Clinical trial NCT03760640
Conditions: Type1 Diabetes Mellitus
Sponsor: Eli Lilly and Company
Start date: 2019-02-18; Completion date: 2019-10-07
Enrollment: 42 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to compare the study drug LY900014 to insulin lispro (Humalog) when both are delivered by the Medtronic MiniMed 670G System in adults with type 1 diabetes (T1D). The study will consist of two treatment periods of 4 weeks.

Detailed description:

Arms: arm 1: Participants received 100 units per milliliter (U/mL) of LY900014 administered via continuous subcutaneous insulin infusion (CSII) by the Medtronic MiniMed 670G insulin pump. arm 2: Participants received 100 U/mL of Insulin lispro (Humalog) administered via CSII by the Medtronic MiniMed 670G insulin pump.
Interventions: intervention 1: LY900014 intervention 2: Insulin Lispro
Intervention descriptions: intervention 1: Administered SC intervention 2: Administered SC

Protocol documents:
Prot_000.pdf: 
Protocol I8B-MC-ITSM (b)
Evaluation of LY900014 in a Medtronic Pump  
NCT03760640
Approval Date: 13-Apr-2019


I8B-MC-ITSM (b)Clinical Protocol
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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 


I8B-MC-ITSM (b) Clinical Protocol
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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


I8B-MC-ITSM (b) Clinical Protocol
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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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LY900014
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 


I8B-MC-ITSM (b) Clinical Protocol
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LY900014
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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LY900014
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


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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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LY900014
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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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.  


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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

SAP_001.pdf: 
Statistical Analysis Plan: I8B-MC-ITSM (V3)
Evaluation of LY900014 in a Medtronic Pump 
NCT03760640
Approval Date: 29-Oct-2019


I8B-MC-ITSM Statistical Analysis Plan Version 3
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1.
Statistical Analysis Plan: 
I8B-MC-ITSM:  Evaluation of LY900014 in a Medtronic 
Pump
Confidential Information
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of Eli Lilly 
and Company or its subsidiaries.  
Note to Regulatory Authorities:  This document may contain protected personal data
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
LY900014
Study I8B-MC-ITSM is a prospective, randomized, double-blind, outpatient, single-center, 
2-treatment, crossover, active-controlled study conducted in patients with type 1 diabetes 
currently using an external CSII pump.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol I8B-MC-ITSM
Phase II
Statistical Analysis Plan version 1 electronically signed and approved by Lilly on 19-
Dec-2018
Statistical Analysis Plan version 2 electronically signed and approved by Lilly on 24-Jan-
2019
Statistical Analysis Plan version 3 electronically signed and approved by Lilly on date 
below
Approval Date: 29-Oct-2019 GMT


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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan:  I8B-MC-ITSM:  Evaluation of LY900014 
in a Medtronic Pump...........................................................................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................7
4.
Study Objectives.................................................................................................................9
5.
Study Design.....................................................................................................................11
5.1.
Summary of Study Design............................................................................................11
5.2.
Determination of Sample Size ......................................................................................13
5.3.
Method of Assignment to Treatment ............................................................................13
6.
A Priori Statistical Methods ..............................................................................................15
6.1.
General Considerations ................................................................................................15
6.2.
Adjustments for Covariates ..........................................................................................20
6.3.
Handling of Dropouts or Missing Data.........................................................................20
6.4.
Multiple Comparisons/Multiplicity...............................................................................20
6.5.
Patient Disposition .......................................................................................................20
6.6.
Patient Characteristics ..................................................................................................21
6.7.
Treatment Compliance .................................................................................................22
6.8.
Concomitant Therapy...................................................................................................22
6.9.
Efficacy Analyses ........................................................................................................22
6.9.1.
Primary Outcome and Methodology.....................................................................22
6.9.2.
Other Secondary Efficacy Analyses .....................................................................22
6.9.3.
Exploratory Efficacy Analyses .............................................................................23
6.10. Safety Analyses............................................................................................................24
6.10.1.
Extent of Exposure...............................................................................................24
6.10.2.
Adverse Events ....................................................................................................24
6.10.3.
Deaths and Other Serious Adverse Events............................................................25
6.10.4.
Hypoglycemic Events and Other Adverse Events.................................................26
6.10.4.1.
Hypoglycemic Events.....................................................................................26
6.10.4.2.
Systemic Hypersensitivity Reaction................................................................28
6.10.4.3.
Infusion Site Reaction.....................................................................................28
6.10.4.4.
Hepatobiliary Events ......................................................................................28
6.10.4.4.1.
Treatment-Emergent Potential Hepatic Disorder.......................................28
6.10.4.5.
Malignant Neoplasm Events...........................................................................29
6.10.5.
Clinical Laboratory Evaluation.............................................................................29


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6.10.6.
Vital Signs and Other Physical Findings...............................................................29
6.10.7.
Pump-related Safety Analyses..............................................................................30
6.10.7.1.
Time until Infusion Set Changes.....................................................................31
6.10.7.2.
Unplanned Infusion Set Changes ....................................................................31
6.10.7.3.
Infusion Set Cannula Length...........................................................................32
6.10.7.4.
Significant Events during Pilot Safety Assessment .........................................32
6.10.8.
Patient Narratives.................................................................................................32
6.11. Important Protocol Deviations......................................................................................33
6.12. Interim Analyses and Data Monitoring.........................................................................33
6.13. CGM Analyses.............................................................................................................33
6.14. Subgroup Analyses.......................................................................................................38
6.15. Clinical Trial Registry Analyses...................................................................................39
7.
Unblinding Plan................................................................................................................40
8.
References ........................................................................................................................41
9.
Appendices .......................................................................................................................42
9.1.
General Derivation Specifications ................................................................................43
9.2.
Glucose in Target Ranges, Hypoglycemia- or Hyperglycemia......................................43
9.3.
Incremental Area under the Glucose Curve (iAUC)......................................................43
9.4.
Mean Sensor Glucose Excursions.................................................................................44
9.5.
Hypoglycemic/Hyperglycemic Episodes ......................................................................44
9.6.
Glucose Variability ......................................................................................................45
9.6.1.
Within-Day Variability ........................................................................................45
9.6.2.
Between-Day Variability......................................................................................46
9.6.3.
Overall Variability ...............................................................................................47
9.6.4.
Risk for Hypo/Hyperglycemia..............................................................................47
9.7.
Daily CGM Data Summary..........................................................................................48
9.8.
AUC ............................................................................................................................48
9.9.
Highest Postprandial Glucose.......................................................................................48
9.9.1.
Time to the highest postprandial glucose within 4 hours after 
Meals ...................................................................................................................48
9.9.2.
Highest Postprandial Glucose Level within 4 hours after 
Meals ...................................................................................................................48
9.10. Other............................................................................................................................48


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Table of Contents
Table
Page
Table ITSM.4.1. Objectives and Endpoints ................................................................................9
Table ITSM.6.1. Patient Populations ........................................................................................15
Table ITSM.6.2. Baseline and Post-Baseline Definitions and Patient Population by Study 
Period and Type of Analysis..........................................................................17
Table ITSM.6.3. Adverse Event Analysis Periods ....................................................................25
Table ITSM.6.4. Summary of Analyses for Endpoints Related to Hypoglycemia......................27
Table ITSM.6.5. Categorical Criteria for Abnormal Treatment-Emergent Blood Pressure 
and Pulse Measurement, and Categorical Criteria for Weight Changes 
for Adults ......................................................................................................30
Table ITSM.6.6. Outcome Measures of CGM Data..................................................................34
Table ITSM 6.7. Guidance Recommended CGM Targets of Glycemic Control ........................37


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Table of Contents
Figure
Page
Figure ITSM.5.1.Illustration of study design for Clinical Protocol I8B-MC-ITSM....................12


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Table of Contents
Appendix
Page
Appendix 1.
Derivation of CGM Variables........................................................................43


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3.
Revision History
Statistical Analysis Plan (SAP) Version 1 was approved prior to the first patient visit.  Version 1 
is based on the Protocol I8B-MC-ITSM (ITSM) approved on 24 October 2018.
Statistical Analysis Plan (SAP) Version 2 was approved prior to the first patient visit.  Version 2 
is based on the Protocol I8B-MC-ITSM (ITSM) (a) amended on 24 January 2019. The main
changes are listed below:

Updated the study design plot according to the amended study design;

Added a listing to describe any significant safety event that occurs during the pilot safety 
assessment;

Changed “treatment group” to “treatment” according to the amended protocol;

Changed the baseline observations for HbA1c and 1,5 AG from “Visit 4 prior to the first 
dose of IP” to “Visit 4 prior to or on the date of the first dose of IP”;

Changed the baseline observations for insulin doses and percentage of time (per week) 
spent in Auto Mode from “Visit 4” to “Last of Visits 2-4”; 

Changed the baseline observations for treatment-emergent adversent events during the 
safety follow-up from “After first dose of IP and Prior to last dose of IP in the 8-Week 
Treatment Period” to “Prior to last dose of IP in the 8-Week Treatment Period”;

Added some clarification language for treatment comparisons in hypoglycemia analyses. 
“Treatment comparisons for severe hypoglycemia will be based upon the data collected 
for 0-4 weeks of each treatment period. Treatment comparisons for other categories of 
hypoglycemia will be only based upon the data collected for 2 to 4 weeks.”;

Changed “average glucose excursion” to “mean sensor glucose excursion” to be 
consistent with the protocol exploratory objective. Similarly, changed “average glucose 
level” and “hourly average glucose level” to “mean sensor glucose level” and “hourly 
mean sensor glucose level”;

Added “iAUC0-3hr” and “iAUC0-4hr” in the CGM outcome measures.
Statistical Analysis Plan (SAP) Version 3 was approved prior to the database lock.  The main
changes are listed below:

Removed the analyses of insulin doses, pump factors, weight, and vital signs for the lead-
in period given the short duration and the fact that there was no titration done

Added the definition of baseline and post-baseline observations for the analysis of insulin 
doses by infusion set wear day 

Added the 7information of SMBG/CGM before the correction bolus in the listing of 
infusion set changes

Added patient narrative


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
Added more derivation details for CGM outcome variables

Removed the analyses of hyperglycemia as measured by CGM>300 mg/dL and added the 
analyses of CGM (181to 250 mg/dL and 54 to 69 mg/dL) to align with categories of 
hyperglycemia recommended in recent international consensus guidance (Battelino 2019)

Added R Shiny plots as part of CGM data presentation

Added details on analyses of unplanned infusion set changes


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4.
Study Objectives
Table ITSM.4.1 shows the objectives and endpoints of the study.
Table ITSM.4.1.
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 (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, Suspected infusion set occlusion 
(unexplained high BG), Infusion site reaction 
(pain, redness or swelling at infusion site), 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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Objectives and Endpoints
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 Humalog 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; 
HbA1c = hemoglobin A1c; ISF = insulin sensitivity factor.


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5.
Study Design
5.1.
Summary of Study Design
Study ITSM is a prospective, randomized, double-blind, outpatient, two-center, 2-treatment, 
crossover, active-controlled study conducted in patients with type 1 diabetes (T1D) currently 
using an external continuous subcutaneous insulin infusion (CSII) pump.  In the 2 treatments, 
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, both inclusive).  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 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.  
Figure ITSM.5.1 illustrates the study design.  


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Figure ITSM.5.1.
Illustration of study design for Clinical Protocol I8B-MC-ITSM.


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Patients who need to discontinue from study treatment will also be discontinued from the study.  
Please refer to Protocol Sections 8.1 and 8.2.  
CareLink Personal Software allows patients to upload data from their insulin pump, continuous 
glucose monitoring (CGM) device, and blood glucose (BG) meter into a web-based program. 
Patients can see detailed reports that help them better understand their BG control and uncover 
patterns missed by meters and logbooks. Patient information is stored and will allow the 
investigator or designee to access to it via CareLink Pro Software. 
In this study, patients will upload data to CareLink Personal remotely on a weekly basis. The
investigator or designee will review patient uploaded CareLink reports weekly for use in clinical
management of the patient. Specified data from CareLink reports will be entered into electronic 
case report forms (eCRFs) per the Schedule of Activities.  In this document, these data are 
referred to as the CareLink report data.
In addition, raw data from CareLink Personal will be downloaded by the site as .csv files. The
data in these files will be used for the analyses of interstitial glucose (including the primary 
objective) and pump-related safety outcomes.  In this document, these files are referred to as the 
CareLink raw data.
5.2.
Determination of Sample Size
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 (Sensor 
Glucose) 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.  
5.3.
Method of Assignment to Treatment
Patients who meet all criteria for enrollment and complete the lead-in period will be randomized 
to double-blind treatment at Visit 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
Stratification will be by hemoglobin A1c (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%).  


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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 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 
investigational product (IP) to each patient randomized to the sequence of treatments.  Site 
personnel will confirm that they have located the correct vials by entering a confirmation number 
found on the vials into the IWRS.


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6.
A Priori Statistical Methods
6.1.
General Considerations
Statistical analysis of this study will be the responsibility of Lilly or its designee.  Any change to 
the data analysis methods described in the protocol will require an amendment ONLY if it 
changes a principal feature of the protocol.  Any other change to the data analysis methods 
described in the protocol, and the justification for making the change, will be described in the 
SAP or the clinical study report (CSR).  Additional exploratory analyses of data will be 
conducted, as deemed appropriate.  
For purposes of analysis, the following populations are defined in Table ITSM.6.1: 
Table ITSM.6.1.
Patient Populations
Population
Description
Entered
All patients who give informed consent.
Enrolled
All patients who receive at least 1 dose of open-label 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.
Pilot  
All patients in the pilot safety assessment.
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 IP use.  
Analyses of hypoglycemia and CGM measures will be conducted using the data from first dose 
to last dose of IP in each 4-week treatment period, and due to the crossover design, treatment 
comparisons will be based upon the derived outcome variables for Week 2 to 4 in each 4-week 
treatment period.  Analyses of the CareLink report data that are transferred to eCRF (eg,
percentage of time spent in Auto Mode, total daily doses during the last 2 weeks) will include all 
data collected, regardless if patients are temporarily off pump or IP during the 2 weeks or not. 
Pump-related safety analyses (eg, infusion set changes) will exclude data (if any) that are
collected while patients are temporarily off pump or off IP.  For analyses of CGM, insulin doses 
and meal information by infusion set wear day, only data from the infusion sets with ≥60 hours
(2.5 days) of wear will be included so that adequate data can be used for by-day (Day 1, Day 2, 
and Day 3) comparison.  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 (Section 6.9.1) at the full 
significance level of 0.10.  No multiplicity adjustment will be made for secondary and
exploratory objectives.


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The definitions of baseline and post-baseline for the safety and efficacy analyses depend on 
which analysis period is being used.  The following analysis periods will be used:

Lead-in Period – from after Visit 2 to Visit 4 

4-Week of Each Randomized Treatment Period while on IP – from first dose to last dose 
of IP in each 4-week randomized treatment period (Period I and Period II) 

4-Week of Each Randomized Treatment Period Regardless of IP use – from the 
beginning to the end of each 4-week randomized treatment period (including all data 
regardless of IP use)

Week 2 to 4 of Each Randomized Treatment Period while on IP – last 2 weeks of each 
4-week randomized treatment period before the last dose of IP

Week 2 to 4 of Each Randomized Treatment Period Regardless of IP – last 2 weeks of 
each 4-week randomized treatment period (including all data regardless of IP use)

Safety Follow-up Period – Visit 801
Table ITSM.6.2 describes the rules for determining the patient population, baseline, and 
postbaseline observations for the different analysis periods.  The data in the lead-in and the 
safety follow-up visit, if summarized, will be for overall, not by treatment.
The data on IP is defined based on the following rules:

for data only measured at an office visit (eg, HbA1c and 1,5 Anhydroglucitol [1,5-AG]), 
if the office visit date (or laboratory sample collection date) is within 14 days of the date 
of last study drug dose of the current randomized treatment period (Period I or Period II), 
then postbaseline data measured at or prior to that office visit will be considered as data 
on IP for the current randomized treatment period.

for data collected as running records with an exact date and/or time stamp such as 
hypoglycemia entries where the date and time of the measures is not tied with the date of 
an office visit, postbaseline data with date and time ≤ (last study drug dose date and time) 
will be considered as data on IP for the current randomized treatment period.
For continuous measures, summary statistics will include sample size, mean, SD, median, 
minimum, and maximum for both the actual and the change from baseline measurements.  Least 
squares (LS) means and standard errors derived from the analysis models will also be displayed 
for the change from baseline measurements.  Treatment comparisons will be displayed showing 
the treatment difference LS means and the 90% CIs for the treatment differences, along with the 
p-values for the treatment comparisons.
Unless otherwise specified, a restricted maximum likelihood based, mixed-effect model repeated
measures (MMRM) analysis will be used to analyze continuous longitudinal variables. The
longitudinal observations for both treatment periods 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 


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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 removed from the 
model. Significance tests will be based on LS 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.  Since Prescott’s exact test is essentially a Fisher’s exact test on the
preference score and treatment sequence, if all events occurred in the same treatment sequence, 
p-values from Prescott’s test will not be calculated. 
For laboratory values, both conventional (CN) and Systeme International (SI) units will be 
presented.  Therefore, both % and mmol/mol will be presented for HbA1c and both mg/dL and 
mmol/L will be presented for glucose measurements.  
Table ITSM.6.2.
Baseline and Post-Baseline Definitions and Patient Population by 
Study Period and Type of Analysis
Study Period/Analysis
Patient Population
Baseline Observations
Post-Baseline 
Observations
Lead-In Period (Overalla only)
TEAEs
Enrolled Population
Prior to first dose of open-
label Humalog (or Visit 2 
date if the dose date is 
missing)
The entire lead-in period 
after first dose of open-
label Humalog and prior to 
first dose of IP (or Visit 4 
date if the dose date is 
missing)
4-Week of Each Randomized Treatment Period While on IP 
(from first to last dose of IP in each  4-week randomized treatment period)
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.))
Randomized Population
From first to last dose of 
open-label Humalog, 
excluding data (if any) that 
are collected while patients
temporarily are off pump or 
off open-label Humalog
From first to last dose of IP 
in each randomized 
treatment period (Period I 
and Period II), excluding 
data (if any) that are 
collected while patients 
temporarily are off pump 
or off IP


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Baseline and Post-Baseline Definitions and Patient Population by Study Period and Type of Analysis
Study Period/Analysis
Patient Population
Baseline Observations
Post-Baseline 
Observations
Time interval until 
infusion set change
All patients in the 
Randomized Population
with a baseline and a 
post-baseline observation
From first to last dose of 
open-label Humalog, 
excluding data (if any) that 
are collected while patients 
temporarily are off pump or 
off open-label Humalog
From first to last dose of IP 
in each randomized 
treatment period (Period I 
and Period II), excluding 
data (if any) that are 
collected while patients 
temporarily are off pump 
or off IP
Hypoglycemia events
Randomized Population
From first to last dose of 
open-label Humalog 
Visits 4, 5, 6, 7, 8, 9 and 10
that fall between first and
last dose of IP in each 
randomized treatment 
period (Period I and 
Period II). More detailed 
analysis period can be 
found in Section 6.10.4.
HbA1c summary 
statistics
All patients in the 
Randomized Population
with a baseline and at 
least one post-baseline 
observation while on IP
Last value of Visits 1-4 prior 
to or on the date of the first 
dose of IP
Visits 7 and 10 while on 
IPd
1,5-AG
All patients in the 
Randomized Population
with a baseline and at 
least one post-baseline 
observation while on IP
Visit 4 prior to or on the date 
of the first dose of IP
Visits 7 and 10 while on IP
Pump factors - CR, ISF, 
and AITb
All patients in the 
Randomized Population
with a baseline and at 
least one post-baseline 
observation
Last value of Visits 2-4 prior 
to or on the date of the first 
dose of IP
Last observation 1 day 
prior to Visit 7 and last 
observation 1 day prior to 
Visit 10 prior to last dose 
in IP of each randomized 
treatment period (Period I 
and Period II) excluding 
data (if any) that are 
collected while patients 
temporarily are off pump 
or off IP


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Baseline and Post-Baseline Definitions and Patient Population by Study Period and Type of Analysis
Study Period/Analysis
Patient Population
Baseline Observations
Post-Baseline 
Observations
4-Week of Each Randomized Treatment Period Regardless of IP use
(from randomization to Week 4 of each randomized treatment period regardless of IP use)
TEAEs 
Randomized Population
Prior to first dose of 
randomized IP (or Visit 4 if 
the dose date is missing) 
Each 4-week randomized 
treatment period regardless 
of IP use
Weight and vital signs
All patients in the 
Randomized Population
with a baseline and a 
post-baseline observation
Last of Visits 2-4
Visits 7 and 10 regardless 
of IP use
Week 2-4 of Each Randomized Treatment Period while on IP 
CGM outcome variables 
All patients in the 
Randomized Population 
(with a baseline and a 
post-baseline observation 
for continuous variables, 
unless otherwise 
specifiedc)
From first to last dose of 
open-label Humalog, 
excluding data (if any) that 
are collected while patients 
temporarily are off pump or 
off open-label Humalog
From first to last dose of IP 
in each randomized 
treatment period (Period I 
and Period II), excluding 
data (if any) that are 
collected while patients 
temporarily are off pump 
or off IP
Week 2-4 of Each Randomized Treatment Period Regardless of IP  
Basal, bolus, and total 
insulin doses, bolus/total 
insulin dose ratiosd
All patients in the 
Randomized Population 
with a baseline and a 
post-baseline observation
Last of Visits 2-4 
Visits 7 and 10 regardless 
of IP use
Basal, bolus, and total 
insulin doses, bolus/total 
insulin dose ratios by 
infusion set wear day, by 
meal, and by infusion set 
wear day and meale
All patients in the 
Randomized Population 
with a baseline and a 
post-baseline observation
Last of Visits 2-4
Last observed value
before/at Visit 7 and 
before/at Visit 10 
regardless of IP use
Percentage of time (per 
week) spent in Auto 
Modef
All patients in the 
Randomized Population 
with a baseline and a 
post-baseline observation
Last of Visits 2-4
Visits 7 and 10 regardless 
of IP use
Safety Follow-Up Visit (Overalla Only)
TEAEs 
All patients in the 
Randomized Population 
who enter the safety 
follow-up period
Prior to first dose of 
randomized IP (or Visit 4 if 
the dose date is missing)
From the date of the last 
visit of the 8-Week 
treatment period + 1 day to 
the end of study
Weight and vital signs 
All patients in the 
Randomized Population 
who enter the safety 
follow-up period
Last of Visits 2-4
Visit 801 


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Abbreviations:  1,5-AG = 1,5-Anhydroglucitol; AIT = active insulin time; BG = blood glucose; CGM = continuous 
glucose monitoring; CR = carb ratio; eCRFs = electronic case report forms; HbA1c = hemoglobin A1c;
IP = investigational product; ISF = insulin sensitivity factor; TEAE = treatment-emergent adverse event.
a
“Overall” means that data will be summarized in total and no by-treatment summary or statistical analysis will be 
included.
b
The pump settings that patients started with in each treatment period (lead-in, Period I and Period II) are captured 
in the eCRF.  Changes during the study are captured in CareLink raw data.  The pump settings that patients 
ended up within each treatment period will be the last observed value from the two data sources 1 day prior to the 
last office visit. 
c
Not required for the duration of hypoglycemic episode because it is possible that some patients may not have any 
hypoglycemic event during the lead-in period to be used as baseline values.                                
d
Mean insulin doses (mean total daily basal and mean total daily bolus) during the last 1 week for Visit 2 and 
during the last 2 weeks for Visits 4, 7, and 10 from the CareLink report will be entered into eCRFs.  These data 
will be used for summary and analyses of mean total daily basal dose, mean total daily bolus dose, mean total 
daily insulin dose, and the ratio of mean total daily bolus dose to mean total daily insulin dose.  
e
Calculated from the CareLink raw data by adding up all insulin doses that fall into the specified time interval
(e.g., a specific infusion set wear day), regardless of whether the pump is in Auto Mode or not. 
f
Captured in the eCRF as “percentage of time spent in Auto Mode per week for the past 1 week” at Visit 2 and as 
“percentage of time spent in Auto Mode per week for the past 2 weeks” at other visits.
6.2.
Adjustments for Covariates
Stratification factors of this study include HbA1c stratum (≤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%).  Stratification factors will be entered into the IWRS for randomization and also collected
in the database by Carelink raw data or central laboratory.  The analysis models will use the 
stratification factors as collected in the database (e.g HbA1c stratum according to the central lab 
at baseline and percentage of time with SG values from 70 to 180 mg/dL over the 2 weeks prior 
to randomization calculated from the CareLink raw data).
Other analyses will include the stratification factors as noted in Sections 6.9 to 6.10.
6.3.
Handling of Dropouts or Missing Data
For continuous variables, missing data will be addressed by using a MMRM analysis for 
continuous longitudinal variables.  The MMRM model provides consistent estimator when data 
is missing at random.  The model implicitly adjusts for missing data through a variance-
covariance structure.  
6.4.
Multiple Comparisons/Multiplicity
Treatment comparisons will be performed for the primary objective (Section 6.9.1) at the full 
significance level of 0.1.  No multiplicity adjustments will be made for secondary and 
exploratory objectives.
6.5.
Patient Disposition
Patient disposition will be displayed in a flowchart showing the number of patients entered, 
enrolled, randomized, and discontinued across the lead-in period, Period I, and Period II.


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Frequency counts and percentages of the Randomized Population completing and discontinuing 
from the study will be presented for overall and by each treatment sequence and period.  Reasons 
for discontinuation from the study will be summarized for overall and by treatment sequence and 
period.  Reasons for discontinuation from the study at Visit 801 will be summarized by treatment 
sequences.
Frequency counts and percentages of all patients entered, enrolled, and discontinued from the 
study during the lead-in period will be summarized.  Reasons for discontinuation during 
screening will be summarized for the Entered Population.  Reasons for discontinuation from the 
study and from the treatment during the lead-in period will be summarized for the Enrolled 
Population.
A listing of the primary reason for study/treatment discontinuation will be generated for the 
Enrolled Population.
A listing will be generated for the Randomized Population, including the following variables but 
not limited to:  investigator ID, patient ID, date of signature of informed consent form, treatment 
sequence assignment, randomization date, first and last dose date in each treatment period (lead-
in, Period I, and Period II). 
6.6.
Patient Characteristics
A summary table for overall and by treatment sequence will be generated for patient 
characteristics at study entry using the Randomized Population.  The following variables will be 
included but not limited to:  age, age groups (<40 and ≥40 years, and <65, ≥65 to <75, ≥75 to 
<85, ≥85 years), sex, country, ethnicity, race, height, weight, body mass index (BMI), BMI 
groups (<25, ≥25 to <30, ≥30 to <35, and ≥35 kg/m2).  No statistical comparisons between 
treatment sequences will be performed.  For continuous variables, the following statistics will be 
provided:  mean, SD, minimum, maximum, and median.  For categorical variables, summary 
statistics will include sample size, frequency, and percentage.  A listing of patient characteristics 
at baseline will be provided.
A similar summary of diabetes characteristics will also be generated.  The following variables 
will be included but not limited to:  duration of diabetes, duration of CSII use, duration of 670G 
use, infusion set cannula length (6 mm or 9 mm), the type of rapid-insulin at study entry, the 
pump speed at study entry and baseline, total daily dose at study entry, percentage of time with 
SG values from 70 to 180 mg/dL over the 2 weeks prior to randomization at study entry, HbA1c 
at study entry and baseline, and HbA1c stratum at baseline.
A listing of patients whose stratification factor value entered into the IWRS (for treatment 
assignment) is different from the clinical database will also be provided.
The total daily insulin dose for the last 3 days prior to screening will be entered into the eCRF.  
The dose at study entry will be calculated as the mean of the doses for the last 3 days prior to the 
visit.  Doses will be summarized in U and U/kg.  Total daily insulin dose will also be presented 
by the definitions in protocol exclusion criterion #19 (≤100 U, >100 U).  


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For the Randomized Population, the number and percentage of patients with historical conditions 
will be summarized using Medical Dictionary for Regulatory Activities (MedDRA) Preferred 
Term (PT) (without regard to System Organ Class [SOC]), and the number and percentage of
patients with preexisting conditions will also be summarized using MedDRA PT (without regard 
to SOC).  Historical conditions are conditions that end prior to informed consent and preexisting 
conditions are conditions that are still ongoing at informed consent.  Events will be ordered by 
decreasing frequency. 
All baseline measures will be summarized for overall and by treatment sequence.  No statistical 
comparison between treatment sequences will be performed given the small sample size of this 
study. 
6.7.
Treatment Compliance
No analysis for treatment compliance is planned for this study.
6.8.
Concomitant Therapy
Concomitant medications will be summarized and compared between treatments using Prescott’s 
exact test for the Randomized Population during the 2 randomized treatment periods (Period I 
and Period II).  The percentages of patients receiving each concomitant medication will be 
summarized by treatment using PT nested within Anatomical Therapeutic Chemical (ATC) 
Level 3 code.  Medications will be ordered by decreasing frequency within ATC level.  
Concomitant medication used during the lead-in period will also be summarized for the Enrolled 
Population.  
6.9.
Efficacy Analyses
6.9.1. Primary Outcome and Methodology
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 6.1. 
The primary analyses will be tested at the full significance level of 0.10, using data collected 
from the Randomized Population, while patients are on IP (ie, from first dose to last dose) and on 
pump.
Derivation and analysis of primary endpoint (derived for 24-hour, daytime and nighttime and by-
meal) and other CGM endpoints are described in Section 6.13.  
6.9.2. Other Secondary Efficacy Analyses
The analyses described in Section 6.9.2 will include data collected from the Randomized
Population.  Details for the CGM analyses are described in Section 6.13.  
For the following secondary efficacy endpoints during the last 2 weeks of each 4-week treatment 
period, an MMRM model similar to that for the primary endpoint will be used:


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
actual and change from baseline in insulin doses, including mean total daily basal (U/day, 
U/kg/day), mean total daily bolus (U/day, U/kg/day), and mean total daily insulin dose
(U/day, U/kg/day) and mean total daily bolus /mean total daily insulin dose ratios (%)

actual and change from baseline in percentage of time (per week) spent in Auto Mode, 
during the last 2 weeks of each 4-week treatment period

actual and change from baseline in percentage of time with sensor glucose values <54 
mg/dL as measured by CGM
In addition, the longitudinal observations of actual and change during each 4-week treatment 
period in HbA1c and 1,5-AG will be summarized by period and by treatment sequence.  No 
treatment comparison will be conducted.
To assess the insulin doses over the course of 3 days of continuous infusion, the mean total daily 
basal and mean total bolus doses during the last 2 weeks of the lead-in and each 4-week 
treatment period, will be derived based upon the CareLink raw data collected on Day 1, Day 2, 
and Day 3 of infusion set wear and summarized by treatment. The insulin doses will also be 
summarized by infusion set wear day, and by both infusion set wear day and meal (0 to 4 hours 
after the start of meals, excluding data collected after the next meal for the current meal).  Only 
data from the infusion sets with ≥60 hours of wear will be included in these doses analyses by 
infusion set wear day. The treatment comparison will be conducted using an MMRM model 
similar to that for the primary endpoint.  
Before the database lock, it was identified that 1 patient had to replace the pump in the middle of 
the study and Auto Mode was unavailable for at least 48 hours, and thus data from this patient 
will be excluded from analysis of percentage of time (per week) spent in Auto Mode.                                            
6.9.3. Exploratory Efficacy Analyses
An MMRM model similar to that for the primary endpoint will be used to analyze actual and 
change from baseline in pump factors that affect insulin dosing. 
The initial settings for pump factors, including carb ratio (CR), active insulin time (AIT), and 
insulin sensitivity factor (ISF), will be captured in eCRF at Visit 2, Visit 4 and Visit 7 for the 
lead-in, Period I and Period II, respectively.  Any changes during any treatment period will be 
captured in the CareLink raw data and associated to meals for CR and ISF.  A listing of pump 
factors will be provided, including data collected at Visit 2 and changes captured in the CareLink
raw data.
Actual and change from baseline in pump factors, including CR by meal, ISF by meal and AIT, 
will be summarized and compared between LY900014 and Humalog using an MMRM models 
as specified in Section 6.1.  Only postbaseline measures at Visit 7 and Visit 10 will be included 
for analyses.
In addition, CGM outcomes that are not included in the primary and secondary efficacy 
endpoints will be analyzed as exploratory efficacy endpoints. Details for the CGM analyses can 
be found in Section 6.13.  


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6.10. Safety Analyses
6.10.1. Extent of Exposure
Duration of exposure to study drug will be summarized based upon CRF data.  The following 
summary statistics will be provided:  n, mean, SD, median, minimum, maximum, and sum (that 
is, total patient-years of exposure).  The number and proportion of patients falling into the 
following different exposure categories will also be summarized:  <7 days (>0 and <7 days), ≥7 
and <14 days , ≥14 and <28 days, and ≥28 days. 
Patients who complete the study treatment period are required to complete a safety follow-up 
visit without study drug; and patients who discontinue the IP unplanned are required to 
discontinue from the study (ITSM Protocol 8.1 to 8.2).  
6.10.2. Adverse Events
Events that are newly reported after the first dose of rapid-acting insulin provided as study drug 
(ie, open-label Humalog used during the lead-in period or IP used during each of the two 4-week 
randomized treatment periods) or are reported to worsen in severity from baseline (defined in 
Table ITSM.6.2 for each specific study period) will be considered treatment-emergent adverse 
events (TEAEs).  Events that continue during more than 1 study period (lead-in, Period I, 
Period II) with the same severity will only be counted once for the first study period.  
The MedDRA Lowest Level Term (LLT) will be used in the treatment-emergent assessment.  
The maximum severity for each LLT during the baseline period will be used as baseline severity.  
For events occurring on the day of first dose of blinded insulin provided in this study during each 
treatment period (lead-in, Period I and Period II), the CRF-collected flag will be used to 
determine whether the event started or worsened post-treatment, and/or the treatment of which 
period the AE should be assigned. 
In an overview table, the number and percentage of patients who experienced a TEAE, 
experienced a serious adverse event (SAE), died due to an AE, and discontinued from study due 
to an AE will be summarized.
The number and percentage of patients with SAEs and who discontinued from the study due to 
an AE will be summarized using MedDRA PT nested within SOC if any such events occurred.  
Prescott’s exact test will be performed for treatment comparison.The number and percentage of 
patients with TEAEs will be summarized by treatment using MedDRA PT nested within SOC.  
Events will be ordered by decreasing frequency within SOC.  As an additional table, the 
percentages of patients with TEAEs will be summarized by treatment using MedDRA PT 
(without regard to SOC).  Events will be ordered by decreasing frequency in total group.  
Statistical comparisons will be applied at both the SOC and PT levels.  Prescott’s exact test will 
be performed for treatment comparison.  
The number and percentage of patients with TEAEs by maximum severity will be summarized
by treatment using MedDRA PT nested within SOC.  For each patient and TEAE on each 
treatment, the maximum severity for the MedDRA PT is the maximum postbaseline severity 


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observed from all associated LLTs mapping to the MedDRA PT during the corresponding 
randomized treatment period for the specified treatment.  No statistical comparison between 
treatments will be conducted.
The number and percentage of patients who experienced a SAE including deaths and SAEs 
temporally associated or preceding deaths will be summarized by treatment using MedDRA PT 
(without regard to SOC).  Events will be ordered by decreasing frequency within SOC.  A listing 
of all SAEs (including data collected during the safety follow-up period) will also be provided.
The number and percentage of patients who discontinued from study in Period I and Period II 
due to an AE will be summarized by treatment using MedDRA PT (without regard to SOC).  
Events will be ordered by decreasing frequency.  A listing of all AEs as reason for study 
discontinuation will also be provided. 
For events that are gender-specific (as defined by MedDRA), the denominator and computation 
of the percentage will include only patients from the given gender.
Table ITSM.6.3 summarizes the planned analyses and the requirement of analysis data for 
different analysis periods. 
Table ITSM.6.3.
Adverse Event Analysis Periods
Analysis Period
Analysis Population
Analysis
IP USE
Treatment
Lead-in Period
Enrolled Population
AE overview; TEAE by 
PT; SAE, 
discontinuation due to 
AE
N/A
Open-label 
Humalog
Treatment Period 
(0-8 Weeks)
Randomized 
Population
AE overview; TEAE by 
PT nested within SOC 
and by PT; TEAEs by 
maximum severity; 
SAE; discontinuation 
due to AE; other notable 
AEs
All data regardless 
of IP use
LY900014, 
Humalog
Safety Follow-up 
Period
All patients in the 
Randomized 
Population who enter 
follow-up period
TEAE by PT
All data 
Overalla
Abbreviations:  AE = adverse event; IP = investigational product; N/A = not applicable/available; PT = preferred 
term; SAE = serious adverse event; SOC = system organ class; TEAE = treatment-emergent adverse event.
a
overall means that data will be summarized in total and no by-treatment summary or statistical analysis will be 
included.
6.10.3. Deaths and Other Serious Adverse Events
The listing of all deaths by patient for the Enrolled Population will be provided as part of the 
SAE listing, regardless of the investigator’s or the sponsor's judgment about causality.  Each 
listing will include study ID, investigator ID, patient ID, treatment sequence, treatment, baseline 
age, sex, associated AE, first and last dose date for open label Humalog and randomized IP, and 
the event date.


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6.10.4. Hypoglycemic Events and Other Adverse Events
The analysis plans for the following AEs are discussed in Section 6.10.4.1 through 
Section 6.10.4.5:

hypoglycemic events

systemic hypersensitivity reaction

infusion site reaction

hepatobiliary events

malignant neoplasm events
These AE analyses will be similar to the TEAE analyses, refer to Table ITSM.6.3 for the 
requirement of analysis data for a specific analysis period. 
6.10.4.1. Hypoglycemic Events
Hypoglycemia events that occur during the study will be captured using a paper diary starting 
from Visit 2 through Visit 801.  Whenever hypoglycemia is suspected, the patient should record 
the blood glucose value, any associated symptoms, and the treatment administered.  A set of 
events is counted as 1 event in analysis if the duration between adjacent events is ≤30 minutes.  
The event with the highest severity will be selected for analysis. Severity will be determined in 
the order of: 1) whether it is a severe hypoglycemia, 2) whether it has symptoms of 
hypoglycemia reported, and 3) the lowest blood glucose value that occurred.  If there are 
multiple events tied in all 3 aspects, the event with the largest number of nonmissing responses 
to the questions of nocturnal hypoglycemia and postmeal time frame will be selected.  If there 
are still multiple events tied, the latest event (based on event time) will be selected.
The following types of hypoglycemia events will be derived in the analysis data sets:  
documented hypoglycemia, severe hypoglycemia, nocturnal hypoglycemia, probable 
symptomatic hypoglycemia, and overall hypoglycemia.  Only severe hypoglycemia will be 
collected as AEs and all episodes of severe hypoglycemia will be considered as SAEs.  
Documented hypoglycemia (including documented symptomatic hypoglycemia, documented 
asymptomatic hypoglycemia, and documented unspecified hypoglycemia) will be based on BG 
≤70 mg/dL and BG <54 mg/dL. 
Table ITSM.6.4 provides detailed statistical methods for each endpoint related to hypoglycemia.  
For these analyses, hypoglycemia events from first dose to last dose of IP will be summarized.  
Additional analyses for other types of hypoglycemic events not mentioned in the table may be 
conducted as needed. 
A listing of patients with at least 1 severe hypoglycemia reported (as SAE) after randomization 
(including Visit 801) will be provided.
A list of MedDRA PTs will be used for the narrow search of potential severe hypoglycemia in 
spontaneously reported AEs.  The events identified through the search strategy that are also 
reported as SAEs will be summarized and compared between treatments.  Prescott’s exact test 
will be used to assess the treatment difference in the proportion of patients with potential severe 
hypoglycemia.


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Table ITSM.6.4.
Summary of Analyses for Endpoints Related to Hypoglycemia
Endpoint
Analysis Perioda
Statistical Method
Rate of hypoglycemic events (per 
patient per year)

All Documentedb

Nocturnalb

Non-Nocturnal (or Daytime) 
(Documented and between 
waking and bedtime)b
0-2, 0-4, 2-4 weeks
Wilcoxon signed-rank test
Incidence of hypoglycemic events

All Documentedb

Nocturnalb

Non-Nocturnal (or 
Daytime)(Documented and 
between waking and 
bedtime)b
0-2, 0-4, 2-4 weeks
If there are ≥5 patients with at least one event 
within the specified time period, a generalized 
linear mixed model with options of the binomial 
distribution and logit link function with 
treatment, period, sequence.  The within-patient 
error will be modeled as a compound symmetry 
without heterogeneous variance-covariance 
matrix.  
If the model does not converge or is not 
conducted due to the lower occurrence of events, 
Prescott’s exact test will be used for analyses.
Endpoint
Analysis Perioda
Statistical Method
Rate of post-meal hypoglycemic events 
(per patient per year) 

Documentedb
≤1, ≤2, ≤4, >4 and 
>2 to ≤4 hours after 
start of a meal 
within 0-2, 0-4, and 
2-4 weeks
Wilcoxon signed-rank test
Incidence of post-meal hypoglycemic 
events 

Documentedb
≤1, ≤2, ≤4, >4  and 
>2 to ≤4 hours after 
start of a meal 
within 0-2, 0-4, and 
2-4 weeks
If there are ≥5 patients with at least one event 
within the specified time period, a generalized 
linear mixed model with options of the binomial 
distribution and logit link function with 
treatment, period, sequence.  The within-patient 
error will be modeled as a compound symmetry 
without heterogeneous variance-covariance 
matrix.
If the model does not converge or is not 
conducted due to the lower occurrence of events, 
Prescott’s exact test will be used for analyses.
Rate of severe hypoglycemic events 
(per patient per year / 100 years)
0-2, 0-4, 2-4 weeks
Exposure adjusted rate per year / 100 years 
(calculated for each patient by total number of 
events divided by total exposure) will be 
provided and Wilcoxon signed-rank test will be 
used for treatment comparison.
Incidence of severe hypoglycemic 
events
0-2, 0-4, 2-4 weeks
Proportion of patients with severe hypoglycemia 
will be reported.  The treatment comparison will 
be based on Prescott’s exact test. 
a
Treatment comparisons for severe hypoglycemia will be based upon the data collected for 0-4 weeks of each 
treatment period. Treatment comparisons for other categories of hypoglycemia will be only based upon the data 
collected for 2 to 4 weeks.
b
Hypoglycemia will be based on the thresholds of blood glucose ≤70 mg/dL and blood glucose <54 mg/dL.


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6.10.4.2. Systemic Hypersensitivity Reaction
The number and proportion of patients experiencing treatment-emergent potential systemic 
hypersensitivity reactions will be summarized and compared by treatment using Prescott’s exact 
test.  The following Standardised MedDRA Query (SMQ) will be used to identify potential 
systemic hypersensitivity reactions from all TEAEs:

anaphylactic reaction (SMQ).  Besides using the narrow and broad terms designated 
within the SMQ, the following search algorithm will also be implemented as another 
approach to determine if a patient had an anaphylactic reaction:  if a patient (had at least 
1 event in Category A) or (had at least 1 event that is in category B and also had at least 
1 event that is in category C) or (had at least 1 event that is in category D and [also had at 
least 1 event in category B or at least 1 event in category C])

angioedema (SMQ)

hypersensitivity (SMQ)
Specifically, the following need to be performed: (1) any narrow or algorithmic term from any 
1 of the 3 SMQs indicated above (that is, combined search across narrow and algorithmic 
portions of all 3 SMQs); (2) any narrow scope term within each SMQ, separately (that is, narrow 
SMQ search); (3) any term within each SMQ, separately (that is, broad SMQ search); (4) narrow 
scope term search within each SMQ, report the PT nested within each SMQ.
A similar summary will be provided for the TEAE reported by the investigator as possibly 
related to study drug.
Note that an individual patient may contribute multiple events.  Also, a single event may satisfy 
multiple SMQs, in which case the event contributes to every applicable SMQ.
6.10.4.3. Infusion Site Reaction
The infusion site reactions will be searched by MedDRA PTs from all TEAEs.  The number and 
percentage of patients experiencing at least one treatment-emergent infusion site reaction will be 
summarized and compared by treatment using Prescott’s exact test. 
For infusion site reactions identified by MedDRA PTs, the presence and severity of erythema, 
induration, pain, pruritus, and edema are collected on the eCRF and will be summarized for each 
treatment.  There will be no statistical comparison between treatments. 
6.10.4.4. Hepatobiliary Events
6.10.4.4.1.
Treatment-Emergent Potential Hepatic Disorder
The percentages of patients with treatment-emergent drug-related hepatic disorder events will be 
summarized and compared by treatment using MedDRA PT nested within each SMQ, and 
ordered by decreasing frequency. The following SMQs based on MedDRA will be used to 
identify potential hepatic disorders:

broad and narrow terms in the Liver related investigations, signs and symptoms SMQ 
(20000008)


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
broad and narrow terms in the Cholestasis and jaundice of hepatic origin SMQ 
(20000009)

broad and narrow terms in the Hepatitis non-infections SMQ (20000010)

broad and narrow terms in the Hepatic failure, fibrosis and cirrhosis and other liver 
damage SMQ (20000013)

narrow terms in the Liver-related coagulation and bleeding disturbances SMQ 
(20000015)
The percentage of patients with any 1 of the terms will be summarized, in addition to the 
percentages for each MedDRA PT. The percentages of patients with potentially drug-related 
hepatic disorders that lead to permanent study discontinuation will be summarized similarly.
6.10.4.5. Malignant Neoplasm Events
The Malignant tumors SMQ will be used to identify treatment-emergent malignant neoplasm 
event. 
6.10.5. Clinical Laboratory Evaluation
The data from safety laboratory measures will be only collected at Visit 1 or Visit 4 for patient 
safety.  Therefore, no by-treatment summary or statistical analysis will be provided.  
6.10.6. Vital Signs and Other Physical Findings
Post-baseline measurements and change from baseline to post-baseline for vital signs (systolic 
blood pressure [SBP], diastolic blood pressure [DBP], pulse rate) and physical characteristics 
(weight, BMI) at the scheduled visits will be summarized by week (relative to the start of each 
randomized treatment period) for patients who have both baseline and at least 1 post-baseline 
result.  
The measurements during the treatment period (0 to 4 weeks during each randomized treatment 
period) will be analyzed by MMRM model with treatment, baseline value of the response 
variable, sequence, period, week (defined from the start of each randomized treatment period), 
and week by treatment interaction as fixed factors and patient as the random factor.  
Change from the minimum value during the baseline period to the minimum value during the 
2 randomized treatment periods for vital signs and physical characteristics will be summarized 
by treatment for patients who have both baseline and at least 1 post-baseline result.  Baseline will 
be the minimum of nonmissing observations in the baseline period.  The minimum value in the 
treatment period will be analyzed.  Similarly, change from the maximum value during the 
baseline period to the maximum value during each of the 2 randomized treatment periods 
(Period I and Period II) for vital signs and physical characteristics will be summarized by 
treatment for patients who have both baseline and at least 1 post-baseline result.  Baseline will be 
the maximum of nonmissing observations in the baseline period.  The maximum value in the 
treatment period will be analyzed.  Planned and unplanned measurements will be included in the 
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The percentages of patients with treatment-emergent high or low vital signs and weight at any 
time after randomization during each of the 2 randomized treatment periods (Period I and 
Period II) will be summarized and compared between treatments using Prescott’s exact test for 
patients who have both baseline and at least 1 postbaseline measurement.  A treatment-emergent 
high result is defined as a change from a value less than or equal to the high limit at all baseline 
visits to a value greater than the high limit at any time that meets the specified change criteria 
during the 2 randomized treatment periods.  A treatment-emergent low result is defined as a 
change from a value greater than or equal to the low limit at all baseline visits to a value less than 
the low limit at any time that meets the specified change criteria during the 2 randomized 
treatment periods.  Table ITSM.6.5 will be used to define the low and high limits and change 
thresholds. 
Table ITSM.6.5.
Categorical Criteria for Abnormal Treatment-Emergent Blood 
Pressure and Pulse Measurement, and Categorical Criteria for 
Weight Changes for Adults
Parameter
Low
High
Systolic BP (mm Hg)
(Supine or sitting – forearm at 
heart level)
≤90 and decrease from baseline ≥20
≥140 and increase from baseline ≥20
Diastolic BP (mm Hg)
(Supine or sitting – forearm at 
heart level)
≤50 and decrease from baseline ≥10
≥90 and increase from baseline ≥10
Pulse (bpm)
(Supine or sitting)
<50 and decrease from baseline ≥15
>100 and increase from baseline ≥15
Weight (kg)
(Consistent clothing and timing 
in relationship to meals and 
voiding)
(Loss) decrease ≥7%
(Gain) increase ≥7%
Abbreviations:  BP = blood pressure.
6.10.7. Pump-related Safety Analyses
The protocol requires that patients change infusion set every 3 days, unless a change is required 
for failure of the infusion set in which case an unplanned infusion set change with noted reason 
needs to be reported in the patient’s study diary and transferred to the eCRF.  Accordingly, all 
infusion set changes captured in the CareLink raw data will be classified into 2 categories:  
planned and unplanned.  An infusion set change will be classified as “unplanned” if there is an
unplanned infusion set change reported in eCRF linked by time (within a 12-hour window, 
considering the fact that the patient-reported infusion set change time for eCRF could be slightly 
off the precise change time stored in the CareLink raw data).  Other infusion set changes will be 
classified as “planned”.  
If there are unplanned infusion set changes reported in the eCRF that do not have linked records 
in the Carelink raw data (potentially due to misreporting), these records will be excluded from 
the calculation of time until infusion set changes and will be reported in the Electronic Trial 


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Master File (eTMF) as permanent data issues.  To be conservative, these infusion set changes 
will be still included in the analysis of rate and incidence of unplanned infusion set changes. 
The incidence (percent of patients with at least 1 event) and rate will be analyzed using 
Prescott’s exact test and Wilcoxon signed-rank test, respectively for planned, unplanned infusion 
set changes for any reason and for each individual reason (pump occlusion alarm, unexplained 
high BG, infusion site reaction [pain, redness or swelling at infusion site], infusion set problem 
[infusion set kinked, pulled out, leaking, reservoir empty, etc.]), by overall (across all infusion 
set wear days) and by infusion set wear day (Day 1, Day 2,and Day 3).
6.10.7.1. Time until Infusion Set Changes
Date and time of all infusion set changes will be captured in the CareLink raw data.  Time 
interval until infusion set change for each infusion set can be derived based upon the CareLink 
raw data by calculating the time difference (hours) between the infusion set change and its 
previous infusion set change.  
For each treatment period (lead-in, Period I and Period II), time interval until infusion set change
(overall, planned, unplanned, or unplanned due to unexplained high BG) will be derived by 
averaging across the corresponding infusion set changes that occur within the period. The 
analyses for time interval (overall and planned) will be then conducted by an MMRM model 
similar to that for the primary endpoint. Time interval until unplanned infusion set change due to 
unexplained high BG will be summarized by treatment.  No treatment comparison will be 
conducted due to the low occurrence.
6.10.7.2. Unplanned Infusion Set Changes
A listing of all unplanned infusion set changes will be generated for the Enrolled Population.  
For each unplanned infusion set change, the following information will be provided:

the most recent SMBG within 1 hour before the infusion set change measured by the 
study meter

the most recent glucose within 1 hour before the infusions set change transferred/entered 
in the pump

the 3 most recent CGM values within 20 minutes before the infusion set change

the reason for the infusion set change

the infusion set wear day on which the infusion set change occurs

the infusion set cannula length at screening

the infusion set cannula length at the time of the infusion set changes
In addition, a listing of unplanned infusion set changes due to unexplained high BG will also be 
generated.  This listing will include the following additional information about the glucose 
response to the correction boluses, if any, that are delivered as 


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“CLOSED_LOOP_BG_CORRECTION” within 1 hour prior to the infusion set change, 
according to the CareLink raw data:

date and time of the correction bolus

the most recent SMBG within 1 hour before the correction bolus measured by the study 
meter

the most recent glucose within 1 hour before the correction bolus transferred/entered in 
the pump

the 3 most recent CGM values within 20 minutes before the correction bolus 

the 3 CGM measures within the time interval of [1 hour -10 minutes, 1 hour +10 minutes] 
following the correction bolus that were collected prior to the infusion set change

the most recent SMBG within 1 hour + 10 minutes following the correction bolus 
measured by the study meter

the most recent glucose within 1 hour + 10 minutes following the correction bolus 
transferred/entered in the pump
6.10.7.3. Infusion Set Cannula Length
A listing of infusion set cannula length changes will be generated for the Enrolled Population.  
For each cannula length change, the following information will be included but not limited to:

date and time of the change

cannula length before and after the change

exposure days to IP of the current study period before and after the change

number of infusion site reactions (with severity) before and after the change

number of unplanned infusion set changes due to “Infusion Site Reaction (Pain, Redness 
or Swelling at Infusion Site)” or due to “Infusion Set Problem (Infusion Set Kinked, 
Pulled Out, Leaking, Reservoir Empty)” before and after the change
6.10.7.4. Significant Events during Pilot Safety Assessment
For the patients in the pilot safety assessment, the following safety events that occur during the 
safety assessment period can be identified from the listings of SAE, AE, and unplanned infusion 
set changes for the study. 

severe hypoglycemia

DKA

unplanned infusion set change due to unexplained hyperglycemia (date, time and reason 
of change)
6.10.8. Patient Narratives
Patient narratives will be provided for all patients in the study who experience any of the 
following “notable” events prior to data cutoff for the submission, if any occur during the study:

deaths


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
SAEs

discontinuations from study (or study drug) due to AEs

pregnancy
A list of patients who meet the criteria for narratives will be provided.
6.11. Important Protocol Deviations
Important protocol deviations, as defined in the Trial Issue Management Plan (TIMP), will be 
summarized by treatment sequence for the Randomized Population.  The listing of important 
protocol deviations for the Randomized Population during the entire study, will be provided in 
the CSR. No per-protocol population is planned for any analyses. 
6.12. Interim Analyses and Data Monitoring 
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the appropriate Lilly medical director, or designee, will be consulted to determine 
whether it is necessary to amend the protocol.
6.13. CGM Analyses
The analyses described in Section 6.13 will include data collected from first dose to last dose of 
study drug (ie, open-label Humalog used during the lead-in period or IP used during each of the 
randomized treatment periods [Period I and Period II]), excluding data (if any) that are collected 
while patients temporarily are off pump or off study treatment. 
All of the variables will be derived for the lead-in period, Period I, and Period II.  For the lead-in 
period, the variables will be derived based upon the data collected during the 2-week open-label 
Humalog treatment period.  For Period I and Period II, the variables will be derived for 0 to 2, 
2 to 4, and 0 to 4 weeks relative to the start of each randomized treatment period, respectively. 
Due to the crossover design, treatment comparisons will be based upon the derived outcome 
variables for 2 to 4 weeks. 
Table ITSM.6.6 lists all numerical measures for CGM data, including all primary, secondary and 
exploratory CGM outcome variables.  
To ensure that the CGM outcome variables are only calculated from CGM session days with 
sufficient data within the 24-hour, daytime (0600 hours to midnight), or nighttime (midnight to 
0600 hours) periods, the following criteria will be used to determine a valid CGM session day to 
be counted into the calculation for a visit:  minimum number of measures per day – at least 70% 
of the total measures that are supposed to be obtained, i.e. 70% of the 288 measures for the 24-
hour period;.
Similarly, for the by-meal outcome variables, the following criteria will be used to determine a 
valid CGM session day for a visit:  minimum number of measures per day – at least 70% of the 
total measures that are supposed to be obtained.  For example, 70% of the 24 measures for the 
iAUC0-2hr after breakfast. 


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The definition and derivation of these variables are described in detail in Appendix 1.
Table ITSM.6.6.
Outcome Measures of CGM Data
Category
Endpoints
24-Hour
Daytimea
Nighttimeb
By Mealc
Efficacy Endpoint:  Glucose in the Target Ranges
Duration (in minutes) and percentage of 
time with sensor glucose values within 
target range 70 to 180 mg/dL [3.9 and 
10.0 mmol/L], both inclusive (Primary 
Efficacy Endpoint)
X
X
X
X
Duration (in minutes) and percentage of 
time with sensor glucose values within 
target range 70 to 140 mg/dL [3.9 and 
7.8 mmol/L], both inclusive
X
X
X
X
Duration (in minutes) and percentage of 
time with sensor glucose values 
180 mg/dL [10.0 mmol/L]
X
X
X
X
Efficacy Endpoint:  Incremental AUCs (iAUCs) (after the start of meals)
iAUC0-1hr
X
iAUC0-2hr
X
iAUC0-3hr
X
iAUC0-4hr
X
Efficacy Endpoint:  Mean Glucose Excursions (after the start of meals) d
mean sensor glucose excursions 0 to 
1 hour
X
mean sensor glucose excursions 0 to 
2 hour
X
mean sensor glucose excursions 0 to 
3 hour
X
mean sensor glucose excursions 0 to 
4 hour
X
Efficacy Endpoint:  Hyperglycemic Episodes
Duration (in minutes) and percentage of 
time with glucose values >180, 181-250 
and >250 mg/dL [10.0, 13.9, and 
16.7 mmol/L] and hyperglycemic 
episodes, defined as at least 10 
consecutive minutes >180, 181-250 and
>250 mg/dL [10.0, 10.1-13.9 and 13.9
mmol/L]
X
X
X
Rate (events/patient/year) and incidence 
(percent of patients with at least 1 event) 
of hyperglycemic episodes, defined as at 
least 10 consecutive minutes >180 and 
>250 mg/dL [10.0 and 13.9 mmol/L]
X
X
X


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Outcome Measures of CGM Data
Category
Endpoints
24-Hour
Daytimea
Nighttimeb
By Mealc
Efficacy Endpoint:  Daily CGM Data Summary
Area under the curve (AUC)
X
X
X
Mean sensor glucose
X
X
X
Median sensor glucose
X
X
X
Hourly mean sensor glucose
X
Hourly median sensor glucose
Efficacy Endpoint:  Glucose Variability and Risk Assessment
Within-Day
CV
X
X
X
X
SD
X
X
X
X
IQR
X
X
X
X
MAGE
X
X
X
X
LBGI:  frequency and extent of low BG 
readings
X
X
X
X
HBGI:  frequency and extent of high BG 
readings
X
X
X
X
BGRI = LBGI + HBGI:  a measure of 
overall variability and risks of hypo- and 
hyperglycemia
X
X
X
Between-Day
CV
X
X
X
SD
X
X
X
MODD
X
X
X
Overalle
CV
X
X
X
SD
X
X
X
IQR
X
X
X
LBGI
X
X
X
HBGI
X
X
X
BGRI 
X
X
X
Efficacy Endpoint:  Highest Postprandial Glucose
Time from start of meal to the highest 
postprandial glucose level (minutes) 
within 4 hours after meal(s) 
X
Highest postprandial glucose level 
within 4 hours after meal(s)
X
Highest postprandial glucose excursion 
level within 4 hours after meal(s)
X


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Outcome Measures of CGM Data
Category
Endpoints
24-Hour
Daytimea
Nighttimeb
By Mealc
Safety Endpoint:  Hypoglycemic Episodesf
Duration (in minutes) and percentage of 
time with sensor glucose values <54, 54-
69and <70mg/dL of hypoglycemic 
episodes,defined as at least 10 
consecutive minutes <54 and <70mg/dL 
[3.0, 3.0-3.8and 3.9 mmol/L]
X 
X 
X
X
Rate (events/patient/year) and incidence 
(percent of patients with at least 1 event) 
of hypoglycemic episodes, defined as at 
least 10 consecutive minutes <54and 
<70mg/dL [3.0 and 3.9 mmol/L]
X 
X 
X
X
Safety Endpoint:  Other
Duration (in minutes) of hypoglycemic 
episode (defined as at least 10 
consecutive minutes <54 and <70mg/dL 
[3.0 and 3.9 mmol/L])
across all hypoglycemic episodes with duration at 
least 10 consecutive minutes
Duration (in minutes) of each individual 
hypoglycemic episode (defined as at 
least 10 consecutive minutes <54 and 
<70mg/dL [3.0 and 3.9 mmol/L])
across all hypoglycemic episodes with duration at 
least 10 consecutive minutes
Abbreviations:  AUC = area under curve; BGRI = blood glucose risk index; CGM = continuous glucose monitoring; 
CV=coefficient of variation; HBGI = high blood glucose index; hr = hour; IQR = interquartile range; LBGI = low 
blood glucose index; MAGE= mean amplitude of glycemic excursions; MODD = mean of daily differences; 
SD=Standard deviation.
a Daytime:  0600 hours to midnight (06:00:00-23:59:59 on the 24-hour clock).
b Nighttime:  midnight to 0600 hours (00:00:00-05:59:59 on the 24-hour clock).
c By meals:  for morning (breakfast), midday (lunch) and evening (dinner) meals and overall (average across all 
meals).  
 
 When 
calculating time in ranges (target, hypo, hyper) for meals (0 to 1 hour, 0 to 2 hours, 0 to 3 hours and 0 to 4 hours), 
any data that are collected after the next mealevent will be excluded.
d Mean sensor glucose measured at different time points (1, 2, 3 or 4 hours) after the start of the meal minus mean 
sensor glucose at the start of meal
e Overall variability refers to the variability calculated based upon all the CGM measurements collected across all 
valid days for each derivation period (e.g. 2 to 4 weeks relative to the start of each of the randomized treatment 
period).
f
CCI
In addition, postprandial hypoglycemia episodes during the following time interval after eachmeal and overall 
will also be derived:  0 to 1 hour, 0 to 2 hours, 2 to 4 hours, 0to 4 hours.  The calculation will exclude the data 
from patients who have had the next meal event(according the CareLink raw data) before the end of time 
interval.


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To assess the glucose control over the course of approximately 3 days of continuous insulin 
infusion, the duration and percentage of time in ranges (target, hypoglycemia or hyperglycemia) 
and incremental AUCs after meals, will be derived based upon the CGM raw data collected on 
each of the infusion set wear days, including Day 1 (>0 and ≤24 hours), Day 2 >24 and ≤48 
hours), and Day 3 (>48 and ≤72 hours) and summarized by treatment. 
Hypoglycemia/hyperglycemia rates as measured by CGM data will be summarized for 1 year.  
The rate of hypoglycemia and hyperglycemia will be compared between treatments using 
Wilcoxon signed-rank test.
The proportion of patients with at least 1 hypoglycemia/hyperglycemia event as measured by 
CGM data in each category (incidence) during a specific period after randomization will be 
analyzed using a generalized linear mixed model with options of the binomial distribution and 
logit link function with treatment, period, and sequence.  The within-patient error will be 
modeled as an unstructured variance-covariance matrix.  Prescott’s exact test will be conducted 
as sensitivity analyses. Similarly, the proportion of patients who have achieved the guidance
(Battelino 2019) recommended CGM targets of glycemic control (Table ITSM 6.7) during the 2 
to 4 weeks of each treatment period will be summarized by treatment and analyzed using the 
same analysis methods.
Table ITSM 6.7.
Guidance Recommended CGM Targets of Glycemic Control
Percentage of time with sensor glucose (24-hour)
Guidance Recommendation
target range
         70-180 mg/d.L (3.9-10.0 mmol/L, both 
inclusive
>70%
hypoglycemia range
        <70 mg/dL (3.9 mmol/L)
<4%
        <54 mg/dL (3.0 mmol/L)
<1%
hyperglycemia range
      >180 mg/dL (10.0 mmol/L)
<25%
     >250 mg/dL (13.9 mmol/L)
<5%
When calculating postprandial-related CGM variables (e.g. time in ranges, within-day 
variability), any data that are collected after the next meal event will be excluded from analyses 
for the current meal.  Time in ranges by meal will be derived for 0 to 1 hour, 0 to 2 hours, 0 to 3 
hours and 0 to 4 hours after the start of each meal while variability by meal will only be derived 
for 0 to 4 hours. The variability for overall (across meals) will be calculated as the average of the 
variability from 3 meals.


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Other than that, all continuous variables (actual and change from baseline, if applicable) will be 
compared between LY900014 and Humalog at Week 4 using the MMRMs defined in 
Section 6.1.
In addition, the following standardized glucose summary reports from the ambulatory glucose 
profile (AGP) will be generated, based upon all the observed CGM data during Weeks 2 to 4 of 
each randomized treatment period, regardless of whether they are collected on valid CGM days:

24-hour period at individual patient level 

24-hour period at the treatment level

0 to 4 hours relative to meal starting time, excluding data collected after the next 
meal event (if any is captured within the interval) at the treatment level

0 to 4 hours relative to meal starting time, by meal (breakfast, lunch, and dinner) 
and by infusion set weay day (Day 1, Day 2, and Day 3), based upon data from 
the infusion sets with ≥60 hours of wear.

0 to 4 hours relative to meal starting time, by meal (breakfast, lunch, and dinner) 
and by infusion set wear day (Day 1, Day 2, and Day 3) by pump bolus speed at 
baseline, including only patients who maintained the pump bolus speed during the 
lead-in, Period I and Period II, based upon data from the infusion sets with ≥60 
hours of wear.  
The following individual patient-level plots will be done in R Shiny, including CGM, and all 
relevant information of SMBG, calibration, infusion set changes dose, carb, or pump settings.  
Details for these R Shiny plots are provided in a separate document. 

individual level 24-hour for any date

individual level 24-hour by infusion set wear day for any infusion set:  Day 1 (>0 
and ≤24 hours); Day 2 >24 and ≤48 hours);  Day 3 (>48 and ≤72 hours)

individual level by meal (overall and by infusion set wear day): breakfast – Day 1
to 3; lunch – Day 1 to 3; dinner – Day 1 to 3
6.14. Subgroup Analyses
The following subgroup will be explored, using the Randomized population, to evaluate 
consistency of treatment effects on the primary endpoint, if there are at least 10 patients in each 
subgroup:

pump bolus delivery speed at baseline (Standard [1.5 U/min], Quick [15 U/min])
including only patients who maintained the pump bolus speed during the lead-in, 
Period I and Period II

hemoglobin A1c stratum (≤7.0%, >7.0%)

percentage of time with SG values from 70 to 180 over the 2 weeks prior to 
randomization (≤75%, >75%)


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The insulin doses will be summarized and analyzed by infusion set wear day (overall, Day 1, 
Day 2, and dDay 3) and by meal (breakfast, lunch, and dinner), by the subgroup defined using
the pump bolus delivery speed at baseline, including only patients who maintained the pump 
bolus speed during the lead-in, Period I, and Period II. Additional exploratory subgroup analyses 
may be performed. No tests for treatment by subgroup interaction will be performed.  
6.15. Clinical Trial Registry Analyses
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.  
Analyses provided for the CTR requirements include the following:
Summary of AEs, provided as a dataset which will be converted to an XML file.  Both SAEs and 
‘Other’ Non-SAEs are summarized by treatment, by MedDRA PT.

An AE is considered ‘Serious’ whether or not it is a TEAE.

An AE is considered in the ‘Other’ category if it is both a TEAE and is not 
serious.  For each Serious AE and ‘Other’ AE, for each term and treatment, the 
following are provided:
o
the number of participants at risk of an event
o
the number of participants who experienced each event term
o
the number of events experienced.

For each SAE, these additional terms are provided for EudraCT:
o
the total number of occurrences causally related to treatment
o
the total number of deaths
o
the total number of deaths causally related to treatment.  

Consistent with www.ClinicalTrials.gov requirements, ‘Other’ AEs that occur in 
fewer than 5% of patients/subjects in every treatment may be excluded if a 5% 
threshold is chosen.  Allowable thresholds include 0% (all events), 1%, 2%, 3%, 
4%, and 5%.  

AE reporting is consistent with other document disclosures for example, the CSR, 
manuscripts, and so forth. 


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


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8.
References
Baghurst PA. Calculating the mean amplitude of glycemic excursion from continuous glucose 
monitoring data: an automated algorithm. Diabetes Technol Ther. 2011;13(3):296-302.
Battelino T, Danne T, Bergenstal RM, Amiel SA, Beck R, Biester T, et al. Clinical Targets for 
Continuous Glucose Monitoring Data Interpretation: Recommendations From the 
International Consensus on Time in Range. Diabetes Care 2019; pii: dci190028. 
Clarke W, Kovatchev B. Statistical tools to analyze continuous glucose monitor data. Diabetes 
Technol Ther. 2009;11(suppl 1):S45-S54.
Hirsch IB. Glycemic variability: It’s not just about A1c anymore! Diabetes Technol Ther. 
2005;7(5):780-783.
Kovatchev BP, Clarke WL, Breton M, Brayman K, McCall A. Quantifying temporal glucose 
variability in diabetes via continuous glucose monitoring: mathematical methods and clinical 
application. Diabetes Technol Ther. 2005;7(6):849–862.
Mazze RS, Strock E, Wesley D, Borgman S, Morgan B, Bergenstal R, Cuddihy R. 
Characterizing glucose exposure for individuals with normal glucose tolerance using 
continuous glucose monitoring and ambulatory glucose profile analysis. Diabetes Technol 
Ther. 2008;10(3):149-159.
Rodbard D. Interpretation of continuous glucose monitoring data: glycemic variability and 
quality of glycemic control. Diabetes Technol Ther. 2009;11(suppl 1):S55-S67.
Service FJ, Molnar GD, Rosevear JW, Ackerman E, Gatewood LC, Taylor WF. Mean amplitude 
of glycemic excursions, a measure of diabetic instability. Diabetes. 1970;19(9):644–655.
Service FJ, O’Brien PC, Rizza RA. Measurements of glucose control. Diabetes Care. 
1987;10(2):225–237.


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9.
Appendices


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Appendix 1.
Derivation of CGM Variables
9.1.
General Derivation Specifications
All CGM variables will be derived for each patient, for each time interval of each study period 
(lead-in, Period I, and Period II), based upon the data from valid CGM session days 
(Section 6.13).  For Period I and Period II, the variables will be derived for 0 to 2, 2 to 4 , and 0
to 4 weeks relative to the start of each randomized treatment period, respectively. 
No missing CGM values will be imputed.
Since the CGM values may not be measured at the exact same time for each day for a specific 
individual patient, due to device changes or gaps in usage, non-overlapping intervals (‘buckets’) 
of 5 minutes over 00:00:00 to 23:59:59 (00:00:00 to 00:04:59, 00:05:00 to 00:09:59, etc.) will be 
used for any derivations requiring time-matched measurements across days within a visit 
(eg, mean of daily difference [MODD]). 
All CGM parameters will be estimated to precision of 1 decimal place, unless stated otherwise.  
All CGM glucose derivations will be conducted in units of mg/dL and mmol/L. 
Only readings collected from valid CGM days while patients are on pump and on IP, will be 
included in the derived.
9.2.
Glucose in Target Ranges, Hypoglycemia- or Hyperglycemia
The percentage of time within a glucose range (target, hypo- or hyperglycemia ranges) will be 
calculated as the number of observations within the specified range divided by the number of 
observations in the time interval (eg, 24-hour period).  The duration (in minutes) within the 
glucose range will then be calculated as the percentage of time within the glucose range times the 
length of the period (24 hour, 18 hour, and 6 hour, for the periods of 24-hour, daytime or 
nighttime, respectively). 
For example, if a patient had a total of 135 observations with glucose values <70 mg/dL 
(3.9 mmol/L) out of a total of 3078 observations recorded during the 24-hour period across days 
for Visit 7, the percentage of time spent in hypoglycemia during the 24-hour period for this 
patient at Visit 7 will be calculated as 135/3078 = 4.4%.  The duration (in minutes) with 
hypoglycemia (glucose value <70 mg/dL [3.9 mmol/L]) during the 24-hour period for this 
patient at Visit 7 will be calculated as the percentage times 1440, (ie, 135/3078*1440 = 
63.2 minutes). 
The percentage and duration in ranges within 0 to 1 hour, 0 to 2 hours, 0 to 3 hours, and 0 to 4
hours after meals will also be derived.
9.3.
Incremental Area under the Glucose Curve (iAUC)
iAUC0-T will be calculated as the average value of iAUC on all valid CGM days during that visit 
with sufficient data to calculate the iAUC0-T (Section 6.13).  For each day, iAUC0-T will be 


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calculated as the sum of areas of all individual trapezoids within the time frame according to the 
formula: 
݅AUC଴ି୘ൌ ෍ܣ݅
௞
௜ୀଵ
ൌ෍ሺܩ௜െܩ଴ሻ൅ሺܩ௜ିଵെܩ଴ሻ
2
∆࢚࢏
௞
௜ୀଵ
 
where Ai is area of the respective trapezoid, Gi is glucose concentration at a particular time, G0 is 
the starting glucose concentration before the start of the meal, is the time interval between 
consecutive CGM values, which should be always 5 minutes unless missing data occur, and k is 
the total number of intervals within the time frame 0-T.  If the intermediate time points are 
missing, the next available time point will be used in calculating the trapezoid area.  Also since it 
is possible that Gi < G0 or Gi-1 < G0, Ai  could also be negative.  G0, the starting glucose 
concentration, will be calculated as the average of the CGM values in the time window [-19, 0] 
mins relative to the start of the meal (at most 3 CGM values); Gk, the last glucose concentration, 
is defined as the average of the CGM values in the window [0, +14] minutes relative to the last 
time point of the time frame (at most 2 CGM values).  For example, to calculate iAUC0-2hr after 
the start of breakfast, Gk will be the average of the CGM values in the window [0, +14] minutes 
relative to the 2 hours after the start of breakfast.  The derivation of each iAUC0-T will require 
that G0 and Gk values are both available.  The derivation iAUC0-T on a specific infusion set wear 
day, requires that time 0 and time T fall on the same infusion set wear day,but it is acceptable 
that the CGM measures in the window [-19,0] for G0 and [0+14] for GT fall on the previous or 
the next infusion set wear day.  
9.4. Mean Sensor Glucose Excursions 
Mean sensor glucose excursions in a postmeal time interval (0-1 hr, 0-2 hr, 0-3 hr or 0-4 hr) will 
be calculated by averaging all excursion values within the time interval.  Excursions will be 
derived by subtracting glucose values by the starting glucose concentration, which is the average 
of the CGM values in the time window [-19, 0] mins relative to the start of the meal (at most 3 
interstatial glucose measures). 
9.5. Hypoglycemic/Hyperglycemic Episodes 
Hypoglycemic/hyperglycemic episodes as measured by CGM data are defined as at least 10 
consecutive minutes below/above the specified threshold, and determined by 3 or more 
consecutive CGM values meeting the criterion.  
The number of distinct hypoglycemic episodes that start will be derived along with days of CGM 
use (Section 6.13) to calculate the rate of hypoglycemic episodes during a 24-hour period.  For 
example, the rate of postprandial hypoglycemic episodes (<70 mg/dL [3.9 mmol/L]), during the 
24-hour period, will be calculated with the following steps: 
 Step 1:  identify all events as runs of 3 or more consecutive CGM values meeting the 
criterion, where the pre-marker glucose value (<70 mg/dL[3.9 mmol/L]).  Consecutive 
implies no gaps in time more than 6 minutes between measurements.  Events will be 
identified without regard for the CGM level prior to the start of the meal event.  


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
Step 2:  Count the number of distinct events over the 24-hour period. 

Step 3:  Calculate rate per month by multiplying count by 30/days of CGM use.  Days of 
CGM use will be calculated as the number of observations during the 24-hour period 
divided by the observation supposed to be measured during the period (288 observations 
for the 24-hour period).
9.6.
Glucose Variability 
Glycemic variability will be evaluated using the notation below:
i represents a time point within a time period (a 24-hour period, daytime or nighttime)
n represents the number of time points within the time period 
k represents a day within a visit
m represents number of days CGM is performed at a visit 
i
k,
BG
represents the glucose value at time point i on day k unless otherwise specified under 
MAGE definition.
9.6.1.Within-Day Variability
For variables assessing within-day variability, first determine the variability within each day, 
then average across days within a visit. 
Within-day glucose standard deviation (SD) (Hirsch 2005; Rodbard 2009):
Within-day glucose coefficient of variation (CV) (Clarke 2009): 
Inter-quartile range (IQR) (Mazze et al. 2008):
                  






m
k
m
k
k
m
IQR
m
IQR
1
1
k)
day 
on 
BG values
all
of
percentile
25th 
  -
(75th 
1
1
























m
k
i
k
i
k
m
k
k
n
m
m
SD
1
2
n
1
i
,
n
1
i
,
1
1
)
n
BG
(BG
1
SD
1









m
k
i
k
k
m
k
k
SD
m
CV
m
CV
1
n
1
i
,
1
100
)
n
BG
(
1
1


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Mean amplitude of glycemic excursions (MAGE) (Service et al. 1970, 1987; Baghurst 2011):  
MAGE is the mean of the excursions between consecutive peaks and nadirs in BG that meet 
qualifying criteria,
where, 
BGk,l = the low point in consecutive BG time points for the kth day (nadir)
BGk,l-h = the high point in consecutive BG time points for the kth day (peak)
p = the number of qualifying excursions:  (BGk,l – BGk,l-h) ≥ 1 SDk and that follow the direction 
of the first qualifying difference within the BG time points for the kth day.
MAGE- and MAGE+ will also be calculated for both negative and positive excursions, in 
addition to MAGE+/- for all positive and negative excursions combined (Baghurst 2011).  The 
peaks and nadirs will be algorithmically (Baghurst 2011; Approach 1), using a variant that 
removes the proposed and unnecessary first step of using a smoothing function.
9.6.2.Between-Day Variability
For variables assessing between-day variability, first determine the variability for each time 
points across days within a visit then average across all time points. 
Between-day glucose standard deviation (SD) (Rodbard 2009):
Between-day glucose coefficient of variation (CV):
Mean of daily differences (MODD):  this parameter is calculated as the mean of absolute 
differences between glucose values at corresponding time points of consecutive days.
p
BG
BG
MAGE
p
1
l
h
l,
l,





k
k
k








1
1
n
1
i
,
1,
n
BG
BG
1
1
MODD
m
k
i
k
i
k
m
























n
i
m
SD
1
2
m
1
k
i
k,
m
1
k
i
k,
n
1
i
i
1
m
)
BG
(BG
n
1
n
1
SD





















n
i
m
k
k
i
m
n
CV
n
CV
1
1
i,
n
1
i
i
100
BG
SD
1
1


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9.6.3.Overall Variability
The CV, SD, IQR, low blood glucose index (LBGI), high blood glucose index (HBGI), and 
blood glucose risk index (BGRI) will be calculated using the standard formulas across collected 
across all valid days for time interval in each randomized treatment period. 
9.6.4.Risk for Hypo/Hyperglycemia
The LBGI has been developed to quantitate both frequency and severity of hypoglycemia.  The 
LBGI has been validated as a predictor of severe hypoglycemia, which is a SAE and could result 
in coma or death if unrecognized and untreated.  The HBGI quantifies both frequency and 
severity of hyperglycemia and has been related to HbA1c and risk for hyperglycemia (Kovatchev 
et al. 2005).  Additionally, both the LBGI and HBGI have a high sensitivity to changes in 
glycemic profiles and control (Kovatchev et al. 2005).  Low blood glucose index is a non-
negative number that increases as the number of low readings increases.  High blood glucose 
index is a non-negative number that increases as the number of high readings increases.
The LBGI, HBGI, and BGRI will be derived for each day of a visit and for overall in the 
following steps:
Step 1:  For each blood glucose (BG [mg/dL]) at the ith time point, compute the following:
f(BGi) = 1.509×[(ln(BGi))1.084-5.381]
This transforms the BG data using a nonlinear transformation that maps the BG range of 20 to 
600 mg/dL to a symmetric interval of

10
,
10

The center of the BG scale is 112.5 mg/dL and is mapped to 0
Step 2:  Compute BG risk for each reading




2
i
i
BG
f
10
BG
rl


if f(BG) < 0; otherwise rl(BGi) = 0




2
i
i
BG
f
10
BG
rh


if f(BG) > 0; otherwise rh(BGi) = 0
Assign the risk of each BG value by applying the above quadratic risk function
Value range from 0 (achieved when BG = 112.5, the center) to 100
Left side of the parabola is risk of hypoglycemia, and the right side is risk of hyperglycemia
Step 3:  Compute LBGI and HBGI



n
1
i
i)
rl(BG
n
1
LBGI



n
1
i
i)
rh(BG
n
1
HBGI


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Step 4:  Compute BGRI 
BGRI = LBGI + HBGI
9.7.
Daily CGM Data Summary
For daily CGM summary variables, first determine the values within each day, then average 
across days within a visit. The hourly mean glucose will be calculated as the mean across all 
CGM values collected, based on actual local time for the subject.
9.8.
AUC
Area under the curve (AUC) during a period (24-hour, daytime, or nighttime) will be calculated 
using the standard linear trapezoidal method as defined previously in Section 9.3, by multiplying 
the sum of trapezoids by (the length of the period)/(the length of the period - total length of gaps 
that are not counted into the calculation of the AUC).
9.9.
Highest Postprandial Glucose
9.9.1. Time to the highest postprandial glucose within 4 hours after 
Meals
Time from start of meal to the highest postprandial glucose level will be calculated as the time 
from start of meal to the maximum glucose value within 4 hours after meals, excluding the data 
from patients who have had the next meal event. If there are multiple time points with the 
maximum glucose value, then the earliest time will be used. 
9.9.2. Highest Postprandial Glucose Level within 4 hours after Meals
Highest postprandial glucose level excursions within 4 hours after meals, will be calculated as 
the maximum glucose value during 0 to 4 hours after start of meal, excluding the data from 
patients who have had the next meal event.
9.10. Other
The duration of each episode of hypoglycemia will be calculated as stop time – start time.


PPD
Leo Document ID = f90bc9b5-63f5-412e-b7e9-fde76bcbf520
Approver:
Approval Date & Time: 29-Oct-2019 17:26:57 GMT
Signature meaning: Approved