCI
7.8. Treatmentafter the End of the Study............................................................................33
7.8.1.
Treatment after Study Completion........................................................................33
7.8.2.
Special Treatment Considerations........................................................................33
8.
Discontinuation Criteria....................................................................................................34
8.1. Discontinuation from Study Treatment.........................................................................34
8.1.1.
Discontinuation of Inadvertently Enrolled Patients...............................................34
8.2. Discontinuation from the Study....................................................................................34
8.3. Lost to Follow-up.........................................................................................................36
9.
Study Assessments and Procedures...................................................................................37
9.1. Efficacy Assessments...................................................................................................37
9.1.1.
Primary Assessments...........................................................................................37
9.1.2.
Secondary Assessments........................................................................................37
9.1.3.
Appropriateness of Assessments..........................................................................37
9.1.4.
Study Procedures.................................................................................................37
9.1.4.1.
Continuous Glucose Monitoring.....................................................................37
9.1.4.3.
Infusion Set Changes......................................................................................38
9.1.4.4.
Diabetes Training...........................................................................................39
9.2. Adverse Events............................................................................................................39
9.2.1.
Serious Adverse Events........................................................................................40
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................41
9.2.2.
Complaint Handling.............................................................................................41
9.3. Treatment of Overdose.................................................................................................42
9.4. Safety...........................................................................................................................42
9.4.1.
Hypoglycemia......................................................................................................42
9.4.2.
Severe Hypoglycemia..........................................................................................43
9.4.3.
Electrocardiograms..............................................................................................43
9.4.4.
Vital Signs...........................................................................................................43
9.4.5.
Laboratory Tests..................................................................................................43
9.4.6.
Safety Monitoring................................................................................................44
9.4.6.1.
Pilot Safety Assessment..................................................................................44
9.4.6.2.
Hepatic Safety Monitoring..............................................................................45
9.5. Pharmacokinetics.........................................................................................................46
9.6. Pharmacodynamics......................................................................................................46
9.7. Pharmacogenomics......................................................................................................46
9.8. Biomarkers...................................................................................................................46
9.9.
Health Economics........................................................................................................46
10. Statistical Considerations..................................................................................................47

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10.1. Sample Size Determination ..........................................................................................47
10.2. Populations for Analyses..............................................................................................47
10.3. Statistical Analyses ......................................................................................................47
10.3.1.
General Statistical Considerations ........................................................................47
10.3.2.
Treatment Comparability .....................................................................................48
10.3.2.1.
Patient Disposition..........................................................................................48
10.3.2.2.
Patient Characteristics ....................................................................................48
10.3.2.3.
Concomitant Therapy .....................................................................................49
10.3.2.4.
Treatment Compliance....................................................................................49
10.3.3.
Efficacy Analyses ................................................................................................49
10.3.3.1.
Primary Analyses ...........................................................................................49
10.3.3.2.
Secondary Analyses........................................................................................49
10.3.3.3.
Exploratory Analyses .....................................................................................49
10.3.4.
Safety Analyses....................................................................................................49
10.3.5.
Subgroup Analyses ..............................................................................................50
10.3.6.
Interim Analyses..................................................................................................50
11.
References ........................................................................................................................51
12.
Appendices .......................................................................................................................52

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List of Tables
Table
Page
Table ITSM.1.
Schedule of Activities....................................................................................10
Table ITSM.2.
Objectives and Endpoints...............................................................................18
Table ITSM.3.
Treatment Regimens......................................................................................29
List of Figures
Figure
Page
Figure ITSM.1.
Illustration of study design for Clinical Protocol I8B-MC-ITSM....................21
List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................53
Appendix 2.
Clinical Laboratory Tests...............................................................................56
Appendix 3.
Study Governance Considerations..................................................................57
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................62
Appendix 5.
Classification of Contraceptive Methods........................................................63
Appendix 6.
Protocol Ammendment I8B-MC-ITSM (b) Evaluation of LY900014 in 
a Medtronic Pump .........................................................................................64

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1. Synopsis
Title of Study: 
Evaluation of LY900014 in a Medtronic Pump.
Rationale: 
The aim of this study is to compare LY900014 and Humalog with respect to the percentage of 
time with glucose values within range (70 to 180 mg/dL) when both are delivered via continuous 
subcutaneous insulin infusion (CSII) by the Medtronic MiniMed 670G System while in Auto 
Mode as much as possible.  
Objective(s)/Endpoints:
Objectives
Endpoints
Primary
1. To compare LY900014 and Humalog with respect 
to the percentage of time with sensor glucose 
values within range (70 to 180 mg/dL) 
1.
Percentage of time with sensor glucose values 
between 70 and 180 mg/dL (both inclusive),
during the last 2 weeks of each 4-week treatment 
period
Secondary
2. To compare LY900014 with Humalog with respect 
to the mean sensor glucose
2.
Mean sensor glucose value (mg/dL), during the 
last 2 weeks of each 4-week treatment period
3. To compare LY900014 and Humalog with respect 
to the percentage of time spent in Auto Mode
3.
Percentage of time (per week) spent in Auto Mode, 
during the last 2 weeks of each 4-week treatment 
period
4. To compare LY900014 with  Humalog with
respect to the percentage of time with sensor 
glucose values in hypoglycemic glucose ranges
4.
Percentage of time with sensor glucose values 
<54 mg/dL during the last 2 weeks of each 4-week 
treatment period
5. To compare LY900014 and Humalog with respect 
to the rate of severe hypoglycemic events
5.
Rate (events/patient/100 years) of severe 
hypoglycemic events during each 4-week 
treatment period
6. To compare LY900014 and Humalog with respect 
to the rate and incidence of documented 
hypoglycemia
6.
Rate (events/patient/year) and incidence (percent 
of patients with events) of documented 
hypoglycemic events, during the last 2 weeks of 
each 4-week treatment period
7. To compare LY900014 and Humalog with
respect to total daily dose
7.
Mean total daily bolus insulin dose and mean total 
daily basal insulin dose during the last 2 weeks of 
each 4-week treatment period

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Summary of Study Design:  
This study is a prospective, randomized, double-blind, outpatient, 2-treatment crossover, 
active-controlled study conducted in patients with type 1 diabetes mellitus (T1D) currently using 
an external CSII.  In the 2 treatment periods, LY900014 and Humalog will be delivered via the 
Medtronic MiniMed 670G system while in Auto Mode as much as possible.
The study is designed to compare LY900014 and Humalog with respect to the duration of time 
glucose values are within range (70 to 180 mg/dL).  
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, each period consisting of 4 weeks of treatment, and a 2-week post-treatment 
safety follow-up.  
Following the lead-in period, a 3-day pilot safety assessment will be conducted at a single site
for the first 10 patients randomized.  This pilot safety assessment will determine if the control 
algorithm in the Medtronic 670G pump can be used safely in patients receiving LY900014.  
Number of Patients:
Approximately 50 participants will be screened to achieve 42 randomized for a total of 
approximately 36 patients to complete the study.
Statistical Analysis:
Statistical analysis of this study will be the responsibility of Lilly or its designee.  Additional 
exploratory analyses of data will be conducted, as deemed appropriate.  
Unless otherwise specified, all efficacy and safety analyses will be conducted on the
Randomized Population.  Analyses of adverse events (AEs) will include all data collected during 
the course of the entire 4-week treatment period for each treatment regardless of investigational 
product (IP) use.  Analyses of hypoglycemia will be conducted from first dose to last dose of IP 
in each 4-week treatment period.  Data collected during the safety follow-up period will not be 
used for comparisons between treatments.  
Unless otherwise noted, all tests of treatment effects will be conducted at a 2-sided alpha level of 
0.10, and confidence intervals (CIs) will be calculated at 90%, 2-sided.  
Treatment comparisons will be performed for the primary objective at the full significance level 
of 0.10. No multiplicity adjustments will be made for the analysis of secondary and exploratory 
objectives.
Baseline is defined as the last nonmissing measurement at or before the randomization visit
(Visit 4), unless otherwise specified and described in the SAP.
The primary objective of this study is to compare LY900014 and Humalog with respect to the 
percentage of time with sensor glucose (SG) values within range (70 to 180 mg/dL), during the 

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last 2 weeks of each 4-week treatment period. The analysis model and selection of covariance
structure are described below.  
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 4-week treatment period 
for each treatment will be included in the analysis.  The model will include the fixed-class effects 
of treatment, period, sequence, strata (hemoglobin A1c; HbA1c [≤7.0%, >7.0%] and percentage 
of time with SG values from 70 to 180 mg/dL over the 2 weeks prior to randomization [≤75%, 
>75%]), and the continuous, fixed covariate of baseline value.  The Kenward-Roger 
approximation will be used to estimate denominator degrees of freedom.  An unstructured 
covariance structure will be used to model the within-patient errors.  If this analysis fails to 
converge, a covariance structure of compound symmetry without heterogeneous variances will 
be used. If the model still does not converge, strata may be deleted from the model.  
Significance tests will be based on least squares means and Type III tests.  SAS PROC MIXED 
will be used to perform the analysis.  
For categorical measures (such as incidence of AEs), summary statistics will include sample 
size, frequency, and percentages.  Prescott’s exact test will be used for treatment comparisons, 
unless otherwise specified.

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2. Schedule of Activities

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Table ITSM.1.
Schedule of Activities
Screen
ing
Lead-In
Study Period I
Study Period II
Safety 
Follow-up
Early 
Termination
Visit
1
2
3a
4
5a
6a
7
8a
9a
10
801
ET
Week of Treatment
-3
-2
-1
0
*
2
4
*
6
8
10
Visit Window (±days)
0
3
3
3
3
3
3
3
3
3
7
Study Logistics
Informed consent signed
X
Eligibility Criteria Reviewed
X
X
Randomization
X
IWRS
X
X
X
X
X
X
X
X
X
X
X
X
Crossover
X
Clinical Assessments
Patient demographics
X
Medical history and preexisting conditions
X
Physical examination/height
X
ECG (12-lead)b
X
Body weight
X
X
X
X
X
X
X
Vital signs:  blood pressure/pulse ratec
X
X
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events 
X
X
X
X
X
X
X
X
X
X
X
Patient Education and Management 
Set standardized high/low glucose alerts
X
X
X
At screening, record pump bolus delivery speed 
(Standard [1.5 U/min] or Quick [15 U/min]).  
At other office visits, confirm and record pump bolus delivery 
speed unchanged from screening.
X
X
X
X
X
At screening, record infusion set cannula length (6mm or 
9mm).
If changed during study, record infusion set cannula length 
(6mm or 9mm) and reason for change.
X
X
X
X
X
Reset pump ISF, CR, and AIT to randomization settings
X
Change infusion set and reservoir at investigative sited
X
X
X
Xe
X
e

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Screen
ing
Lead-In
Study Period I
Study Period II
Safety 
Follow-up
Early 
Termination
Visit
1
2
3a
4
5a
6a
7
8a
9a
10
801
ET
Week of Treatment
-3
-2
-1
0
*
2
4
*
6
8
10
Visit Window (±days)
0
3
3
3
3
3
3
3
3
3
7
Review/Answer questions on Medtronic 670G System, 
Diabetes management education, carbohydrate counting, 
collecting 4-point SMBG profiles, and review hypoglycemia 
and hyperglycemia management guidelinesf,g
X
Review total daily insulin doseh
X
Review pump, CGM, and SMBG data for use in clinical 
decision making 
X
X
X
X
X
X
X
X
X
X
Review/discuss hypoglycemia data
X
X
X
X
X
X
X
X
X
X
Remind patient to upload pump data to CareLink weekly
X
X
X
X
X
X
X
X
X
Ancillary Supplies/Diaries/IP
Dispense infusion sets, reservoirs, BG test strips, and 
ancillary supplies
X
X
X
X
X
Dispense Study Diary
X
X
X
X
Collect Study Diary and review with patient
X
X
X
X
X
Start open-label Humalog at office visit
X
Start non-study rapid-acting analog insulin at office visit
X
Dispense IP
X
X
Collect used and unused study drug and supplies from patient
X
X
X
X
Transfer Diary Data to eCRF
Hypoglycemia events
X
X
X
X
X
X
Unplanned infusion set changes with noted reason(s)
X
X
X
X
X
Transfer CareLink Data to eCRF
Pump settings: ISF, CR, AIT (used to start next treatment)
X
X
X
Mean total daily bolus and basal insulin dosei
X
X
X
X
X
Time in Auto Mode per week (%)i
X
X
X
X
X
Laboratory Assessments 
Follicle-stimulating hormone testj
X
Serum pregnancy test
X
Urine pregnancy test
X

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Screen
ing
Lead-In
Study Period I
Study Period II
Safety 
Follow-up
Early 
Termination
Visit
1
2
3a
4
5a
6a
7
8a
9a
10
801
ET
Week of Treatment
-3
-2
-1
0
*
2
4
*
6
8
10
Visit Window (±days)
0
3
3
3
3
3
3
3
3
3
7
Chemistry panel
X
Urinalysis panel
X
Hematology
X
1.5-Anhydroglucitol
X
X
X
X
Hemoglobin A1c
X
X
X
X
X
Pilot Safety Assessment Specifick
Instruct designated study companion on their responsibilities 
throughout the pilot safety assessment and ensure familiarity 
with basic features of the MiniMed 670G pumpl
X
Ensure patient upload of CareLink Data is completed for 
review
X
Transfer patient diary data entries related to hypoglycemia, 
unexplained hyperglycemia and unplanned infusion set 
changes into eCRF. Review and discuss all patient diary 
entries.
X

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Abbreviations:  AIT = active insulin time; BG = blood glucose, CGM = continuous glucose monitoring; CR = carb ratio; ECG = electrocardiogram; ET = early 
termination; IP = investigational product; ISF = insulin sensitivity factor; IWRS = interactive web-response system; SMBG = self-monitored blood glucose.
* Denotes 3-day safety follow-up telephone visit after the beginning of each study period.
a
Telephone visits are indicated by columns shaded a darker shade of gray.  
b Patients must be supine for approximately 5 to 10 minutes before ECG collection and remain supine but awake during ECG collection.
c
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.  
d All study procedures for a visit should be completed prior to reservoir and infusion set changes during Visits 2, 4, 7, 10 and 801 or ET.
e
At Visit 10 or ET, patients should resume nonstudy insulin. Patients should be instructed to bring their nonstudy insulin with them to the visit in order to 
resume normal therapy.
f
Training may be repeated at other visits, as needed.
g Patients should be instructed to perform, at minimum, a 4-point SMBG profile daily starting at Visit 2.
h From each of the last 3 days prior to screening
i
Mean from the 1 week prior to Visit 2; mean from the 2 weeks prior to visit for Visits 4, 7, 10, and ET.
j
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.
k Patients participating in the pilot safety assessment will complete all activities listed in the schedule of activities in addition to all pilot-specific activities.
These activities do not need to be completed for patients not participating in the pilot safety assessment.
l
Designated study companions must be present to receive instruction at Visit 4.

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3. Introduction
3.1.
Study Rationale
Rapid-acting insulins have been shown to have a more rapid onset of action compared with
human insulin; however, the general consensus is that they are not rapid enough to match 
carbohydrate absorption and many patients are unable to achieve optimal glycemic control.  
An ultra-rapid-acting prandial insulin that would shift the pharmacokinetic (PK) and 
pharmacodynamic (PD) 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 (T1D) and 
type 2 diabetes mellitus (T2D) when delivered by multiple daily injections (MDI), continuous 
subcutaneous insulin infusion (CSII), or in closed loop and hybrid closed loop automated insulin 
delivery systems.
The performance of closed loop and hybrid closed loop insulin delivery systems is limited by the 
relatively slow absorption of current rapid-acting insulin analogs, delaying the onset of action 
and prolonging the duration of action.  This is problematic during times of rapid glucose 
changes, such as in the postprandial period.  It is hypothesized that rapid glucose changes will be 
minimized with an ultra-rapid-acting insulin in a hybrid closed loop system.  The integration of 
an ultra-rapid insulin with an accelerated PK profile into a hybrid closed loop algorithm may
increase time patients spend in the target glucose range.  
The aim of this study is to compare LY900014 and Humalog with respect to the percentage of 
time with glucose values within range (70 to 180 mg/dL) when both are delivered via CSII by 
the Medtronic MiniMed 670G System while in Auto Mode as much as possible.  
3.2.
Background
There have been many advances in the treatment of T1D in the last 20 years; however, reaching 
goals and maintaining glycemic targets remain 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).  Integrated 
insulin pump and continuous glucose monitoring (CGM) systems may provide better diabetes 
management, compared with MDI or with the pump alone. Some studies suggest that when you 
pair pump therapy with the information provided by a glucose sensor, it may significantly 
improve HbA1c levels without increasing the risk of hypoglycemia (Bergenstal et al. 2010, 
Battelino et al. 2012, Bergenstal et al. 2013).
LY900014
LY900014 is comprised of the active ingredient, insulin lispro, and 2 enabling excipients 
(treprostinil and citrate) that facilitate rapid absorption of insulin lispro into the blood stream.  
This novel formulation results in earlier glucose lowering when compared with Humalog.  This 

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faster glucose-lowering response, as demonstrated by the PK and PD profiles of LY900014 when 
compared with Humalog, more closely mimics the time-action profile of normal endogenous 
insulin secretion.  This enhanced activity is expected to provide greater glycemic control as 
dosing relative to the start of a meal can be reduced when compared with the timing required for 
the currently available rapid-acting insulin analogs. Dosing closer to the start of a meal will 
allow patients to better match the needed insulin dose to the carbohydrate content of their meal.  
Medtronic MiniMed 670G System
The Medtronic MiniMed 670G system is intended for continuous delivery of basal insulin and 
administration of insulin boluses for the management of T1D and for the continuous monitoring 
of interstitial glucose levels. The Medtronic MiniMed 670G System consists of the MiniMed 
670G Insulin Pump, the Guardian Link (3) Transmitter, the Guardian Sensor (3), and the 
CONTOUR NEXT Link 2.4 Glucose Meter. The Guardian Sensor (3) is intended to be used for 
detecting sensor glucose (SG) trends and tracking patterns and to be used by the MiniMed 670G 
system to automatically adjust basal insulin levels.  It is indicated for use as an adjunctive device 
to compliment, but not replace standard blood glucose (BG) testing.  
The MiniMed 670G System includes SmartGuard technology. There are 2 levels of SmartGuard 
technology; Suspend and Auto Mode.
The first level of SmartGuard technology automatically suspends insulin when the sensor reaches 
a preset low limit (Suspend on low) or before the low limit is reached (Suspend before low).
When a Suspend before low occurs, insulin delivery will automatically resume when the SG
levels recover. The Suspend on low and Suspend before low features are optional features 
available only when the system is in Manual Mode.
Study I8B-MC-ITSM (ITSM) will use the second level of SmartGuard technology, Auto Mode,
as much as possible.  Auto Mode automatically calculates insulin dose using Guardian Sensor (3) 
data.  Auto Mode is an insulin delivery feature that automatically controls basal insulin delivery 
to regulate glucose levels to a target SG.  The standard target SG setting is 120 mg/dL and the 
target can be set temporarily to 150 mg/dL for exercise and other events. During Auto Mode 
operation, the user must deliver meal boluses. The Bolus feature in Auto Mode requires entry of
either carbohydrate or a BG value, but both may be entered.  Auto Mode then calculates the 
bolus amount needed to cover the meal or correction. Auto Mode Bolus only allows Normal
boluses.  Square Wave, Dual Wave, Easy, Manual, Remote, and Preset bolus types cannot be 
delivered while in Auto Mode.  
Basic requirements for managing Auto Mode include the following:

Periodic BG testing to calibrate the sensor.  Minimum calibration is every 12 hours.

Use of Auto Mode Bolus function to cover meals, and when the pump recommends a 
bolus.  A BG reading above 150 mg/dL causes Auto Mode to automatically calculate if a
correction bolus is needed to decrease BG to the 150 mg/dL correction target.
Safe Basal is an automatic function within Auto Mode. Safe Basal allows for time to perform 
additional actions required to ensure Auto Mode remains active. Safe Basal covers basal needs 

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by delivering insulin at a constant rate and does not adjust insulin delivery based on SG values.
Several conditions can cause a transition into Safe Basal:

Auto Mode has been at the minimum delivery limit for 2.5 hours.

Auto Mode has been at the maximum delivery limit for 4 hours.

Auto Mode detects that sensor might be under reading.

An entered BG is 35% or more different than your current SG value.

No SG data have been received for more than 5 minutes.
After 90 minutes in Safe Basal, if the condition that caused the pump to transition into Safe Basal 
has not been resolved, the pump will enter Manual Mode. The pump will indicate the actions the 
user needs to take to resume Auto Mode delivery of basal insulin.  
Manual Mode refers to system functions other than Auto Mode. If Auto Mode is not 
functioning, the system is in Manual Mode.  
3.3.
Benefit/Risk Assessment
Across Phase 1 clinical studies, LY900014 has consistently demonstrated a faster time-action 
profile than Humalog.  In patients with T1D or T2D treated with MDI insulin therapy, 
LY900014 significantly reduced postprandial glucose excursions compared with Humalog when 
both were dosed by syringe at the start of a test meal.  Two studies (I8B-MC-ITRF and 
I8B-MC-ITSC) in patients with T1D 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.  
Benefits to patients may include improved understanding of insulin requirements and 
optimization of pump settings in a hybrid closed loop system with a faster acting insulin.  
Additionally, close monitoring, frequent visits, real-time CGM and self-monitored blood glucose
(SMBG) all serve to protect subject safety and minimize risk.  
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 Humalog.
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.  Diabetic 
ketoacidosis develops when insulin levels are insufficient to meet the body’s basic metabolic 
requirements.  Diabetic ketoacidosis is an acute metabolic complication of diabetes characterized 
by hyperglycemia, hyperketonemia, and metabolic acidosis.  Signs and symptoms may include 
vomiting, abdominal pain, deep gasping breathing, increased urination, weakness, confusion, and 
occasionally loss of consciousness.  A high BG that is not responding to a correction bolus via 
insulin pump may indicate an infusion set occlusion or insulin pump problem.  

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LY900014
Following the lead-in period, a 3-day pilot safety assessment will be conducted at a single site 
for the first 10 patients randomized.  This pilot safety assessment will determine if the control 
algorithm in the Medtronic 670G pump can be used safely in patients receiving LY900014.  
Safety evaluation in this study will include hypoglycemia, treatment-emergent AEs (TEAEs), 
serious AEs (SAEs), clinical laboratory assessments, vital signs, pump occlusion alarms, and 
unexplained hyperglycemia leading to unplanned infusion set changes.  More information about 
the known and expected benefits, risks, SAEs, and reasonably anticipated AEs of LY900014 can 
be found in the Investigator’s Brochure (IB).  
Detailed information about the known and expected benefits and risks of Humalog may be found 
in the country-specific product labeling (for example, Patient Information Leaflet, Package Insert, 
or Summary of Product Characteristics).  

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LY900014
4.
Objectives and Endpoints
Table ITSM.2 shows the objectives and endpoints of the study.
Table ITSM.2.
Objectives and Endpoints
Objectives
Endpoints
Primary
1. To compare LY900014 and Humalog with respect 
to the percentage of time with sensor glucose 
values within range (70 to 180 mg/dL) 
1.
Percentage of time with sensor glucose values 
between 70 and 180 mg/dL (both inclusive),
during the last 2 weeks of each 4-week treatment 
period
Secondary
2. To compare LY900014 with Humalog with respect 
to the mean sensor glucose
2.
Mean sensor glucose value (mg/dL), during the 
last 2 weeks of each 4-week treatment period
3. To compare LY900014 and Humalog with respect 
to the percentage of time spent in Auto Mode
3.
Percentage of time (per week) spent in Auto Mode, 
during the last 2 weeks of each 4-week treatment 
period
4. To compare LY900014 with  Humalog with
respect to the percentage of time with sensor 
glucose values in hypoglycemic glucose ranges
4.
Percentage of time with sensor glucose values 
<54 mg/dL during the last 2 weeks of each 4-week 
treatment period
5. To compare LY900014 and Humalog with respect 
to the rate of severe hypoglycemic events
5.
Rate (events/patient/100 years) of severe 
hypoglycemic events during each 4-week 
treatment period
6. To compare LY900014 and Humalog with respect 
to the rate and incidence of documented 
hypoglycemia
6.
Rate (events/patient/year) and incidence (percent 
of patients with events) of documented 
hypoglycemic events, during the last 2 weeks of 
each 4-week treatment period
7. To compare LY900014 and Humalog with
respect to total daily dose
7.
Mean total daily bolus insulin dose and mean total 
daily basal insulin dose during the last 2 weeks of 
each 4-week treatment period
Tertiary/Exploratory
8. To compare the safety of LY900014 and Humalog
8.
Adverse events and vital signs
9. To compare LY900014 and Humalog with respect 
to the percentage of time with sensor glucose 
values within range (70 and 140 mg/dL) 
9.
Percentage of time with sensor glucose values 
between 70 and 140 mg/dL (both inclusive),
during the last 2 weeks of each 4-week treatment 
period
10. To compare LY900014 and Humalog with respect 
to the rate and incidence of unplanned infusion set 
changes
10. Rate (events/patient/30 days) and incidence of 
unplanned infusion set changes by reason (Pump 
occlusion alarm, unexplained high BG, Infusion 
site reaction [pain, redness or swelling at infusion 
site], or Infusion set problem [infusion set kinked, 
pulled out, leaking, reservoir empty, etc]), during 
the 4-week treatment period
11. To compare LY900014 and Humalog with respect 
to the percentage of time with sensor glucose 
values in hyperglycemic glucose ranges
11. Percentage of time with sensor glucose values 
>180 mg/dL and >250 mg/dL, during the last 
2 weeks of each 4-week treatment period

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LY900014
Objectives
Endpoints
12. To compare LY900014 and Humalog with respect 
to the 1-hour postprandial sensor glucose 
excursions
12. Mean 1-hour postprandial sensor glucose 
excursions (mean sensor glucose measured 1 hour 
after the start of the meal minus mean sensor
glucose at the start of meal) after breakfast, during 
the last 2 weeks of each 4-week treatment period
13. To compare LY900014 and Humalog with respect 
to the within-patient sensor glucose variability 
13. Coefficient of variation (CV) (standard 
deviation/mean) of sensor glucose values, during 
the last 2 weeks of each 4-week treatment period
14. To evaluate HbA1c of LY900014 and Humalog
14. Summary statistics of actual and change of HbA1c 
during each 4 week treatment period
15. To evaluate 1,5-AG of LY900014 and Humalog
15. Summary statistics of actual and change of 1,5-AG
during each 4-week treatment period
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), during the 4-week treatment period
Abbreviations: 1,5 AG = 1,5 Anhydroglucitol; AIT = active insulin time; BG = blood glucose; CR = carb ratio; 
ISF = insulin sensitivity factor.

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LY900014
5. Study Design
5.1.
Overall Design
This study is a prospective, randomized, double-blind, outpatient, 2-treatment , crossover, 
active-controlled study conducted in patients with T1D currently using an external CSII pump.  
In the 2 treatment periods, LY900014 and Humalog will be delivered via the Medtronic 
MiniMed 670G system with SmartGuard™ technology using AutoMode.  In this study, patients 
will be required to use the Auto Mode insulin delivery function as much as possible.  
The study is designed to compare LY900014 and Humalog with respect to the duration of time 
glucose values are within range (70 to 180 mg/dL).  The study includes a 1-week screening 
period and a 2-week lead-in period followed by a 2-period crossover, each period consisting of 
4 weeks of treatment, and a 2-week post-treatment safety follow-up.  
Following the lead-in period, a 3-day pilot safety assessment will be conducted at a single site in 
the first 10 patients randomized.  This pilot safety assessment will determine if the control 
algorithm in the Medtronic 670G pump can be used safely in patients receiving LY900014.  
Patients randomized into the pilot safety assessment will remain blinded to treatment and 
undergo study procedures in the Schedule of Activities with additions denoted at the bottom.  
These patients will be required to have additional safety oversight in the form of a designated 
study companion (spouse, a partner, or someone living in the household) who is required to be 
with the patient overnight for the first 3 days of the study.  The investigative site will check in 
with the patient at Day 1 via a telephone call.  During the Visit 5 telephone call, the investigator 
will review patient data and determine if the patient can continue study treatment.  More details 
on the pilot safety assessment are described in Section 9.4.6.1.  
The pilot patients will contribute to the total number of patients randomized.  No additional 
patients will be randomized until after a blinded review of the pilot patients’ safety data occurs.  
Within 1 week of all 10 patients completing the 3-day pilot safety assessment, the investigator 
will review the data in consultation with the Sponsor.  After completion of the pilot safety 
assessment, the investigator and the Sponsor will determine if randomization can continue.  
Study governance considerations are described in detail in Appendix 3.
Figure ITSM.1 illustrates the study design.

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LY900014
Figure ITSM.1.
Illustration of study design for Clinical Protocol I8B-MC-ITSM.

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LY900014
5.2.
Number of Participants
Approximately 50 participants will be screened to achieve 42 randomized for a total of 
approximately 36 patients to complete the study.  Pilot patients will contribute to the overall 
number of participants.
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 pilot safety assessment was added to the study design after consultation with FDA in 
December 2018.  The purpose of the pilot will be to assess the safety of LY900014 when 
administered via the Medtronic 670G pump before enrolling a large number of patients.  
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. The 
investigator will reset the patient’s pump to randomization settings. Treatment comparisons will 
use the data collected during the last 2 weeks of each period.  This will minimize carryover effect 
on the primary analysis of efficacy, safety, and exploratory outcomes.  
5.5.
Justification for Dose
The basal and bolus delivery of insulin in this study will be determined based on the individual 
needs of each patient.  LY900014 has the same insulin lispro concentration (100 U/mL) as that 
of commercially available Humalog.  In Phase 3 clinical studies, LY900014 and Humalog were 
substituted unit for unit.  Humalog has been in the market for over 20 years with widespread use 
worldwide and has extensive efficacy and safety data.  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 post dose) are similar between LY900014 and Humalog in T1D CSII.  In addition, the 
total glucodynamic activity measured in euglycemic clamp studies was similar between 
LY900014 and Humalog.

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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.  There are additional criteria for patients who 
participate in the pilot safety assessment of the study.
6.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria at 
screening:
Type of Patient and Disease Characteristics
[1]
Men or women diagnosed (clinically) with T1D for at least 1 year prior to screening and 
continuously using insulin for at least 1 year
Patient Characteristics
[2]
Are at least 18 years of age 
[3]
Male patients:
a) No male contraception required.
[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
Or

I8B-MC-ITSM (b) Clinical Protocol
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LY900014
(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 who are 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 5)
iv) test negative for pregnancy at the time of screening (Visit 1); note:  a 
urine pregnancy test is conducted at Visit 4
[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 or insulin aspart) via CSII for at least the last 30 days prior to screening
[7]
Have HbA1c values ≥6.0 and ≤8.0%, as determined by the central laboratory at 
screening (Visit 1)
[8]
Have a body mass index of ≤35 kg/m2 at screening (Visit 1)
[9]
Are proficient, in the opinion of the investigator, in carbohydrate counting
[10] Are willing to adhere to an infusion set and reservoir change interval of every 
3 days.
[11] Must be using a Medtronic MiniMed 670G insulin pump 
a) For at least 90 days prior to screening in Auto Mode 
b) In Auto Mode at least an average of 70% of the time per week during the 
last 4 weeks prior to screening 
c) With a Medtronic Guardian (3) sensor at least an average of 75% of the 
time per week during the last 4 weeks prior to screening
d) And willing to stay on the 670G pump throughout the study
e) And willing to maintain the bolus delivery speed used at screening for the 
duration of the study
f)
And willing to avoid use of all products containing acetaminophen while 
using the Medtronic Guardian (3) sensor
g) And willing to use study-provided Medtronic MiniMed insulin pump 
reservoirs and Mio infusion sets

I8B-MC-ITSM (b) Clinical Protocol
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LY900014
h) And willing to use the Auto Mode Bolus feature to deliver boluses to cover 
meals and corrections, and whenever the pump recommends a bolus  
[12] Are willing to perform BG testing using their personal Contour Next Link 2.4
meter 4 times each day premeal and bedtime, including for sensor calibrations,
and to confirm hypoglycemia and unexplained hyperglycemia, and willing to 
respond to periodic requests from the pump for BG readings without the need for 
calibration
[13] Have access to a telephone, or alternative means for close monitoring and 
communications
[14] Have refrigeration in the home or have ready access to refrigeration for storage of 
insulin
Informed Consent
[15] Have given written informed consent to participate in this study in accordance 
with local regulations
6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at
screening or at other visits, only when indicated:
Medical Conditions
[16] Have hypoglycemia unawareness as judged by the investigator
[17] Have had more than 1 episode of severe hypoglycemia (defined as requiring 
assistance due to neurologically disabling hypoglycemia) within 6 months prior 
to screening
[18] Have had any emergency department visit or hospitalization due to poor BG 
control (hyperglycemia or DKA) within 6 months prior to screening
[19] Have a total daily insulin dose >100 units, as determined by the average total 
daily insulin dose over the 3 days prior to screening.  
[20] Have significant lipohypertrophy, lipoatrophy, or scars within the subcutaneous 
tissue in areas of infusion, in the opinion of the investigator
[21] Have a history of abscess at an infusion site within the last 90 days prior to 
screening
[22] Have vision loss or hearing loss that does not allow recognition of pump screens, 
alerts, and alarms
[23] 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

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LY900014
[24] 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
[25] Have cardiovascular disease, within the last 6 months prior to screening, defined 
as stroke, decompensated heart failure New York Heart Association Class III or 
IV, (CCNYHA 1994), myocardial infarction, unstable angina pectoris, 
percutaneous transluminal coronary angioplasty or coronary arterial bypass graft.  
[26] 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
[27] 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
[28] 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
[29] Have any hypersensitivity or allergy to any of the insulins or excipients used in 
this trial
[30] 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
Prior/Concomitant Therapy
[31] Have used insulin human inhalation powder (Afrezza®) within 2 weeks prior to 
screening
[32] Are receiving any oral or injectable medication intended for the treatment of 
diabetes other than rapid-acting analog insulin via CSII in the 30 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.

I8B-MC-ITSM (b) Clinical Protocol
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LY900014
[33] Glucocorticoid therapy: are receiving chronic (lasting longer than 7 consecutive 
days) systemic glucocorticoid therapy (including intravenous, IM, subcutaneous, 
and oral), but excluding topical, intraocular, intranasal, intra-articular, and 
inhaled preparations), or have received such therapy within 2 weeks immediately 
prior to screening with the exception of replacement therapy for adrenal 
insufficiency
Prior/Concurrent Clinical Trial Experience
[34] Are currently enrolled in any other clinical study involving an investigational 
product (IP) or any other type of medical research judged not to be scientifically 
or medically compatible with this study
[35] Have participated, within the last 30 days in a clinical study involving an IP.  If 
the previous IP has a long half-life, 3 months or 5 half-lives (whichever is longer) 
should have passed;
Other Exclusions
[36] 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
[37] Are Lilly employees or representatives (including employees, temporary contract 
workers, or designees responsible for the conduct of the study)
[38] Have an irregular sleep/wake cycle (for example, patients who sleep during the
day and work during the night)
[39] 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
Pilot Patients
[40] All patients participating in the pilot safety assessment must have an adult (≥18 years old) 
designated study companion that will reside at the same location overnight during the pilot 
and agree to sleep in the same room with the patient, sleep within hearing distance of the 
CGM and pump alarms, be willing to awaken at least once between 2:00 AM and 4:00 
AM to assist the patient in checking BG, and be willing to assist the patient in 
troubleshooting an alarm if one should occur during the night. The designated study 
companion must agree to these responsibilities for the 3-day duration of the pilot safety 
assessment.

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LY900014
6.3.
Lifestyle Restrictions
During the study, patients must avoid:

donating blood or blood products 

major changes in diet or exercise 

all medications that contain acetaminophen.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened, with the exception of individuals who screen fail due to; 

Inclusion
[11]
Must be using a Medtronic MiniMed 670G insulin pump 
b) In Auto Mode at least an average of 70% of the time per week 
during the last 4 weeks prior to screening 
c) With a Medtronic Guardian (3) sensor at least an average of 75% 
of the time per week during the last 4 weeks prior to screening

Exclusion
[19]
Have a total daily insulin dose >100 units, as determined by the average 
total daily insulin dose over the 3 days prior to screening.  

Or Combination of any above
If an individual screen fails due to one of the reasons listed, the individual may be rescreened 
once, no sooner than 2 weeks after the initial screening. Patients who rescreen are not eligible to 
participate in the pilot safety assessment.  
Retests, outside of rescreening, are not allowed, except for cases when results are not available 
from the original sample.  It is expected that any lab or procedure performed in the initial 
screening be repeated for rescreened patients.  

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LY900014
7. Treatments
7.1.
Treatments Administered
This study involves a comparison of LY900014 and Humalog delivered via CSII using the 
Medtronic MiniMed 670G insulin pump.  Throughout the study, patients will use their personal 
Medtronic MiniMed 670G pump and the study provided, Guardian Link (3) Transmitter, 
Guardian Sensor (3) glucose sensors, and Contour Next Link 2.4 Blood Glucose Meter.  Patients 
will be required to use the reservoirs and infusion sets provided by the investigative site.  
Table ITSM.3 shows the treatment regimens.
All patients not currently using insulin lispro in their pumps will begin using Humalog at the 
beginning of the 2-week lead-in period.  Following the lead-in period, 10 patients will be 
randomized in a double-blind manner to 1 of the 2 treatment sequences in a 1:1 ratio and enter a 
pilot safety assessment.  After completetion of the pilot safety assessment, the investigator along 
with Lilly will determine if randomization can continue.  
Table ITSM.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 meal;
correction bolus as needed;
and basal infusion; 
Humalog
100 U/mL
Individualized dosing
CSII
Mealtime bolus 0-2 min 
prior to start of meal; 
correction bolus as needed; 
and basal infusion 
Abbreviations:  CSII = continuous subcutaneous insulin infusion.
The investigator or his or her designee is responsible for the following:

Explaining the correct use of IP to the patient 

Explaining storage requirements for IP to the patient

Maintaining accurate records of IP dispensing and collection

At the end of the study, returning all used and unused IP to Lilly, or its designee, 
unless the sponsor and sites have agreed all unused medication is to be destroyed 
by the site, as allowed by local law
7.1.1. Packaging and Labeling
Clinical trial materials will be labeled as IP as appropriate, and according to regulatory 
requirements.  Study insulins (LY900014 and Humalog) will be supplied by Lilly or its 
representative, in accordance with current good manufacturing practices and will be supplied 
with lot numbers.
The blinded vials will contain a concentration of 100 U/mL in 10-mL vials of either LY900014 
or Humalog.  

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LY900014
During the lead-in period, Humalog 100 U/mL will be provided in open-label 10-mL vials.
7.1.2. Insulin Pumps
Patients will use their personal Medtronic MiniMed 670G pump, the study provided Contour 
Next Link 2.4 meter, and Medtronic Guardian Sensor (3) Transmitter and sensors throughout the 
study. All patients will be required to use MiniMed reservoirs and Mio infusion sets with 6-mm 
or 9-mm cannula and 32-inch tubing.  If the infusion set cannula length is changed during the 
study, it should be documented.  The Mio infusion set was chosen because of its all-in-one 
design that combines the infusion set with the inserter device.  
7.1.2.1.
Pump Bolus Delivery Speed
Patients will be allowed to use Standard (1.5 U/min) or Quick (15 U/min) pump bolus delivery 
speed.  Patients must maintain the same speed throughout the entire study.
7.1.2.2.
Pump Bolus Delivery Time
Patients will deliver bolus doses to cover carbohydrate intake at 0 to 2 minutes prior to 
consumption.
7.1.2.3.
Pump Alerts
Patients should use the Auto Mode feature of their MiniMed 670G pump as much as possible 
throughout the trial, including use of the Auto Mode Bolus feature to deliver boluses to cover 
meals, and whenever the pump recommends a bolus.  
Factory set Auto Mode Exit High and Low Sensor Glucose Alerts cannot be silenced and are 
always enabled when the pump is in Auto Mode.
The pump will exit Auto Mode based on a set SG threshold:

300 mg/dL or higher for 1 hour

250 mg/dL or higher for 3 hours

50 mg/dL or lower for any period of time.  
Factory set Low Alert cannot be silenced and is always enabled, whether the pump is in Auto 
Mode or Manual Mode.
In addition, study site programmed Sensor Glucose Alerts will be standardized for all patients 
throughout the study. High Alerts will be set to occur when SG reaches >180 mg/dL and Low 
Alerts will be set to occur when SG reaches <70 mg/dL.
7.2.
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 4.  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 Humalog
Sequence B: Humalog    LY900014

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Stratification will be by HbA1c stratum (≤7.0%, >7.0% at Visit 1) and percentage of time with 
SG values from 70 to 180 mg/dL over the 2 weeks prior to randomization (≤75%, >75%).  
Patients will begin using a new reservoir and infusion set prior to leaving the investigative site at 
Visits 2, 4, 7 and 10.  Patients will change the pump reservoir and infusion set every 3 days
unless a change is required due to a failure of the infusion set.
The IWRS will be used to assign all study treatment during the study, including Humalog during 
the lead-in period.  The IWRS will be used to assign vials containing double-blind IP to each 
patient randomized to the treatment sequences.  Site personnel will confirm that they have 
located the correct vials by entering a confirmation number found on the vials into the IWRS.
7.3.
Blinding
This is a double-blind study in which the treatments, LY900014 and Humalog, will have basal 
and bolus doses delivered via CSII.  Investigators, patients, and study site personnel will be 
blinded to assigned dosing regimens throughout the study.  
To preserve the blinding of the study, the Lilly study team will remain blinded throughout the 
study; only a minimum number of Lilly personnel will see the randomization table and treatment 
assignments before the study is complete.  
Emergency unblinding for AEs may be performed through the IWRS.  This option may be used 
ONLY if the patient’s well-being requires knowledge of the patient’s treatment assignment.  
Unblinding events are recorded and reported by the IWRS.  
If an investigator, site personnel performing assessments, or patient is unblinded, the patient 
must be discontinued from the study.  
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted.  Patient safety must always be the first 
consideration in making such a determination.  If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact the Lilly clinical research 
physician (CRP)/clinical research scientist (CRS) prior to unblinding a patient’s treatment 
assignment unless this could delay emergency treatment of the patient.  If a patient’s treatment 
assignment is unblinded, Lilly must be notified immediately.
7.4.
Dosage Modification
See Section 7.1.2
7.5.
Preparation/Handling/Storage/Accountability
The investigator or his or her designee is responsible for the following:

Confirming appropriate temperature conditions have been maintained during 
transit for all study treatment received and any discrepancies are reported and
resolved before use of the study treatment.

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
Ensuring that only participants enrolled in the study may receive IP and only 
authorized site staff may supply or administer study treatment. 

Ensuring all study treatments must be stored in a secure, 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.
o
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.
o
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, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (such as receipt, reconciliation and final disposition records).
7.6.
Treatment Compliance
The investigator or designee will assess compliance of the patient at each visit, based on a review 
of the patient’s CareLink reports, glycemic control, adherence to the visit and treatment schedule, 
and completion of the patient’s study diary.  Patients who are deemed noncompliant will receive 
additional diabetes education and training, as required, and the importance of compliance with 
the protocol will be reinforced.  Patients who, in the opinion of the investigator, are deemed 
consistently noncompliant may be discontinued from the study.  No specific study data will be 
collected to analyze treatment compliance.
7.7.
Concomitant Therapy
The following concomitant medications 

are NOT allowed at any time during the study; 
o
Afrezza® (inhaled insulin)
o
Any noninsulin diabetes treatment therapy
o
Acetaminophen
o
Systemic glucocorticosteroid 

IV, IM, SC, oral

except in the case of replacement therapy for adrenal 
insufficiency

ARE allowed for a maximum of 48 hours during each treatment period
o
Basal insulin

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o
Regular human insulin or a nonstudy rapid-acting analog insulin

ARE allowed at any time
o
Topical, inhaled, intraocular, intra-articular, or intranasal steroid 
preparations
7.8.
Treatment after the End of the Study
7.8.1. Treatment after Study Completion
LY900014 will not be made available to patients after conclusion of the study.  Rapid-acting 
insulin analogs are available in all countries for use as prandial/pump insulin.  
7.8.2. Special Treatment Considerations
After discontinuation of IP at the end of the treatment period or earlier, randomized patients 
should start a nonstudy 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.  If the investigator 
and the sponsor CRP/CRS agree that 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 other than the Medtronic MiniMed 670G.

The patient has not used IP for more than 3 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

A patient experiences any episode of clinically diagnosed Diabetic Ketoacidosis 
(DKA) during the study
o
DKA is defined as an acute metabolic complication of diabetes characterized 
by hyperglycemia, hyperketonemia, and metabolic acidosis. Hyperglycemia 
causes an osmotic diuresis with significant fluid and electrolyte loss. DKA 
causes nausea, vomiting, and abdominal pain and can progress to cerebral 

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edema, coma, and death. DKA is diagnosed by detection of hyperketonemia 
and anion gap metabolic acidosis in the presence of hyperglycemia. 
Treatment involves volume expansion, insulin replacement, and prevention of 
hypokalemia

A patient participating in the pilot experiences any episode of severe hypoglycemia 
during the first 3 days of the pilot safety assessment

A patient experiences >1 episode of severe hypoglycemia during the study

A pilot patient’s designated study companion does not comply with assigned 
responsibilities or is no longer available during pilot and transfer of study companion 
responsibilities is not possible for remainder of pilot safety assessment

Investigator decision
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%)

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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.
Efficacy Assessments
9.1.1. Primary Assessments
Percentage of time in range (%) of target SG values collected.
9.1.2. Secondary Assessments

Percentage of time in range (%) of hypoglycemic SG values collected 

Percentage of time (%) per week spent in Auto Mode

Mean SG value

Rate and incidence of hypoglycemia events

Mean total daily basal insulin dose

Mean total daily bolus insulin dose
9.1.3. Appropriateness of Assessments
All assessments included in this study are generally regarded as reliable and accurate with 
respect to diabetes.
9.1.4. Study Procedures
9.1.4.1.
Continuous Glucose Monitoring
The Medtronic MiniMed 670G System consists of the following devices: 

MiniMed 670G Insulin Pump, 

Guardian Link (3) Transmitter, 

Guardian Sensor (3),

CONTOUR NEXT Link 2.4 Glucose Meter.  
Patients will use all of the System components throughout the trial.  All therapy adjustments 
should be based on measurements obtained using the CONTOUR NEXT Link 2.4 Glucose Meter 
and not on values provided by the Guardian Sensor (3). The Guardian Sensor (3) is intended for 
use with the Medtronic MiniMed 670G system to continuously monitor glucose levels in patients
with diabetes. It is intended to provide an indication of when a finger stick may be required, for 
detecting trends and tracking patterns, and to be used by the Medtronic MiniMed 670G system to 

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automatically adjust basal insulin levels.  The Guardian Sensor (3) is indicated for 7 days of 
continuous use.The sensor must be calibratedat a minimum of every 12 hours, but it is
recommended that thesensor is calibrated 3or4times each day.
Patients must 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 while using the Medtronic MiniMed 670G system.  
Taking medications with acetaminophen, including, but not limited to Tylenol
®,fever reducers, 
or cold medicine, while wearing the sensor may falsely raise SGreadings.
9.1.4.3. Infusion Set Changes
Patients should change their infusion set and reservoir every 3 days.
The patient’s study diarywill be used to collect unplanned infusion set changes, including date 
and time of changeand theprimary reason for unplannedchange.
Pump occlusion alarm,
Unexplained high BG, 
Infusion site reaction (pain, redness or swelling at infusion site), or 

CCI
Infusion set problem (infusion set kinked, pulled out, leaking, reservoir empty, etc.).  
Unexplained hyperglycemia is defined as high BG>300mg/dL that cannot beexplained 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).
Investigators will review pump occlusion alarms,unexplained hyperglycemia, and unplanned
infusion set changeswithpatients at each visit.  

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Any interruption of CSII will need to be documented in the eCRF.  When patients resume use of 
pump following the interruption, the infusion set change should not be entered as an unplanned 
infusion set change in the study diary.
9.1.4.4.
Diabetes Training
Training will include the following:

Verify Contour Next LINK meter is paired and communicating with pump

Frequency of reservoir and infusion set changes

Frequency of sensor changes

Infusion site and sensor site rotation

Responding to pump and sensor alerts and alarms

Unexplained hyperglycemia management

Patient’s ability to carb count

Patient’s ability use the pump’s bolus calculator to determine bolus and correction doses

Patient’s ability to use bolus types appropriately

Patient’s ability to 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 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, the medical 
device or the study procedures 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 informed consent form (ICF) is signed, study site personnel will record via electronic 
data entry the occurrence and nature of each patient’s preexisting conditions, including clinically 
significant signs and symptoms of the disease under treatment in the study.  In addition, site 
personnel will record any change in the condition(s) and any new conditions as AEs. 

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Investigators should record their assessment of the potential relatedness of each AE to protocol 
procedure, IP, via electronic data entry. 
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account the 
disease, concomitant treatment, or pathologies.  
A “reasonable possibility” means that there is a cause and effect relationship between the IP, 
medical 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 department 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 according to SAE-reporting requirements and 
timelines (see Section 9.2) if it is considered reasonably possibly related to study procedure.

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Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms.  This 
24-hour notification requirement refers to the initial SAE information and all follow-up SAE 
information.  Patients with a serious hepatic AE should have additional data collected using the 
eCRF.
Pregnancy (during maternal 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 or she considers the event reasonably possibly related to 
the study treatment or study participation, the investigator must promptly notify Lilly.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to IP or procedure.  United States 21 CFR 
312.32 and European Union Clinical Trial Directive 2001/20/EC and the associated detailed 
guidance 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 guidance.
9.2.2. Complaint Handling
Lilly collects product complaints on IP, materials provided, 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.  

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
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 
instructions.
9.3.
Treatment of Overdose
Excess insulin administration may result in hypoglycemia.  Refer to the IB for LY900014 and 
product label for Humalog.
9.4.
Safety
9.4.1. Hypoglycemia
Patients are encouraged to perform SMBG whenever hypoglycemia may be suspected, either by 
symptoms experienced, CGM reading or perceived increased risk as related to dietary intake, 
physical activity, inadvertent or atypical insulin dosing or when prompted by pump alerts.  All 
patients will be instructed to consider a BG ≤70 mg/dL to be hypoglycemia and treat 
appropriately.
If a hypoglycemic event is suspected, the patient should record the BG value, any associated 
symptoms, and the treatment administered in the study diary.  The patient should contact the site 
as necessary.  All hypoglycemia events (severe and nonsevere) must be reported on the 
hypoglycemia eCRF.  All episodes of severe hypoglycemia must be reported as SAEs on the AE 
eCRF page and on the SAE eCRF page.  Episodes of hypoglycemia not meeting the criteria for 
severe hypoglycemia should not be reported as an AE.  
Hypoglycemia will be described using the following definitions:

Documented Glucose Alert (Level 1); BG ≤70 mg/dL:
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 (Level 2) with similar criterion as 
above except for threshold BG <54 mg/dL 
o
Documented symptomatic hypoglycemia 
o
Documented asymptomatic hypoglycemia
o
Documented unspecified hypoglycemia

Severe Hypoglycemia (Level 3):  during these episodes, patients have an altered mental 
status and cannot assist in their own care, may be semiconscious or unconscious, or 
experience coma with or without seizures, and the event requiring assistance of another 
person to actively administer carbohydrate, glucagon, or other resuscitative actions.  
Blood glucose measurements may not be available during such an event, but neurological 

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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
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).  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.
Additional analysis of hypoglycemia events will be conducted using CGM data alone for 
threshold BG <50 mg/dL and <70 mg/dL.
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 on review of the diary and in discussion with the patient, 
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).
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
patient is still present, to determine whether the patient meets entry criteria and for immediate 
patient management, should any clinically relevant findings be identified.
Electrocardiograms may be obtained at additional times, when deemed clinically necessary.
9.4.4. Vital Signs
For each patient, vital sign measurements should be conducted according to the Schedule of 
Activities (Section 2) including the study-specific requirements.  
9.4.5. Laboratory Tests
For each patient, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2). 

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With the exception of laboratory test results that may unblind the study, Lilly or its designee will 
provide the investigator with the results of laboratory tests analyzed by a central vendor, if a 
central vendor is used for the clinical trial.  
Any clinically significant findings from laboratory tests that result in a diagnosis and that occur 
after the patient receives the first dose of IP should be reported to Lilly or its designee as an AE
via electronic data entry.
9.4.6. Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.
9.4.6.1.
Pilot Safety Assessment
The pilot safety assessment will take place over 3 days following randomization of the first 10 
patients at a single site.  During this time, pilot patients must have a designated study companion 
who is familiar with managing T1D, agree to stay with the patient overnight to assist with 
checking night-time BG and troubleshooting pump alarms.  The designated study companion is 
not required to accompany the patient during day-time hours.  
The investigative site will check in with the patient at Day 1 via a telephone call.  During the 
Visit 5 telephone call, the investigator will review patient data and determine if the patient can 
continue study treatment.  
For 3 nights following the randomization visit (Visit 4), the designated companion must;

agree to sleep in the same room with the patient, 

sleep within hearing distance of the CGM and pump alarms, 

be willing to awaken at least once between 2:00 AM and 4:00 AM to assist the patient in 
checking BG ,  

be willing to assist the patient in troubleshooting an alarm if one should occur during the 
night. 
During the Pilot Safety Assessment the Investigative Site will; 

call each pilot patient to check-in within 1 day post randomization visit 

add diary data to eCRF and run a CareLink report for each patient 3 days post 
randomization visit (Visit 5) enabling the site to; 
o
review hypoglycemia, hyperglycemia, occlusion alarm data, and unplanned 
infusion set changes and reasons  
o
discuss other safety issues found in review of SAEs, AEs, Carelink reports, etc.

decide and document if patient is to continue in the study. 
Safety Criteria
The following prespecified criteria will be reviewed by the investigator, along with medical 
judgment to determine if it is safe to proceed with randomization of additional patients..  

One episode of severe hypoglycemia 

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
More than 1 case of hyperglycemia (BG >300 mg/dL) sustained for more than 2 hours 
and unresponsive to treatment measures

One episode of DKA

Moderate or large urine ketones and BG >300 mg/dL
Expanding the Pilot Safety Assessment
The pilot safety assessment may be terminated or may be expanded to further understand how 
LY900014 interacts with the control algorithm in the Medtronic 670G system if any of the above 
criteria are met or if review of the data collected from SAEs, AEs, Carelink reports, etc. and 
discussions with patients reveals other safety issues in the judgment of the investigator.
Transition from Pilot Safety Assessment to Rest of the Study
Within 1-week of all 10 pilot patients completing the 3-day pilot safety assessment, the 
investigators will review the collected data in consultation with the Sponsor and determine if 
randomization can be opened up for the rest of the study.  The 10 pilot patients will continue 
progressing through the study after completion of the pilot safety assessment so long as they are 
deemed fit to continue by the site, have had no safety issues that would warrant discontinuation 
from the study, and no decision has been made to halt the study.  No additional patients will be 
randomized until after a review of pilot safety data occurs and it is decided if continuing the 
study is warranted.  Following the pilot safety assessment, all sites will receive communication 
from the sponsor to begin randomization of patients not participating in the pilot safety 
assessment.
9.4.6.2.
Hepatic Safety Monitoring
If a study patient experiences elevated ALT ≥3X ULN, ALP ≥2X ULN, or elevated TBL ≥2X 
ULN, liver testing (Appendix 4) should be repeated within 3 to 5 days including ALT, AST, 
ALP, TBL, direct bilirubin, gamma-glutamyl transferase, and creatine kinase to confirm the 
abnormality and to determine if it is increasing or decreasing.  If the abnormality persists or 
worsens, clinical and laboratory monitoring should be initiated by the investigator and in 
consultation with the study medical monitor.  Monitoring of ALT, AST, TBL, and ALP should 
continue until levels normalize or return to approximate baseline levels. 
Hepatic Safety Data Collection
Additional safety data should be collected via the eCRF if 1 or more of the following conditions 
occur: 

Elevation of serum ALT to ≥5X ULN on 2 or more consecutive blood tests

Elevation of serum TBL to ≥2X ULN (except for cases of known Gilbert’s 
syndrome)

Elevation of serum ALP to ≥2X ULN on 2 or more consecutive blood tests

Patient discontinued from treatment due to a hepatic event or abnormality of 
liver tests

Hepatic event considered to be a SAE

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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 42 patients will be randomized in order that approximately 36 patients complete 
the study.
Assuming that a standard deviation (SD) of between-period differences of 10% and a 2-sided 
alpha level of 0.10, 36 completers will provide approximately 90% power to detect a 5% 
difference between LY900014 and Humalog, in the percentage of time with SG values from 70
to 180 mg/dL (inclusive), during the last 2 weeks of each 4-week treatment period.  
Assuming a 12% dropout rate after randomization, approximately 42 patients (21 patients in each 
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 Humalog in the 2-week lead-in 
period.
Randomized
All patients who are randomly assigned to study treatment at Visit 4 and receive at least 
1 dose of the randomly assigned IP.  Treatment will be defined on the basis of the 
treatment the patients are assigned to.
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.  
Unless otherwise specified, all efficacy and safety analyses will be conducted on the
Randomized Population. Analyses of AEs will include all data collected during the course of the 
entire 4-week treatment period for each treatment regardless of IP use.  Analyses of 
hypoglycemia will be conducted from first dose to last dose of IP in each 4-week treatment 
period.  Data collected during the safety follow-up period will only be summarized for overall 
and will not be used for comparisons between treatments.  
Unless otherwise noted, all tests of treatment effects will be conducted at a 2-sided alpha level of 
0.10, and confidence intervals (CIs) will be calculated at 90%, 2-sided.  

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Treatment comparisons will be performed for the primary objective (Section 10.3.3.1) at the full 
significance level of 0.10. 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 4), unless otherwise specified and described in the SAP.
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 4-week treatment period 
for each treatment will be included in the analysis.  The model will include the fixed class effects 
of treatment, period, sequence, strata (HbA1c [≤7.0%, >7.0%] and percentage of time with SG
values from 70 to 180 mg/dL over the 2 weeks prior to randomization [≤75%, >75%]), and the 
continuous, fixed covariate of baseline value.  The Kenward-Roger approximation will be used 
to estimate denominator degrees of freedom.  An unstructured covariance structure will be used 
to model the within-patient errors.  If this analysis fails to converge, a covariance structure of 
compound symmetry without heterogeneous variances will be used. If the model still does not 
converge, strata may be deleted from the model.  Significance tests will be based on least squares
means and Type III tests.  SAS PROC MIXED will be used to perform the analysis.
For categorical measures (such as incidence of AEs), summary statistics will include sample 
size, frequency, and percentages.  Prescott’s exact test will be used for treatment comparisons, 
unless otherwise specified.
10.3.2. Treatment 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 the Randomized Population 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).  

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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 treatments 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 7.6).  No analyses are planned to assess treatment compliance.
10.3.3. Efficacy Analyses
10.3.3.1. Primary Analyses
The primary objective of this study is to compare LY900014 and Humalog with respect to the 
percentage of time with SG values within range (70 to 180 mg/dL, both inclusive), during the 
last 2 weeks of each 4-week treatment period. The analysis model (MMRM) and selection of 
covariance structure are described in Section 10.3.1.
The primary analyses will be conducted on data collected from the Randomized Population, 
while patients are on IP and on pump.  
10.3.3.2. Secondary Analyses
Additional continuous secondary efficacy variables, as well as the change during each 4-week 
treatment period for these variables, will be analyzed by the MMRM model described in 
Section 10.3.1.
10.3.3.3. Exploratory Analyses
Additional continuous exploratory efficacy variables, as well as the change from baseline for 
these variables, will be analyzed by the MMRM model described in Section 10.3.1, unless 
otherwise specified.
10.3.4. Safety Analyses
Safety measures will include AEs, hypoglycemia, vital signs, treatment exposure, and laboratory 
measures.
Events that are newly reported after the first dose of rapid-acting insulin provided as study drug 
(i.e., open-label Humalog used during the lead-in period or IP used during each of the two 
4-week randomized treatment periods) or reported to worsen in severity from baseline (details 
will be described in SAP) will be considered -TEAEs.  Events that continue during more than 1 
study period (lead-in, Period I, and Period II) with the same severity will only be counted once 
for the first study period.
Serious AEs, AEs reported as reason for discontinuation from the IP or study, and TEAEs will be 
summarized in tables using the Medical Dictionary for Regulatory Activities (MedDRA) PT, 
sorted by decreasing frequency within the LY900014 treated-patients . Treatment-emergent AEs 

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will also be summarized by PT sorted by decreasing frequency within SOC for all TEAEs and by 
maximum severity. 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.
The number and proportion of patients with at least 1 event for each type of event will be 
summarized and compared between treatments using Prescott’s exact test.
Hypoglycemia rates will be summarized for periods of 1 year, and 100 years (severe 
hypoglycemia only) for both treatment periods. Wilcoxon Signed-Rank test and Prescott’s exact 
test will be used instead to analyze the rate and incidence of hypoglycemia events, respectively.
10.3.5. Subgroup Analyses
The following subgroup will be explored to evaluate consistency of treatment effects on the
primary endpoint:

Pump bolus delivery speed at screening (Standard [1.5 U/min], Quick [15 U/min])

HbA1c stratum (≤7.0%, >7.0%) 

Percentage of time with SG values from 70 to 180 over the 2 weeks prior to 
randomization (≤75%, >75%)
Additional exploratory subgroup analyses may be performed.
10.3.6. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the appropriate Lilly medical director, or designee, will be consulted to determine 
whether it is necessary to amend the protocol.

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11.
References
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.
Battelino T, Conget I, Olsen B, Schütz-Fuhrmann I, Hommel E, Hoogma R, Schierloh U, Sulli 
N, Bolinder J. The use and efficacy of continuous glucose monitoring in type 1 diabetes 
treated with insulin pump therapy [SWITCH study]. Diabetologia. 2012;55(12):3155-3162.
Bennett P. Classification and diagnosis of diabetes mellitus and impaired glucose tolerance. In: 
Pickup JC, William G, editors. Textbook of diabetes. Vol. 1. 1st ed. Oxford: Blackwell 
Scientific Publications; 1991:p 37-44.
Bergenstal RM, Tamborlane WV, Ahmann A, Buse JB, Dailey G, Davis SN, Joyce C, Peoples T, 
Perkins BA, Welsh JB, Willi SM, Wood MA. Effectiveness of sensor-augmented 
insulin-pump therapy in type 1 diabetes [STAR3 Study]. N Engl J Med. 2010;363:311-320.
Bergenstal RM, Klonoff DC, Garg SK, Bode BW, Meredith M, Slover RH, Ahmann AJ, Welsh 
JB, Lee SW, Kaufman FR. Threshold-based insulin-pump interruption for reduction of
hypoglycemia [ASPIRE in-home study]. N Engl J Med. 2013;369(3):224-232.
[CCNYHA] The Criteria Committee of the New York Heart Association. Nomenclature and 
criteria for diagnosis of diseases of the heart and great vessels. 9th ed. Boston (MA): Little, 
Brown & Company; 1994:253-256.
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.

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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.
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
ECG
electrocardiogram

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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
GCP
good clinical practice
HbA1c
hemoglobin A1c
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for 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
LS
least squares
MDI
multiple daily injections
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed-effect model repeated measure
product complaint
Product complaints are a customer’s written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a Lilly product after it is released for distribution.
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

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SG
sensor glucose
SMBG
self-monitored blood glucose
SOC
system organ class
SUSARs
suspected unexpected serious adverse reactions
T1D
type 1 diabetes mellitus
T2D
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
Serology
Pregnancy test (females only)b
Follicle-stimulating hormonec
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 informed 
consent form (ICF) prior to the performance of any protocol procedures and prior 
to the administration of investigational product.

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 must give assurance that the ethical review board (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 Good Clinical Practice (GCP).
The study site’s ERB(s) should be provided with the following:

the protocol and related amendments and addenda, current IB or Patient 
Information Leaflet, Package Insert, or Summary of Product Characteristics 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 withthe protocol and with the:
consensus ethics principles derived from international ethics guidelines, including 
the Declaration of Helsinki and CouncilforInternationalOrganizationsof
MedicalSciences(CIOMS) International Ethical Guidelines
applicable ICH GCP Guidelines
applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a thirdparty.
Appendix 3.1.5.
Investigator Information
Investigator(s) participating in this study will: 
be a physician with specialty in Endocrinology or Diabetology 
haveexperience with Continuous Subcutaneous Insulin Infusion (CSII) and 
Continuous Glucose Monitoring (CGM)
have clinical trial experience
 
Atlanta Diabetes Associates
1800 Howell Mill Rd; Suite #450 
Atlanta, GA 30318
International Diabetes Center
3800 Park Nicollet Blvd.
Minneapolis, MN 55416
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
PPD
The investigator will sign the final clinical study report (CSR) for this study, indicating 
agreement with the analyses, results, and conclusions of the report.
PPD
PPD
PPD

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The sponsor’s responsible medical officer and statistician will approve the final CSR for this 
study, confirming that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.
Appendix 3.2.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

sponsor start-up training to instruct the investigators and study coordinators.  This 
training will give instruction on the protocol, the completion of the case report 
forms (CRFs), and study procedures.

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax

review and evaluate CRF data and use standard computer edits to detect errors in 
data collection

conduct a quality review of the database
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
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.
An electronic data-capture (EDC) system will be used in this study for the collection of CRF 
data.  The investigator maintains a separate source for the data entered by the investigator or 
designee into the sponsor-provided EDC system.  The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF.
Additionally, clinical outcome assessment data (questionnaires and self-reported diary data) will 
be collected by the subject, via a paper source document and will be transcribed by the 
investigator-site personnel into the EDC system.
Data collected via the sponsor-provided data capture system will be stored with a third party.  
The investigator will have continuous access to the data during the study and until 

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decommissioning of the data-capture system.  Prior to decommissioning, the investigator will 
receive an archival copy of pertinent data for retention.
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and reports will be provided to the investigator for review 
and retention.  Data will subsequently be transferred from the central vendor to the Lilly data 
warehouse.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
Appendix 3.3.
Study and Site Closure
Appendix 3.3.1.
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.
Appendix 3.3.2.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.
Appendix 3.4.
Publication Policy
The publication policy for Study I8B-MC-ITSM is described in the Clinical Trial Agreement.

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Appendix 4.
Hepatic Monitoring Tests for 
Treatment-Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with the Lilly, or its designee, clinical 
research physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils, segmented
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
GGT
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.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.

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Appendix 5.
Classification of Contraceptive Methods
Women of childbearing potential must use either 1 highly effective method of contraception or a 
combination of 2 effective methods of contraception.  The patient may choose to use a 
double-barrier method of contraception (see chart below).

Barrier protection methods without concomitant use of a spermicide are not an effective 
or acceptable method of contraception.  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 6.
Protocol Ammendment I8B-MC-ITSM (b)
Evaluation of LY900014 in a Medtronic Pump
Overview
Protocol I8B-MC-ITSM (b) Evaluation of LY900014 in a Medtronic Pump has been amended.  
The new protocol is indicated by amendment (b) and will be used to conduct the study in place 
of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are described in the 
following table:
Amendment Summary for Protocol I8B-MC-ITSM Amendment (b)
Section # and Name
Section 6.4 Screen Failures
Section 3.3 Benefit/Risk Assessment
Section 5.1 Overall Design
Section 9.4.6.1. Pilot Safety Assessment
Appendix 3.1.5 Investigator Information
Description of Change
Added exception for criteria 11b, 11c and 19.
1.
changing “single-center” to “multi-center” 
2.
adding single site to all references to the pilot safety 
assessment
3.
Deleted Investigator address
Brief Rationale
[11b] and [11c]:  Following a 670G system interruption or 
malfunction, Auto Mode will not activate until the system has 
completed a warm-up period that lasts between 5 and 48 hours 
beginning at midnight after the system is restarted.  If this 
occurs during the 4 weeks prior to screening, the percentage of 
time in Auto Mode and percentage of sensor wear time may be 
negatively impacted.
[19]:  The total daily average dose may exceed 100 units/day 
when carbohydrate consumption is unusually high during the 3 
days prior to screening.Allowing for rescreening of patients for 
whom these criteria apply will potentially increase enrollment 
of qualified study patients.  Lilly believes that allowing these 
patients to rescreen and subsequently be enrolled will not 
negatively impact the study because the initial failure was due 
to a technical or atypical anomaly that has now been corrected.
Due to several factors, including enrollment considerations, the 
protocol is being amended to change from a single-center to a 
multi-center study. Several changes in the text capture this 
transition and also clarify that the pilot safety assessment will 
be performed at only one site.
The implications of the pilot safety assessment apply to all 
sites. No additional patients will be randomized at any site 
until the decision of whether to continue the study is made and 
communicated across sites.  
Lilly believes that including additional investigative sites in 
Study ITRO with expertise in the 670G hybrid closed loop 
system following completion of the pilot safety assessment, 
will expedite enrollment and as well as leverage the experience 
and expertise of multiple investigators. Lilly believes adding 
more sites will not negatively impact the study as the pilot 
safety assessment will have already been completed at a single 
site, however, the results will apply to all sites involved in the 
study.

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LY900014
Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
Section 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. with the exception of individuals who screen fail due to; 

Inclusion
[11]
Must be using a Medtronic MiniMed 670G insulin pump 
b) In Auto Mode at least an average of 70% of the time per week 
during the last 4 weeks prior to screening 
c) With a Medtronic Guardian (3) sensor at least an average of 75% 
of the time per week during the last 4 weeks prior to screening

Exclusion
[19]
Have a total daily insulin dose >100 units, as determined by the average 
total daily insulin dose over the 3 days prior to screening.  

Or Combination of any above
If an individual screen fails due to one of the reasons listed, the individual may be rescreened 
once, no sooner than 2 weeks after the initial screening.  Patients who rescreen are not eligible to 
participate in the pilot safety assessment. 
Retests, outside of rescreening, are not allowed, except for cases when results are not available 
from the original sample. It is expected that any lab or procedure performed in the initial 
screening be repeated for rescreened patients. 
Synopsis Summary of Study Design
This study is a prospective, randomized, double-blind, outpatient, single center, 2-treatment 
crossover, active-controlled study conducted in patients with type 1 diabetes mellitus (T1D) 
currently using an external CSII.  In the 2 treatment periods, LY900014 and Humalog will be 
delivered via the Medtronic MiniMed 670G system while in Auto Mode as much as possible.  
Synopsis Treatment Arms and Duration
Following the lead-in period, a 3-day pilot safety assessment will be conducted at a single site
for the first 10 patients randomized.  This pilot safety assessment will determine if the control 
algorithm in the Medtronic 670G pump can be used safely in patients receiving LY900014.  

I8B-MC-ITSM (b)Clinical Protocol
Page 66
LY900014
Section 3.3 Benefit/Risk Assessment
Following the lead-in period, a 3-day pilot safety assessment will be conducted at a single site
forthe first 10 patients randomized.  This pilot safety assessment will determine if the control 
algorithm in the Medtronic 670G pump can be used safely in patients receiving LY900014.  
Section 5.1 Overall Design
This study is aprospective, randomized, double-blind, outpatient, single-center,2-treatment , 
crossover, active-controlled study conducted in patients with T1D currently
 using an external 
CSIIpump.  In the 2treatment periods, LY900014 and Humalogwill be delivered via the 
Medtronic MiniMed 670G system with SmartGuard™ technologyusing AutoMode.  In this 
study, patients will be required to use the Auto Mode insulin delivery functionas much as 
possible.  
Following the lead-in period, a 3-day pilot safety assessment will be conducted at a single sitein 
the first 10 patients randomized.  This pilot safety assessment will determine if the control 
algorithm in the Medtronic 670G pump can be used safely in patients receiving LY900014.  
Section 9.4.6.1 Pilot Safety Assessment
The pilot safety assessment will take place over 3 days following randomization of the first 10 
patientsat a single site.  
No additional patients will be randomized until after a review of pilot safety data occurs and it is 
decided if continuing the study is warranted.  Following the pilot safety assessment, all sites will 
receive communication from the sponsor to begin randomization of patients not participating in 
the pilot safety assessment.
Appendix 3.1.5. Investigator Information
International DiabetesCenter
3800 Park Nicollet Blvd.
Minneapolis, MN 55416
PPD
PPD

PPD
Leo Document ID = bbac6bf0-e0e0-4d17-b834-02fef40fa4dc
Approver: 
Approval Date & Time: 12-Apr-2019 20:04:25 GMT
Signature meaning: Approved
Approver:
Approval Date & Time: 13-Apr-2019 23:21:49 GMT
Signature meaning: Approved
PPD