Clinical trial NCT02561078
Conditions: Type 2 Diabetes Mellitus
Keywords: insulin pumps concentrated insulin OmniPod
Sponsor: Eli Lilly and Company
Start date: 2015-10-20; Completion date: 2017-05-09
Enrollment: 420 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this study is to evaluate the efficacy and safety of the study drug known as human regular U-500 insulin (U-500R) administered by continuous subcutaneous insulin infusion (CSII) versus multiple daily injections (MDI) in participants with type 2 diabetes mellitus.

Detailed description:

Arms: arm 1: Human regular U-500 insulin administered by CSII and titrated based on blood glucose readings for 26 weeks with a 2-week MDI lead-in. arm 2: Human regular U-500 insulin administered subcutaneously (SC) by MDI three times a day and titrated based on blood glucose readings for 26 weeks.
Interventions: intervention 1: Human regular U-500 insulin (CSII) intervention 2: Human regular U-500 insulin (MDI)
Intervention descriptions: intervention 1: Administered SC intervention 2: Administered SC

Protocol documents:
SAP_004.pdf: 
Statistical Analysis Plan B5K-MC-IBHD (V2)
Safety and Efficacy of Human Regular U-500 Insulin Administered by Continuous Subcutaneous 
Insulin Infusion versus Multiple Daily Injections in Subjects with Type 2 Diabetes Mellitus: A 
Randomized, Open-Label, Parallel Clinical Trial 
NCT02561078 
Approval Date: 31-May-2017


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1.
Statistical Analysis Plan B5K-MC-IBHD:
Safety and Efficacy of Human Regular U-500 Insulin 
Administered by Continuous Subcutaneous Insulin 
Infusion versus Multiple Daily Injections in Subjects with 
Type 2 Diabetes Mellitus:  A Randomized, Open-Label, 
Parallel Clinical Trial
(VIVID:  Evaluating U-500R Infusion versus Injection in 
Type 2 Diabetes Mellitus)
The information contained in this Statistical Analysis Plan (SAP) 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.  This document and its associated 
attachments or appendices are subject to United States Freedom of Information Act 
Exemption 4.
Humulin R U-500 (LY041001)
This is a Phase 3b, randomized, open-label, parallel study comparing human regular insulin U-500 
delivered by continuous subcutaneous insulin infusion (OmniPod® Insulin Management System for 
use with regular human insulin U-500) to delivery by multiple daily injections in high-dose insulin-
requiring patients with type 2 diabetes mellitus who have inadequate glycemic control on existing high 
dose insulins (with or without other insulins/antihyperglycemic agents).
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol B5K-MC-IBHD
Phase 3b
Statistical Analysis Plan Version 1 approved:  17 September 2015
Statistical Analysis Plan Version 2 electronically signed and approved by Lilly on date 
provided below.
Approval Date: 31-May-2017 GMT


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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan B5K-MC-IBHD: Safety and Efficacy of 
Human Regular U-500 Insulin Administered by Continuous 
Subcutaneous Insulin Infusion versus Multiple Daily Injections in 
Subjects with Type 2 Diabetes Mellitus:  A Randomized, Open-
Label, Parallel Clinical Trial ...............................................................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................6
4.
Study Objectives.................................................................................................................8
4.1.
Primary Objective ..........................................................................................................8
4.2.
Secondary Objectives.....................................................................................................8
4.2.1.
Key Secondary Objectives .....................................................................................8
4.2.2.
Other Secondary Objectives ...................................................................................9
4.3.
Exploratory Objectives...................................................................................................9
4.4.
Summary of Study Design............................................................................................10
5.
A Priori Statistical Methods ..............................................................................................12
5.1.
Sample Size Determination ..........................................................................................12
5.2.
General Considerations ................................................................................................12
5.3.
Adjustment for Multiplicity..........................................................................................14
5.4.
Subject Disposition ......................................................................................................15
5.5.
Subject Characteristics .................................................................................................16
5.6.
Concomitant Therapy...................................................................................................17
5.7.
Treatment Compliance .................................................................................................18
5.8.
Protocol Deviations......................................................................................................18
5.9.
Primary Outcome and Methodology.............................................................................30
5.10. Secondary Outcomes and Analyses ..............................................................................31
5.11. Exploratory Efficacy Analysis......................................................................................32
5.12. Exploratory Objectives Analyses..................................................................................34
5.12.1.
Patient Reported Outcome....................................................................................34
5.12.1.1.
TRIM-D .........................................................................................................34
5.12.1.2.
TRIM-DD ......................................................................................................35
5.12.1.3.
OmniPod U-500 System Exit Questionnaire ...................................................35
5.12.2.
Functionality and Safe Use of the OmniPod U-500 System..................................35
5.12.3.
Subgroup Analysis ...............................................................................................35
5.13. Safety Analyses............................................................................................................36
5.13.1.
Study Treatment Exposure ...................................................................................36


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5.13.2.
Hypoglycemic Episodes.......................................................................................36
5.13.2.1.
Hypoglycemic Analyses .................................................................................37
5.13.3.
Treatment Emergent Adverse Events and Serious Adverse 
Events..................................................................................................................38
5.13.4.
Body Weight........................................................................................................38
5.13.5.
Vital Signs ...........................................................................................................39
5.13.6.
Laboratory Measures............................................................................................39
5.14. Rescue Therapy............................................................................................................40
5.15. Exploratory Pharmacogenetic Analysis ........................................................................40
5.16. Interim Analyses ..........................................................................................................40
6.
Unblinding Plan................................................................................................................41
6.1.
Creating the Blind:  General Blinding Requirements....................................................41
6.2.
Details of Maintaining the Blind...................................................................................41
7.
CGM Addendum...............................................................................................................43
7.1.
Addendum Objectives ..................................................................................................43
7.1.1.
Primary Objective ................................................................................................43
7.1.2.
Secondary Objectives...........................................................................................43
7.2.
Determination of Sample Size ......................................................................................44
7.3.
Analytic Variables........................................................................................................44
7.4.
A Priori Statistical Methods .........................................................................................45
8.
References ........................................................................................................................46


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Table of Contents
Table
Page
Table IBHD.4.1.
Planned Subject Recruitment ....................................................................10
Table IBHD.5.1.
Categorization of Important Protocol Deviations.......................................19


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Table of Contents
Figure
Page
Figure IBHD.4.1.
Illustration of study design for clinical protocol B5K-MC-IBHD. .............11
Figure IBHD.5.1.
Graphical approach to adjust multiplicity. .................................................15


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3.
Revision History
This is the second version of the Statistical Analysis Plan (SAP) for Study B5K-MC-IBHD
(IBHD).  This version is based on protocol amendment B5K-MC-IBHD(a) approved on 07 
December 2016.  The first version of the SAP for Study IBHD was approved on 17 September 
2015 based on original protocol B5K-MC-IBHD.
Some changes in the SAP were made on request from the US Food and Drug Administration 
(FDA).
The overall changes and rationale for the changes made to this SAP are as follows:

Elaborated on the safety and efficacy analyses and handling of missing data in 
“Statistical and Analytical Plans” (Sections 5.2, 5.9, 5.10).  The SAP now provides 
for multiple analysis methods of the primary and key secondary objectives to account 
for missing data.  Based on US FDA request, the Intent-to-Treat (ITT) estimand that 
accounts for all observed data, including those for subjects who have stopped study 
drug but continued in the study, will be used for the primary analysis of the All 
Randomized Set (ARS) and will be analyzed using copy reference multiple 
imputation analyses with analysis of covariance (ANCOVA).  For publications and 
regulatory purposes in other regions, the efficacy estimand that includes only data 
observed while subjects were receiving study drug (excludes data after subjects 
discontinued study drug but remained in study) will be used for the primary analysis 
using mixed model repeated measures (MMRM).  Two sets of similar analysis 
approaches (MMRM and multiple imputation based ANCOVA) as those for the 
primary objective will be used for key secondary endpoints.

The Disposition section (Section 5.4) was edited to remove non-essential summary 
analyses. 

Edited “Concomitant Therapy” (Section 5.6) to remove analyses typically not 
included in parallel studies.

Non-essential listings were removed from the SAP.

The analyses for the different groups (Group A and Group A+B) were clarified.  
Analyses for primary and key secondary objectives will be done for Group A and 
Group A+B.  Analyses not for primary and key secondary objectives (including 
exploratory objectives and safety evaluations not used to assess secondary objectives) 
will be done for Group A+B only.  Subgroup analyses will be done for the primary 
objective and for Group A only.

Edited “Hypoglycemic Analyses” (Section 5.13.2.1) to exclude analyses based on the 
alternative definition of hypoglycemia with blood glucose <50 mg/dL.  The 24-hour 
analysis by 2-hour interval of the 1-year rates of documented symptomatic and severe 
hypoglycemia was added.

In Section 5.8 (Protocol Deviations), the table for the important protocol deviations 
was updated. 


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
A new section for the study unblinding plan was added (Section 6). 


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4.
Study Objectives
4.1.
Primary Objective
The primary objective is to demonstrate the change in hemoglobin A1c (HbA1c) of Humulin® R 
U-500 (U-500R) administered by continuous subcutaneous insulin infusion (CSII) is noninferior 
to U-500R administered by multiple daily injection (MDI) therapy from baseline to the 26-week 
in high-dose insulin-requiring patients with type 2 diabetes mellitus (T2DM) who have 
inadequate glycemic control on high-dose non U-500R (>200 and ≤600 units per day) insulins 
(CSII or MDI) and/or high-dose U-500R insulin (MDI) without use of glucagon-like peptide-1 
(GLP-1) receptor agonists or sodium-glucose cotransporter 2 (SGLT2) inhibitors and with or 
without other insulins/antihyperglycemic agents (AHAs).  This population is referred to as 
Group A. 
The following alternative hypothesis will be tested for the primary objective:
H1:  CSII is noninferior to MDI in change in HbA1c using a noninferiority margin (NIM) 
of 0.4%.
The family-wise type I error rate for the primary objective and the following key secondary 
objectives will be controlled at a 2-sided 5% level by the graphical approach (see Section 5.3 for 
details).
4.2.
Secondary Objectives
4.2.1. Key Secondary Objectives
The following 4 key (alternative hypotheses [H#]) secondary objectives at Week 26 are to 
demonstrate for the main study population (Group A [without use of GLP-1 receptor agonists or 
SGLT2 inhibitors, Section 4.4]) that:
H2:  CSII is superior to MDI in change in fasting plasma glucose (FPG).
H3:  CSII is superior to MDI in proportions of subjects achieving HbA1c targets/values <7.0%.
H4:  CSII is superior to MDI in change in HbA1c.
H5:  CSII is superior to MDI in proportions of subjects achieving HbA1c targets/values <7.5%.
The following 5 key (alternative hypotheses [H#]) secondary objectives are to demonstrate the 
objectives at Week 26 for the total study population (Group A [without use of GLP-1 receptor 
agonists or SGLT2 inhibitors] and Group B [those who use GLP-1 receptor agonists or SGLT2 
inhibitors use, Section 4.4]) that:
H6:  CSII is noninferior to MDI in change in HbA1c using NIM of 0.4%.
H7:  CSII is superior to MDI in change in FPG.
H8:  CSII is superior to MDI in proportions of subjects achieving HbA1c targets/values <7.0%.
H9:  CSII is superior to MDI in change in HbA1c.


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H10:  CSII is superior to MDI in proportions of subjects achieving HbA1c targets/values <7.5%.
4.2.2. Other Secondary Objectives
Additional secondary objectives of the study are to compare the efficacy and safety of U-500R 
given by CSII versus MDI at Week 26 for the main study population Group A and Group A+B 
(the total study population) respectively (separately), with respect to the following:

Proportions of subjects achieving HbA1c targets/values (≤6.5% and <8.0%).

Mean change in 7-point self-monitored blood glucose (SMBG) including mean 
SMBG for each time point measurement.

Change in total daily insulin dose (TDD) (unit and unit/kg). 

Proportions of subjects achieving HbA1c targets/values (≤6.5%, <7.0%, <7.5%, 
and <8.0%) without documented symptomatic hypoglycemia (SMBG 
<50 mg/dL).

Rate and incidence of hypoglycemia (documented [documented symptomatic, 
asymptomatic, and unspecified], severe, and nocturnal).

Change in body weight between treatment groups and as a function of change in 
HbA1c.
4.3.
Exploratory Objectives
Exploratory objectives of the study are the following and will be assessed for the total study 
population (Group A+B):

The change in patient reported outcomes including Treatment-Related Impact 
Measure for Diabetes (TRIM-D) and TRIM-D for Diabetes Device (TRIM-DD) 
surveys from baseline to 26-week value.

Assess subject-reported OmniPod pump experience via OmniPod U-500 System 
Exit Questionnaire.

Assess proportion of subjects with an HbA1c ≥9% and <9% at the 26-week value.

Postprandial contributions to total glycemic burden at baseline to 26-week values 
using area under the curve (AUC) analysis of 7-point SMBG profiles.  

Glycemic variability using 7-point SMBG profiles (including within day and 
day-to-day standard deviation [SD], coefficient of variation, average daily risk 
range, and mean of daily differences). 

Examine the relationship between gene variants including, but not limited to, 
insulin receptor, insulin like growth factor-1, melatonin receptor 1B1, 
adiponectin, transcription factor 7-like 2, phosphoinositide-3-kinase, regulatory 
subunit 1 and B-cell CLL/lymphoma 11A on clinical outcomes. 


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
Evaluate subgroups of baseline TDD >2 and ≤2 units/kg, TDD >200 units at 
baseline that fall below TDD 200 units during the study, baseline TDD >400 and 
≤400 units, users of GLP-1 receptor agonists or SGLT2 inhibitors, and geriatric 
subjects (age ≥65 years and ≥75 years) on each of the primary and secondary 
objectives.

Functionality and safe use of the OmniPod U-500 system.
4.4.
Summary of Study Design
Study IBHD is a Phase 3b, multicenter, randomized, open-label, parallel clinical trial comparing 
U-500R administered by CSII (OmniPod U-500 system) to U-500R administered MDI in high-
dose insulin-requiring subjects with T2DM who have inadequate glycemic control on high-dose 
non U-500R (>200 and ≤600 units per day) insulins (CSII or MDI) and/or U-500R insulin (MDI) 
with or without other insulins/AHAs.  The trial design includes:  1-week screening period, 
2-week lead-in period, and a 26-week treatment period (2 week transition to U-500R MDI 
administered TID, 12 weeks titration and 12 weeks maintenance U-500R CSII or MDI).  As 
shown in the following recruitment plan (Table IBHD.4.1), approximately 320 subjects requiring 
high-dose insulin without use of GLP-1 receptor agonists or SGLT2 inhibitors (Group A) and 
approximately 64 to 96 additional subjects who are using GLP-1 receptor agonists or SGLT2 
inhibitors (Group B) with or without other AHAs will be randomized based on a 1:1 ratio to 2 
treatment arms. After Group A has been fully enrolled, Lilly may stop enrollment for Group B, 
even if the minimum recruitment goal for Group B has not been met.  Approximately 240 
(Group A) and 48 to 72 (Group B) subjects are expected to complete the 26-week treatment 
period (assuming a 25% dropout rate).
Table IBHD.4.1.
Planned Subject Recruitment
Group A
Group B GLP-1 or SGLT2 users
(Target range)
Entered
450
90 to 136
Enrolled/Randomized
320
64 to 96
Completed
240
48 to 72
Abbreviations:  GLP-1 = glucagon-like peptide-1; SGLT2 = sodium-glucose cotransporter 2.
The end of the study for each subject is Visit 17 or the early termination (ET) visit for subjects 
who discontinue early.  Figure IBHD.4.1 illustrates the study design.


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Abbreviations:  CSII = continuous subcutaneous insulin infusion; GLP-1 = glucagon-
like peptide-1; HbA1c = hemoglobin A1c; MDI = multiple daily injections; SGLT2 = 
sodium-glucose cotransporter 2.
a
Subjects will continue their pre-study insulin regimens.
b
Subjects will be stratified and randomly assigned equally between treatment
arms by nonusers (Group A) versus users (Group B) of GLP-1 receptor agonists 
or SGLT2 inhibitors, entry HbA1c ≥8.5% or <8.5%, and U-500R at entry versus 
other insulins. 
c
MDI or CSII and will be transitioned to U-500R by MDI.
d
Telephone visits.
Figure IBHD.4.1.
Illustration of study design for clinical protocol B5K-MC-IBHD.


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5.
A Priori Statistical Methods
5.1.
Sample Size Determination
Approximately 320 subjects requiring high-dose insulin without use of GLP-1 receptor agonists 
or SGLT2 inhibitors (Group A) and approximately 64 to 96 additional subjects with use of 
GLP-1 receptor agonists or SGLT2 inhibitors (Group B) will be randomized based on a 1:1 ratio 
to 2 treatment arms.  Approximately 240 (Group A) and 48 to 72 (Group B) subjects are 
expected to complete the 26-week treatment period (assuming a 25% dropout rate).
The sample size was calculated based on the first primary objective for subjects without use of 
GLP-1 receptor agonists or SGLT2 inhibitors (Group A).  The 240 completers will provide 80% 
statistical power to demonstrate the noninferiority (NIM is 0.4%; SD = 1.1%) of U-500R insulin 
CSII versus U-500R MDI in change in HbA1c at 26 weeks at 2-sided alpha = 0.05. 
5.2.
General Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly and Company (Lilly) or its 
designee.
As specified in Section 4.4, based on the use of GLP-1 receptor agonists or SGLT2 inhibitors, 
there are 2 patient populations in this study:  Group A and Group B. Unless otherwise specified, 
all listings will be done for Group A and B combined (Group A+B), with group name included 
in the report. In general, analyses will be performed as follows:

Summary analyses for primary and key secondary objectives will be done for 
Group A and for Group A+B.

Analyses not for primary and key secondary objectives (including exploratory 
objectives and safety evaluations not used to assess secondary objectives) will be 
done for Group A+B only.

Additional analyses of safety evaluations not used to assess secondary objectives 
may be performed for Group A if the graphical approach to test the primary and 
secondary efficacy objectives rejects only null hypotheses for Group A
(Section 5.3).

Analyses for Group B only may also be conducted if deemed appropriate and 
necessary (for example, for any safety concerns or signals).
The analysis population will also be specified for other analyses in the relevant sections such as 
subject characteristics, disposition, concomitant therapy, etc.
Also, the following 5 patient populations are defined for the analyses in this study:
All Randomized Set (ARS) Population: All entered subjects who were randomized at 
Visit 4 (Week 0) into this study.
Full Analysis Set (FAS) Population: All randomized subjects who received at least 
1 dose of U-500R after randomization.


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Completer Set (CS) Population: All FAS subjects who completed study treatment at the 
primary time point (Week 26). 
Per-Protocol (PP) Population: All FAS subjects who completed the 26-week visit 
without important protocol deviations that will impact the primary outcome as defined in 
Section 5.8, and have both baseline and endpoint HbA1c measurements.
Continuous Glucose Monitoring (CGM) Population: A subset of the ARS population
who also participate the CGM addendum.
Unless otherwise specified, both safety and efficacy analyses will be conducted on the ARS, 
including those who discontinued study treatment or were rescued. Sensitivity analyses may be 
done for the FAS, CS, and PP.  The CGM population will be used for CGM analysis.
Separate efficacy analyses for primary and key secondary objectives will be conducted by either 
including or excluding post study treatment discontinuation data based on different purposes (see 
Section 5.9 and Section 5.10).  In general, missing data will not be imputed, unless otherwise
specified, for example, where the Last-Observation-Carried-Forward (LOCF) method or the 
copy reference multiple imputation method (per FDA’s request) is mentioned.
Outcomes (laboratory, vital signs, weight, patient reported outcome questionnaires) measured 
within 5 days of last treatment dose will be considered on treatment and included in the analysis 
during the treatment period.
For data collected as a running record with an exact date stamp such as adverse events (AEs), 
SMBG, and hypoglycemia event where the dates of the measures were not tied with the date of 
an office visit, post-baseline data recorded at or prior to the last study drug dose date will be 
considered as data on treatment and included in the analysis during the treatment period.  
Baseline will be the last value obtained at or prior to the randomization, unless otherwise stated. 
For continuous measurements, summary statistics will include sample size, mean, median, SD,
minimum, and maximum.  Summary statistics for continuous measures will be provided for 
baseline, the actual measurements at each visit, and the change from baseline measurements to 
each visit.  For all continuous variables, both the actual value and change from baseline (if 
available) will be analyzed.
An MMRM model will be used for continuous outcomes with repeated post-baseline 
measurements to compare treatment arms, unless otherwise noted. An ANCOVA or analysis of 
variance (ANOVA) model may also be used for continuous outcomes to compare treatment arms 
at the endpoint using the LOCF method. Treatment comparisons will be performed for the 
treatment difference in least squares means (LSMean).  LSMean (standard error [SE]) by 
treatment group and visit (if applicable), the LSMean difference between treatment groups, along
with 95% confidence limits of the treatment differences and the p-value for the treatment 
comparison will be displayed.  For the change from baseline, p-value for the within-treatment 
difference will also be displayed. 


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All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, unless otherwise 
stated.
The changes on this SAP are based on the protocol amendment B5K-MC-IBHD(a) approved on 
07 December 2016. Any other changes to the data analysis methods described in the protocol, 
and the justifications, will be described in the clinical study report (CSR).  Additional 
exploratory analyses of the data will be conducted as deemed appropriate.
5.3.
Adjustment for Multiplicity
This section explains the graphical approach in detail and illustrates how the graphical approach 
works in practice.  As discussed by Bretz and colleagues (2009), this testing approach controls 
the family-wise type I error rate at alpha=0.05.  
Figure IBHD.5.1 illustrates the graphical approach to adjust multiplicity for the primary and key 
secondary objectives.  In Figure IBHD.5.1 and for the explanations of the scenarios, the 
alternative hypotheses H1 through H10 are defined as follows:
H1:  CSII is noninferior to MDI in change in HbA1c using a NIM of 0.4%.
Key Secondary Objectives:
H2: CSII is superior to MDI in change in FPG.
H3:  CSII is superior to MDI in proportions of subjects achieving HbA1c targets/values 
<7.0%.
H4:  CSII is superior to MDI in change in HbA1c. 
H5:  CSII is superior to MDI in proportions of subjects achieving HbA1c targets/values 
<7.5%.
H6 through H10 are the same as H1 through H5 except that they are combined for the 
total study population Group A (without use of GLP-1 receptor agonists or SGLT2 
inhibitors) and Group B (those who use GLP-1 receptor agonists or SGLT2 inhibitors). 
As shown by Figure IBHD.5.1, the graphical approach begins with testing the noninferiority for 
the primary objective at alpha=0.05.  The numbers (weights) on the arrows depict the proportion 
of alpha which is propagated to the next test if a null hypothesis is rejected.  At each step, all 
hypotheses are tested based on the current alpha assigned to them by the approach.  If, and only 
if, one of the null hypotheses is rejected, then the alpha flows based on the graph and the weights 
are updated based on the preset algorithms and rules as described by Bretz and colleagues
(2009). 


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Figure IBHD.5.1.
Graphical approach to adjust multiplicity.
5.4.
Subject Disposition
All subjects who discontinue from the study will be listed, and the extent of their participation in 
the study (discontinuation visit) will be reported.  The primary reasons for discontinuation will 
be listed for all subjects who have entered the study (signed informed consent).  Reasons for 
discontinuation of study treatment and discontinuation of study will be summarized by treatment 
for the ARS, by visit and for overall study. All of the summaries will be broken down by 
“discontinue study treatment and device but still remain in the study” and “discontinue the 
study.”  All of the summaries will be done for Group A+B. The treatment comparison will be 
based on Fisher’s exact test. 
All entered subjects will be summarized including, but not limited to, total number of subjects
screened, number of ineligible subjects, number of subjects who entered the lead-in period, total 
number of subjects randomized, and total number of subjects for each treatment. Within each 
treatment arm, the following will be summarized:  number of subjects not treated by U-500R, 
number of subjects not treated by U-500R via the administration method to which they were 
assigned, number of subjects included in FAS, number of subjects who completed treatment, the 


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number of subjects who discontinued study treatment but remained in the study and completed 
the study, the number of subjects who discontinued study treatment but remained in the study 
and discontinued study at a later visit, and the number of subjects who discontinued study and 
study treatment at the same visit.
The number of randomized subjects per investigator for each treatment group and overall will be 
summarized.  The listing of treatment assignment for all randomized subjects will be provided.
5.5.
Subject Characteristics
Demographic and baseline characteristics will be summarized separately for Group A and 
Group A+B by each treatment group and overall for the ARS. For continuous measures, the
treatment groups will be compared using an ANOVA. For categorical measures, treatment 
groups will be compared using Fisher’s exact test.
The following baseline parameters will be included (but are not limited to) in the report:

age (years)

age class (≥65, <65 years)

age class (≥75, <75 years)

gender (male, female)

race (White, American Indian or Alaska Native, Asian, Black or African American, 
Native Hawaiian or Other Pacific Islander)

ethnicity (Hispanic, Non-Hispanic)

body weight (kilograms)

height (centimeters)

body mass index (BMI) (kilograms per meters squared)

duration of diabetes (years)

baseline TDD of insulin (units and units/kg body weight)

TDD class (TDD ≤400U or >400U)

TDD class (TDD≤2 U/kg or >2 U/kg)

systolic blood pressure (mm Hg)

diastolic blood pressure (mm Hg)

pulse rate (beats per minute)

baseline HbA1c value (%),

baseline HbA1c stratification (HbA1c <8.5% or ≥8.5%)

fasting plasma glucose (mg/dL)

baseline estimated glomerular filtration rate (eGFR) (mL/min/1.73m2)

baseline eGFR class (chronic kidney disease [CKD] 1:  ≥90 mL/min/1.73m2; CKD 2:  
≥60 and <90 mL/min/1.73m2; CKD stage 3:  ≥30 and <60 mL/min/1.73m2)

baseline AHA class: metformin, dipeptidyl peptidase-4 (DPP-4) inhibitors (sitagliptin, 
saxagliptin, linagliptin, and alogliptin), pioglitazone (Actos), GLP-1 receptor agonists 


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(albiglutide, dulaglutide, or liraglutide), and SGLT2 inhibitors (canagliflozin, 
dapagliflozin, empagliflozin)  

baseline insulin type (basal only, basal/bolus; human, analogues, premix)
o
basal only

human: neutral protamine Hagedorn (NPH) (Humulin N, Novolin 
N), Humulin U-500R (used as basal insulin only)

analogues: detemir (Levemir) or glargine (Lantus), glargine U-300 
(Toujeo)
o
basal/bolus

human basal:  NPH (Humulin N, Novolin N) plus Human insulin 
bolus:  regular (Humulin R, Novolin R)

human basal/bolus:  Humulin U-500R

analogue basal: detemir or glargine plus analogue bolus:  lispro 
(Humalog) or glulisine (Apidra) or aspart (NovoLog, NovoRapid), 
lispro U-200 (Humalog U-200 KwikPen)

premix:  

human: NPH/regular 70/30 (Humulin 70/30, Novolin 
70/30)  

analogues: insulin aspart 70/30 (NovoLog Mix 70/30), 
insulin lispro 75/25 (Humalog Mix 75/25), insulin lispro 
50/50 (Humalog Mix50/50)

others

baseline incidence of hypoglycemic event: documented (documented symptomatic, 
asymptomatic and unspecified), severe and nocturnal; defined as the incidence during the 
2-week lead-in period prior to randomization (Visit 2 through Visit 4)

baseline rate of hypoglycemic events (same categories as for baseline incidence) per 
30 days during the 2-week lead-in period prior to randomization (Visit 2 through Visit 4)
5.6.
Concomitant Therapy
Listings of concomitant medications will be provided. Concomitant medication use will be 
reported based on World Health Organization (WHO) dictionary. Medications will be ordered
by decreasing frequency within Anatomical Therapeutic Chemical (ATC) level 4. For Group A 
and Group A+B, frequencies and percentages of concomitant medication for glycemic control 
used prior to and after randomization will be summarized and compared (using Fisher’s exact 
test) by treatments for ARS. Frequencies and percentages of other general concomitant 
medication used after randomization will be summarized and compared (using Fisher’s exact 
test) by treatments for ARS in Group A+B.  


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5.7.
Treatment Compliance
The analyses described in this section will be done for both Group A and Group A+B. 
Compliance issues, as stated in study protocol Section 9.12, will be listed and summarized as 
protocol deviations and details can be found in this SAP (Section 5.8). Summaries of actual 
value and change from baseline (Visit 4) of TRIM-D compliance transformed score will include 
sample size, mean, SD, median, minimum, and maximum at each assessment at each visit for 
each treatment group and for the ARS population. The actual value and change from baseline in 
compliance scores will be analyzed using an MMRM approach. 
For Group A, the MMRM model will include the following fixed effects:  treatment (U-500R 
CSII, U-500R MDI), weeks on treatment, the interaction between treatment and weeks, and the 
stratification factors (U-500R at entry versus other insulins, entry HbA1c ≥8.5% or <8.5%).  The 
model will also include the corresponding baseline of the response variable. 
For Group A+B, the same MMRM model in Group A above will be used with the addition of the 
stratification factor (nonusers versus users of GLP-1 receptor agonists or SGLT2 inhibitors).
The proportion of subjects who have TRIM-D compliance score ≥80 at endpoint or ET will be 
analyzed using logistic regression including the similar fixed effects used in primary analysis.
5.8.
Protocol Deviations
A listing and summary of important protocol deviations will be generated for ARS for Group 
A+B and Group A (summary only). Important protocol deviations are defined as deviations 
from the study protocol that may compromise the data integrity and subjects’ safety. Important 
protocol deviations are included in Table IBHD.5.1 but these are not all-inclusive. Some 
situations not listed below may be decided on a case-by-case basis by the study team regarding 
whether to be considered as important and/or exclude subjects from the PP population. Subjects
with one or more important protocol deviations that impact the primary efficacy outcome (per-
protocol population exclusion flag [PPFLG]=’Y’ in Table IBHD.5.1) will be excluded from the 
PP population. 


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Table IBHD.5.1.
Categorization of Important Protocol Deviations
Category
Sub-Category
Study Specific
Deviation Description
PPFLG
Methods of Identification
Informed 
Consent
Informed 
Consent Not 
Obtained
Lack of patient 
signature for main 
protocol
1.
Issues with informed consent:  lack 
of patient signature (main protocol )
Y
CRF data indicate the 
Study ICD date missing 
for main study.
Informed 
Consent
Improper 
Consent
NA
2.
Issues with informed consent:  lack 
of PI signature, date signed is after 
V1, lack of patient signature for 
CGM, revised ICD not signed (main 
protocol and CGM addendum) 
N
Monitoring
Eligibility
Inclusion/
Exclusion
No T2DM
3.
No confirmation of T2DM
Y
Medical history CRF data 
indicate missing record
Eligibility
Inclusion/
Exclusion
No T2DM
4.
Not diagnosed with T2DM
Y
Monitoring
Eligibility
Inclusion/
Exclusion
TDD out of range 
at study entry
5.
TDD is out of range (Inclusion 
range is >200U or ≤600U) at Visit 1 
N
Data Management Reports 
and Monitoring
Eligibility
Inclusion/
Exclusion
TDD out of range 
at study entry
6.
4.TDD is out of range (Inclusion 
range is >200U or ≤600U) at Visit 4
Y
Data Management Reports 
and Monitoring
Eligibility
Inclusion/
Exclusion
HbA1c out of the 
range at study 
entry
7.
HbA1c out of the range at study 
entry:  (Inclusion range ≥7.5% and 
≤12.0) at Visit 1 
Y
GLS data
Eligibility
Inclusion/
Exclusion
Age out of range
8.
Age out of range (>85 or <18 yrs) 
N
Edits or monitoring
Eligibility
Inclusion/
Exclusion
BMI out of range 
at study entry
9.
BMI out of range at study entry:  
(Inclusion range ≥25kg/m2 and
≤50kg/m2) at Visit 1
Y
Edits
Eligibility
Inclusion/
Exclusion
Unstable Body 
Weight at Visit 1
10. Unstable Body Weight at Visit 1 
Y
Monitoring
Eligibility
Inclusion/
Exclusion
Took prohibited 
conmed at entry
11. Prohibited Conmed Therapy at 
study entry
N
Edits and Monitoring
Eligibility
Inclusion/
Exclusion
Took pioglitazone 
45mg at entry
12. Took pioglitazone 45 mg at study 
entry
Y
Edits and Monitoring


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Categorization of Important Protocol Deviations
Category
Sub-Category
Study Specific
Deviation Description
PPFLG
Methods of Identification
Study 
Procedures
Excluded 
Conmeds
Took prohibited 
conmed 
13. Prohibited Conmed Therapy at any 
time during the trial
N
Edits and Monitoring
Study 
Procedures
Excluded 
Conmeds
Took pioglitzone 
45 mg
14. Took Pioglitazone 45 mg at any 
time during the trial
Y
Edits and Monitoring
Eligibility
Inclusion/
Exclusion
AHA therapy not 
stable
15. AHA Therapy not stable per 
protocol requirements prior to 
Visit 1
N
Monitoring
Eligibility
Inclusion/
Exclusion
Diagnosed with 
other types of 
diabetes aside from 
T2DM
16. Diagnosed with T1DM or other 
types of diabetes aside from T2DM 
Y
Monitoring
Eligibility
Inclusion/
Exclusion
Liver disease
17. Have obvious clinical or 
radiographic signs/symptoms of 
liver disease (except nonalchoholic 
fatty liver disease), cirrhosis, acute 
or chronic hepatitis, or alanine 
aminotransferase (ALT/SGPT) 
and/or aspartate aminotransferase 
(AST/SGOT) levels ≥2.5X upper 
limit of normal (ULN), alkaline 
phosphatase ≥2X ULN or total 
bilirubin ≥2X ULN (with the 
exception of known Gilbert 
syndrome) as defined by central 
laboratory. 
N
Monitoring and GLS data 
Eligibility
Inclusion/
Exclusion
Chronic kidney 
disease Stage 4 and 
higher
18. Have chronic kidney disease 
Stage 4 and higher (eGFR 
<30 mL/min/1.73 m2) or history of 
renal transplantation.  
N
GLS data and monitoring


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Categorization of Important Protocol Deviations
Category
Sub-Category
Study Specific
Deviation Description
PPFLG
Methods of Identification
Eligibility
Inclusion/
Exclusion
History of more 
than 1 severe 
hypoglycemia
episode
19. Have history of more than 1 episode 
of severe hypoglycemia requiring 
assistance of another person, 
resulting in coma, seizures, or 
disorientation within the 6 months 
prior to Visit 1. 
N
CRF or monitoring
Eligibility
Inclusion/
Exclusion
Received U-500R 
insulin by CSII
20. Have received U-500R insulin by 
CSII in the 3 months prior to 
Visit 1. 
Y
CRF or monitoring
Eligibility
Inclusion/
Exclusion
Had a blood 
transfusion or 
severe blood loss
21. Have had a blood transfusion or 
severe blood loss within 3 months 
prior to Visit 1or have known 
hemoglobinopathy, hemolytic 
anemia, or sickle cell anemia that is 
known to interfere with HbA1c 
measurement.
Y
CRF or monitoring
Eligibility
Inclusion/
Exclusion
Known allergy to 
human insulin 
preparations
22. Have known allergy to human 
insulin preparations or excipients 
contained in these products or prior 
history of suspected antibodies to 
human insulin. 
N
Monitoring
Eligibility
Inclusion/
Exclusion
Taking chronic 
systemic 
glucocorticoid 
therapy
23. Are taking chronic (lasting longer 
than 14 consecutive days) systemic 
glucocorticoid therapy (excluding 
topical, intra-articular, intraocular, 
and inhaled prescriptions), or have 
received any systemic 
glucocorticoid therapy within the 
4 weeks immediately prior to 
Visit 1.  
Y
CRF or monitoring


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Categorization of Important Protocol Deviations
Category
Sub-Category
Study Specific
Deviation Description
PPFLG
Methods of Identification
Eligibility
Inclusion/
Exclusion
Have an irregular 
sleep/wake cycle
24. Have an irregular sleep/wake cycle 
(for example, subjects who sleep 
during the day and work during the 
night), in the investigator’s opinion. 
N
Monitoring
Eligibility
Inclusion/
Exclusion
Intention to fasting
25. Intend to participate in an extended 
period of fasting during the study 
period (for religious or other 
purposes.)  
N
Medical History; 
Monitoring
Eligibility
Inclusion/
Exclusion
Took prohibited 
conmed at entry
26. Have used rosiglitazone, 
sulfonylurea/glinides, pramlintide, 
once-weekly or twice-daily 
exenatide, or other AHAs not listed 
in the inclusion criteria in the 3 
months prior to Visit 1 are taking 
AHA doses exceeding the 
respective product labels, or have a 
contraindication to current AHA 
usage per respective product labels. 
N
CRF or monitoring
Eligibility
Inclusion/
Exclusion
Took weight loss 
drugs
27. Have used any weight loss drugs 
(for example, prescription drugs:  
lorcaserin, orlistat, phentermine, 
phentermine/topiramate, 
naltrexone/bupropion, or over-the-
counter weight loss medications and 
herbal supplements) in the 3 months 
prior to Visit 1.  
N
CRF or monitoring
Eligibility
Inclusion/
Exclusion
History of bariatric 
surgery
28. Have a history of bariatric surgery 
including Roux-en-Y gastric bypass 
surgery, gastric banding, and/or 
gastric sleeve.  
Y
CRF or monitoring


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Categorization of Important Protocol Deviations
Category
Sub-Category
Study Specific
Deviation Description
PPFLG
Methods of Identification
Eligibility
Inclusion/
Exclusion
History of 
malignancy
29. Have a history or an active or 
untreated malignancy, or in 
remission from a clinically 
important malignancy (other than 
basal cell or squamous cell skin 
cancer, in situ carcinomas of the 
cervix, colon or prostate that is 
considered cured) during the last 
5 years before Visit 1 (if 
malignancy occurred >5 years ago, 
subject is eligible with 
documentation of disease-free state 
since treatment.)   
N
CRF or monitoring
Eligibility
Inclusion/
Exclusion
Hearing loss 
and/or vision 
impairment
30. Important hearing loss and/or vision 
impairment deemed by the 
investigator to interfere with the 
safe use of the OmniPod U-500 
System.  
N
Monitoring
Eligibility
Inclusion/
Exclusion
Cardiac disease
31. Have cardiac disease with 
functional status that is Class III or 
IV according to the New York Heart 
Association Cardiac Disease 
Classification. 
N
Monitoring


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Categorization of Important Protocol Deviations
Category
Sub-Category
Study Specific
Deviation Description
PPFLG
Methods of Identification
Eligibility
Inclusion/
Exclusion
Breastfeeding or 
pregnant
32. Are women breastfeeding or 
pregnant or intend to become 
pregnant during the course of the 
study; are men who intend to 
impregnate their partners; or are 
sexually active of procreation 
potential not actively practicing 
birth control by a method 
determined by the investigator to be 
medically acceptable.  
N
CRF or monitoring
Eligibility
Inclusion/
Exclusion
Investigator-site 
personnel and 
family
33. Are investigator-site personnel 
directly affiliated with this study 
and/or their immediate families.  
Immediate family is defined as 
spouse, parent, child, or sibling, 
whether biological or legally 
adopted. 
N
Monitoring
Source Documentation –
should catch that all I/E 
were checked
Eligibility
Inclusion/
Exclusion
Lilly, Insulet, or 
TPO employee
34. Are Lilly or Insulet employees or 
are employees of third-party 
organizations (TPOs) involved in 
study who require exclusion of their 
employees.  
N
Monitoring
Source Documentation –
should catch that all I/E 
were checked


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Categorization of Important Protocol Deviations
Category
Sub-Category
Study Specific
Deviation Description
PPFLG
Methods of Identification
Eligibility
Inclusion/
Exclusion
Currently in any 
other clinical trials
35. Are currently enrolled in, or 
discontinued within the last 30 days, 
from a clinical trial involving an 
investigational product or non-
approved use of a drug or device 
(other than the study treatment used 
in this study), or concurrently
enrolled in any other type of 
medical research judged not to be 
scientifically or medically 
compatible with this study, and any 
subjects who have previously 
completed or withdrawn from this 
study.  
Y
Summary or Monitoring
Source Documentation –
should catch that all I/E 
were checked
Eligibility
Inclusion/
Exclusion
Unwilling or 
unable to 
independently 
perform study 
procedures
36. Are unwilling or unable to 
independently perform study 
procedures, such as monitoring 
SMBG levels, recording diary data, 
and/or administering medication via 
syringe or CSII as applicable, or 
have any illness or condition 
(including known drug or alcohol 
abuse or psychiatric disorder) within 
the 6 months prior to Visit 1, that 
precludes subject from following 
and completing the protocol 
according to the investigator’s 
judgment.  Subjects may not use a 
proxy to perform collection 
procedures, administer medication 
or record data.  
N
Monitoring
Source Documentation –
should catch that all I/E 
were checked


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Categorization of Important Protocol Deviations
Category
Sub-Category
Study Specific
Deviation Description
PPFLG
Methods of Identification
Study 
Procedures
Other
Missing HbA1c at 
V4 and/or V17
37. Missing primary efficacy measures 
at primary time point:  specifically, 
missing HbA1c values at Visit 4 
and/or Visit 17.  
Y
GLS data and monitoring
Study 
Procedures
Other
Missing fasting 
plasma glucose (by 
laboratory 
measurement) at 
V4 and/or V17
38. Missing secondary efficacy 
measures at primary time point:  
specifically, missing fasting plasma 
glucose (FPG) values by laboratory 
measurement at Visit 4 and/or Visit 
17.  
N
GLS data 
Study 
Procedures
Other
Random (as 
opposed to fasting) 
plasma glucose at 
V4 and/or V17
39. Fasting plasma glucose (by 
laboratory measurement) later 
determined to be a random draw at 
Visit 4 and/or Visit 17.  
N
GLS data
Study 
Procedures
Visit Schedule 
Criteria
Missed office visit 
or visit window 
exceeds 3 weeks
40. Any missed office visit during the 
entire study or visit window 
intervals exceed 3 weeks outside of 
expected visit dates for in-office 
visits that significantly impacted the 
accuracy or reliability of the study 
data (does not include the allowable 
deviation time per study schedule).
N
Monitoring – Source 
Documentation
Study 
Procedures
Other
Subject continues
study after 
pregnant
41. If the subject continues in the study 
after becoming pregnant post study 
enrollment. 
N
Monitoring
Study 
Procedures
Violation of 
Discontinuation 
Criteria
Subject continues
treatment after 
meeting DC 
criteria 
42. Subject does not DC the study 
treatment or study while he/she 
should have DCd based on protocol 
criteria:  Section 8.3.2 and 
Section 8.3.3 in study protocol.
Y
Monitoring
Study 
Procedures
Other
Subjects change 
AHA dose
43. Subject changes their dose of 
noninsulin pre-study AHA 
medications.
Y
InForm or Monitoring


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Categorization of Important Protocol Deviations
Category
Sub-Category
Study Specific
Deviation Description
PPFLG
Methods of Identification
Investigational 
Product
Treatment 
Assignment/ 
Randomization 
error
IWRS data entry 
errors that impact 
patient 
stratification
44. IWRS data entry errors that impact 
patient stratification (data entry 
error into IWRS- prior to 
randomization)
N
Check to match IWRS to 
visits
Safety 
SAE
Failure to report 
SAE
45. Failure to report an SAE as required 
by protocol/GCP standards  
N
Monitoring - Make sure 
SAEs are listed;  Source 
documentation
Investigational 
Product
Other
Incorrect study 
treatment
46. Incorrect study treatment (post 
randomization) will be reviewed on 
a case by case basis (includes drug 
dispensing errors and failure to 
maintain their randomization 
treatment – CSII or MDI).
Y
Monitoring
Administrative/
Oversight
Suspected 
Misconduct
Suspected Fraud
47. Suspected Fraud 
N
Monitoring
Administrative/
Oversight
Suspected 
Misconduct
Suspected Fraud
48. Confirmed Fraud 
Y
Monitoring
Investigational 
Product
Other
Use of expired CT 
Material <7 days
49. Use of expired CT Material less 
than 7 consecutive days
N
Monitoring
Investigational 
Product
Other
Use of expired CT 
Material ≥7 days
50. Use of expired CT Material for at 
least 7 consecutive days
Y
Monitoring
Investigational 
Product
Patient took 
study drug not fit 
for use
Received drug that 
was declared “Not 
Fit for Use” <7 
consecutive days
51. Subject received drug that was 
declared “Not Fit For Use” for less 
than 7 days  
N
Monitoring
Investigational 
Product
Patient took 
study drug not fit 
for use
Received drug that 
was declared “Not 
Fit for Use” ≥7 
consecutive days
52. Subject received drug that was 
declared “Not Fit for Use” for at 
least 7 consecutive days
Y
Monitoring
Administrative/
Oversight
Suspected 
Misconduct
Suspected 
scientific 
misconduct
53. Suspected Scientific misconduct 
N
Monitoring


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Categorization of Important Protocol Deviations
Category
Sub-Category
Study Specific
Deviation Description
PPFLG
Methods of Identification
Administrative/
Oversight
Suspected 
Misconduct
Confirmed 
scientific 
misconduct
54. Only confirmed scientific 
misconduct will lead to exclusion 
from per-protocol population.
Y
Monitoring
Investigational 
Product
Compliance
Off study drug for 
>7 consecutive 
days
55. Subject off study drug for more than 
7 consecutive days
Y
Monitoring
Investigational 
Product
Compliance
Subject <80% 
compliant with 
algorithm
56. If the investigator determines that 
that patient is noncompliant (<80% 
compliant with algorithm) and 
should be discontinued.
Y
Monitoring
Study 
Procedures
Other
Lack of initiation 
of rescue therapy
57. Lack of initiation of rescue therapy 
despite meeting rescue criteria.
N
Monitoring
Study 
Procedures
Other
Inappropriate 
rescue
58. Inappropriate rescue despite not 
meeting rescue criteria.
Y
Monitoring; Source 
Documents
Investigational 
Product
Compliance
Took more than 
the prescribed 
study treatment
59. Is judged by the investigator to have 
intentionally or repeatedly taken 
more or less than the prescribed 
amount of medication that may 
cause patient safety concerns.
N
Monitoring
Study 
Procedures
Other
Other, Not 
specified
60. Other, not specified (i.e. delay in 
randomization, investigator used PI 
discretion vs. titration tools, staff 
member not listed on 1572, site did 
not use IWRS to dispense 
medication or Pod, dosing error)
N
Monitoring
Eligibility
Inclusion/Exclusi
on
Subject switched 
to U-500R prior to 
V4
61. Subject did not continue their pre-
study insulin regimen until Visit 4; 
subject switched from their baseline 
insulin to U-500R at Visit 1
Y
Monitoring


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Categorization of Important Protocol Deviations (Abbreviations)
Abbreviations:  AHA = antihyperglycemic agents; BMI = body mass index; Conmed = concomitant medication; CGM = continuous glucose monitoring; CRF = 
case report form; CSII = continuous subcutaneous insulin infusion; DC = discontinue; DCd = discontinued; GLS = Generic Laboratory System; HbA1c = 
hemoglobin A1c; ICD = informed consent document; I/E = inclusion/exclusion; IWRS = Interactive Web Response System; MDI = multiple daily injections; N 
= no; NA = not applicable; PPFLG = per-protocol population exclusion flag; SAE = serious adverse event; SGOT = serum glutamic oxaloacetic transaminase; 
SGPT = serum glutamic pyruvic transaminase; SMBG = self-monitored blood glucose; T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus; TDD 
= total daily dose; ULN = upper limit of normal; V = visit; Y = yes.


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5.9.
Primary Outcome and Methodology
The primary efficacy measure is change from baseline to the 26-week HbA1c value.  The 
primary analysis will be conducted for the ARS population in Group A.  There will be 2 primary 
analysis methods for different purposes as follows.
1. Per FDA’s request, the analysis method will use the copy reference approach to impute 
missing data based on multiple imputations with a pattern mixture model (later referred 
to as ‘copy reference multiple imputation analysis’).  This analysis will include post study 
treatment discontinuation data.  The reference is all observed data from all randomized 
subjects in the U-500R MDI arm who discontinued study treatment but completed the 
study without missing data.  After imputation, an ANCOVA with baseline HbA1c as a 
covariate, treatment (U-500R CSII, U-500R MDI) and the stratification factor (U-500R at 
entry versus other insulins) as fixed effects will be used to analyze the 26-week HbA1c 
including imputed values. 
If in the reference group mentioned above there is only a limited number of subjects and 
this leads to a failure in performing the proposed multiple imputation analysis, the 
reference will be changed to include all observed data from all randomized subjects in the 
U-500R MDI arm who do not have missing data. 
2. For manuscripts and other non-FDA submission purposes, an MMRM model that does 
not include post study treatment discontinuation data and adjusts for missing data through 
an observed-data-likelihood-based approach will be used.  The model will include the 
following fixed effects:  treatment (U-500R CSII, U-500R MDI), weeks on treatment, the 
interaction between treatment and weeks, and the stratification factor (U-500R at entry 
versus other insulins).  The model will also include baseline HbA1c as a covariate. 
As a sensitivity analysis to the missing at random assumption of MMRM model, a stress 
test will be performed.  The missing data are first imputed with the missing at random 
assumption.  Prior to multiple-imputation analysis, in the CSII arm the imputed values 
will be replaced by the imputed value plus delta.  Multiple values of delta within a 
clinically reasonable and meaningful range will be tested (delta=0.1, 0.2, 0.3, 0.4) to 
assess if the conclusion from the MMRM primary analysis changes.
For the MMRM model, the Kenward-Roger approximation will be used to estimate denominator 
degrees of freedom. An unstructured covariance matrix will be used to model the within-subject 
errors. If the unstructured covariance configuration results in a lack of convergence, then the 
following variance-covariance matrix will be used (in order) until one converges:
Heterogeneous Toeplitz; Heterogeneous First Order Autoregressive; Heterogeneous Compound 
Symmetry; Toeplitz; First Order Autoregressive; Compound Symmetry. If all variance-
covariance matrices selected fail to converge, Variance Components will be used as the next 
attempt at convergence.
The test for the primary objective of non-inferiority will be performed at the 0.05 significance 
level using the LSMean estimate of the difference in change in HbA1c between the 2 treatments 


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at Week 26.  Non-inferiority will be established if the upper limit of a 2-sided 95% confidence 
interval (CI) for the difference (U-500R CSII minus U-500R MDI) is below the NIM of 0.4%.
Using the LSMean estimate of the difference in change in HbA1c between the 2 treatments, 
superiority will be established if the upper limit of a 2-sided 95% CI for the difference (U-500R 
CSII minus U-500R MDI) is below 0.
The following supportive and sensitivity analyses will also be conducted:

If the following sets are different from ARS, then similar copy reference 
multiple imputation and MMRM analyses will be done for the FAS (subjects 
who were randomized and received at least 1 dose of the study insulin through 
the administration method they were assigned to), all completer set (subjects 
who complete the study treatment), and the per-protocol population (subjects 
included in the ARS who have completed the study without important 
protocol deviations that will impact the primary outcome).

An ANCOVA model with similar fixed effects as in the copy reference 
multiple imputation analysis using LOCF method for the ARS will also be 
performed.

For the analysis performed for the ARS population for Groups A+B, the 
analysis model will include an additional stratification factor (nonusers versus 
users of GLP-1 receptor agonists or SGLT2 inhibitors) as a fixed effect.
5.10. Secondary Outcomes and Analyses
For Group A and Group A+B in the ARS population, similar to the primary analysis, 2 sets of 
analysis approaches (copy reference multiple imputation and MMRM) will be used to analyze 
the change from baseline for the following key secondary endpoints 1 and 2 at Week 26.  For
endpoint 3, only MMRM analysis will be performed.
1) FPG (by laboratory measurement)
2) 7-point SMBG
3) total daily insulin dose (TDD)
For Group A, the MMRM model will include the following fixed effects:  treatment (U-500R 
CSII, U-500R MDI), weeks on treatment, the interaction between treatment and weeks, and the 
stratification factors (U-500R at entry versus other insulins, entry HbA1c ≥8.5% or <8.5%).  The 
model will also include the corresponding baseline of the response variable. For the copy 
reference approach, the ANCOVA model will include the following fixed effects:  treatment 
(U-500R CSII, U-500R MDI), the stratification factors (U-500R at entry versus other insulins,
entry HbA1c ≥8.5% or <8.5%) and the corresponding baseline measures.
For Group A+B, the same MMRM model and ANCOVA models in Group A above will be used 
with the addition of the stratification factor (nonusers versus users of GLP-1 receptor agonists or 
SGLT2 inhibitors).
For SMBG, the average of the 2 non-consecutive-day values for scheduled visits will be used. 


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Total daily dose will be calculated as the sum of maximum total bolus dose and basal dose at 
each visit.  The maximum total bolus dose of the 3 days prior to each scheduled visit for each 
subject will be used to calculate the TDD value for data summary and statistical analysis to avoid 
the underestimated TDD due to missed meal(s). The basal dose will be only collected for 1 day 
prior to each visit and used to calculate TDD for each visit. Body weight at each visit will be 
used for TDD (units/kg) calculation. Summary statistics will be done for both actual values and 
change from baseline (CFBL) values.  The percentages of bolus and basal doses from TDD in 
the U-500R CSII group will be summarized by visit.
Similar to the primary analysis, 2 sets of analysis approaches (repeated-measure [or longitudinal]
logistic regression excluding post study treatment discontinuation data and the multiple 
imputations based logistic regression including post study treatment discontinuation data) will be 
applied to assess the following secondary objectives in the following values at Week 26:

proportions of subjects achieving HbA1c targets/values (≤6.5%, <7.0%, 
<7.5%, and <8.0%)

proportions of subjects achieving HbA1c targets/values (≤6.5%, <7.0%, 
<7.5%, and <8.0%) without documented symptomatic hypoglycemia (SMBG 
<50 mg/dL)
The logistic regression model will include similar fixed effects as in the above ANCOVA and 
MMRM models.  The proportion of subjects achieving HbA1c targets with no documented 
symptomatic hypoglycemia (from baseline to the corresponding visit) will be analyzed using 
similar logistic regression models including the baseline documented symptomatic hypoglycemia 
event rate as a covariate.
Analyses to assess the following 2 secondary objectives are presented in Section 5.13 since those 
are considered safety measures:

rate and incidence of hypoglycemia (documented [documented symptomatic, 
asymptomatic, and unspecified], severe, and nocturnal)

change in body weight between treatment groups and as a function of change 
in HbA1c
5.11. Exploratory Efficacy Analysis
As mentioned in Section 5.2, exploratory objectives will be analyzed for Group A+B. Summary 
statistics for both actual values and CFBL values will be reported for each treatment by visit for 
the following parameters related to 7-point SMBG:

within-day glucose variability measured by the SD of 7-point SMBG

between-day glucose variability measured by the SD of the SMBG during the 
2-nonconsecutive-day measurement within the same scheduled visit

within-day and between-day glucose coefficient of variation (CV) of 7-point 
SMBG (Clarke and Kovatchev 2009)

average daily risk range (ADRR) defined by (Kovatchev et al. 2006)


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
mean of daily differences (MODD) calculated as the average of the difference 
between values on different days within the same scheduled visit but at the 
same time
Each of the parameters above will be analyzed using an MMRM model which includes the 
following fixed effects:  treatment (U-500R CSII, U-500R MDI), weeks on treatment, the 
interaction between treatment and weeks, and the stratification factors (U-500R at entry versus 
other insulins, entry HbA1c ≥8.5% or <8.5%, and nonusers versus users of GLP-1 receptor 
agonists or SGLT2 inhibitors).  The model will also include the corresponding baseline of the 
response variable.  An ANCOVA will also be used to compare treatment arms at endpoint using 
the LOCF method.  The ANCOVA model will include the same fixed effects in the MMRM 
model but without the terms involving weeks
The postprandial contribution to total hyperglycemia will be further explored (Riddle et al. 
2011).  The daily blood glucose (BG) response to meals will be estimated by calculating the 
incremental AUC of daytime BG from the overall glucose profile. Four areas were calculated 
geometrically from the seven-point curve as follows: 
1) normal glycemic exposure (AUCN): 100 mg/dLx24 h = 2,400 mg/dL per hour of 
exposure 
2) basal hyperglycemia (BHG) (AUCB): the area between 100 mg/dL and a line 
projected rightward for 24 hours from the fasting (before breakfast) glucose value 
in the profile (the area is taken to represent the daily abnormal glycemic exposure 
resulting from BHG)
3) postprandial hyperglycemia (PPHG) (AUCP): the area above the line projected
rightward from the fasting sample before breakfast and below the line connecting 
the 6 remaining points, minus any area below the line projected from the basal 
value, if applicable (this area is considered a reflection of the postprandial 
glycemic responses to breakfast, lunch, and dinner) 
4) total glucose (AUCG): the total area under the glucose curve is the sum of the 
other 3 areas [AUCG = AUCN + AUCB + AUCP]. As a result, the relative 
contributions of postprandial and fasting BG to the total BG increment were 
calculated, respectively, by using the following equations: [AUCP/(AUCB + 
AUCP)] x100% for the postprandial contribution and [ AUCB/(AUCB + AUCP)] 
x 100% for the basal contribution. Negative values were set to zero. 
Analyses include Mean (SD) of and Pearson correlation (p-value) between HbA1c CFBL at 
Week 26 (LOCF) and each of CFBL of: AUCB, AUCP, AUCG, BHG contribution and PHG
contribution at Week 26 (LOCF). The AUCB and AUCP will be analyzed separately by fitting 
ANCOVA model with baseline corresponding parameter as a covariate, treatment as fixed effect 
to compare the treatment effect. 
Total hyperglycemia (%) separated by BHG and PPHG will be plotted for each treatment in bar 
chart format with x-axis for different HbA1c category (<6.5%, 6.5% to <7%, 7% to <7.5%, 7.5
to <8%, ≥8%, and overall).


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Proportions of subjects with HbA1c ≥9% or <9% at Week 26 will be reported and will be 
analyzed using the same logistic regression model used in the analysis of the proportions of 
subjects achieving different HbA1c targets in Section 5.10.
5.12. Exploratory Objectives Analyses
As mentioned in Section 5.2, exploratory objectives will be analyzed for ARS in Group A+B
unless otherwise specified.
The plan of analysis for the exploratory pharmacogenetic objective is in Section 5.15 of this 
document.
5.12.1. Patient Reported Outcome
The TRIM-D and TRIM-DD will be administered at Visit 4 (Week 0, prior to randomization), at
Visit 13 (Week 14) and at Visit 17 (Week 26) or ET if subjects do not complete the full 26 weeks 
of the study. 
If a respondent answers at least half of the items in a multi-item domain (or half plus one in the 
case of domains with an odd number of items) then a domain score should be calculated. The 
average score (across completed items in the same domain) for that respondent will be used to 
estimate any missing item in that domain. For example, if a respondent leaves 1 item in the 
5-item Diabetes Management domain blank, substitute the respondent’s average score (across the 
4 answered Diabetes Management items) for the missing score for that item.
For both TRIM-D and TRIM-DD, the domain score and overall score will be transformed to a 
0-100 scales by Domain = (raw score – lowest possible raw score)/possible raw score range 
*100. The transformed score will be used for the analysis purpose.
5.12.1.1. TRIM-D
The TRIM-D consists of 28 items which are measured on a 5-point scale, where a higher score 
indicates a better health state. In addition to an overall score, the TRIM-D items make up the 
5 domains of impact: treatment burden (6 items), daily life (5 items), diabetes management 
(5 items), compliance (4 items) (see Section 5.7), and psychological health (8 items). The 
domains of daily life, compliance, and psychological health need to be reverse coded for scoring.
Summaries of domain and overall transformed scores will include sample size, mean, SD, 
median, minimum, and maximum at each assessment at each visit for each treatment group and 
for the ARS population. The actual value and change from baseline (Visit 4) will be summarized 
for the overall analysis population. The actual value and change from baseline in domain 
transformed scores and total transformed scores of TRIM-D will be analyzed using an MMRM 
approach. The MMRM model will include the following fixed effects:  treatment (U-500R CSII, 
U-500R MDI), weeks on treatment, the interaction between treatment and weeks, and the 
stratification factors (U-500R at entry versus other insulins, entry HbA1c ≥8.5% or <8.5% and 
nonusers versus users of GLP-1 receptor agonists or SGLT2 inhibitors).  The model will also 
include the corresponding baseline measures as a covariate. The covariance matrix will be 
chosen in the same order as the primary analysis. 


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The proportion of subjects who have TRIM-D compliance transformed score ≥80 at endpoint or 
ET will be analyzed using logistic regression with the following fixed effects: treatment 
(U-500R CSII, U-500R MDI) and the stratification factors (U-500R at entry versus other 
insulins, entry HbA1c ≥8.5% or <8.5%, and nonusers versus users of GLP-1 receptor agonists or 
SGLT2 inhibitors).  
5.12.1.2. TRIM-DD
The TRIM-DD consists of 8 items which are measured on a 5-point scale, where a higher score 
indicates a better health state. In addition to an overall score, the TRIM-DD items make up the 
2 domains of impact: device function (5 items) and bother of device (3 items). The bother of 
device domain need to be reverse coded for scoring.
Summaries of domain and overall transformed scores will include sample size, mean, SD, 
median, minimum, and maximum at each assessment at each visit for each treatment group and 
for the ARS population. The actual value and change from baseline (Visit 4) in domain and total 
transformed scores of TRIM-DD will be summarized and analyzed using an MMRM approach.
The MMRM model will include the following fixed effects:  treatment (U-500R CSII, U-500R 
MDI), weeks on treatment, the interaction between treatment and weeks, and the stratification 
factors (U-500R at entry versus other insulins, entry HbA1c ≥8.5% or <8.5%, and nonusers 
versus users of GLP-1 receptor agonists or SGLT2 inhibitors).  The model will also include the 
corresponding baseline values as a covariate. The covariance matrix will be chosen in the same 
order as the primary analysis. 
5.12.1.3. OmniPod U-500 System Exit Questionnaire
The percentage of subjects giving each answer to each question on the OmniPod U-500 System 
Exit Questionnaire will be summarized. The percentage will also be broken down by gender, 
and age ranges (18 to <25, 25 to <35, 35 to <45, 45 to <55, 55 to <65, 65 to <75, and ≥75 years).
5.12.2. Functionality and Safe Use of the OmniPod U-500 System
The functionality and safe use of the OmniPod U-500 system will be evaluated by an assessment 
of device complaint data, subject reported hazard alarms, and clinically relevant hyperglycemia 
possibly related to site occlusion.  A listing of reported hazard alarms associated with routine and 
non-routine site changes as well as a listing of non-routine site changes with no alarms 
associated with hyperglycemia will be provided.
5.12.3. Subgroup Analysis
For the primary objective (Section 4.1 of the SAP), the following subgroup analyses will be 
performed for Group A if at least 20 subjects in each treatment group are in each of the 
subgroups: baseline TDD >2 and ≤2 units/kg, baseline TDD >400 and ≤400 units, TDD 
>200 units at baseline that fall below TDD 200 units during the study and TDD >200 units at 
baseline that stay 200 units or above during the study, and geriatric subjects (age <65 and
≥65 years; and age< 75 and ≥75 years). Within each strata of the specific subgroup, analysis will 
be performed using the similar model for the primary efficacy analysis using MMRM.  To assess 
treatment by subgroup interaction, analysis will be conducted by adding subgroup as a main 


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effect and interaction term between treatment and subgroup, the 3-way interaction of the primary 
treatment arms, visit, and the subgroup variable will also be added for the MMRM analysis
model. The interaction effects will be tested at significance level of 0.10.
5.13. Safety Analyses
Safety measures will include hypoglycemic events, AEs/treatment-emergent adverse events 
(TEAEs), body weight, vital signs (systolic and diastolic blood pressures and pulse rate), 
treatment exposure, and laboratory measures. In general, safety summary analyses will be done 
for Group A+B.  However, hypoglycemic event and weight analyses assessing secondary 
objectives will be done for both Group A and Group A+B.  All safety measures will be 
summarized for ARS by treatment for the 26-week treatment period.  If listings are provided, 
they will contain data after the subjects discontinue the study treatment.  For treatment 
comparisons of frequency and proportion of event variables (such as AEs and hypoglycemia 
events), Fisher’s exact test will be used, unless otherwise specified.  
5.13.1. Study Treatment Exposure
Exposure to each treatment during the treatment period of the study will be calculated for each 
subject and summarized by treatment group for ARS using first dosing and last dosing 
information.  If a subject’s first dosing date/time is missing, it will be replaced by the 
randomization date/time.  If a subject’s last dosing date/time is missing, it will be replaced by 
the last visit date/time up to discontinuation of study treatment or completion date/time 
(whichever is earlier).  Total subject-years will be included in the summaries.  The mean of 
exposure will be compared between treatment groups using a two-sample t-test.
5.13.2. Hypoglycemic Episodes
Hypoglycemia is defined and categorized as follows:
Documented hypoglycemia:

Documented symptomatic hypoglycemia:  an event during which typical symptoms of 
hypoglycemia are accompanied by SMBG ≤70 mg/dL.

Asymptomatic hypoglycemia:  an event not accompanied by typical symptoms of
hypoglycemia but with SMBG ≤70 mg/dL.

Unspecified or unclassifiable hypoglycemia:  an event during which SMBG ≤70 mg/dL
but no information relative to symptoms of hypoglycemia was recorded.

Severe hypoglycemia:  an event accompanied by neuroglycopenic symptoms that results
in cognitive impairment such that the patient requires assistance of another person to 
actively administer carbohydrates, glucagon, or perform other resuscitative actions. 
During these episodes, the patient has an altered mental status, and cannot assist in their 
care, is semiconscious or unconscious, or experienced coma with or without seizures, and 
may require parenteral therapy. Plasma glucose measurements may not be available 
during such an event, but neurological recovery attributable to the restoration of SMBG
concentration to normal is considered sufficient evidence that the event was induced by a 


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low SMBG concentration (SMBG ≤70 mg/dL). The determination of a hypoglycemic 
event as an episode of severe hypoglycemia is made by the investigator.

Nocturnal hypoglycemia:  any hypoglycemic event (documented hypoglycemia or 
severe hypoglycemia) that occurs between bedtime and waking.
5.13.2.1. Hypoglycemic Analyses
Hypoglycemic analyses will be conducted on the ARS population.  The same categories and 
subcategories defined in Section 5.13.2 will be used for summary and modeling purposes.
The hypoglycemic event rate (per 30 days and per 1 year), incidence (number) and percent of 
subjects reporting at least 1 hypoglycemic episode for a given treatment at certain week intervals
will be summarized. The week intervals include: lead-in period (-2, 0], treatment period
including (0, 2], (2 to 8], (8 to 26], (0 to 26] weeks. Note that the closed brackets will indicate to 
include a value/week; whereas, parentheses will indicate not to include the corresponding 
value/week. For example, (0 to 2] means all values between Week 0 and Week 2, including 
Week 2, but not including Week 0.
Treatment comparison of the incidence of hypoglycemia (documented [documented 
symptomatic, asymptomatic, and unspecified], severe, and nocturnal) will be done using logistic 
regression for each week interval, excluding poststudy treatment discontinuation data. For the 
analysis in Group A, the logistic model will include baseline hypoglycemia event rate for week 
interval (-2, 0] of the corresponding category of the dependent hypoglycemia variable 
standardized by 30 days (or 1 year) as covariates, treatment (U-500R CSII, U-500R MDI), and 
the stratification factors (U-500R at entry versus other insulins, entry HbA1c ≥8.5% or <8.5%) 
as fixed effects. For the analysis in Group A+B, the stratification factor (and nonusers versus 
users of GLP-1 receptor agonists or SGLT2 inhibitors) will be added into the model.
For summary purpose, the rate per 30 days calculated between 2 visits is defined as the total 
number of episodes for all subjects between the visits divided by the total actual number of 
exposure days between the visits, and then multiplied by 30 days.  A similar definition will be 
used to calculate the rate per subject per 365 days (1 year). 
The analysis approach for the rate of hypoglycemia is based on a negative binomial model with 
log link function, excluding post study treatment discontinuation data. The response variable is 
the hypoglycemic event count per visit per subject. For Group A, the model will include
baseline hypoglycemia event rate for week interval (-2, 0] of the corresponding category of the 
dependent hypoglycemia variable standardized by 30 days as covariates, treatment (U-500R 
CSII, U-500R MDI), and the stratification factors (U-500R at entry versus other insulins, entry 
HbA1c ≥8.5% or <8.5%) as fixed effects. For the analysis in Group A+B, the stratification 
factor (nonusers versus users of GLP-1 receptor agonists or SGLT2 inhibitors) will be added into 
the model. The logarithm of exposure days (standardized by 30 days) between visits will be 
used as the offset variable. In LSMeans statement, Observed Margin (OM) option will be added 
to specify weighting scheme for LSMean computation as determined by the input data set. The
LSMean of hypoglycemia rate per 30-days by treatment for each week interval will be reported, 


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and the rate ratio between treatments will also be presented. Wilcoxon signed-rank test may be 
performed as sensitivity analysis.  
The 1-year rate of documented symptomatic and severe hypoglycemia (with BG ≤70 mg/dL) for 
every 2-hour interval (0:00-1:59, 2:00-3:59, 22:00-23:59) over the 26 week post-randomization 
period will be summarized.  The rate of hypoglycemia will also be analyzed using a negative 
binomial model.  The response variable is the hypoglycemic event count per 2-hour interval per 
subject.  The analysis approach will be similar to the hypoglycemia rate analysis approach above 
for Group A and Group A+B. 
5.13.3. Treatment Emergent Adverse Events and Serious Adverse 
Events
Adverse events will be summarized as TEAEs (defined as events that are newly reported after 
randomization Visit 4 or reported to worsen in severity from randomization Visit 4) for ARS by 
treatment. The frequency and proportion of subjects experiencing at least 1 of each reported 
TEAE will be summarized by System Organ Class (SOC), Preferred Term (PT), and treatment 
group.  Events will be ordered by decreasing frequency within SOC. The frequency and 
proportion comparisons will be analyzed using Fisher’s exact test.  The frequency and proportion 
of subjects experiencing at least 1 of each reported TEAE that are assessed as possibly related to 
the study drug, device, procedures will also be summarized, separately.
All SAEs (including severe hypoglycemic events) will be listed by subject including SOC, 
Medical Dictionary for Regulatory Activities (MedDRA) PT, severity, and relationship to the 
study disease, drug, device, or procedure for all subjects. The listing will contain data after the 
subjects discontinue the study treatment.
If a sufficient number of SAEs are reported, then a frequency and proportion summary, similar to 
the summary for TEAEs, will be included for the ARS. 
Discontinuations due to AEs and SAEs will be listed separately, by subject (including specific 
AE and SAE information and whether they discontinue only the study treatment or study 
treatment and the study), and summarized (if a sufficient number of events are reported) by SOC, 
PT, and treatment group. 
5.13.4. Body Weight
The body weight actual value and CFBL based on actual value at visits will be analyzed by 
MMRM models similar to that which will be used in the primary analysis for the ARS 
population.  An ANCOVA model will also be used as a sensitivity analysis. A scatter plot that 
includes a regression line of LOCF weight CFBL by LOCF HbA1c CFBL will be presented.  
For Group A, the MMRM model will include the following fixed effects:  treatment (U-500R 
CSII, U-500R MDI), weeks on treatment, the interaction between treatment and weeks, and the
stratification factors (U-500R at entry versus other insulins, entry HbA1c ≥8.5% or <8.5%).  The 
model will also include the corresponding baseline of the response variable. The ANCOVA 
model will include the following fixed effects: treatment (U-500R CSII, U-500R MDI), the 


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stratification factors (U-500R at entry versus other insulins, entry HbA1c ≥8.5% or <8.5%), and
the baseline weight as covariate.
For Group A+B, the same MMRM model and ANCOVA models in Group A above will be used 
with the addition of the stratification factor (nonusers versus users of GLP-1 receptor agonists or 
SGLT2 inhibitors).
5.13.5. Vital Signs
Systolic blood pressure, diastolic blood pressure, and pulse rate will be summarized at each 
scheduled visit including baseline for the ARS in Group A+B. Additionally, CFBL for all 
postrandomization visits will be summarized. The CFBL and actual value at visits will be
analyzed using a MMRM model with the following fixed effects:  treatment (U-500R CSII, U-
500R MDI), weeks on treatment, the interaction between treatment and weeks, and the 
stratification factors (U-500R at entry versus other insulins, entry HbA1c ≥8.5% or <8.5%, 
nonusers versus users of GLP-1 receptor agonists or SGLT2 inhibitors).  The model will also 
include the corresponding baseline measures as a covariate. The actual value and CFBL based 
on LOCF endpoint will be analyzed using ANCOVA model, as a sensitivity analysis. The 
ANCOVA model will include the same fixed effects in the MMRM model but without the terms 
involving weeks.
5.13.6. Laboratory Measures
As applicable per protocol, measures within the following panels will be summarized at 
Screening (Visit 1), Visit 4 (Week 0), Visit 13 (Week 14), and Visit 17 (Week 26) or endpoint 
(LOCF):

chemistry (creatinine, uric acid)

c-peptide

eGFR

lipids (total cholesterol, calculated low-density lipoprotein cholesterol [LDL-C], high-
density lipoprotein cholesterol [HDL-C], triglycerides [TG], and free fatty acids [FFAs])

liver test panel (alanine aminotransferase [ALT], aspartate aminotransferase [AST], 
gamma-glutamyl transferase, alkaline phosphatase)
Treatment-emergent high, low, and abnormal values will be summarized for each lab measure
listed above. A treatment-emergent high value is defined as a value that was normal or low at 
baseline and subsequently found to be above the normal range at any post-baseline visit.  A 
treatment-emergent low value is defined as a value that was normal or high at baseline and 
subsequently found to be below the normal range at any post-baseline visit.  A treatment-
emergent abnormal value is defined as a value that was normal at baseline and subsequently 
found to be abnormal at any post-baseline visit; however, for ALT/serum glutamic pyruvic 
transaminase (SGPT) or AST/serum glutamic oxaloacetic transaminase (SGOT) ≥2.5X upper 
limit of normal (ULN) will be used as the abnormal threshold. The proportion comparisons 
between 2 treatment groups will be analyzed using Fisher’s exact test. 


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Actual value, percentage CFBL in lipids panel (total cholesterol, calculated LDL-C, HDL-C, TG, 
FFAs), and CFBL in other measures will be summarized and analyzed. If only one post-baseline 
measurement is scheduled, then an ANCOVA model will be used; if more than one post-baseline 
measurement is scheduled, then an MMRM model will be used. The MMRM model will include 
the following fixed effects:  treatment (U-500R CSII, U-500R MDI), weeks on treatment, the 
interaction between treatment and weeks, and the stratification factors (U-500R at entry versus 
other insulins, entry HbA1c ≥8.5% or <8.5%, nonusers versus users of GLP-1 receptor agonists 
or SGLT2 inhibitors).  The model will also include the corresponding baseline measures as a 
covariate.  The ANCOVA model will include the same fixed effects in the MMRM model but 
without the terms involving weeks.
5.14. Rescue Therapy
A listing of all subjects receiving rescue therapy will be provided. The listing will include, but 
not be limited to, subject ID, treatment group, rescue therapy date, and dose.
5.15. Exploratory Pharmacogenetic Analysis
Pharmacogenetic analyses will be documented in a stand-alone PGx SAP and conducted by Lilly 
diabetes PGx statistics group or its designees.
5.16. Interim Analyses
A DMC (Data Monitoring Committee) will have access to unblinded data for their review(s).  
Only the DMC is authorized to evaluate unblinded interim safety analyses.  The DMC will be 
composed of individuals internal and external to Lilly who are not part of the study team and will 
monitor the safety of U-500R administered CSII or MDI and may recommend changes to the 
protocol, including termination.  The analysis plans for the DMC are specified in the DMC 
Charter.  


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6.
Unblinding Plan
The purpose of this blinding and unblinding plan is to detail procedures in place to minimize bias 
while preparing for or conducting any summary or analysis of Study IBHD’s data for DMC 
reports, trial level safety reports (TLSR), or CSRs.  Additionally, this plan identifies who will be 
unblinded for the interim data analysis in support of the DMC meetings.
6.1.
Creating the Blind:  General Blinding Requirements
Study IBHD is a Phase 3b, multicenter, randomized, open-label, parallel clinical trial comparing 
U-500R administered by CSII (OmniPod U-500 system) to U-500R administered MDI in high-
dose insulin-requiring subjects with T2DM.  Treatment blinding of the investigators, subjects, 
and study site personnel is not feasible due to differences in the appearance and functionality of 
the delivery devices.  To minimize bias, aggregate review of summary data by the study team 
(that is, clinical research physician/clinical research scientist (CRP/CRS) overseeing the global 
conduct of the study, statisticians, and statistical analysts) will remain blinded with respect to 
treatment assignment until after the final database is locked.  Unblinding of the subject study 
treatment assignment may occur in the course of individual subject consultation between the 
investigator and the study team (principally between the investigator and the CRP/CRS) or 
during review of SAEs.  No systematic unblinding of study treatment assignments will be 
solicited by the study team.  
Besides the above discussion about treatment assignment, the following 5 case report forms 
(CRFs) will be blinded/scrambled to the study team (that is, CRP/CRS overseeing the global 
conduct of the study, statisticians, and statistical analysts) at an individual level, because they 
contain information which will lead to unblinding of treatment assignment:

QS_OMNI (OMNI1001)

DE_HAZ (OPHA1001)

EX_BASAL (EX1001_F3)

EX_BOLUS (EX1001_F4)

EX_RESCUE (EX1001_F5)
6.2.
Details of Maintaining the Blind
For TLSR and DMC and the final data:  treatment assignments and the 5 CRF forms will 
remain blinded to study team as defined in Section 6.1. 

treatment assignments will be scrambled by data management group before raw data 
transfer

the unblinded raw data for the 5 CRF forms together with other raw data will be 
transferred to:  CLUWE/lillyce/qa/ly041001/b5k_mc_ibhd/prelock/data/raw/dm/edc
The study team as defined in Section 6.1 does not have access to this folder.
The DMC Statistical Analysis Center (SAC) statistician, who is outside of the study team, will 
scramble the QS_OMNI (OMNI1001) and DE_HAZ (OPHA1001) by reassigning the patient 


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IDs using a random patient list generated from all study patient IDs.  The DMC SAC statistician
will blind EX_BASAL, by removing basal dose records (PAGE=”EX1001_F3”), which are the 
only information specific to CSII-arm subjects in this dataset.  The bolus doses (EX_BOLUS 
[EX1001_F4]) and rescue doses (EX_RESCUE [EX1001_F5]) will be rounded to the nearest 
increment of 5.
Then  the blinded data for each data transfer will be saved to:

TLSR1:  CLUWE/lillyce/qa/ly041001/b5k_mc_ibhd/safety_review1/data/raw/shared

TLSR2:  CLUWE/lillyce/qa/ly041001/b5k_mc_ibhd/safety_review2/data/raw/shared

DMC:  CLUWE/lillyce/qa/ly041001/b5k_mc_ibhd/dmc_blinded1/data/raw/shared

FINAL TEST DATA:  
CLUWE/lillyce/qa/ly041001/b5k_mc_ibhd/final/data/raw/shared
The study team statistician and analysts have access to this folder that contains blinded data
For DMC:  summary of treatment assignments and the 5 CRF forms will be unblinded to the 
following who are all external to the study team:

LRL Senior Management Designee

SAC Statistician and DMC Secretary

DMC Chairperson

DMC Voting Members
The DMC SAC statistician will use the unblinded SDTM and ADaM data to generate TFL 
outputs, at the following locations respectively. 

SDTM folder: 
CLUWE/lillyce/qa/ly041001/b5k_mc_ibhd/dmc_unblinded1/data/observed/restricted

ADaM folder: 
CLUWE/lillyce/qa/ly041001/b5k_mc_ibhd/dmc_unblinded1/data/analysis/restricted 

TFL folder:  
CLUWE/lillyce/qa/ly041001/b5k_mc_ibhd/dmc_unblinded1/output/restricted
The study team does not have access to these folders.


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7.
CGM Addendum
Unless otherwise specified, all discussions in this section are within the context of the CGM 
addendum only. Subjects who choose to participate in Protocol Addendum IBHD(1) will sign an 
addendum-specific informed consent form (ICF).  The commercial CGM device (Dexcom G4 
Platinum) that will be used for this addendum is labeled to collect data for 7 consecutive days.  
These subjects will be asked to perform CGM on 3 occasions for up to 7 days per occasion as 
indicated in the Study Schedule.  Continuous glucose monitoring should occur during the week 
prior to Visit 4 (Week 0), Visit 13 (Week 14), and Visit 17 (Week 26). 
7.1.
Addendum Objectives
7.1.1. Primary Objective
The primary objective of this addendum is to compare glycemic control change from baseline to 
end of treatment period of within-day glucose variability as measured by mean daily SD of the
interstitial glucose measurements between CSII and MDI.
7.1.2. Secondary Objectives
The secondary objectives for the CGM addendum are:
1) To compare glycemic control change from baseline to endpoint of the treatment period 
between CSII and MDI as assessed by CGM based on mean daily AUC and percentage 
of time:

≤70 mg/dL

≤50 mg/dL

≥180 mg/dL

≤70 mg/dL during the nocturnal period between midnight and 0600 hours

≤50 mg/dL during the nocturnal period between midnight and 0600 hours

>70 mg/dL to ≤120 mg/dL
2) To compare the low blood glucose index (LBGI) and high blood glucose index (HBGI) 
during the nocturnal period defined as midnight to 0600 hours and during a 24-hour 
period between CSII and MDI at end of treatment period
3) To compare the combined BG risk index (sum of the LBGI and HBGI) during the 
nocturnal period defined as midnight to 0600 hours and during a 24-hour period between 
CSII and MDI at end of treatment period
4) To evaluate the insulin-on-board (IOB, 6- or 8-hour) pump settings by analysis of mean 
glucose AUC between bolus doses at breakfast and lunch and between bolus doses at 
lunch and dinner, respectively, for CSII treatment at end of treatment period
5) To evaluate optimal bolus timing (15 or 30 minutes prior to meal) response by analysis of 
mean glucose AUC for 4 hours after the start of the meal at end of treatment period


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7.2.
Determination of Sample Size
The CGM data collected in this addendum will be for exploratory purposes; therefore, the 
sample size is not based on power consideration.  Assuming 25% dropout rate, 27 subjects in 
each treatment arm (54 total) are needed to have 20 completers in each treatment arm (40 total).  
7.3.
Analytic Variables
A third party organization (TPO) will collect and compile the CGM data. Besides the CGM raw 
data, the TPO will also provide the analytic variables for each patient as follows:

daily SD of the CGM glucose measures

daily amplitude of glycemic excursion (MAGE) index and continuous overall net 
glycemic action (CONGA)

daily AUC and percentage of time when glucose measures are:
o
≤70 mg/dL
o
≤50 mg/dL
o
≥180 mg/dL
o
≤70 mg/dL during the nocturnal period between midnight and 0600 hours
o
≤50 mg/dL during the nocturnal period between midnight and 0600 hours
o
>70 mg/dL to ≤120 mg/dL

daily LBGI, HBGI, and the combined BG risk index (sum of the LBGI and HBGI) 
during the nocturnal period (defined as midnight to 0600 hours) and during a 24-hour 
period

daily AUC between bolus doses at breakfast and lunch and daily AUC between bolus 
doses at lunch and dinner, respectively

daily AUC for 4 hours after the start of each meal
MAGE is the mean of the differences between consecutive peaks and nadirs in BG, provided that 
the absolute value of difference was greater than the SD (Service et al. 1970).  CONGA is the SD 
of the difference between the current and previous observations and measures the overall intra-
day variation of glucose recorded by CGM (McDonnell et al. 2005).  
The LBGI (Kovatchev et al. 2005) has been developed to quantitate both frequency and severity 
of hypoglycemia.  The LBGI has been validated as a predictor of severe hypoglycemia 
(Kovatchev et al. 2003; Kovatchev et al. 1998), which is a SAE and could result in coma or 
death if unrecognized and untreated.  The HBGI quantifies both frequency and severity of 
hyperglycemia (Kovatchev et al. 2005) and has been related to HbA1c and risk for 
hyperglycemia (Kovatchev et al. 2003).  Additionally, the LBGI and HBGI both have a high 
sensitivity to changes in glycemic profiles and control (Kovatchev et al. 2002).  The LBGI and 
HBGI will be derived values.


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7.4.
A Priori Statistical Methods
Baseline characteristics will be summarized by treatment arm.  Means will be analyzed using an 
analysis of variance model.  Proportions will be analyzed using Fisher’s exact test.
The primary objective measure is mean daily SD calculated as the mean of the optimal values for 
each visit.  An MMRM model will be used to analyze the actual measurements and change from 
baseline of the continuous dependent variables.  The model will include fixed effects such as 
treatment, weeks on treatment (considered as categorical variable), the interaction between 
treatment and weeks, and the stratification factors.  Subject will be considered as a random 
effect.  The corresponding baseline values will be included as a covariate.  
For the MMRM model, the Kenward-Roger approximation will be used to estimate denominator 
degrees of freedom. An unstructured covariance matrix will be used to model the within-subject 
errors. If the unstructured covariance configuration results in a lack of convergence, then the 
following variance-covariance matrix will be used (in order) until one converges:
Heterogeneous Toeplitz; Heterogeneous First Order Autoregressive; Heterogeneous Compound 
Symmetry; Toeplitz; First Order Autoregressive; Compound Symmetry. If all variance-
covariance matrices selected fail to converge, Variance Components will be used as the next 
attempt at convergence.
If the model still does not converge after changing to different covariance structures, then the 
stratification factors will be removed from the model. If the model still does not converge, then 
an ANCOVA analysis which only includes baseline and the 26-week values will be performed.
The similar variable calculation method and MMRM approach will be used for all other 
secondary objectives.  Model specifications, such as fixed effects, covariates, and repeated 
measurement structures need to be carefully adjusted according to the specific objectives and 
measurements. For Secondary Objective 4, only those subjects assigned to CSII arm will be 
analyzed; therefore, the treatment effect and its interactions with other effects will be removed 
from the model. For Secondary Objective 5, the interaction between optimal bolus timing (15 or 
30 minutes prior to meal) and treatment will be added into the MMRM model; the interaction 
between optimal bolus timing and weeks will also be added. Depending on the model 
convergence situation, the interaction between treatment and weeks may be removed.
Other measures of variability of the interstitial glucose measurements may be analyzed as 
sensitivity analyses (for example, MAGE index and CONGA).


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8.
References
Bretz F, Maurer W, Brannath W, Posch M. A graphical approach to sequentially rejective 
multiple test procedures. Stat Med. 2009;28(4):586-604.
Clarke W, Kovatchev BP. Statistical tools to analyze continuous glucose monitor data. Diabetes 
Technol. Ther. 2009;11(Suppl 1):S45–S54.
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.
Kovatchev BP, Cox DJ, Gonder-Frederick LA, Young-Hyman D, Schlundt D, Clarke W. 
Assessment of risk for severe hypoglycemia among adults with IDDM: validation of the low 
blood glucose index. Diabetes Care. 1998;21(11):1870-1875.
Kovatchev BP, Cox DJ, Gonder-Frederick L, Clarke WL. Methods for quantifying self-
monitoring blood glucose profiles exemplified by an examination of blood glucose patterns in 
patients with type 1 and type 2 diabetes. Diabetes Technol Ther. 2002;4(3):295-303.
Kovatchev BP, Cox DJ, Kumar A, Gonder-Frederick L, Clarke WL. Algorithmic evaluation of 
metabolic control and risk of severe hypoglycemia in type 1 and type 2 diabetes using self-
monitoring blood glucose data. Diabetes Technol Ther. 2003;5(5):817-828.
McDonnell CM, Donath SM, Vidmar SI, Werther GA, Cameron FJ. A novel approach to 
continuous glucose analysis utilizing glycemic variation. Diabetes Technol Ther. 
2005;7(2):253-263.
Riddle M, Umpierrez G, DiGenio A, Zhou R, Rosenstock J. Contributions of basal and 
postprandial hyperglycemia over a wide range of HbA1c levels before and after treatment 
intensification in type 2 diabetes. Diabetes Care. 2011;34(12):2508-2514.
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.


Leo Document ID = 1ed8f1f4-ce4f-4fa2-8837-5e530a6c5940
Approver: 
Approval Date & Time: 31-May-2017 17:03:54 GMT
Signature meaning: Approved
PPD

Prot_003.pdf: 
Protocol B5K-MC-IBHD 
 
Safety and Efficacy of Human Regular U-500 Insulin Administered by Continuous Subcutaneous 
Insulin Infusion versus Multiple Daily Injections in Subjects with Type 2 Diabetes Mellitus: A 
Randomized, Open-Label, Parallel Clinical Trial 
 
 
NCT02561078 
 
Approval Date: 11-Jun-2015 
 


B5K-MC-IBHD Clinical Protocol
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LY041001
  
1. Protocol B5K-MC-IBHD
Safety and Efficacy of Human Regular U-500 Insulin 
Administered by Continuous Subcutaneous Insulin 
Infusion versus Multiple Daily Injections in Subjects with 
Type 2 Diabetes Mellitus:  A Randomized, Open-Label, 
Parallel Clinical Trial
(VIVID: Evaluating U-500R Infusion versus Injection in Type 
2 Diabetes Mellitus)
Confidential Information
The information contained in this protocol 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 Humulin (LY041001), unless 
such persons are bound by a confidentiality agreement with Eli Lilly and Company or its subsidiaries.  
This document and its associated attachments are subject to United States Freedom of Information 
Act (FOIA) Exemption 4.  
Humulin (LY041001)
This is a Phase 3b, randomized, open-label, parallel study comparing human regular insulin U-500 
delivered by continuous subcutaneous insulin infusion (OmniPod® Insulin Management System for 
use with regular human insulin U-500) to delivery by multiple daily injections in high-dose insulin-
requiring patients with type 2 diabetes mellitus who have inadequate glycemic control on existing high 
dose insulins (with or without other insulins/antihyperglycemic agents).
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly on date provided below.
Approval Date: 11-Jun-2015 GMT


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LY041001
2. Synopsis
Study Rationale
This prospective, randomized clinical trial will provide clinical information on the use of human 
regular U-500 insulin (Humulin® R U-500; U-500R) in high-dose insulin-requiring patients with 
type 2 diabetes mellitus (T2DM).  Gaps in scientific and clinical knowledge for U-500R include 
initial dosing and transition from high-dose U-100 insulin therapy, dose titration including use of 
multiple daily injections (MDI) delivered three times daily (TID), administration safety in 
combination with antihyperglycemic agents (AHAs), and transition from U-500R MDI to 
continuous subcutaneous insulin infusion (CSII).  Delivery of U-500R by CSII is used in patient 
care in United States (US) clinical practice (Reutrakul et al. 2011; Lane et al. 2013; Eby et al. 
2014), but this mode of administration is not approved by the US Food and Drug Administration 
(FDA).  A prospective, randomized clinical trial is needed to evaluate the efficacy and safety of 
U-500R delivered by CSII as compared to U-500R by MDI delivered TID, using a novel version 
of the OmniPod® Insulin Management System that is intended to deliver U-500 insulin with 
dosage in insulin units (U) without converting to U-100 “pump units” (Lane et al. 2009; Segal et 
al. 2010; Lane et al. 2010; Cochran et al. 2014), which is what would be required if U-500 
insulin were to be used in a U-100 insulin system.


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Clinical Protocol Synopsis:  Study B5K-MC-IBHD
Name of Investigational Product:
Human regular U-500 insulin; Humulin® R U-500; U-500R (LY041001)
Title of Study:  Safety and Efficacy of Human Regular U-500 Insulin Administered by Continuous Subcutaneous 
Insulin Infusion versus Multiple Daily Injections in Subjects with Type 2 Diabetes Mellitus: A Randomized, Open-
Label, Parallel Clinical Trial (VIVID:  Evaluating U-500R Infusion versus Injection in Type 2 Diabetes Mellitus)
Number of Planned Subjects: Approximately 320 subjects requiring high dose insulin without use of glucagon-
like peptide-1 (GLP-1) receptor agonists or sodium-glucose transporter protein (SGLT2) inhibitors (Group A) and 
approximately 64 to 96 additional subjects with use of GLP-1 receptor agonists or SGLT2 inhibitors (Group B),
with or without other insulins/AHAs will be randomized based on a 1:1 ratio to two treatment arms.  After Group A 
has been fully enrolled, Lilly may stop enrollment for Group B, even if the minimum recruitment goal for Group B 
has not been met.  Approximately 240 (Group A) and 48 to 72 (Group B) subjects are expected to complete the 26-
week treatment period (assuming a 25% dropout rate).  
Entered: Approximately 586 subjects (450 in Group A plus an additional 90 to 136 in Group B)
Enrolled/Randomized: Approximately 416 subjects (320 in Group A plus an additional 64 to 96 in Group B)
Completed: Approximately 312 subjects (240 in Group A plus an additional 48 to 72 in Group B)
Phase of Development:  3b
Length of Study:  18 months
Estimated first patient visit:  October 2015                           Estimated last patient visit:  December 2016
Objectives:
The primary objective is to demonstrate the change in glycated hemoglobin A1c (HbA1c) of U-500R administered 
by CSII is noninferior to U-500R administered by MDI therapy from baseline to the 26-week in high-dose insulin-
requiring patients with T2DM who have inadequate glycemic control on high-dose non U-500R (>200 and ≤600 
units per day) insulins (CSII or MDI) and/or high-dose U-500R insulin (MDI) without use of GLP-1 receptor 
agonists or SGLT2 inhibitors and with or without other insulins/AHAs. This population is referred to as Group A.
The following hypothesis will be tested for the primary objective: 
H1: CSII is noninferior to MDI in change in HbA1c using a noninferiority margin (NIM) of 0.4%.
The family-wise type I error rate for the primary objective and the following key secondary objectives will be 
controlled at a two-sided 5% level by the graphical approach.
Key Secondary Objectives:
The following 4 key (alternative hypotheses [H#]) secondary objectives at Week 26 are to demonstrate for the main 
study population (Group A [without use of GLP-1 receptor agonists or SGLT2 inhibitors]) that:
H2: CSII is superior to MDI in change in fasting plasma glucose (FPG).
H3: CSII is superior to MDI in proportions of subjects achieving HbA1c targets/values <7.0%.
H4: CSII is superior to MDI in change in HbA1c.
H5: CSII is superior to MDI in proportions of subjects achieving HbA1c targets/values <7.5%.
The following 5 key (alternative hypotheses [H#]) secondary objectives are to demonstrate the objectives at Week 
26 for the total study population (Group A [without use of GLP-1 receptor agonists or SGLT2 inhibitors] and Group 
B [those who use GLP-1 receptor agonists or SGLT2 inhibitors use]) that:
H6: CSII is noninferior to MDI in change in HbA1c using a NIM of 0.4%.
H7: CSII is superior to MDI in change in fasting plasma glucose (FPG).
H8: CSII is superior to MDI in proportions of subjects achieving HbA1c targets/values <7.0%.
H9:  CSII is superior to MDI in change in HbA1c.
H10: CSII is superior to MDI in proportions of subjects achieving HbA1c targets/values <7.5%.


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LY041001
Other Secondary Objectives:
Additional secondary objectives of the study are to compare the efficacy and safety of U-500R given by CSII versus 
MDI at Week 26 for the main study population (Group A) and the total study population (Groups A and B),
respectively (separately), with respect to the following:

Proportions of subjects achieving HbA1c targets/values (≤6.5% and <8%);

Mean change in 7-point self-monitored blood glucose (SMBG) including mean SMBG for each time point 
measurement;

Change in TDD (unit and unit/kg);

Proportions of subjects achieving HbA1c targets/values (≤6.5%, <7.0%, <7.5%, and <8.0%) without 
documented symptomatic hypoglycemia (SMBG <50 mg/dL);

Rate and incidence of hypoglycemia (documented [documented symptomatic, asymptomatic, and 
unspecified], severe, and nocturnal);

Change in body weight between treatment groups and as a function of change in HbA1c;
Exploratory Objectives:

The change in patient reported outcomes including Treatment-Related Impact Measure for Diabetes 
(TRIM-D) and TRIM-D for Diabetes Device (TRIM-DD) surveys from baseline to 26-week value.

Assess subject-reported OmniPod pump experience via OmniPod U-500 System Exit Questionnaire

Assess proportions of subjects with an HbA1c ≥9% and <9% at the 26-week value.

Postprandial contributions to total glycemic burden at baseline to 26-week values using area under the 
curve (AUC) analysis of 7-point SMBG profiles.  

Glycemic variability using 7-point SMBG profiles (including within day and day-to-day standard deviation
[SD], coefficient of variation, average daily risk range, and mean of daily differences). 

Examine the relationship between gene variants including, but not limited to, insulin receptor, 
insulin-like growth factor-1, melatonin receptor 1B1, adiponectin, transcription factor 7-like 2, 
phosphoinositide-3-kinase, regulatory subunit 1, and B-cell CLL/lymphoma 11A on clinical 
outcomes.

Evaluate subgroups of baseline TDD >2 and ≤2 units/kg, TDD >200 units at baseline that fall below TDD 
200 units during the study, baseline TDD >400 and ≤400 U, users of GLP-1 receptor agonists or SGLT2 
inhibitors, and geriatric subjects (age ≥65 years and ≥75 years) for each of the primary and secondary 
objectives.

Functionality and safe use of the OmniPod® U-500 system (Insulet Corporation; Bedford, MA).
Study Design:  This is a Phase 3b, multicenter, randomized, open-label, parallel clinical trial comparing U-500R 
administered by CSII (OmniPod U-500 system) to U-500R administered MDI in high-dose insulin-requiring patients 
with T2DM who have inadequate glycemic control on high-dose non U-500R (>200 and ≤600 units per day)
insulins (CSII or MDI) and/or U-500R insulin (MDI) with or without other insulins/AHAs.  The trial design 
includes a 1-week screening period, a 2-week lead-in period, and a 26-week treatment period (2 week transition to 
U-500R MDI administered TID, 12 weeks titration, and 12 weeks maintenance U-500R CSII or MDI).
Diagnosis and Main Criteria for Inclusion and Exclusions:  
Planned subject population is men and women diagnosed with T2DM requiring high-dose insulin who have 
inadequate glycemic control.
Inclusion Criteria: Aged ≥18 to ≤85 years; are currently prescribed non U-500R insulin/analog by CSII or MDI or 
U-500R insulin by MDI with syringe and vial with or without AHAs for ≥3 months at a TDD >200 but ≤600 U; 
HbA1c ≥7.5% but ≤12.0%; body mass index ≥25 but ≤50 kg/m2; history of stable body weight; concomitant AHA
therapy may include metformin, dipeptidyl peptidase-4 inhibitors (sitagliptin, saxagliptin, linagliptin, and 
alogliptin), pioglitazone (doses ≤30 mg/day), GLP-1 receptor agonists (albiglutide, dulaglutide, or liraglutide [Group 
B only]), and SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin [Group B only]).  Subjects’ AHA
therapy must have been stable for ≥3 months (except GLP-1 receptor agonists must have been stable for ≥4 months).
Exclusion Criteria:  Type 1 diabetes mellitus or other types of diabetes; or alanine aminotransferase and/or aspartate 
aminotransferase (ALT/AST) ≥2.5x the upper limit of normal; chronic kidney disease Stage 4 and higher (estimated 


B5K-MC-IBHD Clinical Protocol
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LY041001
glomerular filtration rate <30 mL/minute/1.73m2 as measured by MDRD formula); history of >1 episode of severe 
hypoglycemia (defined as hypoglycemia requiring the assistance of a another person) within the prior 6 months; 
have received U-500R insulin by CSII in the 3 months prior to Visit 1; recent blood transfusion or severe blood loss 
within 3 months prior to Visit 1; known hemoglobinopathy, hemolytic anemia, sickle cell anemia; chronic systemic 
glucocorticoid therapy; use of weight loss drugs in 3 months prior to Visit 1; women who are pregnant, 
breastfeeding, or are sexually active and of childbearing potential but are not using appropriate contraception; men 
who intend to impregnate their partners; received sulfonylureas/glinides in the 3 months prior to Visit 1, or other 
injectable or oral AHA therapy not listed in the inclusion criteria in the prior 3 months; bariatric surgery; active or 
untreated malignancy; significant hearing loss or vision impairment; cardiac disease with functional status New 
York Heart Association Class III or IV; irregular sleep/wake cycle; use of nonapproved investigational drug within 1 
month prior to trial.
Investigational Drug Product, Dosage, and Mode of Administration or Intervention:
Human regular U-500 insulin, per titration algorithm administered by CSII via OmniPod U-500 system
Planned Duration of Treatment:  
Lead-in period:  2 weeks
Treatment period:  26 weeks 
Reference Therapy, Dose, and Mode of Administration or Comparative Intervention:  
Human regular U-500 insulin, per titration algorithm administered subcutaneously by MDI
Criteria for Evaluation: 
Efficacy:  

HbA1c

FPG

7-point SMBG

TDD
Safety: 

Adverse events (AEs) and treatment-emergent adverse events (TEAEs)

Incidence and rate of hypoglycemic episodes (documented [documented symptomatic, asymptomatic, and 
unspecified], severe, and nocturnal)

Body weight

Vital signs

Study treatment exposure

Clinical laboratory tests

Product complaints
Exploratory:

Functionality and safe use of the OmniPod U-500 system 

Patient reported outcomes:  TRIM-D, TRIM-DD

Pump-specific assessment: OmniPod U-500 System Exit Questionnaire
Statistical Methods:  
Approximately 320 subjects requiring high-dose insulin without use of GLP-1 receptor agonists or SGLT2 inhibitors
(Group A) and approximately 64 to 96 additional subjects with use of GLP-1 receptor agonists or SGLT2 inhibitors
(Group B) will be randomized based on a 1:1 ratio to two treatment arms.  Approximately 240 (Group A) and 48 to 
72 (Group B) subjects are expected to complete the 26-week treatment period (assuming a 25% dropout rate).
The sample size was calculated based on the first primary objective for subjects without use of GLP-1 receptor 
agonists or SGLT2 inhibitors (Group A).  The 240 completers will provide 80% statistical power to demonstrate the 
noninferiority (NIM is 0.4%; SD=1.1%) of U-500R insulin CSII versus U-500R MDI in change in HbA1c at 26 
weeks at a 2-sided alpha = 0.05.
Adjustment for Multiplicity:  A graphical approach will be used to adjust multiplicity for the primary and key 
secondary objectives.  This approach will control the family-wise Type 1 error rate at alpha=0.05. 


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LY041001
Randomization Details:  Stratify by entry HbA1c ≥8.5% or <8.5%, nonusers versus users of GLP-1 receptor agonists
or SGLT2 inhibitors, and U-500-R at entry versus other insulins.
Safety Committee and Interim Analysis:
Trial level safety reviews (TLSRs) using selected blinded safety data will be conducted throughout the study by the 
study team.  In addition, a DMC (Data Monitoring Committee) will have access to unblinded data for their 
review(s).  Only the DMC is authorized to evaluate unblinded interim safety analyses.  The DMC will be composed 
of individuals internal and external to Lilly who are not part of the study team and will monitor the safety of U-500R
administered CSII or MDI and may recommend changes to the protocol, including termination.  Unblinding details 
are specified in the unblinding plan section of the Statistical Analysis Plan (SAP) and/or DMC Charter.  The timing 
and frequency of these data reviews will be stated in the DMC charter.  In the event of any patient safety concerns, 
the DMC will communicate to the study team so that the clinical research physician/clinical research scientist can 
inform the investigator of appropriate action.  Study sites will receive information about interim results ONLY if 
they need to know for the safety of their subjects. 
If an unplanned interim analysis is deemed necessary, the appropriate Lilly regulatory scientist will be consulted to 
determine whether it is necessary to amend the protocol.
Primary Efficacy: 
The primary efficacy measure is change from baseline (last nonmissing value at or prior to the treatment starting at 
Visit 4) to the 26-week HbA1c value, which will be summarized and analyzed using a mixed-model repeated 
measures (MMRM) approach for the All Randomized Set (ARS) population.  The baseline is selected to be the last 
value on or prior to the treatment starting visit: Visit 4 (Week 0).  Neither last-observation-carried-forward (LOCF) 
method nor other imputation methods will be used for the outcome measures. However, LOCF method will be used 
for sensitivity analysis.  The MMRM model adjusts for missing data through an observed-data-likelihood-based 
approach.  The model will include the following fixed effects:  treatment (U-500R CSII, U-500R MDI), weeks on 
treatment, the interaction between treatment and weeks, and the appropriate stratification factor (nonusers versus 
users of GLP-1 receptor agonists or SGLT2 inhibitors and U-500R at entry versus other insulins).  The model will 
also include baseline HbA1c as a covariate.  An unstructured covariance matrix will be first modeled for the 
repeated measures of each subject.  If the analysis fails to converge, the following variance-covariance matrix will 
be used (in order) until one converges:
1.
Heterogeneous compound symmetry;
2.
Compound symmetry;
3.
First-order autoregressive.
The test for the first primary objective of noninferiority will be performed at the 0.05 significance level using the 
least-squares (LS) mean estimate of the difference in change in HbA1c between the two treatments at Week 26.  
Noninferiority will be established if the upper limit of a 2-sided 95% confidence interval (CI) for the difference 
(U 500R CSII minus U-500R TID) is below the NIM of 0.4%.
Using the LS mean estimate of the difference in change in HbA1c between the 2 treatments, superiority will be 
established if the upper limit of a two-sided 95% CI for the difference (U-500R CSII minus U-500R MDI) is 
below 0.
The following supportive and sensitivity analyses will also be conducted:

If the following sets are different from the ARS, then similar MMRM analyses will be done for the Full 
Analysis Set (subjects who were randomized and received at least 1 dose of the study insulin through the 
administration method they were assigned to), All Completer Set (subjects who complete the study), and the 
Per-Protocol Population (subjects included in the ARS who have completed the study without significant 
protocol violations).

An ‘analysis of covariance’ model with similar fixed effects as in the MMRM analysis using LOCF method 
for the ARS population.
Secondary Efficacy:
Similar MMRM models for the ARS population will be used to analyze the change from baseline for the following 


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values at week 26:
1)
FPG (by laboratory measurement)
2)
7-point SMBG
3)
Total Daily Insulin dose (TDD)
Baseline values will be the last value obtained for each subject at or prior to the randomization visit: Visit 4, unless 
otherwise stated.  The MMRM model will include similar fixed effects as in the primary analysis, with the 
corresponding baseline measures included as a covariate.  The model specifications will be carefully adjusted as 
appropriate.
For the following values at week 26:

Proportions of subjects achieving HbA1c targets/values (≤6.5%; <7.0%; <7.5% and <8.0%). 

Proportions of subjects achieving HbA1c targets/values (≤6.5%; <7.0%; <7.5% and <8.0%) without 
documented symptomatic hypoglycemia (SMBG <50 mg/dL).
Treatment comparisons will be analyzed using a repeated-measure logistic regression model including subject to 
account for the repeated measurements and similar fixed effects as in the above MMRM models.  The proportion of 
subjects achieving HbA1c targets with no documented symptomatic hypoglycemia (from baseline to corresponding 
visit) will be analyzed using a similar repeated-measure logistic regression model including the baseline documented 
symptomatic hypoglycemia event rate as a covariate.
Safety Analyses:
All of the secondary objectives related to safety will be analyzed for Group A and for the total study population 
(Groups A and B combined). All safety measures will be summarized for ARS by treatment and by visit for the 
26-week treatment period. Safety measures will also be listed for those patients who discontinue study treatment but 
still remain in the study for safety monitoring purpose. These listings will contain data after the patients discontinue 
study treatment. For treatment comparisons of frequency and proportion of event variables (such as AEs and 
hypoglycemia events), the conventional Fisher’s exact test or Pearson’s chi-square test are appropriate to use. 
Hypoglycemia:  (documented [documented symptomatic, asymptomatic, and unspecified], severe, and nocturnal
episodes):  The rate per 30 days calculated between 2 visits is defined as the total number of episodes for all subjects 
between the visits divided by the total actual number of exposure days between the visits, and then multiplied by 
30 days.  A similar definition will be used to calculate the rate per subject per 365 days (year).  For documented 
(documented symptomatic, asymptomatic and unspecified), severe, and nocturnal hypoglycemic episodes, the 
following analyses will be conducted.  The incidence and percentage of subjects with at least 1 hypoglycemic event 
will be analyzed using Fisher’s exact test or Pearson’s chi-square test, as appropriate.  The rate of hypoglycemia 
events per 30 days and per 365 days will be analyzed using a repeated-measure negative binomial regression model 
with similar fixed effects as in the primary analysis model.  Baseline hypoglycemia event rate for the corresponding 
category of the dependent hypoglycemia variable will be included as a covariate, as well as the stratification factors.
Body Weight:  The body weight change will be analyzed separately by MMRM models similar to that which will be 
used in the primary analysis for the ARS population.  The model specifications will be adjusted as appropriate.


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TEAEs and serious adverse events (SAEs): Adverse events will be listed by subject, system organ class, preferred 
term, severity, and relationship to the study disease, drug, device, or procedure.  Adverse events will be summarized 
as TEAEs during treatment period (defined as events that are newly reported after randomization Visit 4 or reported 
to be worsened in severity from randomization Visit 4) for ARS by treatment and visit. The frequency and 
proportion of subjects experiencing at least 1 of each reported TEAE will be summarized for treatment period.  The 
frequency and proportion comparisons will be analyzed using Fisher’s exact test or Pearson’s chi-square test, as 
appropriate.  The frequency and proportion of subjects experiencing at least 1 of each reported TEAE that are 
assessed as possibly related to the study disease, drug, device, or procedures will also be summarized. All SAEs 
(including severe hypoglycemic events) will be listed by subject with similar information as the AE listing.  If a 
sufficient number of SAEs are reported, then a frequency and proportion summary, similar to the summary for 
TEAEs, will be included for the ARS.  
Vital Signs:  Systolic and diastolic blood pressures and pulse will be summarized by visit and for endpoints (LOCF).  
Change from baseline to the last visit of each period for actual endpoint and endpoint (LOCF) will be summarized.
Study Treatment Exposure:  Exposure to each treatment will be calculated for each subject and summarized by 
treatment.  Total subject-years will be included in the summaries.
Laboratory Measures (chemistry, hematology, lipids): Treatment-emergent high, low, and abnormal values will be 
summarized for each lab measure.
Further details of analyses will be provided in the SAP.  
Patient Reported Outcome Measures: As an exploratory objective, the TRIM-D and TRIM-DD measures will be 
used to compare the change in diabetes treatment and diabetes treatment device on patient’s functioning, well-being 
and quality-of-life outcomes from baseline to the 26-week values between treatment groups.  These analyses will be 
performed on the ARS using a MMRM model (similar to the primary/secondary analyses).  Summaries of the 
continuous variables will include sample size, mean, SD, median, minimum, maximum, LS mean and standard error 
(SE) of LS mean.


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3. Table of Contents
Safety and Efficacy of Human Regular U-500 Insulin 
Administered by Continuous Subcutaneous Insulin Infusion 
versus Multiple Daily Injections in Subjects with Type 2 
Diabetes Mellitus:  A Randomized, Open-Label, Parallel 
Clinical Trial
(VIVID: Evaluating U-500R Infusion versus Injection in Type 2 
Diabetes Mellitus)  
Section
Page
1.
Protocol B5K-MC-IBHD Safety and Efficacy of Human Regular 
U-500 Insulin Administered by Continuous Subcutaneous Insulin 
Infusion versus Multiple Daily Injections in Subjects with Type 2 
Diabetes Mellitus:  A Randomized, Open-Label, Parallel Clinical 
Trial....................................................................................................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................9
4.
Abbreviations and Definitions...........................................................................................16
5.
Introduction ......................................................................................................................20
6.
Objectives.........................................................................................................................23
6.1.
Primary Objective ........................................................................................................23
6.2.
Secondary Objectives...................................................................................................23
6.2.1.
Key Secondary Objectives ...................................................................................23
6.2.2.
Other Secondary Objectives .................................................................................24
6.3.
Exploratory Objectives.................................................................................................24
7.
Investigational Plan...........................................................................................................25
7.1.
Summary of Study Design............................................................................................25
7.1.1.
Diaries .................................................................................................................26
7.1.2.
Type 2 Diabetes Lifestyle Counseling ..................................................................27
7.1.3.
Blood Glucose Monitoring ...................................................................................27
4-Point SMBG................................................................................................27
7.1.3.1.
7-Point SMBG................................................................................................27
7.1.3.2.
0300 Hours SMBG.........................................................................................28
7.1.3.3.
7.1.4.
Screening Period..................................................................................................28
7.1.5.
Lead-In Period .....................................................................................................28
7.1.6.
Randomization.....................................................................................................28
7.1.7.
Treatment Period..................................................................................................28


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Transition to U-500R MDI .............................................................................29
7.1.7.1.
U-100 Insulin Syringe for Administering U-500R MDI ..................................29
7.1.7.2.
CSII Pump Training........................................................................................29
7.1.7.3.
7.2.
Discussion of Design and Control ................................................................................29
8.
Study Population...............................................................................................................31
8.1.
Inclusion Criteria..........................................................................................................31
8.2.
Exclusion Criteria ........................................................................................................32
8.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................34
8.3.
Discontinuations ..........................................................................................................34
8.3.1.
Discontinuation of Inadvertently Enrolled Subjects ..............................................34
8.3.2.
Discontinuation of Study Treatment .....................................................................35
8.3.3.
Subject Discontinuation from the Study ...............................................................35
8.3.4.
Subjects Lost to Follow-Up..................................................................................36
8.3.5.
Discontinuation of Study Sites .............................................................................36
8.3.6.
Discontinuation of the Study ................................................................................36
9.
Treatment..........................................................................................................................37
9.1.
Treatments Administered .............................................................................................37
9.2.
Materials and Supplies .................................................................................................37
9.3.
Method of Assignment to Treatment ............................................................................38
9.4.
Rationale for Selection of Doses in the Study...............................................................38
9.5.
Lead-in Period..............................................................................................................39
9.6.
Randomization.............................................................................................................39
9.7.
Transition to U-500R MDI...........................................................................................39
9.7.1.
Dosing Using U-100 Insulin Syringes ..................................................................40
9.7.2.
CSII Training.......................................................................................................41
9.7.3.
Intensified Dose Titration Period..........................................................................41
9.7.4.
Maintenance Dose Titration Period ......................................................................41
9.8.
Treatment Periods ........................................................................................................41
9.8.1.
CSII .....................................................................................................................41
CSII Treatment Group Algorithms..................................................................42
9.8.1.1.
CSII Basal Rate ..............................................................................................44
9.8.1.2.
9.8.1.2.1.
Adding a Basal Rate for Nocturnal Hypoglycemia ....................................44
9.8.1.2.2.
Adding a Basal Rate for Dawn Phenomenon.............................................44
CSII Bolus Dosing..........................................................................................44
9.8.1.3.
9.8.1.3.1.
CSII Bolus Settings...................................................................................44
9.8.2.
MDI.....................................................................................................................45
MDI Treatment Group Algorithms .................................................................45
9.8.2.1.
9.9.
Special Treatment Considerations ................................................................................46


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9.9.1.
Rescue Therapy....................................................................................................46
9.9.2.
Continued Access to Study Treatment..................................................................47
9.10. Blinding .......................................................................................................................47
9.11. Concomitant Therapy...................................................................................................47
9.11.1.
Concomitant Medications Including Antihyperglycemic 
Agents..................................................................................................................47
9.12. Treatment Compliance .................................................................................................48
10.
Efficacy, Patient Reported Outcomes, Safety Evaluations, Sample 
Collection and Testing, and Appropriateness of Measurements .........................................49
10.1. Efficacy Measures........................................................................................................49
10.1.1.
Primary Efficacy Measure....................................................................................49
10.1.2.
Secondary Efficacy Measures...............................................................................49
Fasting Plasma Glucose..................................................................................49
10.1.2.1.
7-point SMBG................................................................................................49
10.1.2.2.
Total Daily Insulin Dose.................................................................................49
10.1.2.3.
10.2. Patient Reported Outcomes ..........................................................................................49
10.2.1.
TRIM-D and TRIM-D Device..............................................................................49
10.3. OmniPod U-500 System Exit Questionnaire.................................................................50
10.4. Safety Evaluations........................................................................................................50
10.4.1.
Adverse Events ....................................................................................................50
Serious Adverse Events ..................................................................................51
10.4.1.1.
10.4.1.1.1.
Suspected Unexpected Serious Adverse Reactions....................................52
10.4.2.
Hypoglycemia......................................................................................................53
10.4.3.
Body Weight........................................................................................................54
10.4.4.
Other Safety Measures .........................................................................................54
Vital signs ......................................................................................................54
10.4.4.1.
Physical Examinations....................................................................................54
10.4.4.2.
Electrocardiograms.........................................................................................54
10.4.4.3.
Clinical Laboratory Tests................................................................................54
10.4.4.4.
Concomitant Medications ...............................................................................54
10.4.4.5.
Functionality and Safe Use of OmniPod U-500 System ..................................54
10.4.4.6.
10.4.5.
Safety Monitoring ................................................................................................54
10.4.6.
Complaint Handling.............................................................................................55
10.5. Sample Collection and Testing .....................................................................................55
10.5.1.
Samples for Study Qualification and Health Monitoring.......................................56
10.5.2.
Pharmacogenetic Samples for Biomarker Research ..............................................56
10.5.3.
Nonpharmacogenetic Biomarker Stored Samples .................................................57
10.6. Appropriateness of Measurements................................................................................57


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11.
Data Quality Assurance.....................................................................................................58
11.1. Data Capture System....................................................................................................58
12.
Sample Size and Statistical Methods .................................................................................60
12.1. Determination of Sample Size ......................................................................................60
12.2. Statistical and Analytical Plans.....................................................................................60
12.2.1.
General Considerations ........................................................................................60
12.2.2.
Adjustment for Multiplicity..................................................................................60
12.2.3.
Subject Disposition ..............................................................................................63
12.2.4.
Subject Characteristics .........................................................................................63
12.2.5.
Concomitant Therapy...........................................................................................63
12.2.6.
Treatment Compliance .........................................................................................63
12.2.7.
Primary Outcome and Methodology.....................................................................63
12.2.8.
Secondary Efficacy Analyses ...............................................................................64
12.2.9.
Exploratory Analyses...........................................................................................65
Patient Reported Outcomes Analyses..............................................................65
12.2.9.1.
12.2.9.1.1.
TRIM-D and TRIM-DD............................................................................65
OmniPod U-500 System Exit Questionnaire ...................................................65
12.2.9.2.
Functionality and Safe Use of the OmniPod U-500 
12.2.9.3.
System............................................................................................................65
12.2.10. Safety Analyses....................................................................................................66
Hypoglycemia ................................................................................................66
12.2.10.1.
Body Weight ..................................................................................................66
12.2.10.2.
Treatment-Emergent Adverse Events and Serious 
12.2.10.3.
Adverse Events...............................................................................................66
Vital Signs......................................................................................................67
12.2.10.4.
Study Treatment Exposure..............................................................................67
12.2.10.5.
Laboratory Measures ......................................................................................67
12.2.10.6.
12.2.11. Safety Committee.................................................................................................67
12.2.12. Interim Analyses ..................................................................................................68
13.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................69
13.1. Informed Consent.........................................................................................................69
13.2. Ethical Review.............................................................................................................69
13.3. Regulatory Considerations ...........................................................................................69
13.3.1.
Investigator Information.......................................................................................70
13.3.2.
Protocol Signatures ..............................................................................................70
13.3.3.
Final Report Signature .........................................................................................70
14.
References ........................................................................................................................71


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List of Tables
Table
Page
Table IBHD.7.1. Planned Subject Recruitment ........................................................................25
Table IBHD.9.1. Treatment Regimens......................................................................................37
Table IBHD.9.2. Study Devices................................................................................................38
Table IBHC.9.3. Transition from entry insulin to U-500R MDI.................................................40
Table IBHD.9.4. Basal Titration Scheme for CSII ....................................................................43
Table IBHD.9.5. Bolus Titration Scheme for CSII....................................................................43
Table IBHD.9.6. Bolus Titration Scheme for MDI Delivered TID ............................................46
Table IBHD.9.7. Concomitant Medications and Conditions for Use .........................................48


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List of Figures
Figure
Page
Figure IBHD.7.1.Illustration of study design for Clinical Protocol B5K-MC-IBHD..................26
Figure IBHD.12.1.
Graphical approach to adjust multiplicity. ...........................................62


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List of Attachments
Attachment
Page
Attachment 1.
Protocol IBHD Study Schedule......................................................................74
Attachment 2.
Protocol IBHD Clinical Laboratory Tests ......................................................78
Attachment 3.
World Health Organization (WHO) Classification of Diabetes.......................79
Attachment 4.
New York Heart Association (NYHA) Cardiac Disease Classifications .........80


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4. Abbreviations and Definitions
Term
Definition
Adverse event (AE)
Adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
AHA
antihyperglycemic agent
ALT/SGPT
alanine aminotransferase (serum glutamic pyruvic transaminase)
ARS
All randomized set
AST/SGOT
aspartate aminotransferase (serum glutamic oxaloacetic transaminase)
AUC
Area under the curve
BG
blood glucose
BID
twice daily
CGM
continuous glucose monitoring
CHO
carbohydrate
CI
confidence interval
Complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
Compliance
Adherence to all the trial-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements.
Consent
The act of obtaining informed consent for participation in a clinical trial from subjects 
deemed eligible or potentially eligible to participate in the clinical trial.  Subjects entered 
into a trial are those who sign the informed consent form directly or through their legally 
acceptable representatives.
CRP/CRS
Clinical research physician/ Clinical research scientist: 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
DMC
Data monitoring committee 
ECG
electrocardiogram


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Term
Definition
eCRF
electronic clinical report form:  An electronic form for recording study participants’ data 
during a clinical study, as required by the protocol.
Efficacy
Efficacy is the ability of a treatment to achieve a beneficial intended result under 
controlled conditions.
End of trial (study)
End of trial is the date of the last visit or last scheduled procedure shown in the Study 
Schedule for the last active subject in the study.
Enroll
The act of assigning a subject to a treatment.  Subjects who are enrolled in the trial are 
those who have been assigned to a treatment.
Enter
Subjects entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ET
early termination
FAS
full analysis set
FDA
Food and Drug Administration
FPG
fasting plasma glucose (central laboratory value)
GCP
good clinical practice
GLP-1
glucagon-like peptide-1
HbA1c
glycated hemoglobin A1c
ICF
informed consent form
Informed consent
A process by which a subject voluntarily confirms his or her willingness to participate in 
a particular trial, after having been informed of all aspects of the trial that are relevant to 
the subject’s decision to participate. Informed consent is documented by means of a 
written, signed, and dated informed consent form.  
Institutional Review 
Board/ Ethical 
Review Board 
(IRB/ERB)
A board or committee (institutional, regional, or national) composed of medical and 
nonmedical members whose responsibility is to verify that the safety, welfare, and 
human rights of the subjects participating in a clinical study are protected.
IOB
Insulin-on-board:  Active insulin circulating in the body from previous bolus doses
Investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible 
leader of the team and may be called the principal investigator.
ITT
Intention to treat:  The principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a subject (that is, planned 
treatment regimen) rather than the actual treatment given.  It has the consequence that 
subjects allocated to a treatment group should be followed up, assessed, and analyzed as 
members of that group irrespective of their compliance to the planned course of 
treatment.


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Term
Definition
IWRS
interactive web response system
LOCF
last observation carried forward
LS mean
least-squares mean
MDI 
multiple daily injections
MDRD
Modification of Diet in Renal Disease
MET
metformin
MMRM
mixed-model repeated measures
NIM
Noninferiority margin
PDM
Personal diabetes manager
PRO
patient-reported outcomes
Randomize
The act of assigning a subject to a treatment.  Subjects who are randomized in the trial 
are those who have been assigned to a treatment.
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.  In this study, screening 
involves invasive or diagnostic procedures and/or tests (for example, diagnostic 
psychological tests, x-rays, blood draws).  For this type of screening, informed consent 
for these screening procedures and/or tests shall be obtained; this consent may be 
separate from obtaining consent for the study.
SD
standard deviation
SE
standard error
SGLT2
sodium-glucose cotransporter 2 
SMBG
self-monitored blood glucose
Subject
An individual who is or becomes a participant in clinical research, either as a recipient of 
the investigational product(s) or as a control.  A subject may be either a healthy human 
or a patient.
SUSAR
suspected unexpected serious adverse reaction
TDD
total daily dose
TID
three times daily


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Term
Definition
TPO
third party organization
Treatment-emergent 
adverse event (TEAE)
Treatment-emergent adverse event:  Any untoward medical occurrence that either occurs 
or worsens at any time after treatment baseline and that does not necessarily have to have 
a causal relationship with this treatment.
TRIM-D
treatment-related impact measure for diabetes
TRIM-DD
treatment-related impact measure for diabetes device
T1DM
type 1 diabetes mellitus
T2DM
type 2 diabetes mellitus
U-500R
human regular U-500 insulin; Humulin® R U-500 insulin
ULN
Upper limit of normal
US
United States
VAS
visual analog scale
WHO
World Health Organization


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5. Introduction
Although human regular U-500 insulin (Humulin® R U-500; U-500R) has been available in the 
United States (US) market for more than 50 years, its clinical use has increased over the past 
5 years due to the worsening epidemics of type 2 diabetes mellitus (T2DM) and obesity (Lane et 
al. 2009; Segal et al. 2010; Cochran et al. 2014).  
According to published clinical reports and expert clinical reviews, high-dose insulin-treated
insulin-resistant patients (requiring >200 units of U-100 insulin) have been treated successfully 
and safely with U-500R by injection, resulting in improved glycemic control (glycated 
hemoglobin A1c [HbA1c] reductions between 1% and 2%) with uncommon reports of severe 
hypoglycemia (Neal 2005; Ballani et al. 2006; Lane et al. 2009; Nayyar et al. 2010; Dailey et al. 
2010; Quinn et al. 2011; Ziesmer et al. 2012; Boldo and Comi 2012; Reutrakul et al. 2012; Jones 
and Idris 2013; Hood et al. 2015). U-500R is typically dosed utilizing multiple-daily injections 
(MDI) with either twice daily (BID) or three times daily (TID) dosing (Humulin R U-500 
package insert; de la Peña et al. 2011; Reutrakul et al. 2012). One small (N=28) randomized 
controlled trial of U-500R was recently published reporting a significant mean HbA1c reduction
of 1.0% to 1.7% from baseline to 24-week endpoint (p=0.0001) with no reported episodes of 
severe hypoglycemia when combined with metformin and/or exenatide (Distiller et al. 2014).  
The effect of U-500R begins within 30 minutes, has a peak similar to that observed with human 
regular U-100 insulin (U-100R), and has a relatively long duration of activity (up to 24 hours) 
following a single dose as compared with U-100R (de la Peña et al. 2011). Similarly, a U-500R 
pharmacokinetic/pharmacodynamics simulation modeling study indicated the steady-state basal 
pharmacokinetic/pharmacodynamics effect from both BID and TID dosing appears to support 
use of U-500R as insulin monotherapy (de la Peña. 2014). A recently completed randomized, 
controlled Phase 4 trial (B5K-US-IBHC) comparing TID versus BID U-500R monotherapy over 
24 weeks in 325 subjects demonstrated that U-500R as insulin monotherapy is safe and 
efficacious (HbA1c reduction of 1.1% to 1.2% [Hood et al. 2015]). 
Clinical expert reviews recommend MDI delivered TID injections for all dosage ranges of 
U-500R (Cochran et al. 2005; Lane et al. 2009; Segal et al. 2010; Reutrakul et al. 2012; Cochran 
et al. 2014).  A number of clinical case series (Knee et al. 2003; Schwartz 2004; Lane 2006; 
Bulchandani et al. 2007; Lane et al. 2010; and Reutrakul et al. 2011) have also reported use of 
U-500R by continuous subcutaneous insulin infusion (CSII), a practice that may account for 
approximately one quarter of current U-500R therapy according to recent large retrospective 
real-world claims database analysis (Eby et al. 2014).  These U-500 CSII therapy case series 
have shown improvements in HbA1c from 1.2% (Lane et al. 2010) to 3.5% (Knee et al. 2003), 
and a mean reduction of 1.64% in a review by Reutrakul et al. (2012) which reported severe 
hypoglycemia in 2 (n=55) subjects.  The largest and longest case series (N=59; mean duration of 
follow up 49 months [range: 12 to 114 months]; Lane et al. 2013) reported 1.0% mean decrease 
in HbA1c (from 8.3% to 7.3%) sustained over 66 months of U-500 CSII therapy with severe 
hypoglycemia rate (defined by blood glucose [BG] ≤50 mg/dL or “blood glucose requiring 
treatment [regardless of value])”) at 0.1 episodes per patient per year.  


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The aforementioned studies with U-500R in CSII therapy lacked controls, were predominately 
retrospective, and included a small number of subjects (60 subjects per study; total: 
114 subjects).  Additionally, delivery by CSII in currently marketed insulin pumps requires dose 
transition to “U-100 insulin pump units” (one-fifth of actual U-500R dose per volume; Lane et 
al. 2006; Lane et al. 2009; Lane et al. 2010; Segal et al. 2010; and Cochran et al. 2014), which 
has the potential to result in dosing confusion and medication errors.
In summary, there is a clear clinical need to study the use of U-500 by CSII in a prospective, 
randomized clinical trial. Thus, Lilly has developed protocol B5K-MC-IBHD to evaluate the
efficacy and safety of U-500R delivered by CSII as compared to U-500R MDI delivered TID.
The CSII system uses a novel insulin pump device that is not commercially available with 
internal software appropriate for U-500 insulin dosage in U-500 insulin units.  
Input obtained from T2DM patient interviews for this protocol development indicates a wide 
spectrum of knowledge and ability to utilize CSII features by patients.  The current trial design 
was developed to meet the needs of high-dose insulin-requiring patients who could benefit from 
improved glycemic control with CSII.  The unique properties of U-500R demonstrate that it can 
be used as both basal and bolus therapy in MDI or CSII regimens (CSII 50% basal and 50% 
bolus) (Hirsch 2010; de la Peña et al. 2011; Hood et al. 2015). The functionality of the OmniPod 
U-500 system in the trial allows for those patients requiring simpler interface, as well as those 
who would benefit from increased individualization.  For example, the CSII treatment arm will 
initially utilize 2 basal rates for simplicity but allow for individualization up to 4 basal rates if 
needed.  Additionally, a variety of bolus options will be available including boluses based on 
carbohydrate (CHO) counting, fixed meal doses, or doses based on meal sizes (small, medium,
or large). 
It is estimated that 10% to 18% of patients treated with U-500R are on concomitant noninsulin 
injectable therapy, including glucagon-like peptide-1 (GLP-1) receptor agonist therapy (Eby et 
al. 2013, 2014 and Data on File).  Although the percentage of U-500R used in combination with 
sodium-glucose co-transporter 2 (SGLT2) inhibitors is unknown, combination of SGLT2 
inhibitors with U-100 insulin has risen by 4-fold to 1.4% (July 2013 to April 2014 [IMS Data on 
File]).  GLP-1 receptor agonists and SGLT2 inhibitors have been used in insulin-sparing and 
weight attenuating strategies and have shown clinical utility in combination with U-500R or 
U-100 insulin (Lane et al. 2011; Rosenstock et al. 2014).  Two study population groups 
(Groups A and B) will be stratified by nonuse or use of these therapies.  Subjects in each group 
will be randomly assigned equally between treatment arms.  Study population Group A will 
include patients who are not using GLP-1 receptor agonists or SGLT2 inhibitors. The study 
population Group B will include patients who are using GLP-1 receptor agonists or SGLT2
inhibitors.  Group A will be the primary analysis population.  Combined Groups A and B will be 
included in the key and other secondary objectives. The use of GLP-1 receptor agonists or
SGLT2 inhibitors is also intended for exploratory analyses.  
Appropriate testing supporting use of the U-500R in the OmniPod U-500 Insulin Management 
System in clinical trials has been completed.  More detailed information about the known and 
expected benefits and risks of U-500R may be found in the U-500R package insert.  More 


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detailed information regarding the use of the OmniPod U-500 system may be found in the 
OmniPod U-500 Insulin Management System User Guide.


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6. Objectives
6.1.
Primary Objective
The primary objective is to demonstrate the change in HbA1c of U-500R administered by CSII is 
noninferior to U-500R administered by MDI therapy from baseline to the 26-week in high-dose 
insulin-requiring patients with T2DM who have inadequate glycemic control on high-dose non 
U-500R (>200 and ≤600 units per day) insulins (CSII or MDI) and/or high-dose U-500R insulin 
(MDI) without use of GLP-1 receptor agonists or SGLT2 inhibitors and with or without other 
insulins/antihyperglycemic agents (AHAs).  This population is referred to as Group A. 
The following hypothesis will be tested for the primary objective:
H1: CSII is noninferior to MDI in change in HbA1c using a noninferiority margin (NIM)
of 0.4%.
The family-wise type I error rate for the primary objective and the following key secondary 
objectives will be controlled at a two-sided 5% level by the graphical approach, which will be 
discussed in detail in the Statistical Analysis Plan (SAP).
6.2.
Secondary Objectives
6.2.1. Key Secondary Objectives
The following 4 key (alternative hypotheses [H#]) secondary objectives at Week 26 are to 
demonstrate for the main study population (Group A [without use of GLP-1 receptor agonists or
SGLT2 inhibitors, Section 7.1]) that:
H2: CSII is superior to MDI in change in fasting plasma glucose (FPG).
H3: CSII is superior to MDI in proportions of subjects achieving HbA1c targets/values <7.0%.
H4: CSII is superior to MDI in change in HbA1c.
H5: CSII is superior to MDI in proportions of subjects achieving HbA1c targets/values <7.5%.
The following 5 key (alternative hypotheses [H#]) secondary objectives are to demonstrate the 
objectives at Week 26 for the total study population (Group A [without use of GLP-1 receptor 
agonists or SGLT2 inhibitors] and Group B [those who use GLP-1 receptor agonists or SGLT2 
inhibitors use, Section 7.1]) that:
H6: CSII is noninferior to MDI in change in HbA1c using NIM of 0.4%.
H7: CSII is superior to MDI in change in FPG.
H8: CSII is superior to MDI in proportions of subjects achieving HbA1c targets/values <7.0%.
H9: CSII is superior to MDI in change in HbA1c.
H10: CSII is superior to MDI in proportions of subjects achieving HbA1c targets/values <7.5%.


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6.2.2. Other Secondary Objectives
Additional secondary objectives of the study are to compare the efficacy and safety of U-500R
given by CSII versus MDI at Week 26 for the main study population Group A and the total study 
population (Groups A and B) respectively (separately), with respect to the following:

Proportions of subjects achieving HbA1c targets/values (≤6.5% and <8.0%).

Mean change in 7-point self-monitored blood glucose (SMBG) including mean 
SMBG for each time point measurement.

Change in TDD (unit and unit/kg).

Proportions of subjects achieving HbA1c targets/values (≤6.5%, <7.0%, <7.5%, 
and <8.0%) without documented symptomatic hypoglycemia (SMBG 
<50 mg/dL).

Rate and incidence of hypoglycemia (documented [documented symptomatic, 
asymptomatic, and unspecified], severe, and nocturnal).

Change in body weight between treatment groups and as a function of change in 
HbA1c.
6.3.
Exploratory Objectives

The change in patient reported outcomes including Treatment-Related Impact 
Measure for Diabetes (TRIM-D) and TRIM-D for Diabetes Device (TRIM-DD) 
surveys from baseline to 26-week value.

Assess subject-reported OmniPod pump experience via OmniPod U-500 System 
Exit Questionnaire.

Assess proportion of subjects with an HbA1c ≥9% and <9% at the 26-week value.

Postprandial contributions to total glycemic burden at baseline to 26-week values
using area under the curve (AUC) analysis of 7-point SMBG profiles.  

Glycemic variability using 7-point SMBG profiles (including within day and 
day-to-day standard deviation [SD], coefficient of variation, average daily risk 
range, and mean of daily differences).

Examine the relationship between gene variants including, but not limited to, 
insulin receptor, insulin like growth factor-1, melatonin receptor 1B1, 
adiponectin, transcription factor 7-like 2, phosphoinositide-3-kinase, regulatory 
subunit 1 and B-cell CLL/lymphoma 11A on clinical outcomes. 

Evaluate subgroups of baseline TDD >2 and ≤2 units/kg, TDD >200 units at 
baseline that fall below TDD 200 units during the study, baseline TDD >400 and 
≤400 units, users of GLP-1 receptor agonists or SGLT2 inhibitors, and geriatric 
subjects (age ≥65 years and ≥75 years) on each of the primary and secondary 
objectives.

Functionality and safe use of the OmniPod U-500 system.


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7. Investigational Plan
7.1.
Summary of Study Design
Study B5K-MC-IBHD is a Phase 3b, multicenter, randomized, open-label, parallel clinical trial 
comparing U-500R administered by CSII (OmniPod U-500 system) to U-500R administered
MDI in high-dose insulin-requiring patients with T2DM who have inadequate glycemic control
on high-dose non U-500R (>200 and ≤600 units per day) insulins (CSII or MDI) and/or U-500R 
insulin (MDI) with or without other insulins/AHAs.  The trial design includes: 1-week screening
period, 2-week lead-in period, and a 26-week treatment period (2 week transition to U-500R
MDI administered TID, 12 weeks titration and 12 weeks maintenance U-500R CSII or MDI).  
As shown in the following recruitment plan (Table IBHD.7.1), approximately 320 subjects 
requiring high-dose insulin without use of GLP-1 receptor agonists or SGLT2 inhibitors (Group 
A) and approximately 64 to 96 additional subjects who are using GLP-1 receptor agonists or
SGLT2 inhibitors (Group B) with or without other AHAs will be randomized based on a 1:1 
ratio to two treatment arms.  After Group A has been fully enrolled, Lilly may stop enrollment 
for Group B, even if the minimum recruitment goal for Group B has not been met.  
Approximately 240 (Group A) and 48 to 72 (Group B) subjects are expected to complete the 
26-week treatment period (assuming a 25% dropout rate).
Table IBHD.7.1.
Planned Subject Recruitment
Group A
Group B GLP-1 or SGLT2 users
(Target range)
Entered
450
90 to 136
Enrolled/Randomized
320
64 to 96
Completed
240
48 to 72
Abbreviations:  GLP-1 = glucagon-like peptide-1; SGLT2 = sodium-glucose cotransporter 2.
The end of the study for each subject is Visit 17 or the early termination (ET) visit for subjects
who discontinue early.  Figure IBHD.7.1 illustrates the study design.


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Abbreviations:  CSII = continuous subcutaneous insulin infusion; MDI = multiple daily injections.
a
Subjects will continue their pre-study insulin regimens.
b
Subjects will be stratified and randomly assigned equally between treatment arms by nonusers (Group A) versus 
users (Group B) of GLP-1 receptor agonists or SGLT2 inhibitors, entry HbA1c ≥8.5% or <8.5%, and U-500R at 
entry versus other insulins.
c
MDI or CSII and will be transitioned to U-500R by MDI.
d
Telephone visits.
Figure IBHD.7.1.
Illustration of study design for Clinical Protocol B5K-MC-IBHD.
7.1.1. Diaries
As indicated in the study schedule (Attachment 1), starting at Visit 1 (Week -3) subjects will be 
given a study diary at each office visit and instructed to record 4- point, and 7-point SMBG 
values, insulin doses, hypoglycemic episodes, adverse events (AEs), illnesses, concomitant 
medications, infusion site changes, and reasons for nonroutine infusion site changes (post-
randomization and transition to U-500R) through the end of participation in the study or at ET, if 
applicable.  Investigators should encourage subjects to measure BG values during the symptoms 
of hypoglycemia and record BG values in their study diaries.  Investigative staff will review the 
study diaries and transfer data to electronic case report forms (eCRFs) at each office visit 
beginning at Visit 2 (Week -2), with the exception of 4-point SMBG values. Investigative staff 
will also record any additional AEs and episodes of hypoglycemia that are reported by subjects 
and that have occurred since the previous entry on the eCRFs, even when the event was initially 
not entered into the study diary. Study diaries are considered source information and are to be 
returned to the investigator (or designee) at each office visit.


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7.1.2. Type 2 Diabetes Lifestyle Counseling
Per the study schedule (Attachment 1), qualified medical staff will provide diabetes management 
counseling including diet, exercise, and education about the signs, symptoms, and treatment of 
hypoglycemia, should it occur.  Subjects should continue their usual exercise habits and 
generally follow stable meal plans (consistent meal size and time of day) throughout the course 
of the study.  Instruction on how to assess CHO content and caloric content of meals may be 
incorporated into the counseling.  Dietary counseling may be reviewed throughout the study as 
needed.  Subjects are not to initiate a weight loss program during the trial.
7.1.3. Blood Glucose Monitoring
The U-500R dosage will be based on subjects’ individual needs, as assessed by SMBG results
obtained from monitoring at home.  Site personnel may request additional BG monitoring from 
subjects and/or assess BG values at other times during the study in order to make dose
adjustment decisions.  Subjects should record both 4- and 7-point SMBG measurements, as well 
as insulin doses, in the subject diary provided.
4-Point SMBG
7.1.3.1.
Subjects will be instructed to record 4-point SMBGs daily beginning with the screening period.  
The 4-point SMBG consists of BG measurements at:

Pre-morning meal (fasting)

Pre-midday meal

Pre-evening meal

Bedtime (at least 2 hours after the evening meal)
7-Point SMBG
7.1.3.2.
All subjects will be instructed to record 7-point SMBG profiles on any 2 nonconsecutive days in 
the 2 weeks prior to visits as outlined in the study schedule (Attachment 1); profiles should 
include weekend day(s), if possible.  The timing of the 7-point SMBG measurement over a 
24-hour period is as follows:

Pre-morning meal (fasting)

2 hours after the morning meal

Pre-midday meal

2 hours after the midday meal

Pre-evening meal

2 hours after the evening meal

0300 hours


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0300 Hours SMBG
7.1.3.3.
Subjects will also be instructed to record their 0300 hours BG within 48 hours of each increase in 
insulin dose titration at telephone and office visits (preferably the first night after the dosage 
adjustment).  The investigator or site personnel will ask the subjects about these BG 
measurements and the investigator will recommend dosage titrations based on glucose targets 
within the CSII (Section 9.8.1.1) and MDI (Section 9.8.2.1) algorithms during telephone and 
office visits.
7.1.4. Screening Period
This study contains a 1-week screening period between Visit 1 (Week -3) and Visit 2 (Week -2),
which allows for the evaluation and assessment of potential subjects’ eligibility against the 
inclusion and exclusion criteria (Sections 8.1 and 8.2, respectively).  Subjects may be 
prescreened for inclusion/exclusion criteria that are available from their subject files, including 
any laboratory values on file collected within the previous 30 days, in compliance with local 
privacy regulations.  Subjects will continue their pre-study insulin and AHA regimens and doses 
(per inclusion/exclusion criteria in Sections 8.1 and 8.2).  Refer to Attachment 1 for the study 
schedule of screening period activities.
7.1.5. Lead-In Period
Eligible subjects will begin a 2-week lead-in period at Visit 2 (Week -2) according to the Study 
Schedule (Attachment 1).  The lead-in period is intended to stabilize HbA1c related to study 
effect (Gale et al. 2007) and verify insulin dose.  Subjects entering the trial at Visit 1 will 
continue their pre-study insulin regimen.  Subjects will also continue taking pre-study AHA
regimens and doses (per inclusion/exclusion criteria in Sections 8.1 and 8.2) and should not 
discontinue or change doses during the study, apart from specific instructions provided in 
Section 9.11.
7.1.6. Randomization 
Study subjects who have completed all screening procedures will be randomized at a 1:1 ratio to 
the two treatment arms (U-500R CSII or MDI) using interactive web-response system (IWRS) at
Visit 4 (Section 9.6).
A review of subjects’ understanding of daily glucose monitoring and emphasis on adherence, 
4-point and 7-point SMBG profile, use of glucose meters, hypo- and hyperglycemia, and 
completion of subjects’ diary will be conducted.
7.1.7. Treatment Period
At Visit 4 through Visit 17 or ET, subjects will be treated with U-500R based on titration 
algorithms.  The total treatment period for this study will be 26 weeks (2 week transition to 
U-500R MDI administered TID, 12 weeks titration and 12 weeks maintenance U-500R CSII or 
MDI).  
During the Treatment Period, Visits 8, 9, 11, 12, 14, and 16 will be telephone visits only and 
subjects will not be required to return to the study site.  At office visits (Visits 5, 6, 7, 10, 13, 15,


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and 17), clinical assessments and required procedures should occur as outlined in the Study 
Schedule (Attachment 1).  Adverse event and product complaint collection should occur at each 
office and telephone visit.
Apart from scheduled telephone visits, per the Study Schedule (Attachment 1), subjects will be 
instructed to call the study site office if a serious adverse event (SAE) or device-related event 
occurs, or for any concern at any time.  Specific reasons may include but are not limited to:  
hospital admission for any reason, persistent or severe hypoglycemia, recommendations for 
changes of medication from another provider, injection device or study glucose meter 
malfunction, questions about study treatment and dose changes, or scheduled surgical or dental 
procedures.
Subjects will continue taking noninsulin pre-study AHAs (per inclusion/exclusion criteria in 
Sections 8.1 and 8.2 and allowed concomitant therapies in Section 9.11) and should not 
discontinue or change doses during the study.
Transition to U-500R MDI
7.1.7.1.
A 2-week transition period is included in the 26-week treatment period and will follow 
randomization. The transition period is intended to transition all subjects safely from their 
current insulin regimen to U-500R TID 40:30:30 (Section 9.5), and to titrate U-500R according 
to the TID algorithm (Section 9.8.2.1). The highest 24-hour TDD from the past 3 days will be 
utilized for calculation of the U-500R TID dose and the dose split into the ratio of 40:30:30. 
Those subjects already on U-500R TID at entry can continue their pre-entry U-500R TID 
proportions at the discretion of the investigator.  At Visit 6 through Visit 17 or ET, subjects will 
be treated with either U-500R CSII (Section 9.8.1.1) or U-500R MDI delivered TID 
(Section 9.8.2.1) based on titration algorithms and the treatment to which they are randomized. 
U-100 Insulin Syringe for Administering U-500R MDI
7.1.7.2.
All subjects will receive training on the appropriate use of U-100 insulin syringes for drawing up 
and administering correct doses of U-500R, including the conversion of insulin units of U-500R 
to the unit markings (one-fifth of actual volume) on the U-100 insulin syringe (Section 9.7.1).
CSII Pump Training
7.1.7.3.
Subjects assigned to U-500R CSII treatment will receive training on the OmniPod U-500 system
at 2 visits (Visit 5 [Week 1] and Visit 6 (Week 2).  At Visit 5, subjects will be introduced to the 
basics of pump usage (ie, basal rates, boluses, and filling Pods).  At Visit 6, subjects will receive 
hands-on training on the U-500 OmniPod System.  Additional subject training can be considered 
at the investigator’s discretion after consulting with Lilly clinical research physician 
(CRP)/clinical research scientist (CRS) (Section 9.7.2).
7.2.
Discussion of Design and Control
This is a randomized, open-label, parallel study comparing U-500R administered by CSII 
(OmniPod U-500 system) to U-500R administered by MDI in high-dose insulin-requiring
patients with T2DM who have inadequate glycemic control on existing high-dose non U-500R 
(>200 and ≤600 units per day) insulins (CSII or MDI), and/or U-500R insulin MDI with or 


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without other insulins/AHAs.  Delivery of U-500R insulin by CSII in currently marketed insulin 
pumps requires dose conversion to “U-100 pump units” (one-fifth of U-500R insulin dose per 
volume), which potentially could result in dosing confusion.  The OmniPod Insulin Management 
System for use with U-500 insulin (OmniPod U-500 system) software has been developed so that 
1 unit of insulin is delivered with every 4 pulses of the drive mechanism (for example, the 
OmniPod U-500 system would deliver 0.25 units per pulse compared to 0.05 units per pulse in 
the conventional U-100 OmniPod insulin pump).  The volume delivered in 1 pulse is the same 
for the U-100 and U-500 insulin pumps; thus due to higher concentration, fewer pulses are 
required by the U-500 pump to deliver the same insulin dose (4 pulses for 1-unit for U-500 
insulin versus 20 pulses for 1-unit for U-100 insulin).  
The majority (86%) of patients currently using U-500R have T2DM (Eby et al. 2013).  Because 
patients with type 1 diabetes mellitus (T1DM) constitute a small proportion of U-500R users and 
could have a different response to the algorithms and/or CSII delivery system, they are excluded 
from this study.
The total treatment period for this study will be 26 weeks.  The 26-week duration of treatment in 
this study was selected because it allows enough time for insulin therapy to be intensified, and 
permits sufficient time to show glycemic improvement and stabilization as measured by HbA1c, 
FPG, SMBG values, and TDD.  
After Visit 1 (screening), subjects who meet all of the inclusion criteria (Section 8.1) and none of 
the exclusion criteria (Section 8.2) will remain on their pre-study treatment for a 2 week lead-in 
period at Visit 2 (Week -2).  This lead-in period is intended to stabilize HbA1c related to study 
effect (Gale et al. 2007) and verify actual insulin dose.  Following the lead-in, subjects will be 
randomized at Visit 4 (Week 0) in an open-label fashion based on a 1:1 ratio to U-500R 
treatment by MDI or U-500R treatment by CSII.  A 2-week transition to U-500R by MDI 
administered TID, regardless of insulin or combination thereof at Visit 2 (Week -2) (Section 9.5) 
will begin after randomization (Visit 4 [Week 0]) utilizing the TID algorithm with weekly 
titrations (Section 9.8.2.1).  The transition period is to ensure safe transition to U-500R insulin 
from entry insulin (as applicable).  After completion of the 2-week transition period, 24-weeks of 
U-500R delivered by MDI versus CSII will begin. 
The primary and key secondary objectives will be assessed in subjects from Group A (without
use of GLP-1 receptor agonists or SGLT2 inhibitors) and combined for the total study population 
Group A and Group B (those who use GLP-1 receptor agonists or SGLT2 inhibitors). 
The study will be performed open-label since blinding of the investigators, subjects, and study 
site personnel could not be accomplished given the differing modes of delivery of U-500R (CSII 
versus MDI). To minimize bias, aggregate review of summary data by the study team (that is, 
CRP/CRS overseeing the global conduct of the study, statisticians, and statistical analysts) will 
remain blinded until after the final database is locked (Section 9.10).


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8. Study Population
Individuals who do not meet the inclusion criteria for participation in this study (screen failure) 
may be re-screened once.  The interval between screen and re-screen should be at least 2 weeks.  
When re-screening is performed, the individual must sign a new informed consent form (ICF) 
and will be assigned a new identification number.
Entered subjects who meet all inclusion criteria ([1] through [7]) and are not excluded by 
exclusion criteria ([8] through [28]) will initiate the lead-in period at Visit 2 (Week -2).
Prior to randomization at Visit 4, all subjects will be re-confirmed for inclusion criteria [1], [2]
and [7] and exclusion criteria [18].
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
8.1.
Inclusion Criteria
Subjects are eligible to be included in the study only if they meet all of the following criteria:
Diagnosed with T2DM (World Health Organization [WHO] Classification of 
[1]
Diabetes [Attachment 3]).
Current TDD >200 but ≤600 units of non U-500R insulin/analog (basal; 
[2]
premixed; or basal/bolus by any injection device [MDI; pens and/or syringe/vial 
or CSII]) and/or U-500R by MDI with syringe and vial for ≥3 months at entry. 
o
If TDD of U-500R and other insulins are combined, then insulin other 
than U-500R not to exceed 25% of TDD.
HbA1c ≥7.5% and ≤12.0% as measured by the central laboratory at Visit 1.
[3]
Aged ≥18 to ≤85 years.
[4]
Body mass index ≥25 but ≤50 kg/m2.
[5]
Have a history of stable body weight (not varying by greater than 5% for at least 
[6]
3 months prior to study entry).
Concomitant AHA therapy may include metformin (MET), dipeptidyl peptidase-4
[7]
inhibitors (sitagliptin, saxagliptin, linagliptin, and alogliptin), and/or pioglitazone 
(doses ≤30 mg/day). Subjects’ AHA therapy must have been stable for ≥3 months
See exclusion criteria [18] and [19] for excluded medications.


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o
Approximately 64 to 96 subjects using GLP-1 receptor agonists
(albiglutide, dulaglutide, or liraglutide) or SGLT2 inhibitors 
(canagliflozin, dapagliflozin, empagliflozin) will be enrolled in Study 
Group B.  (GLP-1 receptor agonists must have been stable for ≥4 months). 
After the enrollment of this group is completed, subjects using GLP-1 
receptor agonists or SGLT2 inhibitors will no longer be enrolled in the 
study.  After Group A has been fully enrolled, Lilly may stop enrollment 
for Group B, even if the minimum recruitment goal for Group B has not 
been met.
8.2.
Exclusion Criteria
Subjects will be excluded from study if they meet any of the following criteria:
Diagnosed with T1DM or other types of diabetes apart from T2DM (WHO 
[8]
Classification of Diabetes Attachment 3; ADA 2014).
Have obvious clinical or radiographic signs or symptoms of liver disease (except 
[9]
nonalcoholic fatty liver disease), cirrhosis, acute or chronic hepatitis, or alanine 
aminotransferase (ALT/SGPT) and/or aspartate aminotransferase (AST/SGOT) 
levels ≥2.5X upper limit of normal (ULN), alkaline phosphatase ≥2X ULN or 
total bilirubin ≥ 2X ULN (with the exception of known Gilbert syndrome) as 
defined by central laboratory.
Have chronic kidney disease Stage 4 and higher (estimated glomerular filtration 
[10]
rate <30 mL/minute/1.73m2 as measured by Modification of Diet in Renal 
Disease [MDRD] formula) (NKF 2007) or history of renal transplantation.
Have history of more than 1 episode of severe hypoglycemia requiring assistance 
[11]
of another person, resulting in coma, seizures, or disorientation within the 
6 months prior to Visit 1.
Have received U-500R insulin by CSII in the 3 months prior to Visit 1.
[12]
Have had a blood transfusion or severe blood loss within 3 months prior to Visit 1 
[13]
or have known hemoglobinopathy, hemolytic anemia, or sickle cell anemia that is 
known to interfere with HbA1c measurement.
Have known allergy to human insulin preparations or excipients contained in 
[14]
these products or prior history of suspected antibodies to human insulin.
Are taking chronic (lasting longer than 14 consecutive days) systemic 
[15]
glucocorticoid therapy (excluding topical, intra-articular, intraocular, and inhaled 
prescriptions), or have received any systemic glucocorticoid therapy within the 
4 weeks immediately prior to Visit 1.
Have an irregular sleep/wake cycle (for example, subjects who sleep during the 
[16]
day and work during the night), in the investigator’s opinion.
Intend to participate in an extended period of fasting during the study period (for 
[17]
religious or other purposes).


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Have used rosiglitazone, sulfonylurea/glinides, pramlintide, once-weekly or 
[18]
twice-daily exenatide, or other AHAs not listed in the inclusion criteria in the
3 months prior to Visit 1, are taking AHA doses exceeding the respective product 
labels, or have a contraindication to current AHA usage per respective product 
labels (for example, for MET:  serum creatinine ≥1.4 mg/dL in women or 
≥1.5 mg/dL in men).  
Have used any weight loss drugs (for example, prescription drugs; lorcaserin, 
[19]
orlistat, phentermine, phentermine/topiramate, naltrexone/bupropion, or over-the-
counter weight loss medications) in the 3 months prior to Visit 1.
Have a history of bariatric surgery including Roux-en-Y gastric bypass surgery, 
[20]
gastric banding, and/or gastric sleeve.
Have a history of an active or untreated malignancy, or in remission from a 
[21]
clinically significant malignancy (other than basal cell or squamous cell skin 
cancer, in situ carcinomas of the cervix, colon, or prostate that is considered 
cured) during the last 5 years before Visit 1 (if a malignancy occurred >5 years 
ago, subject is eligible with documentation of disease-free state since treatment).  
Significant hearing loss and/or vision impairment deemed by the investigator to 
[22]
interfere with the safe use of OmniPod U-500 system.
Have cardiac disease with functional status that is New York Heart Association 
[23]
(NYHA) Class III or IV per New York Heart Association Cardiac Disease 
Functional Classification [Attachment 4] or have congestive heart failure 
requiring pharmacologic treatment.
Are women breastfeeding or pregnant, or intend to become pregnant during the 
[24]
course of the study; are men who intend to impregnate their partners; or are 
sexually active of procreation potential not actively practicing birth control by a 
method determined by the investigator to be medically acceptable.
Are investigator site personnel directly affiliated with this study and/or their 
[25]
immediate families.  Immediate family is defined as a spouse, parent, child, or 
sibling, whether biological or legally adopted.
Are Lilly or Insulet employees, or are employees of third party organizations 
[26]
(TPOs) involved in study that require exclusion of their employees.
Are currently enrolled in, or discontinued within the last 30 days, from a clinical 
[27]
trial involving an investigational product or nonapproved use of a drug or device
(other than the study treatment used in this study), or concurrently enrolled in any 
other type of medical research judged not to be scientifically or medically 
compatible with this study, and any subjects who have previously completed or
withdrawn from this study.


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Are unwilling or unable to independently perform study procedures, such as 
[28]
monitoring SMBG levels, recording diary data, and/or administering medication 
via syringe or CSII as applicable, or have any illness or condition (including 
known drug or alcohol abuse or psychiatric disorder) within the 6 months prior to 
Visit 1, that precludes subject from following and completing the protocol 
according to the investigator’s judgment.  Subjects may not use a proxy to 
perform collection procedures, administer medication, or record data.
8.2.1. Rationale for Exclusion of Certain Study Candidates
Exclusion criterion [8] ensures that subjects with T1DM or other types of diabetes (except 
T2DM) will be excluded from the study due to the potentially different response to the 
algorithms and/or device.  Exclusion criteria [9], [10], [13], [14], [16], [17], [21], and [23]
represent clinical situations that may prevent subjects from completing the protocol, or may 
influence the efficacy or safety of study regimens, or are serious conditions that pose a risk for 
morbidity and mortality.  Exclusion criterion [11] addresses the potential difficulty of 
distinguishing if severe hypoglycemia is related to study drugs, or to counter-regulatory 
deficiencies, or to the natural history of the disease in subjects with recurring episodes.  
Exclusion criterion [12] relates to the potential of sub-optimal glycemic control and possible
changes in quality of life when changing from U-500R CSII therapy.  Exclusion criterion [15]
relates to the negative effect of steroid therapy on the management of diabetes and need for 
altered dosing titration of insulin.  Exclusion criterion [18] excludes medications that are 
restricted by product label (exenatide), may cause HbA1c-lowering not attributable to the study 
insulin regimens or the combination of AHAs being studied, or which could confound 
interpretation of the results, or may influence the safety of study regimens.  Exclusion criteria
[19], [20] and [27] prevent a situation in which positive or negative outcomes may not be clearly 
attributable to the regimens in this study.  Exclusion criterion [22] would prevent the subject 
from safely using the OmniPod U-500 system.  Exclusion criterion [24] ensures the safety of 
unborn or newborn children.  Exclusion criteria [25] and [26] reduce potential bias due to 
conflict of interest.  Exclusion criterion [28] excludes subjects who may be unwilling or unable 
to perform study procedures per protocol instructions for their safety.
8.3.
Discontinuations
8.3.1. Discontinuation of Inadvertently Enrolled Subjects
The criteria for enrollment must be followed explicitly.  If the investigator site identifies a 
subject who did not meet enrollment criteria and who was inadvertently enrolled, the sponsor 
must be notified.  If the sponsor identifies a subject who did not meet enrollment criteria and 
who was inadvertently enrolled, the investigator site will be notified.  A discussion must occur 
between the sponsor CRP/CRS and the investigator to determine whether the subject may 
continue in the study, with or without study treatment.  Inadvertently enrolled subjects may be 
maintained in the study and on study treatment when the Lilly CRP/CRS agrees with the 
investigator that it is medically appropriate for that subject. The subject may not continue in the 
study with or without study treatment if the Lilly CRP/CRS does not agree with the 


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investigator’s determination it is medically appropriate for the subject to continue.  The 
investigator must obtain documented approval from the Lilly CRP/CRS to allow the 
inadvertently enrolled subject to continue in the study with or without study treatment.
8.3.2. Discontinuation of Study Treatment
Subjects will be discontinued from the study treatment in the following circumstances:

If Exclusion Criteria [9] (with the exception of the hepatic laboratory values; 
Section 10.4.5), [11] to [15], [18] to [21], [23] and [24] are observed or 
develop after study enrollment, the subject will be discontinued from the study 
treatment at the next visit or sooner. 

If in the investigators judgment, the subject is not at least 80% compliant with 
study treatment (i.e.; investigator recommended dose adjustments based on 
algorithms)

If the subject is off study medication for more than 7 consecutive days during 
the study treatment period.
In the event that the subject is discontinued from the study treatment, the investigator should 
encourage the subject to remain in the study for continued safety monitoring. 
8.3.3. Subject Discontinuation from the Study
If exclusion criterion [25] through [28] is observed or develops after entry or enrollment,
the subject will be discontinued from the study at the next site visit or sooner in the event 
of a safety exclusion criterion.  
Subjects who discontinue the study early will have ET procedures performed as shown in the 
Study Schedule (Attachment 1).  For information as to how efficacy and safety analyses will be 
conducted for subjects who are discontinued from study treatment, see Sections 12.2.3 and
12.2.10, respectively.
The subject may be discontinued from the study if:

Enrollment in any other clinical trial involving an investigational product or enrollment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study.

Investigator decision
o
The investigator decides that the subject should be discontinued from the study
(this can be for safety reasons, such as for recurrent hypoglycemia, or it can be for 
any reason).
o
If the subject, 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 subject requests to be withdrawn from the study.


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
Sponsor decision
o
Lilly or its designee stops the study or stops the subject’s participation in the 
study for medical, safety, regulatory, or other reasons consistent with applicable 
laws, regulations, and good clinical practice (GCP).

Adverse event 
o
If the investigator decides that the subject should be withdrawn because of a SAE, 
treatment emergent adverse event (TEAE), or a clinically significant laboratory 
value, study treatment is to be discontinued and appropriate measures are to be 
taken.  Lilly or its designee is to be alerted immediately.  Refer to Safety 
Evaluations Section 10.4.
8.3.4. Subjects Lost to Follow-Up
A subject 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 subjects who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.
Site personnel, or an independent third party, will attempt to collect the vital status of the subject
within legal and ethical boundaries for all subjects randomized, including those who did not get 
study treatment.  Public sources may be searched for vital status information.  If vital status is 
determined, this will be documented and the subject will not be considered lost to follow up.
Lilly personnel will not be involved in any attempts to collect vital status information.
8.3.5. Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ethical review board 
(ERB) of the study site judges it necessary for medical, safety, regulatory, or other reasons 
consistent with applicable laws, regulations, and GCP.
8.3.6. Discontinuation of the Study
The study will be discontinued if Lilly judges it necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP.


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9. Treatment
9.1.
Treatments Administered
This study involves a comparison of U-500R administered by CSII with U-500R administered by 
MDI.  Table IBHD.9.1 shows the treatment regimens.
Table IBHD.9.1.
Treatment Regimens
Regimen
Dose
U-500R CSII
Per titration algorithm
(continuous infusion, injectable solution)
U-500R MDI
Per titration algorithm
(TID, injectable solution)
Abbreviations:  CSII = continuous subcutaneous insulin infusion; MDI = multiple daily injections; TID = three 
times daily.
The investigator or his/her designee is responsible for the following:

explaining the correct use of the investigational agent(s) to the subject/site 
personnel,

verifying that subject clearly understands instructions and is able to demonstrate 
understanding, maintaining accurate records of study treatment dispensing and 
collection, and returning all unused medication or devices to Lilly or its designee 
at the end of the study.
Note:  In some cases, sites may destroy the material if, during the investigator site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical trial materials.  In all other cases, the site has to return used or 
unused material to Lilly or designee.
Subjects will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with study treatment or drug delivery system so that the situation can be 
assessed.
9.2.
Materials and Supplies
Subjects should continue taking their noninsulin pre-study AHA doses throughout the study, as 
applicable.  Pre-study AHAs must be used as described in their respective product labeling.
Supplies and appropriate instructions for use will be provided for both treatment groups 
beginning at screening Visit 1 (Week -3). Study drug and additional supplies will be provided at 
Visits 4, 5, and as needed thereafter per the Study Schedule (Attachment 1).
Subjects will be assigned to treatment arm at randomization Visit 4 (Week 0).  Appropriate pump 
training will be provided for the CSII group (Section 9.7.2).  The OmniPod U-500 system


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supplies for infusion including PDM and Pod with fill syringe will be provided at Visit 6 
(Week -2) and as needed thereafter per the study schedule.  
U-500R will be provided in 20-mL vials (10,000 U) for use by CSII or MDI.  Unopened U-500R
vials or U-500R vials not in-use should be stored in a refrigerator (2° to 8°C [36° to 46°F]), but 
not in the freezer. Once opened, the U-500R vial can be kept unrefrigerated as long as it is kept 
as cool as possible (below 30°C [86°F]) and away from heat and light.  In-use vials must be used 
within 40 days or be discarded, even if they still contain U-500R.  
The respective labeling information will be provided with the insulin pump and supplies, the 
disposable syringes, and the study drug as applicable.  In addition, a commercially available BG 
meter will be provided with necessary supplies and instructions at Visit 1 (Week -3). Clinical 
trial materials will be labeled according to the respective country’s regulatory requirements.
Table IBHD.9.2.
Study Devices
Regimen
Device
Device Details
U-500R CSII
OmniPod U-500 systema
CSII
U-500R MDI
BD U-100 insulin syringe and needle
0.5 mL syringe for ≤250-U dose; or
1.0 mL syringe for >250-U dose; 
31 gauge; 6 mm length needle
Abbreviations:  BD = Becton Dickinson; CSII = continuous subcutaneous insulin infusion; MDI = multiple daily 
injections; U = unit.
a
The OmniPod U-500 system is an investigational device.
9.3.
Method of Assignment to Treatment
Subjects will continue on their pre-study insulin regimens until Visit 4 (Week 0). After re-
confirmation of eligibility, subjects who meet specific criteria (Section 8) for enrollment will be 
randomized at Visit 4 (Week 0) to open-label treatment with U-500R administered by one of two 
treatment regimens:  MDI or CSII. However, subjects randomized to CSII will not initiate U-
500R administered by CSII until transition to U-500R is complete (Section 9.7). Assignment to 
treatment arms will be determined by a computer-generated random sequence using an IWRS.  
9.4.
Rationale for Selection of Doses in the Study
Protocol IBHD dosing transition to U-500R MDI and titration regimens for the CSII and MDI
treatment groups are guided by initial insulin TDD (based on the highest TDD recorded in the 
3 days before Visit 2), screening HbA1c (Visit 1), subsequent glucose monitoring, literature 
expert reviews (Lane 2006; Lane et al. 2009; Hirsch 2010, Lane et al. 2010; Segal et al. 2010; 
Reutrakul et al. 2012), efficacy and safety results from one Phase 4 clinical study 
(B5K-US-IBHC [Hood et al, 2015]), results from simulations performed using a systems 
physiology model of diabetes (Entelos PhysioLab® Modeler) based on data from previous 
pharmacodynamics/pharmacokinetics studies (de la Peña et al. 2011) of U-500R and U-100 
Humulin regular insulin) and on expert protocol consultant advice.
Fasting and bolus for CSII and MDI therapy plasma-equivalent glucose target ranges are 80 to
140 mg/dL. Recommended administration of U-500R bolus doses, within approximately


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30 minutes before meals by CSII or MDI dosing, is based on label advice and recent 
pharmacodynamics/pharmacokinetics study results in obese, healthy subjects that demonstrate 
both prandial and basal activity of U-500R (de la Peña et al. 2011).  Administration of U-500R 
bolus doses 15 minutes before meals will be assessed in a subset of subjects participating in the 
continuous glucose monitoring (CGM) addendum to demonstrate glycemic impact.  If the shorter 
bolus time period is found to be equally efficacious, there may be a potential benefit on
adherence.
9.5.
Lead-in Period 
The 2-week lead-in period of the trial includes the interval between Visit 2 and Visit 4.  
Subjects’ current diet (particularly caloric intake) and exercise levels will be reviewed during 
lead-in and at subsequent visits throughout the study, as needed, to assess adherence to the 
lifestyle advice discussed at Visit 2 (Week -2) as part of subject training and education.  Subjects 
should be encouraged to eat 3 meals a day plus a snack before bedtime (21 grams CHO Extend 
Bar®, Extend Nutrition, St. Louis, MO or equivalent) to support U-500R dosing per CSII or MDI
during the study.  
Subjects will continue taking prestudy AHAs and doses (per inclusion/exclusion criteria in 
Sections 8.1 and 8.2 and allowed concomitant therapies in Section 9.11) and should not 
discontinue or change doses during the study. Refer to Study Schedule for details of events 
(Attachment 1).
9.6.
Randomization
At Visit 4 (Week 0), if subjects have been re-confirmed for trial eligibility (Section 8), they will 
be randomized at a 1:1 ratio to the two treatment arms (CSII or MDI) using IWRS (Section 9.3). 
Subjects will be stratified by entry HbA1c ≥8.5% or <8.5%, nonusers versus users of GLP-1
receptor agonists or SGLT2 inhibitors, and U-500R at entry versus other insulins.
Subjects in the study will continue taking noninsulin pre-study AHA regimens (per 
inclusion/exclusion criteria in Sections 8.1and 8.2) and allowed concomitant therapies. Subjects 
should not discontinue or change doses during the study (Section 9.11).  Subjects will transition 
to U-500R MDI for 2 weeks and then initiate 24 weeks of CSII or MDI treatment (Section 9.7).
Subjects who discontinue prior to randomization will be considered screen failures.  No ET 
activities will be applicable.
9.7.
Transition to U-500R MDI 
All subjects will administer U-500R MDI delivered TID (40:30:30 unless otherwise noted) 
during the transition period (Weeks 0-2).  Transition to U-500R MDI will follow the criteria 
below in Table IBHC.9.3.  Subjects will have their insulin adjusted weekly by the investigator 
using the algorithm from Section 9.8.2.1.


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Table IBHC.9.3. Transition from entry insulin to U-500R MDI
Insulin Regimen (Screening)
HbA1c
(Screening)
Mean SMBG
(Screening to Week -2)
Conversion from Screening 
TDD to U-500R TID Dose
Insulin with or without U-500R
>8%
>183 mg/dL
1:1
Insulin with or without U-500R
>8%
≤183 mg/dL
Reduce TDD by 20%
Insulin with or without U-500R
≤8%
--
Reduce TDD by 20%
U-500R only
--
--
1:1
Abbreviations: HbA1c = hemogloblin A1c; SMBG=self-monitored blood glucose; MDI = multiple daily injections; 
TID= three times daily; TDD=total daily dose.
Subjects treated with U-100 and/or other concentrated insulin (with or without U-500R) at 
screening Visit 1 (Week -3) with HbA1c levels >8% and a mean SMBG (recorded prior to 
Visit 4 [Week 0]) value >183 mg/dL (corresponding to HbA1c value of >8.0% [estimated 
average glucose; Nathan et al. 2008]) at Visit 4 should be transitioned to U-500R using 1:1 
dosage conversion.  
Subjects treated with U-100 and/or other concentrated insulin (with or without U-500R) at 
screening Visit 1 (Week -3) with HbA1c levels >8% and a mean SMBG (recorded prior to 
Visit 4 [Week 0]) value ≤183 mg/dL (corresponding to HbA1c value of ≤8.0%) at Visit 4, should 
transition by reducing their U-500R TDD by 20%.
Subjects treated with U-100 and/or other concentrated insulin (with or without U-500R) at 
screening Visit 1 (Week -3) with HbA1c ≤8% should transition to U-500R at Visit 4 (Week 0)
by reducing their U-500R TDD by 20%, regardless of SMBG value.
Subjects treated with U-500R insulin only at screening Visit 1 (Week -3) should transition to 
U-500R TID with proportion 40:30:30 using a 1:1 dosage conversion at Visit 4 (Week 0), 
regardless of HbA1c and/or SMBG.  Those subjects already on U-500R TID at entry can 
continue their pre-entry U-500R TID proportions at the discretion of the investigator. 
Investigators may also deviate from the proportion, if deemed necessary, for the safety or 
well-being of the subject (that is, due to a safety concern).  Any major deviation from the 
recommended proportion must be discussed with Lilly CRP/CRS.
9.7.1. Dosing Using U-100 Insulin Syringes
The units marked on a U-100 insulin syringe do not accurately reflect the unit dose of U-500R 
insulin because U-500R is 5 times more concentrated than U-100 insulin, and thus only one-fifth
of the volume is needed to give an equivalent dose to U-100 insulin.  Site personnel should 
instruct subjects on the dose conversion of calculated U-500R to the U-100 insulin syringe unit 
markings (examples below and conversion charts are also provided in the U-500R package insert
and Subject Information on U-500R).
The U-100 insulin 0.5 mL syringes should be used for administration for all U-500R doses 
≤250 U.  All U-500R doses >250 units should be administered using 1.0 mL U-100 insulin 
syringes. 


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For example:

155 units of U-500R has a volume equivalent to 31 units markings on a 0.5 mL 
U-100 insulin syringe (155 divided by 5=31).

100 units of U-500R has a volume equivalent to 20 units markings on a 0.5 mL 
U-100 insulin syringe (100 divided by 5=20).

300 units of U-500R has a volume equivalent to 60 units markings on a 1.0 mL 
U-100 insulin syringe (300 divided by 5=60).
9.7.2. CSII Training 
Subjects randomized to the CSII treatment arm will be trained on the use of the OmniPod U-500 
system after randomization at Visits 5 and 6 (Weeks 1 and 2). CSII training will include but not 
be limited to pre-pump training regarding basal rates and bolus dosing, initial PDM and Pod 
setup, setting basal rates (including temporary basal rate) and boluses (CHO counting, fixed 
dosages or meal sizes), and responding to hazard alarms. The OmniPod U-500 system basics of 
pump usage (ie, basal rates, boluses, and filling Pods) will be introduced to subjects at Visit 5 
(Week 1) and the hands on training will occur at Visit 6 (Week 2) (Section 7.1.7.3.).
9.7.3. Intensified Dose Titration Period
The 12-week intensified dose titration period of the trial will extend from Visit 6 (Week 2) to 
Visit 13 (Week 14) and will include investigator-driven dosage titration according to the 
titration algorithms (Sections 9.8.1.1 and 9.8.2.1) at weekly intervals starting on Visit 6 through 
8 (Weeks 2 through 4) and biweekly starting at Visit 9 through 13 (Weeks 6 through 14) 
(Attachment 1).  Additional dosage titrations per algorithms may be made more frequently if 
needed per investigator’s judgment during this period.
9.7.4. Maintenance Dose Titration Period
The 12-week maintenance dose titration period of the trial will extend from Visit 13 (Week 14) 
to the final visit, Visit 17 (Week 26) or ET visit.  Dose titrations by the investigator will be 
completed in an identical manner to those during the intensified dose titration period 
(Sections 9.8.1.1 and 9.8.2.1) but will be at 3-week intervals (Attachment 1).  Additional dosage 
titrations per algorithms may also be made more frequently if needed per investigator’s judgment 
during this period.
9.8.
Treatment Periods
9.8.1. CSII
The OmniPod U-500 system is designed to deliver U-500 insulin in insulin units without 
converting to U-100 insulin ‘pump units’ (Section 7.2).  Beginning at Visit 6 (Week 2), all CSII 
subjects will be instructed to change their OmniPod U-500 system Pod every 2 to 3 days
(depending on TDD) during the treatment period.  Subjects will be instructed to inspect Pod 
cannula insertion sites for signs of redness, swelling, or leakage and to respond to any CSII 
alarms (Bolderman et al. 2013).


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For subjects randomized to CSII: 

The OmniPod U-500 system Pod should be filled in the clinic with U-500R 
during Visit 6.

The highest 24-hour TDD from the past 3 days will be utilized for calculation of 
the CSII doses.  

50% of the TDD will be basal split into 2 rates:
o
2100 to 0600 hours 10% basal rate reduction  
o
0600 to 2100 hours for the calculated basal rate 

50% of the TDD will be bolus split into the following ratio:
o
40:30:30 (Section 9.8.1.3) for fixed bolus doses.
o
Suggested initial setting for insulin:  CHO ratio should be programmed between
1:3 and 1:5.
CSII Treatment Group Algorithms
9.8.1.1.
Subjects in the CSII group will have their basal rates (Table IBHD.9.4) and bolus doses 
(Table IBHD.9.5) adjusted at each study visit (office and telephone) by the investigator
according to the CSII titration algorithms. Investigators may deviate from the algorithms, if 
deemed necessary, for the safety or well-being of the subject (that is, due to illness or other 
safety concern).  Any major deviation from the algorithm must be discussed with Lilly. The 
CSII bolus titration scheme (Table IBHD.9.5) will be divided into 2 dosing bins:  TDD 
<400 units and TDD ≥400 units.  Subjects will have their U-500R adjusted according to the TDD 
at the time of adjustment.
Subjects taking <400 units TDD at Visit 6 (Week 2) should use a 1:10 correction factor with a 
target of 100 mg/dL starting at 25 mg/dL above target for all mealtime boluses.  Subjects taking 
≥400 units TDD at Visit 6 (Week 2) should use a 1:5 correction factor with a target of 
100 mg/dL starting at 25 mg/dL above target for all mealtime boluses.  If, in the opinion of the 
investigator, the subject would benefit from a different correction factor, the investigator should 
discuss this with the Sponsor.  
Note:  Subjects should be instructed to hold their U-500R bolus dose if a meal is skipped.


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Table IBHD.9.4.
Basal Titration Scheme for CSII
Median SMBG
(mg/dL)
Titration of Corresponding
Basal Rate for All Dose Rangesa
<80
-5%
80-140
0
141-190
+5%
191-230
+10%
>230
+15%
3-day median SMBG measure
Dose adjusted
Pre-Morning Meal, 0300 hoursb
Overnight infusion
Pre-Evening Meal
Daytime infusion
Abbreviations:  CSII = continuous subcutaneous insulin infusion; SMBG = self-monitored blood glucose.
a
Any plasma glucose (SMBG or lab) measurement <50 mg/dL or ≤70 mg/dL at 0300 hours during the week,
investigator should reduce corresponding basal dose by 10-20% as soon as it occurs or notification of the reading 
occurs. 
b
If subject acquires more than the 2 initial basal rates, adjusted basal doses will continue to be based on the pre-
morning meal and 0300 hours, and pre-evening meal SMBG.
Table IBHD.9.5.
Bolus Titration Scheme for CSII
Median SMBGa,b,c
(mg/dL)
Dosing Bin for TDD <400 U
Titration (U)
Dosing Bin for TDD ≥400 U
Titration (U)
<80
-5
-10
80-140
0
0
141-190
+2.5
+5
191-230
+5
+10
>230
+7.5
+15
3 Day Median SMBGd
Adjusted Dose
Pre-midday meal
Pre-morning meal
Pre-evening meal
Pre-midday meal
Bedtimee
Pre-evening meal
Abbreviations:  CSII = continuous subcutaneous insulin infusion; CHO = carbohydrate; SMBG = self-monitored 
blood glucose; TDD = total daily dose; U = units.
a
Each of the 3 bolus doses is adjusted independently based on the median of 3 corresponding SMBG values 
(preferably most recent 3 days).
b
Any plasma glucose (SMBG or lab) measurement <50 mg/dL, investigator should reduce corresponding bolus 
dose by 10-20% as soon as it occurs or notification of the reading occurs. 
c
If the algorithm adjustment leads to overlapping basal and bolus adjustments, the investigator has the discretion 
to reduce the bolus adjustment for safety.
d
If the subject is using CHO meal sizes or CHO counting for boluses and their SMBGs are not in the target range 
for the corresponding meal at the visits (telephone or office) for algorithm titrations, then the principal 
investigator should adjust (increase or decrease) the insulin CHO ratio by approximately 10% to 15%.
e
In the event that nocturnal hypoglycemia occurs requiring a reduction in the overnight basal rate, the investigator 
may reduce the pre-dinner dose even if the bedtime SMBG median is in the target range of 80-140 mg/dL.
Note:  All CSII basal and bolus doses will be rounded to the nearest 0.25 units.


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CSII Basal Rate
9.8.1.2.
The overnight basal rate from 2100 to 0600 hours is adjusted based on the median fasting pre-
breakfast SMBG from the past 3 values (most recent 3 days recommended) and the basal rate 
from 0600 to 2100 hours is adjusted based on pre-dinner SMBG (most recent 3 days 
recommended).  The principal investigator may increase the number of basal rates up to 4 basal 
rates during the trial, if in the investigator’s opinion the subject needs further individualization of 
basal rates based on blood sugar trends, such as nocturnal hypoglycemia or the dawn 
phenomenon indicating a need for the change(s).
9.8.1.2.1. Adding a Basal Rate for Nocturnal Hypoglycemia
If a subject has persistent nocturnal hypoglycemia, an additional basal rate reduction can be 
added.  For example, if a subject has persistent nocturnal hypoglycemia between 2100 hours and 
midnight after the initial 10% reduction in the basal rate between 2100 and 0600 hours, an 
additional basal rate reduction can be added in the time period from 2000 hours to midnight (that 
is, 20% reduction between 2000 hours and midnight with 10% reduction continuing between 
midnight and 0600 hours).  Alternatively, the investigator may decide to suspend the basal rate 
overnight.
9.8.1.2.2. Adding a Basal Rate for Dawn Phenomenon
If a subject has significant dawn phenomenon leading to persistent hyperglycemia, an additional 
basal rate increase can be added based on investigator discretion.  For example, if a subject has 
persistent hyperglycemia from 0600 to 1000 hours, an additional basal rate increase of 10% can 
be added from 0600 to 1000 hours.
CSII Bolus Dosing
9.8.1.3.
Subjects should bolus 30 minutes prior to meals except for a subset of the subjects in the CGM 
addendum who will be assigned to bolus 15 minutes prior to meals.  
Subjects should be encouraged to eat a bedtime snack (Extend Bar 21 gm CHO or equivalent)
without administering a bolus for the snack.  Note:  If the subject has an allergy or intolerance to 
the Extend Bar, then the subject may substitute a bedtime snack between 15 and 25 grams CHO.
9.8.1.3.1. CSII Bolus Settings
The investigator has the option of prescribing 3 bolus options. Table IBHD.9.5 should be 
followed for dosage adjustments. The U500 OmniPod system bolus calculator should be set to 
one of the following bolus options (according to principal investigator discretion):

Use fixed bolus regimen based on previous mealtime insulin requirements.  Bolus 
dose will be imputed manually (that is, the user would enter their BG value and 
answer ‘use for bolus calcs?’ with ‘yes’; answer ‘are you going to eat now’ with
‘no’ and then override the suggested bolus based on the fixed bolus dose size). 

A mealtime bolus utilizing CHO meal sizes. Adjust dose based on a preset CHO meal 
size (for example:  small = 30 gram CHO; medium = 60 gram CHO; and large = 90 gram 
CHO).

A mealtime bolus for the corresponding meal if the subject is using CHO counting.


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Note: Subjects should be encouraged to maintain the bolus option throughout the study.
All subjects should have the insulin-on-board (IOB) setting programmed at 6 hours except for a 
subset of the subjects participating in the CGM Addendum who will have the IOB set at 8 hours. 
The clinical protocol addendum will assess alternative IOB based on U-500R time action profile.
9.8.2. MDI
For MDI subjects, initial doses of U-500R will be determined according to Section 9.7; dosage 
titrations per bolus titration schedule (Table IBHD.9.6) will occur at the same visits (telephone or 
office) as for CSII subjects.  
MDI subjects should also bolus U-500R 30 minutes prior to meals except for a subset of 
the subjects participating in the CGM addendum who will bolus 15 minutes prior to 
meals.  
Subjects should be instructed to eat a bedtime snack (Extend Bar 21 gm CHO or 
equivalent).
Subjects should be instructed to use a U-100 insulin syringe to draw up the U-500R dose
(Section 9.7.1).  All bolus doses will be rounded to the nearest 5 units.
MDI Treatment Group Algorithms
9.8.2.1.
Subjects in the MDI group will have their insulin dosages adjusted at each study visit (office and 
telephone) by the investigator according to the TID titration algorithm (Table IBHD.9.6).  The 
MDI bolus titration scheme will be divided into 2 dosing bins; TDD <400 units and TDD 
≥400 units.  Subjects will have their U-500R adjusted according to the TDD at the time of 
adjustment.
Note:  Subjects should be instructed to reduce their U-500R dose by 50% if a meal is skipped.


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Table IBHD.9.6.
Bolus Titration Scheme for MDI Delivered TID
Median SMBGa,b
(mg/dL)
Dosing Bin for TDD <400 U Titration (U)
Dosing Bin for TDD ≥400 U Titration
(U)
<80
-10
-20
80-140
0
0
141-190
+5
+10
191-230
+10
+20
>230
+15
+30
3 Day Median SMBG
Dose Adjusted
Pre-midday meal
Pre-morning meal
Pre-evening meal
Pre-midday meal
Pre-morning meal, 0300 hours
Pre-evening meal
Abbreviations:  MDI = multiple daily injections; SMBG = self-monitored blood glucose; TDD = total daily dose; 
TID = three times daily; U = units.
a
Each of the 3 bolus doses are adjusted independently based on the median of 3 corresponding SMBG values 
(preferably most recent 3 days).
b
Any plasma glucose (SMBG or lab) measurement below 50 mg/dL or ≤70 mg/dL at 0300 hours, investigator 
should reduce corresponding bolus dose by 10%-20% as soon as it occurs or notification of the reading occurs.
9.9.
Special Treatment Considerations 
9.9.1. Rescue Therapy
Rescue therapy should be initiated in the following circumstances:

If median of 3 fasting SMBG >300 mg/dL over a 3-day period is unexplained from 
previous week, starting at Visit 10 through Visit 13 (Weeks 8 through 14).

If HbA1c value at Visit 13 (Week 14) is ≥10.0% and decreased by <0.4% compared to 
Visit 10 (Week 8) HbA1c.

If HbA1c value at Visit 15 (Week 20) is ≥10.0% and decreased by <0.4% compared to 
Visit 13 (Week 14) HbA1c.
Subjects receiving U-500R MDI will be rescued by the addition of a bedtime U-500R dose 
(increase injections to 4-times daily therapy).  A suggested starting dose for the rescue dose 
would be 10% of TDD, but this may be modified based on investigator judgment.
Subjects receiving CSII U-500R will be rescued by the addition of a bedtime U-500R dose 
delivered by CSII.  A suggested starting dose for the rescue dose would be 5% to 10% of TDD, 
but this may be modified based on investigator judgment.
Subjects should be instructed to record their 0300-hour BG within 24 hours after adding a rescue 
dose and subjects should also be encouraged to record their 0300-hour BG 2 to 3 times the first 
2 weeks after adding a rescue dose.
Every attempt should be made to keep these subjects in the study.  Change in treatment regimen 
should be recorded in the eCRF.  


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9.9.2. Continued Access to Study Treatment
The U-500R insulin used in this study is commercially available in the US and is therefore 
available for subjects after the conclusion of this study.
9.10. Blinding
This is an open-label study.  Treatment blinding of the investigators, subjects, and study site 
personnel is not feasible due to differences in the appearance and functionality of the delivery 
devices.  To minimize bias, aggregate review of summary data by the study team (that is, 
CRP/CRS overseeing the global conduct of the study, statisticians, and statistical analysts) will 
remain blinded until after the final database is locked. Unblinding of the subject study treatment 
assignment may occur in the course of individual subject consultation between the investigator 
and the study team (principally between the investigator and the CRP/CRS) or during review of 
SAEs. No systematic unblinding of study treatment assignments will be solicited by the study 
team.  
9.11. Concomitant Therapy
All concomitant therapies that are part of routine care are allowed and may be used during the 
study with the exception of those specifically outlined in Sections 8.1 and 8.2.  Subjects who 
take any excluded concomitant therapy will be discontinued from the study treatment at the next 
visit or sooner.  In emergency/urgent situations, subjects may cease taking study medication for 
7 consecutive days and may be treated instead with nonstudy insulin during that time.  If a 
subject takes nonstudy insulin for more than 7 consecutive days, then discontinuation criteria 
apply (Section 8.3.2).
9.11.1. Concomitant Medications Including Antihyperglycemic Agents
Subjects will be allowed to continue to use any concomitant medications with the exception of
those listed in the exclusion criteria.  A list of selected concomitant medications that have an 
effect on glucose metabolism, and their conditions for use, is presented in Table IBHD.9.7.  The 
subject should be encouraged to report any new concomitant medications after initiating the 
medication.  Please check with the study team if you have any concerns or questions about a 
medication the subject is taking.  


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Table IBHD.9.7.
Concomitant Medications and Conditions for Use
Drug Class
As Needed
Chronic Use
Conditions for Use
Metformin
N
Y
DPP-4 inhibitors
N
Y
Pioglitazone
N
Y
Dosages ≤30 mg daily
SGLT2 inhibitors
N
Ya
Rosiglitazone
N
N
Alpha glucosidase inhibitors
N
N
Bromocriptine
N
N
Sulfonylureas/glinides
N
N
GLP-1 receptor agonists (except exenatide)
N
Ya
Pramlintide
N
N
Niacinb
N
Y/N
Bile acid resin bindersb
N
Y/N
Systemic glucocorticoids (excluding ocular topical, 
other topical, or inhaled preparations)
Y if ≤2 weeks 
N
Abbreviations:  DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1; N = No; SGLT2 = Sodium-
glucose transporter protein; Y = Yes.
a
Allowed for study population Group B only.
b
Low doses are acceptable.
9.12. Treatment Compliance
Subject compliance with study medication will be assessed at each applicable study visit.  
Compliance will be based on adherence to the Study Schedule (Attachment 1), compliance with 
appropriate assigned injection method (CSII versus MDI), completion of the subject’s diary, and 
any other parameters the investigator deems necessary.  Compliance will be assessed by direct 
questioning and returned study materials.  
Subjects who are deemed significantly noncompliant will be discontinued from the study
treatment.  A subject will be considered significantly noncompliant if he or she:

misses more than 7 consecutive days of study medication during the study. 

is judged by the investigator to have intentionally or repeatedly taken more than the 
prescribed amount of medication that may cause patient safety concerns. 

is not at least 80% compliant with study treatment (ie, PI recommended doses 
adjustments based on algorithms).


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10.
Efficacy, Patient Reported Outcomes, Safety 
Evaluations, Sample Collection and Testing, and 
Appropriateness of Measurements
Study procedures and their timing (including tolerance limits for timing) are summarized in the 
Study Schedule (Attachment 1).
10.1. Efficacy Measures 
10.1.1. Primary Efficacy Measure
The primary efficacy measure for this study is change in HbA1c from baseline (last nonmissing 
value at or prior to the treatment starting Visit 4) to the 26-week value.
10.1.2. Secondary Efficacy Measures
The following secondary efficacy measures will be collected at the times shown in the Study 
Schedule (Attachment 1).  The secondary objectives are summarized in Section 6.2.
Fasting Plasma Glucose
10.1.2.1.
Change in mean FPG levels will be compared between treatments.
7-point SMBG
10.1.2.2.
Mean plasma glucose will be analyzed for each individual time point using the 7-point SMBG.  
The 7-point SMBG is a subject self-administered plasma glucose test that utilizes measurements 
at specific time points over a 24-hour period.  The timing of the 7-point SMBG measurement is 
described in Section 7.1.3.2.
Total Daily Insulin Dose
10.1.2.3.
Change in TDD (unit and unit/kg) as basal/bolus for the CSII arm and by bolus dosing for the 
MDI arm from baseline to 26-week value will be calculated and analyzed.
10.2. Patient Reported Outcomes
The self-reported questionnaires will be administered, according to the Study Schedule 
(Attachment 1).  
10.2.1. TRIM-D and TRIM-D Device
The TRIM-D and TRIM-DD scales are valid and reliable patient-reported outcome (PRO) 
measures, which capture the full range of impact of diabetes treatment on subject functioning 
and well-being across T1DM and T2DM subjects, as well as across all currently available 
delivery systems and treatments (oral agents, GLP-1 receptor agonist pens, inhaled- or pump-
delivered insulin, and insulin delivered with syringe/pens) (Brod et al. 2009).  The TRIM-D 
consists of 28 items, and the TRIM-DD consists of 8 items.  In both of these PROs, items are 
measured on a 5-point scale, where the higher score indicates a better health state.  In addition to 
an overall score, the TRIM-D items make up the 5 domains of impact:  Treatment Burden 
(6 items), Daily Life (5 items), Diabetes Management (5 items), Compliance (4 items), and 


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Psychological Health (8 items).  In addition to an overall score, the TRIM-DD items include the 
domain’s device function (5 items) and bother of device (3 items).
The TRIM-D and TRIM-DD will be administered at Visit 4 (Week 0, prior to randomization), at 
Visit 13 (Week 14) and at Visit 17 (Week 26) or ET if subjects do not complete the full 26 weeks 
of the study.
10.3. OmniPod U-500 System Exit Questionnaire
An OmniPod U-500 system exit questionnaire will be administered to subjects in the CSII group 
at Visit 17 (Week 26) or at ET if subjects terminate.
10.4. Safety Evaluations
Investigators are responsible for monitoring the safety of subjects who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the subject.
The investigator is responsible for the appropriate medical care of subjects during the study.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious, considered related to the study treatment or the study, related to the study 
device (U-500 OmniPod system), or that caused the subject to discontinue before completing the 
study.  The subject should be followed until the event is resolved or explained.  Frequency of 
follow-up evaluation is left to the discretion of the investigator.
Safety evaluations include the following:

Frequency and incidence of AEs and TEAEs

Incidence/rate of hypoglycemia (documented [documented symptomatic, 
asymptomatic, and unspecified], severe, and nocturnal)

Body weight

Vital signs

Study treatment exposure

Clinical laboratory tests abnormalities

Product complaints
10.4.1. Adverse Events
Lilly has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent.  
Lack of drug effect is not an AE in clinical studies because the purpose of the clinical study is to 
establish drug effect.


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Cases of pregnancy that occur during maternal or paternal exposures to study treatment or drug 
delivery system should be reported.  Data on fetal outcome and breastfeeding are collected for 
regulatory reporting and drug safety evaluation.
Study site personnel will record the occurrence and nature of each subject’s preexisting 
conditions, including clinically significant signs and symptoms of the disease under treatment in 
the study.
After the ICF is signed, site personnel will record any change in the condition(s) and the 
occurrence and nature of any AEs.  All AEs related to protocol procedures are reported to Lilly 
or designee.
In addition, all AEs occurring after the subject receives the first dose of study treatment must be 
reported to Lilly or its designee via the eCRF.
Any clinically significant findings (vital sign measurements, laboratory measures, and treatment 
exposure) that result in a diagnosis should be reported to Lilly or its designee.
Investigators will be instructed to report to Lilly or its designee their assessment of the potential 
relatedness of each AE to protocol procedure, study treatment, and/or drug delivery system via 
eCRF.  
The investigator decides whether he or she interprets the observed AEs as either related to 
disease, to the study medication, study procedure, study device, or other concomitant treatment 
or pathologies.  To assess the relationship of the AE to study treatment, the following 
terminologies are defined:
Related:  a direct cause and effect relationship between the study treatment and the AE is 
likely
Possibly related:  a cause and effect relationship between the study treatment and the AE 
has not been demonstrated at this time and is not probable, but is also not impossible
Unrelated:  without question, the AE is definitely not associated with the study 
treatment.
As per Lilly’s standard operating procedures, all “related” and “possibly related” AEs and SAEs 
will be defined as related to study treatment.
If a subject’s dosage is reduced, or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to Lilly or its designee via eCRF the circumstances and data 
leading to any such dosage reduction or discontinuation of treatment.
Serious Adverse Events
10.4.1.1.
Serious adverse event collection begins after the subject has signed informed consent and has 
received study treatment.  If a subject experiences an SAE after signing informed consent, but 
prior to receiving study treatment, the event will NOT be reported as serious unless the 
investigator feels the event may have been caused by a protocol procedure.


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Planned surgeries should not be reported as SAEs unless the underlying medical condition has 
worsened during the course of the study.
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.  
An SAE is any AE from this study that results in one of the following outcomes:

Death 

Severe hypoglycemia (as defined in Section 10.4.2)

Initial or prolonged inpatient hospitalization

A life-threatening experience (that is, immediate risk of dying)

Persistent or significant disability/incapacity

Congenital anomaly/birth defect

Considered significant by the investigator for any other reason
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse drug events when, based upon appropriate 
medical judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.
When a condition related to the U-500 OmniPod system necessitates medical or surgical 
intervention to preclude either permanent impairment of a body function or permanent damage to 
a body structure, the serious outcome of “required intervention” will be assigned.
Serious adverse events occurring up to and including the subject’s last study visit will be 
collected, regardless of the investigator’s opinion of causation, in the clinical data collection 
database and the pharmacovigilance system at the sponsor.
The investigator does not need to actively monitor subjects for AEs once the trial has ended, 
unless provided otherwise in the protocol.  However, if an investigator becomes aware of SAEs
occurring to a subject after the subject’s participation in the trial has ended, the investigator 
should report the SAEs to the Sponsor, regardless of the investigator’s opinion of causation; the 
SAEs will be entered in the pharmacovigilance system by the sponsor.
Information on SAEs expected in the study population independent of drug exposure and that 
will be assessed by the Sponsor in aggregate periodically during the course of the trial may be 
found in the USPI.
10.4.1.1.1.Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the USPI and that the investigator identifies as related to study treatment or procedure.  United 


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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 recording 
and expedited reporting of SUSARs that are consistent with global regulations and the associated 
detailed guidance.
10.4.2. Hypoglycemia
As a secondary objective, the rate/incidence of hypoglycemia will be analyzed and compared 
between treatment groups.  Subjects are encouraged to perform SMBG whenever hypoglycemia 
may be suspected, either by symptoms experienced or perceived increased risk as related to 
dietary intake, physical activity, or inadvertent or atypical insulin dosing.  All subjects will be 
instructed to treat a SMBG ≤70 mg/dL as hypoglycemia by ingesting 15 gram of CHO (for 
example, 4 ounces of juice or 3 to 5 gram glucose tabs). All subjects will be advised to contact 
the site if they experience severe hypoglycemia or SMBG <50 mg/dL.
Hypoglycemia is defined as ≤70 mg/dL (Seaquist et al. 2013) and categorized as follows:

Documented hypoglycemia
o
Documented symptomatic – an event that: 
1. is accompanied by with signs/symptoms of hypoglycemia, and
2. is accompanied by a measured SMBG concentrations of ≤70 mg/dL.  
o
Asymptomatic hypoglycemia an event that:
1. is not accompanied with signs/symptoms of hypoglycemia, and
2. is accompanied with a measured SMBG concentration of ≤70 mg/dL.
o
Unspecified hypoglycemia an event during that:
1. no relative signs/symptoms of hypoglycemia are recorded, and
2. is accompanied with a measured SMBG concentration of ≤70 mg/dL. 

Severe hypoglycemia: An event accompanied by neuroglycopenic symptoms 
that result in cognitive impairment such that the patient requires assistance of 
another person to actively administer CHO, glucagon, or perform other 
resuscitative actions.  During these episodes, the patient has an altered mental 
status, and cannot assist in their care, is semiconscious or unconscious, or 
experienced coma with or without seizures, and may require parenteral therapy.  
Plasma glucose measurements may not be available during such an event, but 
neurological recovery attributable to the restoration of SMBG concentration to 
normal is considered sufficient evidence that the event was induced by a low 
SMBG concentration (≤70 mg/dL).

Nocturnal hypoglycemia:  Any hypoglycemic event (documented hypoglycemia 
or severe hypoglycemia) that occurs between bedtime and waking. 


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10.4.3. Body Weight
The scale should be zeroed out before the subject is weighed.  Subjects should remove their 
shoes and any additional layers of clothing (such as sweaters or coats) and empty their pockets 
before being weighed.  If possible, subjects should also be given the opportunity to empty 
bladder/bowel before being weighed.  The weight value should be recorded in the source 
documentation and the eCRF.
10.4.4. Other Safety Measures
Vital signs
10.4.4.1.
Blood pressure and pulse, as well as height and weight, will be measured and recorded at the 
indicated visits per the Study Schedule (Attachment 1).  Blood pressure will be measured using a 
standard blood pressure meter to obtain the systolic and diastolic pressures with the subject
sitting for at least 5 minutes prior to the measurement.
Physical Examinations
10.4.4.2.
Complete physical examinations will be performed at Visit 1 according to the Study Schedule 
(Attachment 1).
Electrocardiograms
10.4.4.3.
For each subject, 12-lead digital electrocardiograms (ECGs) will be performed locally at Visit 1 
according to the Study Schedule (Attachment 1).  Subjects must be supine for approximately 
5 to 10 minutes before ECG collection and remain supine but awake during ECG collection.  
The ECGs will be interpreted by a qualified physician (the investigator or qualified designee) at 
the site as soon after the time of ECG collection as possible, and ideally while the subject is still 
present, to determine whether the subject meets entry criteria at the relevant visit(s) and for 
immediate subject management, should any clinically relevant findings be identified.  
Investigators must document their review of ECG reports.
Clinical Laboratory Tests
10.4.4.4.
Clinical laboratory tests will be conducted at the indicated visits per the Study Schedule 
(Attachment 1) and Clinical Laboratory Tests (Attachment 2).
Concomitant Medications
10.4.4.5.
Concomitant medication usage will be assessed at office visits, per the Study Schedule 
(Attachment 1).  Concomitant medications allowed in this study are discussed in Section 9.11
and Table IBHD.9.7.
Functionality and Safe Use of OmniPod U-500 System
10.4.4.6.
The functionality issues, hazards alarms, and safe use of the OmniPod U-500 system will be 
evaluated at study visits and/or by an assessment of device complaint data. 
10.4.5. Safety Monitoring
The Lilly CRP or CRS will monitor safety data throughout the course of the study.


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Lilly will review SAEs within timeframes mandated by company procedures.  The Lilly 
CRP/CRS will, as is appropriate, consult with the functionally independent Global Patient Safety 
therapeutic area physician or clinical scientist, and periodically review:

Trends in safety data

Laboratory analytes

AEs

Product complaints
If a study subject experiences elevated ALT or AST ≥3X ULN, elevated total bilirubin ≥2X 
ULN, or alkaline phosphatase ≥2X ULN, clinical and laboratory monitoring should be initiated 
by the investigator.  Details for hepatic monitoring depend upon the severity and persistence of 
observed laboratory test abnormalities.  To ensure subject safety and comply with regulatory 
guidance, the investigator is to consult with the Lilly designated medical monitor regarding 
collection of specific recommended clinical information and follow-up laboratory tests.
10.4.6. Complaint Handling
Lilly collects product complaints on study treatment and drug delivery systems used in clinical 
studies in order to ensure the safety of study participants, monitor quality, and to facilitate 
process and product improvements.
Complaints related to unblinded drug delivery systems (with exception of U-500 OmniPod 
system) are reported directly to the manufacturers of those drugs/devices in accordance with the 
package insert.
The investigator or his/her designee is responsible for handling the following aspects of the 
product complaint process in accordance with the instructions provided for this study:

Recording a complete description of the product complaint reported and any 
associated AEs using the study-specific complaint forms provided for this 
purpose.

The completed product complaint form must be faxed within 24 hours to Lilly or 
its designee.
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint form with the product.
10.5. Sample Collection and Testing
The Study Schedule (Attachment 1) lists the schedule for sample collections in this study.  The 
Clinical Laboratory Tests (Attachment 2) lists the laboratory tests that will be performed for this 
study.  


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10.5.1. Samples for Study Qualification and Health Monitoring
Standard laboratory tests including chemistry, hematology, and urinalysis panels will be 
performed. The Clinical Laboratory Tests (Attachment 2) lists the specific tests that will be 
performed for this study.  Clinical laboratory tests will be analyzed by a central laboratory 
selected by Lilly.  
Blood and urine samples will be collected per standard procedures at the times specified in the 
Study Schedule (Attachment 1).  Blood will be collected by venipuncture.
Investigators must document their review of each laboratory safety report.
Samples collected for specified laboratory tests will be destroyed within 60 days of receipt of 
confirmed test results.  Tests are run and confirmed promptly whenever scientifically 
appropriate.  When scientific circumstances warrant, however, it is acceptable to retain samples 
to batch the tests run, or to retain the samples until the end of the study to confirm that the results 
are valid.  Certain samples may be retained for a longer period, if necessary, to comply with 
applicable laws, regulations, or laboratory certification standards.
10.5.2. Pharmacogenetic Samples for Biomarker Research
Samples will be stored and analysis may be performed on genetic variants thought to play a role 
in insulin sensitivity, efficacy, beta cell function, hypoglycemia risk, and TDD requirements 
(Section 6.3) including, but not limited to, Insulin receptor, Insulin like Growth Factor-1, 
Melatonin Receptor 1B1, adiponectin and transcription factor 7-like 2, Phosphoinositide-3-
Kinase, Regulatory Subunit 1 and B-Cell CLL/Lymphoma 11A to evaluate their association with 
observed clinical outcomes to U-500R (a one-time collection, as noted in the Study Schedule
[Attachment 1]).
There is growing evidence that genetic variation may impact a subject’s response to therapy.  
Variable response to therapy may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion, the mechanism of action of the drug, the disease 
etiology and/or the molecular subtype of the disease being treated.  Therefore, where local 
regulations and ERBs allow, a blood sample will be collected for pharmacogenetic analysis.  
In the event of an unexpected AE or the observation of unusual response, the pharmacogenetic 
samples may be genotyped and analysis may be performed to evaluate a genetic association with 
response to U-500R.  These investigations may be limited to a focused candidate gene study or, 
if appropriate, genome-wide analysis may be performed to identify regions of the genome 
associated with the variability observed in drug response.  The pharmacogenetic samples will 
only be used for investigations related to disease and drug or class of drugs under study in the 
context of this clinical program.  They will not be used for broad exploratory unspecified disease 
or population genetic analysis.
The samples will be coded with the subject number and stored for up to a maximum 15 years 
after the last subject visit for the study at a facility selected by the Sponsor.  The samples and any 
data generated from them can only be linked back to the subject by investigator site personnel.  
The duration allows the Sponsor to respond to regulatory requests related to study treatment.


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Pharmacogenetic data will not be provided to the investigators nor will it be shared with patients 
in the trial. Samples will be destroyed according to a process consistent with local regulation.
10.5.3. Nonpharmacogenetic Biomarker Stored Samples
Collection of samples for nonpharmacogenetic biomarker research is a required part of this 
study.  Urine and blood (serum and plasma) samples will be collected as specified in the Study 
Schedule (Attachment 1).
Samples may be used for research to understand the pathophysiology of T2DM or its 
complications, the mechanism of action, efficacy, and/or adverse effects related to U-500R.  In 
addition, samples may be used to develop research methods and/or validate diagnostic tools or 
assays.  Nonpharmacogenetic biomarker data from stored samples will not be provided to the 
investigators nor will it be shared with patients in the trial.
Samples will be identified by the subject number (coded) and stored for up for a maximum of 
15 years after the last subject visit for the study at a facility selected by the Sponsor.
10.6. Appropriateness of Measurements
All efficacy and safety assessments included in this study are generally regarded as reliable and 
accurate with respect to management of T2DM.


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11.
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.

Provide start-up training to instruct the investigators and study coordinators.  This 
training will give instruction on the protocol, the completion of the eCRFs, 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 eCRF data and use standard computer edits to detect errors 
in data collection.

Conduct a quality review of the database.
To reduce missing data in the study, subjects who are discontinued from study treatment before 
study completion will be encouraged to remain in the study for continued safety monitoring (see 
Section 8.3.2).  In addition, study site investigators will be trained on the importance of complete 
data collection.
Lilly or its representatives will periodically check a sample of the subject 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.
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the investigator will keep records of laboratory tests, clinical notes, and subject medical 
records in the subject files as original source documents for the study.  If requested, the 
investigator will provide the Sponsor, applicable regulatory agencies, and applicable ERBs with 
direct access to original source documents.
11.1. Data Capture System
An electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into the Sponsor-provided electronic data capture system.  Case
report form data will be encoded and stored in a clinical trial database.  Data managed by a 
central vendor, such as laboratory test data, will be stored electronically in the central vendor’s 
database system.  Data will subsequently be transferred from the central vendor to the Lilly 
generic labs system.
Any data for which paper documentation provided by the subject will serve as the source 
document will be identified and documented by each site in that site’s study file.  Paper 
documentation provided by the subject may include, for example, a paper diary to collect PRO 
measures (for example, a rating scale), a daily dosing schedule, or an event diary.


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Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.


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12.
Sample Size and Statistical Methods
12.1. Determination of Sample Size
Approximately 320 subjects requiring high-dose insulin without use of GLP-1 receptor agonists 
or SGLT2 inhibitors (Group A) and approximately 64 to 96 additional subjects with use of GLP-
1 receptor agonists or SGLT2 inhibitors (Group B) will be randomized based on a 1:1 ratio to 
two treatment arms.  Approximately 240 (Group A) and 48 to 72 (Group B) subjects are 
expected to complete the 26-week treatment period (assuming a 25% dropout rate).
The sample size was calculated based on the first primary objective for subjects without use of 
GLP-1 receptor agonists or SGLT2 inhibitors (Group A).  The 240 completers will provide 80%
statistical power to demonstrate the noninferiority (NIM is 0.4%; SD=1.1%) of U-500R insulin 
CSII versus U-500R MDI in change in HbA1c at 26 weeks at 2-sided alpha = 0.05. 
12.2. Statistical and Analytical Plans
12.2.1. General Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.
Unless otherwise specified, both safety and efficacy analyses will be conducted on the ARS, 
including those rescued.  This set includes all randomized patients and is defined based on the 
intention-to-treat (ITT) principle.  Sensitivity analysis may be done for the Full Analysis Set 
(FAS) that includes ARS subjects who received at least 1 dose of the U-500R via the 
administration method to which they were assigned.
In general, missing data will not be imputed, unless otherwise specified, eg, where the LOCF 
method is mentioned.
Baseline will be the last value obtained at or prior to the randomization, unless otherwise stated. 
Separate listings for safety data will also be done for those patients who discontinue study 
treatment but still remain in the study for safety monitoring purpose. These listings will contain 
data after the patients discontinue the study treatment.
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, unless otherwise 
stated.
Changes 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 changes to the data analysis methods 
described in the protocol, and the justifications, will be described in the clinical study report.  
Additional exploratory analyses of the data will be conducted as deemed appropriate.
12.2.2. Adjustment for Multiplicity
This section explains the graphical approach in detail and illustrates how the graphical approach 
works in practice.  As discussed in Bretz et al. 2009, this testing approach controls the 


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family-wise type I error rate at alpha=0.05.  More details of this method will be documented in 
the SAP.
Figure IBHD.12.1 illustrates the graphical approach to adjust multiplicity for the primary and 
key secondary objectives.  In Figure IBHD.12.1 and for the explanations of the scenarios, the 
alternative hypotheses H1 through H10 are defined as follows:
H1: CSII is noninferior to MDI in change in HbA1c using a NIM of 0.4%.
Key Secondary Objectives:
H2: CSII is superior to MDI in change in FPG.
H3: CSII is superior to MDI in proportions of subjects achieving HbA1c targets/values 
<7.0%.
H4: CSII is superior to MDI in change in HbA1c. 
H5: CSII is superior to MDI in proportions of subjects achieving HbA1c targets/values 
<7.5%.
H6 through H10 are the same as H1 through H5 except that they are combined for the total study 
population Group A (without use of GLP-1 receptor agonists or SGLT2 inhibitors) and Group B
(those who use GLP-1 receptor agonists or SGLT2 inhibitors). 
As shown by the Figure IBHD.12.1, the graphical approach begins with testing the noninferiority 
for the primary objective at alpha=0.05.  The numbers (weights) on the arrows depict the 
proportion of alpha which is propagated to the next test if a null hypothesis is rejected.  At each 
step, all hypotheses are tested based on the current alpha assigned to them by the approach.  If,
and only if one of the null hypotheses is rejected, then the alpha flows based on the graph, and 
the weights are updated based on the preset algorithms and rules as described in Bretz et al.
2009.


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Figure IBHD.12.1.
Graphical approach to adjust multiplicity.
One of the possible scenarios for the graphical approach is given below (step by step) for 
illustration only: 

The null hypothesis for H1 is rejected at alpha=0.05, so H2 will be tested at 
alpha=0.01 and H3 will be tested at alpha=0.04.

The null hypothesis for H3 is rejected at alpha=0.04, so based on the graph 
(Figure IBHD.12.1), 99% of the alpha (0.0396) from H3 will flow to H2 and 1%
of the alpha (0.0004) from H3 will flow to H4.  Therefore, H2 will be tested at 
alpha=0.01+0.0396=0.0496 and H4 will be tested at alpha=0+0.0004=0.0004.  

The null hypothesis for H2 is rejected at alpha=0.0496, so based on the updated
graph and weights, 100% of its alpha will flow to H4 and H4 will be tested at 
alpha=0.0004+0.0496=0.05.

The null hypothesis for H4 cannot be rejected at alpha=0.05, so the graphical approach 
stops here.


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12.2.3. Subject Disposition
All subjects who discontinue from the study will be identified, and the extent of their 
participation in the study (discontinuation visit; whether remain in the study after discontinuation 
of study treatment for safety monitoring) will be reported.  If known, a reason for their 
discontinuation will be given.  The primary reasons for discontinuation will be listed for all 
subjects who have entered the study (signed informed consent) and will be summarized for the 
lead-in period.  Reasons for discontinuation of study treatment and study will also be 
summarized by treatment for the ARS, by visit and for overall study.  All of the summaries will 
be broken down by “discontinue study treatment but remain for safety monitoring” and 
“discontinue both study treatment and the study”. The treatment comparison will be based on 
Fisher’s exact test or Pearson’s chi-square test, as appropriate.  
12.2.4. Subject Characteristics
The subject characteristics and demographic variables will be recorded at Screening (Visit 1; 
Week -3) and will be listed and summarized by treatments.  The summaries will include 
descriptive statistics such as:  mean, SD, sample size, median, minimum, and maximum for 
continuous variables; and frequency, percentage, and number of subjects for categorical 
variables.  The treatment groups will be compared using an analysis of variance model for 
continuous measurements and Fisher’s exact test for categorical measurements.  In addition, 
these analyses will be conducted for baseline hypoglycemic episodes collected from Visit 2 to 
Visit 4.
12.2.5. Concomitant Therapy
Frequencies and percentages of concomitant medication used prior to and after randomization 
(by visit), will be summarized by treatments.  Antihyperglycemic agents will be summarized by 
treatment at entry, randomization, and the end of study.  AHA usage change and AHA mean 
daily-dose change from baseline to the end of study will be summarized by treatment.  Treatment
comparisons will be conducted.  
12.2.6. Treatment Compliance
No specific study data will be collected for analysis for treatment compliance except as it is 
collected in Patient Reported Outcomes Questionnaires.
12.2.7. Primary Outcome and Methodology
The primary efficacy measure is change from baseline (last nonmissing value at or prior to the 
treatment starting at randomization) to the 26-week HbA1c value, which will be summarized and 
analyzed using a MMRM approach for the ARS.  The baseline is selected to be the last value on 
or prior to the randomization visit: Visit 4 (Week 0).  Neither LOCF method nor other 
imputation methods will be used for the outcome measures. However, LOCF method will be 
used for sensitivity analysis.  The MMRM model adjusts for missing data through an observed-
data-likelihood-based approach.  The model will include the following fixed effects:  treatment 
(U-500R CSII, U-500R MDI), weeks on treatment, the interaction between treatment and weeks, 


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and the appropriate stratification factor (nonusers versus users of GLP-1 receptor agonists or
SGLT2 inhibitors and U-500R at entry versus other insulins).  The model will also include 
baseline HbA1c as a covariate.  An unstructured covariance matrix will be first modeled for the 
repeated measures of each subject.  If the analysis fails to converge, the following variance-
covariance matrix will be used (in order) until one converges:
1.
Heterogeneous compound symmetry;
2.
Compound symmetry;
3.
First-order autoregressive.
The test for the first primary objective of noninferiority will be performed at the 0.05 
significance level using the LS mean estimate of the difference in change in HbA1c between the 
two treatments at Week 26.  Noninferiority will be established if the upper limit of a 2-sided 95% 
confidence interval (CI) for the difference (U-500R CSII minus U-500R MDI) is below the NIM 
of 0.4%.
Using the LS mean estimate of the difference in change in HbA1c between the 2 treatments, 
superiority will be established if the upper limit of a two-sided 95% CI for the difference 
(U-500R CSII minus U-500R MDI) is below 0.
The following supportive and sensitivity analyses will also be conducted:

If the following sets are different from ARS, then similar MMRM analyses will be done 
for the FAS (subjects who were randomized and received at least 1 dose of the study 
insulin through the administration method they were assigned to), all completer set 
(subjects who complete the study), and the per-protocol population (subjects included in 
the ARS who have completed the study without significant protocol violations).

An “analysis of covariance” model with similar fixed effects as in the MMRM analysis
using LOCF method for the ARS.
12.2.8. Secondary Efficacy Analyses
Similar MMRM models for the ARS will be used to analyze the change from baseline for the 
following values at week 26:
1)
FPG (by laboratory measurement)
2)
7-point SMBG
3)
Total Daily Insulin dose (TDD)
Baseline values will be the last value obtained for each subject at or prior to the randomization 
visit: Visit 4, unless otherwise stated.  The MMRM model will include similar fixed effects as in 
the primary analysis, with the corresponding baseline measures included as a covariate.  The 
model specifications will be carefully adjusted as appropriate.


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For the following values at week 26:

Proportions of subjects achieving HbA1c targets/values (≤6.5%; <7.0%; <7.5% and 
<8.0%). 

Proportions of subjects achieving HbA1c targets/values (≤6.5%; <7.0%; <7.5% and 
<8.0%) without documented symptomatic hypoglycemia (SMBG <50 mg/dL).
Treatment comparisons will be analyzed using a repeated-measure logistic regression model 
including subject to account for the repeated measurements and similar fixed effects as in the 
above MMRM models.  The proportion of subjects achieving HbA1c targets with no 
documented symptomatic hypoglycemia (from baseline to the corresponding visit) will be 
analyzed using a similar repeated-measure logistic regression model including the baseline 
documented symptomatic hypoglycemia event rate as a covariate. 
12.2.9. Exploratory Analyses
Patient Reported Outcomes Analyses
12.2.9.1.
As an exploratory objective, the TRIM-D and TRIM-DD measures will be used to compare the 
change in diabetes treatment and diabetes treatment device on patient’s functioning, well-being,
and quality-of-life outcomes from baseline to the 26-week values between treatment groups.  
12.2.9.1.1.TRIM-D and TRIM-DD
The TRIM-D and TRIM-DD will be administered at Visit 4 (Week 0, prior to randomization), at 
Visit 13 (Week 14) and at Visit 17 (Week 26) or ET if subjects do not complete the full 26 weeks 
of the study.
Summaries of the domain and overall scores will include sample size, mean, SD, median, 
minimum, maximum, LS mean and standard error (SE) of LS mean.  The changes from baseline 
in domain scores and total scores of TRIM-D and TRIM-DD will be analyzed using MMRM 
model (similar to the primary/secondary analyses). For change from baseline, LS means and SE 
of LS means will be reported by treatment group.  For treatment difference of change, LS means, 
SE of LS means, 95% CI, and p-value will be reported.
OmniPod U-500 System Exit Questionnaire
12.2.9.2.
An OmniPod U-500 System Exit Questionnaire will be administered to CSII subjects at Visit 17
(Week 26) or at ET if subjects do not complete the full 26 weeks of the study.
Descriptive statistics will be provided to summarize the results from the U-500 System Exit 
Questionnaire. 
Functionality and Safe Use of the OmniPod U-500 System
12.2.9.3.
The functionality and safe use of the OmniPod U-500 system will be evaluated by an assessment 
of device complaint data and subject reported hazard alarms and clinically relevant 
hyperglycemia possibly related to site occlusion.  Lilly should be contacted for CSII device 
complaints and will provide the data to be listed.  The reported hazard alarms as well as the 
“Infusion Site Change” from the diary will be listed also. 


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12.2.10.
Safety Analyses
As stated in Section 6.2, all of the secondary objectives will be analyzed for Group A and for the 
total study population (Groups A and B combined).  Safety measures will include hypoglycemic 
events, body weight, AEs and TEAEs, vital signs (systolic and diastolic blood pressures and 
pulse), study treatment exposure, and laboratory measures.  As stated in Section 12.2.1, all safety 
measures will be summarized for ARS by treatment and by visit for the 26-week treatment 
period. Safety measures will also be listed for those patients who discontinue study treatment 
but still remain in the study for safety monitoring purpose. These listings will contain data after 
the patients discontinue the study treatment. For treatment comparisons of frequency and 
proportion of event variables (such as AEs and hypoglycemia events), the conventional Fisher’s 
exact test or Pearson’s chi-square test are appropriate to use.  Further details of analyses will be 
provided in the SAP.
Hypoglycemia
12.2.10.1.
The rate per 30 days calculated between 2 visits is defined as the total number of episodes for all 
subjects between the visits divided by the total actual number of exposure days between the 
visits, and then multiplied by 30 days.  A similar definition will be used to calculate the rate per 
subject per 365 days (year).
For documented (documented symptomatic, asymptomatic and unspecified), severe and 
nocturnal hypoglycemic episodes, the following analyses will be conducted.  The incidence and 
percentage of subjects with at least 1 hypoglycemic event will be analyzed using Fisher’s exact 
test or Pearson’s chi-square test, as appropriate.  The rate of hypoglycemic events per 30 days
and per 365 days will be analyzed using a repeated-measure negative binomial regression model 
with similar fixed effects as in the primary analysis model.  Baseline hypoglycemic event rate for
the corresponding category of the dependent hypoglycemia variable will be included as a 
covariate, as well as the stratification factors.  
Body Weight
12.2.10.2.
Baseline values used for the weight analysis will be obtained for each subject at or prior to 
randomization. The body weight change will be analyzed by MMRM models similar to that 
which will be used in the primary analysis for the ARS population.  The MMRM model will 
include similar fixed and random effects, as in the primary analysis, with the corresponding 
baseline measures included as a covariate.  The model specifications will be adjusted as 
appropriate.
Treatment-Emergent Adverse Events and Serious Adverse Events
12.2.10.3.
Adverse events will be listed by subject, system organ class, preferred term, severity, and 
relationship to the study disease, drug, device, or procedure.  Adverse events will be summarized 
as TEAEs during treatment period (defined as events that are newly reported after randomization 
Visit 4 or reported to be worsened in severity from randomization Visit 4) for ARS by treatment
and visit. Similar listings will be done for subjects who discontinued study treatment but still 
remain in the study for safety monitoring purpose. These listings will contain data after the 
patients discontinue the study treatment.


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The frequency and proportion of subjects experiencing at least 1 of each reported TEAE will be 
summarized by system organ class, preferred term, and treatment group for treatment period.  
The frequency and proportion comparisons will be analyzed using Fisher’s exact test or 
Pearson’s chi-square test, as appropriate.  The frequency and proportion of subjects experiencing
at least 1 of each reported TEAE that are assessed as possibly related to the study disease, drug, 
device, or procedures will also be summarized. 
All SAEs (including severe hypoglycemic events) will be listed by subject with similar 
information as the AE listing.  If a sufficient number of SAEs are reported, then a frequency and 
proportion summary, similar to the summary for TEAEs, will be included for the ARS.  
Discontinuations due to TEAEs and SAEs will be listed separately, by subject (including 
information about whether they discontinue only the study treatment or study treatment and the 
study), and summarized (if a sufficient number of events are reported) by treatment. All of the 
summaries will be broken down by “discontinue study treatment but remain for safety 
monitoring” and “discontinue both study treatment and the study.”
Vital Signs
12.2.10.4.
Systolic and diastolic blood pressures and pulse will be summarized by visit and additionally for 
endpoints (LOCF).  Additionally, change from baseline to the last visit of each period for actual 
value and endpoint (LOCF) will be summarized.
Study Treatment Exposure
12.2.10.5.
Exposure to each treatment will be calculated for each subject and summarized by treatment.  
Total subject-years will be included in the summaries.
Laboratory Measures
12.2.10.6.
As applicable per protocol, measures within the following panels will be summarized at 
Screening (Visit 1), Visit 4 (Week 0), Visit 13 (Week 14), and Visit 17 (Week 26) or endpoint 
(LOCF):

Chemistry 

Hematology 

Lipids
Treatment-emergent high, low, and abnormal values will be summarized for each lab measure.
A treatment-emergent high value is defined as a value that was normal or low at baseline and 
subsequently found to be above the normal range at any post-baseline visit.  A treatment-
emergent low value is defined as a value that was normal or high at baseline and subsequently 
found to be below the normal range at any post-baseline visit.  A treatment-emergent abnormal 
value is defined as a value that was normal at baseline and subsequently found to be abnormal at 
any post-baseline visit.
12.2.11.
Safety Committee
Trial level safety reviews using selected blinded safety data will be conducted throughout the 
study by the study team.  


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12.2.12.
Interim Analyses
A DMC (Data Monitoring Committee) will have access to unblinded data for their review(s).  
Only the DMC is authorized to evaluate unblinded interim safety analyses.  The DMC will be 
composed of individuals internal and external to Lilly who are not part of the study team and will 
monitor the safety of U-500R administered CSII or MDI and may recommend changes to the 
protocol, including termination.  Unblinding details are specified in the unblinding plan section 
of the SAP and/or DMC Charter.  The timing and frequency of these data reviews will be stated 
in the DMC charter.  In the event of any patient safety concerns, the DMC will communicate to
the study team so that the CRP/CRS can inform the investigator of appropriate action.  Study 
sites will receive information about interim results ONLY if they need to know for the safety of 
their subjects.
If an unplanned interim analysis is deemed necessary, the appropriate Lilly regulatory scientist
will be consulted to determine whether it is necessary to amend the protocol.


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13.
Informed Consent, Ethical Review, and Regulatory 
Considerations
13.1. Informed Consent
The investigator is responsible for ensuring that the subject understands the potential risks and 
benefits of participating in the study, including answering any questions the subject may have 
throughout the study and sharing in a timely manner any new information that may be relevant to 
the subject’s willingness to continue his or her participation in the trial.
The ICF will be used to explain the potential risks and benefits of study participation to the 
subject in simple terms before the subject is entered into the study, and to document that the
subject is satisfied with his or her understanding of the risks and benefits of participating in the 
study and desires to participate in the study.  
The investigator is responsible for ensuring that informed consent is given by each subject or 
legal representative.  This includes obtaining the appropriate signatures and dates on the ICF 
prior to the performance of any protocol procedures and prior to the administration of study 
treatment.
As used in this protocol, the term “informed consent” includes all consent and assent given by 
subjects or their legal representatives.
13.2. Ethical Review
Lilly or its representatives must approve all ICFs before they are used at investigative sites.  All 
ICFs must be compliant with the International Conference on Harmonisation (ICH) guideline on
GCP.  
The investigator must give assurance that the ERB was properly constituted and convened as 
required by 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 sites.  The ERB(s) will review the protocol as required.
The study site’s ERB(s) should be provided with the following:

IBHD Subject Information, Humulin R U-500 USPI, OmniPod U-500 Insulin 
Management System User Guide, and updates during the course of the study

ICF

Relevant curricula vitae
13.3. Regulatory Considerations
This study will be conducted in accordance with:

Consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International Organizations
of Medical Sciences  International Ethical Guidelines.


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
The ICH GCP Guideline [E6].

Applicable laws and regulations.
The investigator or designee will promptly submit the protocol to applicable ERB(s).
Some of the obligations of the Sponsor will be assigned to a TPO.
An identification code assigned to each subject will be used in lieu of the subject’s name to 
protect the subject’s identity when reporting AEs and/or other trial-related data.
13.3.1. Investigator Information
Physicians with a specialty in internal medicine or endocrinology with extensive experience in 
intensive insulin therapy including CSII therapy may participate as investigators in this clinical 
trial.
13.3.2. 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.
13.3.3. Final Report Signature
The clinical study report-coordinating investigator will sign the final clinical study report for this 
study, indicating agreement that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.  
The Sponsor’s responsible medical officer and statistician will approve the final clinical study 
report for this study, confirming that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.


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MJ. Long-term follow up of patients on U-500 insulin: a case series. Pract Diab Int. 
2010;27(5):194-197. 
Neal JM. Analysis of effectiveness of human U-500 insulin in patients unresponsive to 
conventional insulin therapy. Endocr Pract. 2005;11(5):305-307. 
Quinn SL, Lansang MC, Mina D. Safety and effectiveness of U-500 insulin therapy in patients 
with insulin-resistant type 2 diabetes mellitus. Pharmacotherapy. 2011;31(7):695-702. 
Reutrakul S, Brown RL, Koh CK, Hor TK, Baldwin D. Use of U-500 regular insulin via 
continuous subcutaneous insulin infusion: clinical practice experience. J Diabetes Sci Technol. 
2011;5(4):1025-1026. 
Reutrakul S, Wroblewski K, Brown R. Clinical use of U-500 regular insulin: review and meta-
analysis. J Diabetes Sci Technol. 2012;6(2):412-420.
Rosenstock J, Jelaska A, Frappin G, Salsali A, Kim G, Woerle HJ, Broedl UC; EMPA-REG 
MDI Trial Investigators. Improved glucose control with weight loss, lower insulin doses, and 
no increased hypoglycemia with empagliflozin added to titrated multiple daily injections of 
insulin in obese inadequately controlled type 2diabetes. Diabetes Care. 2014 
Jul;37(7):1815-1823.
Schwartz FL. A caution regarding U-500 insulin by continuous subcutaneous infusion. Endocr 
Pract. 2004;10(2):163-164.
Segal AR, Brunner JE, Burch FT, Jackson JA. Use of concentrated insulin human regular 
(U-500) for patients with diabetes. Am J Health Syst Pharm. 2010;67(18):1526-1535. 
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, Heller SR, Rodriguez H,
Rosenzweig J, Vigersky R. Hypoglycemia and diabetes: a report of a workgroup of the 
American Diabetes Association and the Endocrine Society. Diabetes Care. 
2013;36(5):1384-1395.
Ziesmer AE, Kelly KC, Guerra PA, George KG, Dunn FL. U-500 regular insulin use in insulin 
resistant type 2 diabetic veteran patients. Endocr Pract. 2012;18(1):34-38.


B5K-MC-IBHD Clinical Protocol
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Attachment 1.
Protocol IBHD Study Schedule


LY041001
B5K-MC-IBHD Clinical Protocol
Page 75
Study Schedule, Protocol B5K-MC-IBHD
Perform procedure as indicated. 
Visit 6:  CSII Treatment Arm Begins
S
Lead- In
R
Transition
Treatment Period
ETa
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Week of Study (week prior to visit)
-3
-2
-1
0
1
2
3
4
6
8
10
12
14
17
20
23
26
Allowable Range (± d=days, w=weeks)
-
1w
3d
1w
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
1w
Telephone (T) or Office (O) Visit
O
O
T
O
O
O
O
T
T
O
T
T
O
T
O
T
O
Informed consent 
X
Confirm eligibility
X
Xb
Demographic data
X
Randomization
X
IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessmentsc
Subjects fast prior to visit
X
X
X
X
Clinical chemistry/hematology
X
X
X
X
X
Estimated glomerular filtration rate 
(eGFR)
X
X
X
X
X
Lipid panel
X
X
X
X
Urinalysis
X
X
X
Pregnancy testd
X
HbA1c
X
X
X
X
X
X
X
Fasting plasma glucose
X
X
X
X
C-peptide
X
X
X
Pharmacogenetic sample for storage
X
Nonpharmacogenetic biomarkers sample 
storage (plasma, serum, urine)
X
X
X
X
X
X
X
Clinical Assessments
ECG
X
Medical history
X
Preexisting conditions
X
Physical examination
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


LY041001
B5K-MC-IBHD Clinical Protocol
Page 76
Visit 6:  CSII Treatment Arm Begins
S
Lead- In
R
Transition
Treatment Period
ETa
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Week of Study (week prior to visit)
-3
-2
-1
0
1
2
3
4
6
8
10
12
14
17
20
23
26
Allowable Range (± d=days, w=weeks)
-
1w
3d
1w
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
1w
Telephone (T) or Office (O) Visit
O
O
T
O
O
O
O
T
T
O
T
T
O
T
O
T
O
Clinical Assessments, Cont.
Assess/record BG and hypoglycemic 
eventse
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Eventse
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
Height
X
Training on 7-point SMBG profiles
X
Subject records 7-point SMBG profilesf
X
X
X
Health Outcomes Questionnaires
TRIM-D
Xg
X
X
X
TRIM-DD
Xg
X
X
X
Pump Specific Endpoint Assessment
OmniPod U-500 Exit Questionnaire for 
CSII subjects
X
Xh
Study Drug/Devices/Diaries
Dispense and training of glucose meter
X
Education on diabetes lifestyle and diet
X
X
Training on OmniPod U-500
(CSII treatment arm only)
Xi
Xj
Dispense study diary
X
X
X
X
X
X
X
X
X
Collect study diary
X
X
X
X
X
X
X
X
X
X
Dispense study drug
X
Xk
Xk
Xk
Xk
Xk
Xk
Collect study drug
X
X
X
X
X
X
X
X
Dispense subject supplies
X
X
X
X
X
X
X
X
X
Dispense OmniPod U-500 supplies
(CSII treatment arm only)
X
X
X
X
X


LY041001
B5K-MC-IBHD Clinical Protocol
Page 77
Study Schedule, Protocol B5K-MC-IBHD

Visit 6:  CSII Treatment Arm Begins
S
Lead- In
R
Transition
Treatment Period
ETa
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Week of Study (week prior to visit)
-3
-2
-1
0
1
2
3
4
6
8
10
12
14
17
20
23
26
Allowable Range (± d=days, w=weeks)
-
1w
3d
1w
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
1w
Telephone (T) or Office (O) Visit
O
O
T
O
O
O
O
T
T
O
T
T
O
T
O
T
O
Study Drug/Devices/Diaries, Cont
Dispense nutrition bars
X
X
X
X
X
X
X
X
Adjust/record insulin dose
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Product complaints
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviations:  AE = adverse event; BG = blood glucose; CRF = case report form; d = day; ET = early termination; HbA1c = Hemoglobin A1c; IWRS = 
interactive web response system; O = office, R = randomization, S = screening; SAE = serious adverse event; SMBG = self-monitored blood glucose; T = 
telephone; TRIM-D = treatment-related impact measure for diabetes; TRIM-DD = treatment-related impact measure for diabetes device; w = week.
a
Early termination visit only performed on subjects who did not complete the full 26 weeks of the study.
b
Prior to randomization at Visit 4, all subjects will be re-confirmed for inclusion criteria [1], [2], and [7] and exclusion criteria [18].
c
Central laboratory unless otherwise specified.  Laboratory tests may be performed at any time at the investigator’s discretion in the event of an adverse event.
d
Serum screening pregnancy test will be performed at Visit 1 for women of childbearing potential by a Lilly-designated central laboratory.  A urine pregnancy 
test may be repeated locally for any follow-up visits.
e
Hypoglycemic and AEs should be collected in the subject’s diary and will be discussed during telephone visits and at the next onsite visit for each subject 
unless a severe hypoglycemic event occurs (SAE that needs to be reported immediately).
f
Subjects will be instructed to record 7-point SMBG profiles on 2 nonconsecutive days (including a weekend day if possible) in the 2 weeks prior to Visits 4, 
13, and 17.
g
Health outcomes questionnaires will be administered prior to randomization during this office visit.
h
OmniPod U-500 System Exit Questionnaire will be administered to CSII subjects at ET if subjects terminate during treatment period.  
i
Subjects will be introduced to the basics of the OmniPod U-500 system at investigator site before beginning CSII treatment but will not be given the device.
j
Subjects will receive hands-on training of the OmniPod U-500 system at investigator site using study drug and will be given device to begin CSII treatment.
k
Study drug assessed and dispensed based on need and expiration.


B5K-MC-IBHD Clinical Protocol
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LY041001
Attachment 2.Protocol IBHD Clinical Laboratory Tests
Clinical Laboratory Testsa
Hematology
Clinical Chemistry
Urinalysis
Hemoglobin
BUN
Bilirubin
Hematocrit
Creatinine
Blood
MCH
Uric acid
Glucose
MCHC
LDH
Ketones
MCV
Albumin
Urine leukocyte esterase
Platelets
Total Protein
Nitrite
Erythrocyte count (RBC)
Calcium
pH
RBC Morphology
Magnesium
Protein
Leukocytes (WBC)
Chloride
Specific gravity
WBC Differential
Potassium
Urobilinogen
     Neutrophils, segmented
Sodium
b Microscopic
     Lymphocytes
Phosphorus
     Monocytes
Bicarbonate
eGFR (MDRD equation)
     Eosinophils
CK
     Basophils
Total bilirubin
Direct bilirubin
HbA1c
Alkaline phosphatase
Glucose, fasting plasma
Alanine aminotransferase (ALT)
C-peptide
Aspartate aminotransferase (AST)
Gamma-Glutamyl Transferase
(GGT)
CDC Lipid Panel
Pregnancy Test (females only)
     Cholesterol
     Triglycerides
Storage Samples
     HDL
Non-PGx Biomarkers: 
Urine, Serum, Plasma
     LDL (calculated)
PGx:  DNA Whole Blood
     FFA
Abbreviations:  BUN = blood urea nitrogen; CDC = Centers for Disease Control and Prevention; CK = creatine 
kinase; DNA = deoxyribonucleic acid; FFA= free fatty acids; HbA1c = hemoglobin A1c; HDL = high density 
lipoprotein; LDH = lactic acid dehydrogenase; LDL = low-density lipoprotein; MCH = mean cell hemoglobin; 
MCHC = mean cell hemoglobin concentration; MCV = mean corpuscular volume; PGx = pharmacogenetics; 
RBC = red blood cells; WBC = white blood cells; eGFR = estimated glomerular filtration rate; MDRD = 
Modification of Diet in Renal Disease.
a
Assayed by Lilly-designated central laboratory.
b
Microscopic evaluation if any listed urinalysis analyte is positive.


B5K-MC-IBHD Clinical Protocol
Page 79
LY041001
Attachment 3.World Health Organization (WHO) 
Classification of Diabetes
Type 1 Diabetes Mellitus:  Type 1 diabetes mellitus is judged to be present when the classical 
symptoms of diabetes (thirst, polyuria, wasting and stupor, or coma) are associated with readily 
detectable concentrations of glucose and ketone bodies in the blood and urine.  Insulin treatment 
is necessary not only to control hyperglycemia but also to prevent spontaneous ketosis and death
(Alberti and Zimmet 1998).
Type 2 Diabetes Mellitus:  Type 2 diabetes mellitus, although often asymptomatic, may also 
present with classical hyperglycemic symptoms (thirst, polyuria, weight loss), but despite 
hyperglycemia, ketone bodies are present in only low concentrations in the blood and urine.  
Coma is rare in type 2 diabetes but may result from extreme hyperglycemia and hyperosmolarity; 
lactic acidosis or ketoacidosis can also occur in fulminating illness (for example, severe infection 
or mesenteric artery thrombosis) due to an acute increase in insulin requirements, but 
spontaneous ketosis does not occur.  Some patients with type 2 diabetes later progress to a state 
of absolute insulin deficiency (Alberti and Zimmet 1998).


B5K-MC-IBHD Clinical Protocol
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LY041001
Attachment 4.New York Heart Association (NYHA) Cardiac 
Disease Classifications
Functional Capacity (CCNYHA 1994):
Class I.
Patients with cardiac disease but without resulting limitation of physical activity.  Ordinary 
physical activity does not cause undue fatigue, palpitation, or dyspnea.
Class II.
Patients with cardiac disease resulting in slight limitation of physical activity.  They are 
comfortable at rest.  Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal 
pain.
Class III.
Patients with cardiac disease resulting in marked limitation of physical activity. They are 
comfortable at rest.  Less than ordinary activity causes fatigue, palpitation, or dyspnea.
Class IV.
Patients with cardiac disease resulting in inability to carry on any physical activity without 
discomfort.  Symptoms of heart failure at rest.  If any physical activity is undertaken, discomfort 
increases.


Leo Document ID = 460cc50b-5a42-4436-8875-746da1a692d6
Approver:
Approval Date & Time: 11-Jun-2015 17:36:11 GMT
Signature meaning: Approved
Approver:
Approval Date & Time: 11-Jun-2015 17:47:05 GMT
Signature meaning: Approved
PPD
PPD

Prot_005.pdf: 
Protocol B5K-MC-IBHD(a) 
 
Safety and Efficacy of Human Regular U-500 Insulin Administered by Continuous Subcutaneous 
Insulin Infusion versus Multiple Daily Injections in Subjects with Type 2 Diabetes Mellitus: A 
Randomized, Open-Label, Parallel Clinical Trial 
 
NCT02561078 
 
Approval Date: 07-Dec-2016 
 


B5K-MC-IBHD(a) Clinical Protocol 
Page 1
LY041001
1. Protocol B5K-MC-IBHD(a)
Safety and Efficacy of Human Regular U-500 Insulin 
Administered by Continuous Subcutaneous Insulin 
Infusion versus Multiple Daily Injections in Subjects with 
Type 2 Diabetes Mellitus:  A Randomized, Open-Label, 
Parallel Clinical Trial
(VIVID: Evaluating U-500R Infusion versus Injection in Type 
2 Diabetes Mellitus)
Confidential Information
The information contained in this protocol 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 Humulin (LY041001), unless 
such persons are bound by a confidentiality agreement with Eli Lilly and Company or its subsidiaries.  
This document and its associated attachments are subject to United States Freedom of Information 
Act (FOIA) Exemption 4.  
Humulin (LY041001)
This is a Phase 3b, randomized, open-label, parallel study comparing human regular insulin U-500 
delivered by continuous subcutaneous insulin infusion (OmniPod® Insulin Management System for 
use with regular human insulin U-500) to delivery by multiple daily injections in high-dose insulin-
requiring patients with type 2 diabetes mellitus who have inadequate glycemic control on existing high 
dose insulins (with or without other insulins/antihyperglycemic agents).
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly:  11 June 2015
Amendment (a) Electronically Signed and Approved by Lilly
on approval date provided below.
Approval Date: 07-Dec-2016 GMT


B5K-MC-IBHD(a) Clinical Protocol 
Page 2
LY041001
2. Synopsis
Study Rationale
This prospective, randomized clinical trial will provide clinical information on the use of human 
regular U-500 insulin (Humulin® R U-500; U-500R) in high-dose insulin-requiring patients with 
type 2 diabetes mellitus (T2DM).  Gaps in scientific and clinical knowledge for U-500R include 
initial dosing and transition from high-dose U-100 insulin CSII or from non-U-500R and/or U-
500R MDI insulin therapy; dose titration including use of multiple daily injections (MDI) 
delivered three times daily (TID), administration safety in combination with antihyperglycemic 
agents (AHAs); and transition to continuous subcutaneous insulin infusion (CSII). Delivery of 
U-500R by CSII is used in patient care in United States (US) clinical practice (Reutrakul et al.
2011; Lane et al. 2013; Eby et al. 2014), but this mode of administration is not approved by the 
US Food and Drug Administration (FDA).  A prospective, randomized clinical trial is needed to 
evaluate the efficacy and safety of U-500R delivered by CSII as compared to U-500R by MDI
delivered TID, using a novel version of the OmniPod® Insulin Management System that is 
intended to deliver U-500 insulin with dosage in insulin units (U) without converting to U-100 
“pump units” (Lane et al. 2009; Segal et al. 2010; Lane et al. 2010; Cochran et al. 2014), which 
is what would be required if U-500 insulin were to be used in a U-100 insulin system.


B5K-MC-IBHD(a) Clinical Protocol 
Page 3
LY041001
Clinical Protocol Synopsis:  Study B5K-MC-IBHD(a)
Name of Investigational Product:
Human regular U-500 insulin; Humulin® R U-500; U-500R (LY041001)
Title of Study:  Safety and Efficacy of Human Regular U-500 Insulin Administered by Continuous Subcutaneous 
Insulin Infusion versus Multiple Daily Injections in Subjects with Type 2 Diabetes Mellitus: A Randomized, Open-
Label, Parallel Clinical Trial (VIVID:  Evaluating U-500R Infusion versus Injection in Type 2 Diabetes Mellitus)
Number of Planned Subjects: Approximately 320 subjects requiring high dose insulin without use of glucagon-
like peptide-1 (GLP-1) receptor agonists or sodium-glucose transporter protein (SGLT2) inhibitors (Group A) and 
approximately 64 to 96 additional subjects with use of GLP-1 receptor agonists or SGLT2 inhibitors (Group B),
with or without other insulins/AHAs will be randomized based on a 1:1 ratio to two treatment arms.  After Group A 
has been fully enrolled, Lilly may stop enrollment for Group B, even if the minimum recruitment goal for Group B 
has not been met.  Approximately 240 (Group A) and 48 to 72 (Group B) subjects are expected to complete the 26-
week treatment period (assuming a 25% dropout rate).  
Entered: Approximately 586 subjects (450 in Group A plus an additional 90 to 136 in Group B)
Enrolled/Randomized: Approximately 416 subjects (320 in Group A plus an additional 64 to 96 in Group B)
Completed: Approximately 312 subjects (240 in Group A plus an additional 48 to 72 in Group B)
Phase of Development:  3b
Length of Study:  18 months
Estimated first patient visit:  October 2015                           Estimated last patient visit:  December 2016
Objectives:
The primary objective is to demonstrate the change in glycated hemoglobin A1c (HbA1c) of U-500R administered 
by CSII is noninferior to U-500R administered by MDI therapy from baseline to the 26-week in high-dose insulin-
requiring patients with T2DM who have inadequate glycemic control on high-dose non U-500R (>200 and ≤600 
units per day) insulins (CSII or MDI) and/or high-dose U-500R insulin (MDI) without use of GLP-1 receptor 
agonists or SGLT2 inhibitors and with or without other insulins/AHAs. This population is referred to as Group A.
The following hypothesis will be tested for the primary objective: 
H1: CSII is noninferior to MDI in change in HbA1c using a noninferiority margin (NIM) of 0.4%.
The family-wise type I error rate for the primary objective and the following key secondary objectives will be 
controlled at a two-sided 5% level by the graphical approach.
Key Secondary Objectives:
The following 4 key (alternative hypotheses [H#]) secondary objectives at Week 26 are to demonstrate for the main 
study population (Group A [without use of GLP-1 receptor agonists or SGLT2 inhibitors]) that:
H2: CSII is superior to MDI in change in fasting plasma glucose (FPG).
H3: CSII is superior to MDI in proportions of subjects achieving HbA1c targets/values <7.0%.
H4: CSII is superior to MDI in change in HbA1c.
H5: CSII is superior to MDI in proportions of subjects achieving HbA1c targets/values <7.5%.
The following 5 key (alternative hypotheses [H#]) secondary objectives are to demonstrate the objectives at Week 
26 for the total study population (Group A [without use of GLP-1 receptor agonists or SGLT2 inhibitors] and Group 
B [those who use GLP-1 receptor agonists or SGLT2 inhibitors use]) that:
H6: CSII is noninferior to MDI in change in HbA1c using a NIM of 0.4%.
H7: CSII is superior to MDI in change in fasting plasma glucose (FPG).
H8: CSII is superior to MDI in proportions of subjects achieving HbA1c targets/values <7.0%.
H9:  CSII is superior to MDI in change in HbA1c.
H10: CSII is superior to MDI in proportions of subjects achieving HbA1c targets/values <7.5%.


B5K-MC-IBHD(a) Clinical Protocol 
Page 4
LY041001
Other Secondary Objectives:
Additional secondary objectives of the study are to compare the efficacy and safety of U-500R given by CSII versus 
MDI at Week 26 for the main study population (Group A) and the total study population (Groups A and B),
respectively (separately), with respect to the following:

Proportions of subjects achieving HbA1c targets/values (≤6.5% and <8%);

Mean change in 7-point self-monitored blood glucose (SMBG) including mean SMBG for each time point 
measurement;

Change in TDD (unit and unit/kg);

Proportions of subjects achieving HbA1c targets/values (≤6.5%, <7.0%, <7.5%, and <8.0%) without 
documented symptomatic hypoglycemia (SMBG <50 mg/dL);

Rate and incidence of hypoglycemia (documented [documented symptomatic, asymptomatic, and 
unspecified], severe, and nocturnal);

Change in body weight between treatment groups and as a function of change in HbA1c;
Exploratory Objectives:

The change in patient reported outcomes including Treatment-Related Impact Measure for Diabetes 
(TRIM-D) and TRIM-D for Diabetes Device (TRIM-DD) surveys from baseline to 26-week value.

Assess subject-reported OmniPod pump experience via OmniPod U-500 System Exit Questionnaire

Assess proportions of subjects with an HbA1c ≥9% and <9% at the 26-week value.

Postprandial contributions to total glycemic burden at baseline to 26-week values using area under the 
curve (AUC) analysis of 7-point SMBG profiles.  

Glycemic variability using 7-point SMBG profiles (including within day and day-to-day standard deviation 
[SD], coefficient of variation, average daily risk range, and mean of daily differences). 

Examine the relationship between gene variants including, but not limited to, insulin receptor, 
insulin-like growth factor-1, melatonin receptor 1B1, adiponectin, transcription factor 7-like 2, 
phosphoinositide-3-kinase, regulatory subunit 1, and B-cell CLL/lymphoma 11A on clinical 
outcomes.

Evaluate subgroups of baseline TDD >2 and ≤2 units/kg, TDD >200 units at baseline that fall below TDD 
200 units during the study, baseline TDD >400 and ≤400 U, users of GLP-1 receptor agonists or SGLT2 
inhibitors, and geriatric subjects (age ≥65 years and ≥75 years) for each of the primary and secondary 
objectives.

Functionality and safe use of the OmniPod® U-500 system (Insulet Corporation; Bedford, MA).
Study Design:  This is a Phase 3b, multicenter, randomized, open-label, parallel clinical trial comparing U-500R 
administered by CSII (OmniPod U-500 system) to U-500R administered MDI in high-dose insulin-requiring patients 
with T2DM who have inadequate glycemic control on high-dose non U-500R (>200 and ≤600 units per day) 
insulins (CSII or MDI) and/or U-500R insulin (MDI) with or without other insulins/AHAs.  The trial design 
includes a 1-week screening period, a 2-week lead-in period, and a 26-week treatment period (2 week transition to 
U-500R MDI administered TID, 12 weeks titration, and 12 weeks maintenance U-500R CSII or MDI).
Diagnosis and Main Criteria for Inclusion and Exclusions:  
Planned subject population is men and women diagnosed with T2DM requiring high-dose insulin who have 
inadequate glycemic control.
Inclusion Criteria: Aged ≥18 to ≤85 years; for 2 weeks prior to Visit 1, TDD >200 but ≤600 units of non U-500R 
insulin/analog (basal; premixed; or basal/bolus by any injection device [MDI; pens and/or syringe/vial or CSII]) 
and/or U-500R by MDI with syringe and vial.  Type of insulin must be stable for ≥3 months at entry. If TDD of
U-500R and other insulins are combined, then insulin other than U-500R not to exceed 25% of TDD; HbA1c ≥7.5% 
but ≤12.0%; body mass index ≥25 but ≤50 kg/m2; history of stable body weight; concomitant AHA therapy may 
include metformin, dipeptidyl peptidase-4 inhibitors (sitagliptin, saxagliptin, linagliptin, and alogliptin), pioglitazone 
(doses ≤30 mg/day), GLP-1 receptor agonists (albiglutide, dulaglutide, or liraglutide [Group B only]), and SGLT2 
inhibitors (canagliflozin, dapagliflozin, empagliflozin [Group B only]).  Subjects’ AHA therapy must have been 
stable for ≥3 months (except GLP-1 receptor agonists must have been stable for ≥4 months).


B5K-MC-IBHD(a) Clinical Protocol 
Page 5
LY041001
Exclusion Criteria:  Type 1 diabetes mellitus or other types of diabetes; or alanine aminotransferase and/or aspartate 
aminotransferase (ALT/AST) ≥2.5x the upper limit of normal; chronic kidney disease Stage 4 and higher (estimated 
glomerular filtration rate <30 mL/minute/1.73m2 as measured by MDRD formula); history of >1 episode of severe 
hypoglycemia (defined as hypoglycemia requiring the assistance of a another person) within the prior 6 months; 
have received U-500R insulin by CSII in the 3 months prior to Visit 1; recent blood transfusion or severe blood loss 
within 3 months prior to Visit 1; known hemoglobinopathy, hemolytic anemia, sickle cell anemia; chronic systemic 
glucocorticoid therapy; use of weight loss drugs in 3 months prior to Visit 1; women who are pregnant, 
breastfeeding, or are sexually active and of childbearing potential but are not using appropriate contraception; men 
who intend to impregnate their partners; received sulfonylureas/glinides in the 3 months prior to Visit 1, or other 
injectable or oral AHA therapy not listed in the inclusion criteria in the prior 3 months; bariatric surgery; active or 
untreated malignancy; significant hearing loss or vision impairment; cardiac disease with functional status New 
York Heart Association Class III or IV; irregular sleep/wake cycle; use of nonapproved investigational drug within 1 
month prior to trial.
Investigational Drug Product, Dosage, and Mode of Administration or Intervention:
Human regular U-500 insulin, per titration algorithm administered by CSII via OmniPod U-500 system
Planned Duration of Treatment:  
Lead-in period:  2 weeks
Treatment period:  26 weeks 
Reference Therapy, Dose, and Mode of Administration or Comparative Intervention:  
Human regular U-500 insulin, per titration algorithm administered subcutaneously by MDI
Criteria for Evaluation: 
Efficacy:  

HbA1c

FPG

7-point SMBG

TDD
Safety: 

Adverse events (AEs) and treatment-emergent adverse events (TEAEs)

Incidence and rate of hypoglycemic episodes (documented [documented symptomatic, asymptomatic, and 
unspecified], severe, and nocturnal)

Body weight

Vital signs

Study treatment exposure

Clinical laboratory tests

Product complaints
Exploratory:

Functionality and safe use of the OmniPod U-500 system 

Patient reported outcomes:  TRIM-D, TRIM-DD

Pump-specific assessment: OmniPod U-500 System Exit Questionnaire
Statistical Methods:  
Approximately 320 subjects requiring high-dose insulin without use of GLP-1 receptor agonists or SGLT2 inhibitors 
(Group A) and approximately 64 to 96 additional subjects with use of GLP-1 receptor agonists or SGLT2 inhibitors 
(Group B) will be randomized based on a 1:1 ratio to two treatment arms.  Approximately 240 (Group A) and 48 to 
72 (Group B) subjects are expected to complete the 26-week treatment period (assuming a 25% dropout rate).
The sample size was calculated based on the first primary objective for subjects without use of GLP-1 receptor 
agonists or SGLT2 inhibitors (Group A).  The 240 completers will provide 80% statistical power to demonstrate the 
noninferiority (NIM is 0.4%; SD=1.1%) of U-500R insulin CSII versus U-500R MDI in change in HbA1c at 26 
weeks at a 2-sided alpha = 0.05.


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Adjustment for Multiplicity:  A graphical approach will be used to adjust multiplicity for the primary and key 
secondary objectives.  This approach will control the family-wise Type 1 error rate at alpha=0.05. 
Randomization Details:  Stratify by entry HbA1c ≥8.5% or <8.5%, nonusers versus users of GLP-1 receptor agonists
or SGLT2 inhibitors, and U-500-R at entry versus other insulins.
Safety Committee and Interim Analysis:
Trial level safety reviews (TLSRs) using selected blinded safety data will be conducted throughout the study by the 
study team.  In addition, a DMC (Data Monitoring Committee) will have access to unblinded data for their 
review(s).  Only the DMC is authorized to evaluate unblinded interim safety analyses.  The DMC will be composed 
of individuals internal and external to Lilly who are not part of the study team and will monitor the safety of U-500R 
administered CSII or MDI and may recommend changes to the protocol, including termination.  Unblinding details 
are specified in the unblinding plan section of the Statistical Analysis Plan (SAP) and/or DMC Charter.  The timing 
and frequency of these data reviews will be stated in the DMC charter.  In the event of any patient safety concerns, 
the DMC will communicate to the study team so that the clinical research physician/clinical research scientist can 
inform the investigator of appropriate action.  Study sites will receive information about interim results ONLY if 
they need to know for the safety of their subjects. 
If an unplanned interim analysis is deemed necessary, the appropriate Lilly regulatory scientist will be consulted to 
determine whether it is necessary to amend the protocol.
Primary Efficacy: The primary efficacy measure is change from baseline to the 26-week HbA1c value.  The primary 
analysis will be conducted for the All Randomized Set (ARS) population in Group A.  There will be two primary 
analysis methods for different purposes as follows.
1.
Per FDA’s request, the analysis method will use the copy reference approach to impute missing 
data based on multiple imputations with a pattern mixture model (later referred to as ‘copy 
reference multiple imputation analysis’). This analysis will include post study treatment 
discontinuation data.  The reference is all observed data from all randomized subjects in the same 
treatment arm who discontinued study treatment but completed the study without missing data.  
After imputation, an analysis of covariance (ANCOVA) with baseline HbA1c as a covariate, 
treatment (U-500R CSII, U-500R MDI) and the stratification factor (U-500R at entry versus other 
insulins) as fixed effects will be used to analyze the 26-week HbA1c including imputed values. 
If in the reference group mentioned above there is only a limited number of subjects and this leads 
to a failure in performing the proposed multiple imputation analysis, the reference will be changed 
to include all observed data from all randomized subjects in the same treatment arm who do not 
have missing data. 
2.
For manuscripts and other non-FDA submission purposes, a MMRM model that does not include 
post study treatment discontinuation data and adjusts for missing data through an observed-data-
likelihood-based approach will be used.  The model will include the following fixed effects:  
treatment (U-500R CSII, U-500R MDI), weeks on treatment, the interaction between treatment 
and weeks, and the stratification factor (U-500R at entry versus other insulins).  The model will 
also include baseline HbA1c as a covariate.
As a sensitivity analysis to the missing at random assumption of MMRM model, a stress test will 
be performed.  The missing data are first imputed with the missing at random assumption.  Prior to 
multiple-imputation analysis, in the CSII arm the imputed values will be replaced by the imputed 
value plus delta.  Multiple values of delta within a clinically reasonable and meaningful range will 


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be tested to assess if the conclusion from the MMRM primary analysis changes.
The test for the primary objective of noninferiority will be performed at the 0.05 significance level using the least-
squares (LS) mean estimate of the difference in change in HbA1c between the two treatments at Week 26.  
Noninferiority will be established if the upper limit of a 2-sided 95% confidence interval (CI) for the difference 
(U 500R CSII minus U-500R TID) is below the NIM of 0.4%.
Using the LS mean estimate of the difference in change in HbA1c between the 2 treatments, superiority will be 
established if the upper limit of a two-sided 95% CI for the difference (U-500R CSII minus U-500R MDI) is 
below 0.
The following supportive and sensitivity analyses will also be conducted:

If the following sets are different from ARS, then similar copy reference multiple imputation and MMRM 
analyses will be done for the FAS (subjects who were randomized and received at least 1 dose of the study 
insulin through the administration method they were assigned to), all completer set (subjects who complete 
the study treatment), and the per-protocol population (subjects included in the ARS who have completed 
the study without important protocol deviations that will impact the primary outcome).

An ANCOVA model with similar fixed effects as in the copy reference multiple imputation analysis using 
LOCF method for the ARS will also be performed.

For the analysis performed for the total study population (Groups A and B), the analysis model will include 
additional stratification factor (nonusers versus users of GLP-1 receptor agonists or SGLT2 inhibitors) as 
fixed effect.
Secondary Efficacy:
Similar to the primary analysis, two sets of analysis approaches (copy reference multiple imputation and MMRM) 
will be used to analyze the change from baseline for the following key secondary endpoints 1 and 2 at Week 26.  For 
endpoint 3, only MMRM analysis will be performed.
1)
FPG (by laboratory measurement)
2)
7-point SMBG
3)
Total Daily Insulin dose (TDD)
The MMRM or ANCOVA models will include terms similar to those in the primary analysis with the appropriate 
stratification factors as fixed effect, with the corresponding baseline measures included as a covariate.  
Similar to the primary analysis, two sets of analysis approaches (repeated-measure logistic regression excluding post
study treatment discontinuation data and the multiple imputations based logistic regression including post study 
treatment discontinuation data) will be applied to assess the following secondary objectives in the following values 
at Week 26:

Proportions of subjects achieving HbA1c targets/values (≤6.5%, <7.0%, <7.5%, and <8.0%). 

Proportions of subjects achieving HbA1c targets/values (≤6.5%, <7.0%, <7.5%, and <8.0%) without 
documented symptomatic hypoglycemia (SMBG <50 mg/dL)
The logistic regression model will include similar fixed effects as in the above ANCOVA and MMRM models.  The 
proportion of subjects achieving HbA1c targets with no documented symptomatic hypoglycemia (from baseline to 
the corresponding visit) will be analyzed using similar logistic regression models including the baseline documented 


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symptomatic hypoglycemia event rate as a covariate. 
Safety Analyses:
All of the secondary objectives related to safety will be analyzed for Group A and for the total study population 
(Groups A and B combined). All safety measures will be summarized for ARS including the data after subjects 
discontinue study treatment and device but still remain in the study by treatment and by visit for the 26-week 
treatment period.  Safety measures will also be listed for those patients who discontinue study treatment but still 
remain in the study for safety monitoring purpose. These listings will contain data after the patients discontinue 
study treatment. For treatment comparisons of frequency and proportion of event variables (such as AEs and 
hypoglycemia events), the conventional Fisher’s exact test or Pearson’s chi-square test are appropriate to use. 
Hypoglycemia:  (documented [documented symptomatic, asymptomatic, and unspecified], severe, and nocturnal 
episodes):  The rate per 30 days calculated between 2 visits is defined as the total number of episodes for all subjects 
between the visits divided by the total actual number of exposure days between the visits, and then multiplied by 
30 days.  A similar definition will be used to calculate the rate per subject per 365 days (year).  For documented 
(documented symptomatic, asymptomatic and unspecified), severe, and nocturnal hypoglycemic episodes, the 
following analyses will be conducted.  The incidence and percentage of subjects with at least 1 hypoglycemic event 
will be analyzed using Fisher’s exact test or Pearson’s chi-square test, as appropriate.  The rate of hypoglycemia 
events per 30 days and per 365 days will be analyzed using a negative binomial regression model with similar fixed 
effects as in the primary MMRM analysis model.  Baseline hypoglycemia event rate for the corresponding category 
of the dependent hypoglycemia variable will be included as a covariate, as well as the stratification factors. 
Body Weight:  The body weight change will be analyzed separately by MMRM models similar to that used in the 
primary analysis for the ARS population.  The model specifications will be adjusted as appropriate.
TEAEs and serious adverse events (SAEs):  Adverse events will be listed by subject, system organ class, preferred 
term, severity, and relationship to the study disease, drug, device, or procedure.  Adverse events will be summarized 
as TEAEs during treatment period (defined as events that are newly reported after randomization Visit 4 or reported 
to be worsened in severity from randomization Visit 4) for ARS by treatment and visit. The frequency and 
proportion of subjects experiencing at least 1 of each reported TEAE will be summarized for treatment period.  The 
frequency and proportion comparisons will be analyzed using Fisher’s exact test or Pearson’s chi-square test, as 
appropriate.  The frequency and proportion of subjects experiencing at least 1 of each reported TEAE that are 
assessed as possibly related to the study disease, drug, device, or procedures will also be summarized.  All SAEs 
(including severe hypoglycemic events) will be listed by subject with similar information as the AE listing.  If a 
sufficient number of SAEs are reported, then a frequency and proportion summary, similar to the summary for 
TEAEs, will be included for the ARS.  
Vital Signs:  Systolic and diastolic blood pressures and pulse will be summarized by visit and for endpoints (LOCF).  
Change from baseline to the last visit of each period for actual endpoint and endpoint (LOCF) will be summarized.
Study Treatment Exposure:  Exposure to each treatment will be calculated for each subject and summarized by 
treatment.  Total subject-years will be included in the summaries.
Laboratory Measures (chemistry, hematology, lipids):  Treatment-emergent high, low, and abnormal values will be 
summarized for each lab measure.
Further details of analyses will be provided in the SAP.  
Patient Reported Outcome Measures: As an exploratory objective, the TRIM-D and TRIM-DD measures will be 
used to compare the change in diabetes treatment and diabetes treatment device on patient’s functioning, well-being 
and quality-of-life outcomes from baseline to the 26-week values between treatment groups.  These analyses will be 
performed on the ARS using a MMRM model (similar to the primary/secondary analyses).  Summaries of the 
continuous variables will include sample size, mean, SD, median, minimum, maximum, LS mean and standard error 
(SE) of LS mean.


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3. Table of Contents
Safety and Efficacy of Human Regular U-500 Insulin 
Administered by Continuous Subcutaneous Insulin Infusion 
versus Multiple Daily Injections in Subjects with Type 2 
Diabetes Mellitus:  A Randomized, Open-Label, Parallel 
Clinical Trial
(VIVID: Evaluating U-500R Infusion versus Injection in Type 2 
Diabetes Mellitus)  
Section
Page
1.
Protocol B5K-MC-IBHD(a) Safety and Efficacy of Human Regular 
U-500 Insulin Administered by Continuous Subcutaneous Insulin 
Infusion versus Multiple Daily Injections in Subjects with Type 2 
Diabetes Mellitus:  A Randomized, Open-Label, Parallel Clinical 
Trial....................................................................................................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................9
4.
Abbreviations and Definitions...........................................................................................16
5.
Introduction ......................................................................................................................20
6.
Objectives.........................................................................................................................23
6.1.
Primary Objective ........................................................................................................23
6.2.
Secondary Objectives...................................................................................................23
6.2.1.
Key Secondary Objectives ...................................................................................23
6.2.2.
Other Secondary Objectives .................................................................................24
6.3.
Exploratory Objectives.................................................................................................24
7.
Investigational Plan...........................................................................................................25
7.1.
Summary of Study Design............................................................................................25
7.1.1.
Diaries .................................................................................................................26
7.1.2.
Type 2 Diabetes Lifestyle Counseling ..................................................................27
7.1.3.
Blood Glucose Monitoring ...................................................................................27
4-Point SMBG................................................................................................27
7.1.3.1.
7-Point SMBG................................................................................................27
7.1.3.2.
0300 Hours SMBG.........................................................................................28
7.1.3.3.
7.1.4.
Screening Period..................................................................................................28
7.1.5.
Lead-In Period .....................................................................................................28
7.1.6.
Randomization.....................................................................................................28
7.1.7.
Treatment Period..................................................................................................28


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Transition to U-500R MDI .............................................................................29
7.1.7.1.
U-100 Insulin Syringe for Administering U-500R MDI ..................................29
7.1.7.2.
CSII Pump Training........................................................................................29
7.1.7.3.
7.2.
Discussion of Design and Control ................................................................................29
8.
Study Population...............................................................................................................31
8.1.
Inclusion Criteria..........................................................................................................31
8.2.
Exclusion Criteria ........................................................................................................32
8.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................34
8.3.
Discontinuations ..........................................................................................................34
8.3.1.
Discontinuation of Inadvertently Enrolled Subjects ..............................................34
8.3.2.
Discontinuation of Study Treatment .....................................................................35
8.3.3.
Subject Discontinuation from the Study ...............................................................35
8.3.4.
Subjects Lost to Follow-Up..................................................................................36
8.3.5.
Discontinuation of Study Sites .............................................................................36
8.3.6.
Discontinuation of the Study ................................................................................36
9.
Treatment..........................................................................................................................37
9.1.
Treatments Administered .............................................................................................37
9.2.
Materials and Supplies .................................................................................................37
9.3.
Method of Assignment to Treatment ............................................................................38
9.4.
Rationale for Selection of Doses in the Study...............................................................38
9.5.
Lead-in Period..............................................................................................................39
9.6.
Randomization.............................................................................................................39
9.7.
Transition to U-500R MDI...........................................................................................39
9.7.1.
Dosing Using U-100 Insulin Syringes ..................................................................40
9.7.2.
CSII Training.......................................................................................................41
9.7.3.
Intensified Dose Titration Period..........................................................................41
9.7.4.
Maintenance Dose Titration Period ......................................................................41
9.8.
Treatment Periods ........................................................................................................41
9.8.1.
CSII .....................................................................................................................41
CSII Treatment Group Algorithms..................................................................42
9.8.1.1.
CSII Basal Rate ..............................................................................................44
9.8.1.2.
9.8.1.2.1.
Adding a Basal Rate for Nocturnal Hypoglycemia ....................................44
9.8.1.2.2.
Adding a Basal Rate for Dawn Phenomenon.............................................44
CSII Bolus Dosing..........................................................................................44
9.8.1.3.
9.8.1.3.1.
CSII Bolus Settings...................................................................................44
9.8.2.
MDI.....................................................................................................................45
MDI Treatment Group Algorithms .................................................................45
9.8.2.1.
9.9.
Special Treatment Considerations ................................................................................46


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9.9.1.
Rescue Therapy....................................................................................................46
9.9.2.
Continued Access to Study Treatment..................................................................47
9.10. Blinding .......................................................................................................................47
9.11. Concomitant Therapy...................................................................................................47
9.11.1.
Concomitant Medications Including Antihyperglycemic 
Agents..................................................................................................................47
9.12. Treatment Compliance .................................................................................................48
10.
Efficacy, Patient Reported Outcomes, Safety Evaluations, Sample 
Collection and Testing, and Appropriateness of Measurements .........................................49
10.1. Efficacy Measures........................................................................................................49
10.1.1.
Primary Efficacy Measure....................................................................................49
10.1.2.
Secondary Efficacy Measures...............................................................................49
Fasting Plasma Glucose..................................................................................49
10.1.2.1.
7-point SMBG................................................................................................49
10.1.2.2.
Total Daily Insulin Dose.................................................................................49
10.1.2.3.
10.2. Patient Reported Outcomes ..........................................................................................49
10.2.1.
TRIM-D and TRIM-D Device..............................................................................49
10.3. OmniPod U-500 System Exit Questionnaire.................................................................50
10.4. Safety Evaluations........................................................................................................50
10.4.1.
Adverse Events ....................................................................................................50
Serious Adverse Events ..................................................................................51
10.4.1.1.
10.4.1.1.1.
Suspected Unexpected Serious Adverse Reactions....................................52
10.4.2.
Hypoglycemia......................................................................................................53
10.4.3.
Body Weight........................................................................................................54
10.4.4.
Other Safety Measures .........................................................................................54
Vital signs ......................................................................................................54
10.4.4.1.
Physical Examinations....................................................................................54
10.4.4.2.
Electrocardiograms.........................................................................................54
10.4.4.3.
Clinical Laboratory Tests................................................................................54
10.4.4.4.
Concomitant Medications ...............................................................................54
10.4.4.5.
Functionality and Safe Use of OmniPod U-500 System ..................................54
10.4.4.6.
10.4.5.
Safety Monitoring ................................................................................................54
10.4.6.
Complaint Handling.............................................................................................55
10.5. Sample Collection and Testing .....................................................................................55
10.5.1.
Samples for Study Qualification and Health Monitoring.......................................56
10.5.2.
Pharmacogenetic Samples for Biomarker Research ..............................................56
10.5.3.
Nonpharmacogenetic Biomarker Stored Samples .................................................57
10.6. Appropriateness of Measurements................................................................................57


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11.
Data Quality Assurance.....................................................................................................58
11.1. Data Capture System....................................................................................................58
12.
Sample Size and Statistical Methods .................................................................................60
12.1. Determination of Sample Size ......................................................................................60
12.2. Statistical and Analytical Plans.....................................................................................60
12.2.1.
General Considerations ........................................................................................60
12.2.2.
Adjustment for Multiplicity..................................................................................60
12.2.3.
Subject Disposition ..............................................................................................63
12.2.4.
Subject Characteristics .........................................................................................63
12.2.5.
Concomitant Therapy...........................................................................................63
12.2.6.
Treatment Compliance .........................................................................................63
12.2.7.
Primary Outcome and Methodology.....................................................................63
12.2.8.
Secondary Efficacy Analyses ...............................................................................65
12.2.9.
Exploratory Analyses...........................................................................................65
Patient Reported Outcomes Analyses..............................................................65
12.2.9.1.
12.2.9.1.1.
TRIM-D and TRIM-DD............................................................................65
OmniPod U-500 System Exit Questionnaire ...................................................66
12.2.9.2.
Functionality and Safe Use of the OmniPod U-500 
12.2.9.3.
System............................................................................................................66
12.2.10. Safety Analyses....................................................................................................66
Hypoglycemia ................................................................................................66
12.2.10.1.
Body Weight ..................................................................................................67
12.2.10.2.
Treatment-Emergent Adverse Events and Serious 
12.2.10.3.
Adverse Events...............................................................................................67
Vital Signs......................................................................................................67
12.2.10.4.
Study Treatment Exposure..............................................................................67
12.2.10.5.
Laboratory Measures ......................................................................................68
12.2.10.6.
12.2.11. Safety Committee.................................................................................................68
12.2.12. Interim Analyses ..................................................................................................68
13.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................69
13.1. Informed Consent.........................................................................................................69
13.2. Ethical Review.............................................................................................................69
13.3. Regulatory Considerations ...........................................................................................69
13.3.1.
Investigator Information.......................................................................................70
13.3.2.
Protocol Signatures ..............................................................................................70
13.3.3.
Final Report Signature .........................................................................................70
14.
References ........................................................................................................................71


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List of Tables
Table
Page
Table IBHD.7.1. Planned Subject Recruitment ........................................................................25
Table IBHD.9.1. Treatment Regimens......................................................................................37
Table IBHD.9.2. Study Devices................................................................................................38
Table IBHD.9.3. Transition from entry insulin to U-500R MDI ................................................40
Table IBHD.9.4. Basal Titration Scheme for CSII ....................................................................43
Table IBHD.9.5. Bolus Titration Scheme for CSII....................................................................43
Table IBHD.9.6. Bolus Titration Scheme for MDI Delivered TID ............................................46
Table IBHD.9.7. Concomitant Medications and Conditions for Use .........................................48


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List of Figures
Figure
Page
Figure IBHD.7.1.Illustration of study design for Clinical Protocol B5K-MC-IBHD..................26
Figure IBHD.12.1.
Graphical approach to adjust multiplicity. ...........................................62


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List of Attachments
Attachment
Page
Attachment 1.
Protocol IBHD Study Schedule......................................................................74
Attachment 2.
Protocol IBHD Clinical Laboratory Tests ......................................................78
Attachment 3.
World Health Organization (WHO) Classification of Diabetes.......................79
Attachment 4.
New York Heart Association (NYHA) Cardiac Disease Classifications .........80


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4. Abbreviations and Definitions
Term
Definition
Adverse event (AE)
Adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
AHA
antihyperglycemic agent
ALT/SGPT
alanine aminotransferase (serum glutamic pyruvic transaminase)
ARS
All randomized set
AST/SGOT
aspartate aminotransferase (serum glutamic oxaloacetic transaminase)
AUC
Area under the curve
BG
blood glucose
BID
twice daily
CGM
continuous glucose monitoring
CHO
carbohydrate
CI
confidence interval
Complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
Compliance
Adherence to all the trial-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements.
Consent
The act of obtaining informed consent for participation in a clinical trial from subjects 
deemed eligible or potentially eligible to participate in the clinical trial.  Subjects entered 
into a trial are those who sign the informed consent form directly or through their legally 
acceptable representatives.
CRP/CRS
Clinical research physician/ Clinical research scientist: 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
DMC
Data monitoring committee 
ECG
electrocardiogram


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Term
Definition
eCRF
electronic clinical report form:  An electronic form for recording study participants’ data 
during a clinical study, as required by the protocol.
Efficacy
Efficacy is the ability of a treatment to achieve a beneficial intended result under 
controlled conditions.
End of trial (study)
End of trial is the date of the last visit or last scheduled procedure shown in the Study 
Schedule for the last active subject in the study.
Enroll
The act of assigning a subject to a treatment.  Subjects who are enrolled in the trial are 
those who have been assigned to a treatment.
Enter
Subjects entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ET
early termination
FAS
full analysis set
FDA
Food and Drug Administration
FPG
fasting plasma glucose (central laboratory value)
GCP
good clinical practice
GLP-1
glucagon-like peptide-1
HbA1c
glycated hemoglobin A1c
ICF
informed consent form
Informed consent
A process by which a subject voluntarily confirms his or her willingness to participate in 
a particular trial, after having been informed of all aspects of the trial that are relevant to 
the subject’s decision to participate. Informed consent is documented by means of a 
written, signed, and dated informed consent form.  
Institutional Review 
Board/ Ethical 
Review Board 
(IRB/ERB)
A board or committee (institutional, regional, or national) composed of medical and 
nonmedical members whose responsibility is to verify that the safety, welfare, and 
human rights of the subjects participating in a clinical study are protected.
IOB
Insulin-on-board:  Active insulin circulating in the body from previous bolus doses
Investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible 
leader of the team and may be called the principal investigator.
ITT
Intention to treat:  The principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a subject (that is, planned 
treatment regimen) rather than the actual treatment given.  It has the consequence that 
subjects allocated to a treatment group should be followed up, assessed, and analyzed as 
members of that group irrespective of their compliance to the planned course of 
treatment.


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Term
Definition
IWRS
interactive web response system
LOCF
last observation carried forward
LS mean
least-squares mean
MDI 
multiple daily injections
MDRD
Modification of Diet in Renal Disease
MET
metformin
MMRM
mixed-model repeated measures
NIM
Noninferiority margin
PDM
Personal diabetes manager
PRO
patient-reported outcomes
Randomize
The act of assigning a subject to a treatment.  Subjects who are randomized in the trial 
are those who have been assigned to a treatment.
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.  In this study, screening 
involves invasive or diagnostic procedures and/or tests (for example, diagnostic 
psychological tests, x-rays, blood draws).  For this type of screening, informed consent 
for these screening procedures and/or tests shall be obtained; this consent may be 
separate from obtaining consent for the study.
SD
standard deviation
SE
standard error
SGLT2
sodium-glucose cotransporter 2 
SMBG
self-monitored blood glucose
Subject
An individual who is or becomes a participant in clinical research, either as a recipient of 
the investigational product(s) or as a control.  A subject may be either a healthy human 
or a patient.
SUSAR
suspected unexpected serious adverse reaction
TDD
total daily dose
TID
three times daily


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Term
Definition
TPO
third party organization
Treatment-emergent 
adverse event (TEAE)
Treatment-emergent adverse event:  Any untoward medical occurrence that either occurs 
or worsens at any time after treatment baseline and that does not necessarily have to have 
a causal relationship with this treatment.
TRIM-D
treatment-related impact measure for diabetes
TRIM-DD
treatment-related impact measure for diabetes device
T1DM
type 1 diabetes mellitus
T2DM
type 2 diabetes mellitus
U-500R
human regular U-500 insulin; Humulin® R U-500 insulin
ULN
Upper limit of normal
US
United States
VAS
visual analog scale
WHO
World Health Organization


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5. Introduction
Although human regular U-500 insulin (Humulin® R U-500; U-500R) has been available in the 
United States (US) market for more than 50 years, its clinical use has increased over the past 
5 years due to the worsening epidemics of type 2 diabetes mellitus (T2DM) and obesity (Lane et 
al. 2009; Segal et al. 2010; Cochran et al. 2014).  
According to published clinical reports and expert clinical reviews, high-dose insulin-treated
insulin-resistant patients (requiring >200 units of U-100 insulin) have been treated successfully 
and safely with U-500R by injection, resulting in improved glycemic control (glycated 
hemoglobin A1c [HbA1c] reductions between 1% and 2%) with uncommon reports of severe 
hypoglycemia (Neal 2005; Ballani et al. 2006; Lane et al. 2009; Nayyar et al. 2010; Dailey et al. 
2010; Quinn et al. 2011; Ziesmer et al. 2012; Boldo and Comi 2012; Reutrakul et al. 2012; Jones 
and Idris 2013; Hood et al. 2015). U-500R is typically dosed utilizing multiple-daily injections 
(MDI) with either twice daily (BID) or three times daily (TID) dosing (Humulin R U-500 
package insert; de la Peña et al. 2011; Reutrakul et al. 2012). One small (N=28) randomized 
controlled trial of U-500R was recently published reporting a significant mean HbA1c reduction
of 1.0% to 1.7% from baseline to 24-week endpoint (p=0.0001) with no reported episodes of 
severe hypoglycemia when combined with metformin and/or exenatide (Distiller et al. 2014).  
The effect of U-500R begins within 30 minutes, has a peak similar to that observed with human 
regular U-100 insulin (U-100R), and has a relatively long duration of activity (up to 24 hours) 
following a single dose as compared with U-100R (de la Peña et al. 2011). Similarly, a U-500R 
pharmacokinetic/pharmacodynamics simulation modeling study indicated the steady-state basal 
pharmacokinetic/pharmacodynamics effect from both BID and TID dosing appears to support 
use of U-500R as insulin monotherapy (de la Peña. 2014). A recently completed randomized, 
controlled Phase 4 trial (B5K-US-IBHC) comparing TID versus BID U-500R monotherapy over 
24 weeks in 325 subjects demonstrated that U-500R as insulin monotherapy is safe and 
efficacious (HbA1c reduction of 1.1% to 1.2% [Hood et al. 2015]). 
Clinical expert reviews recommend MDI delivered TID injections for all dosage ranges of 
U-500R (Cochran et al. 2005; Lane et al. 2009; Segal et al. 2010; Reutrakul et al. 2012; Cochran 
et al. 2014).  A number of clinical case series (Knee et al. 2003; Schwartz 2004; Lane 2006; 
Bulchandani et al. 2007; Lane et al. 2010; and Reutrakul et al. 2011) have also reported use of 
U-500R by continuous subcutaneous insulin infusion (CSII), a practice that may account for 
approximately one quarter of current U-500R therapy according to recent large retrospective 
real-world claims database analysis (Eby et al. 2014).  These U-500 CSII therapy case series 
have shown improvements in HbA1c from 1.2% (Lane et al. 2010) to 3.5% (Knee et al. 2003), 
and a mean reduction of 1.64% in a review by Reutrakul et al. (2012) which reported severe 
hypoglycemia in 2 (n=55) subjects.  The largest and longest case series (N=59; mean duration of 
follow up 49 months [range: 12 to 114 months]; Lane et al. 2013) reported 1.0% mean decrease 
in HbA1c (from 8.3% to 7.3%) sustained over 66 months of U-500 CSII therapy with severe 
hypoglycemia rate (defined by blood glucose [BG] ≤50 mg/dL or “blood glucose requiring 
treatment [regardless of value])”) at 0.1 episodes per patient per year.  


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The aforementioned studies with U-500R in CSII therapy lacked controls, were predominately 
retrospective, and included a small number of subjects (60 subjects per study; total: 
114 subjects).  Additionally, delivery by CSII in currently marketed insulin pumps requires dose 
transition to “U-100 insulin pump units” (one-fifth of actual U-500R dose per volume; Lane et 
al. 2006; Lane et al. 2009; Lane et al. 2010; Segal et al. 2010; and Cochran et al. 2014), which 
has the potential to result in dosing confusion and medication errors.
In summary, there is a clear clinical need to study the use of U-500 by CSII in a prospective, 
randomized clinical trial. Thus, Lilly has developed protocol B5K-MC-IBHD to evaluate the
efficacy and safety of U-500R delivered by CSII as compared to U-500R MDI delivered TID.
The CSII system uses a novel insulin pump device that is not commercially available with 
internal software appropriate for U-500 insulin dosage in U-500 insulin units.  
Input obtained from T2DM patient interviews for this protocol development indicates a wide 
spectrum of knowledge and ability to utilize CSII features by patients.  The current trial design 
was developed to meet the needs of high-dose insulin-requiring patients who could benefit from 
improved glycemic control with CSII.  The unique properties of U-500R demonstrate that it can 
be used as both basal and bolus therapy in MDI or CSII regimens (CSII 50% basal and 50% 
bolus) (Hirsch 2010; de la Peña et al. 2011; Hood et al. 2015). The functionality of the OmniPod 
U-500 system in the trial allows for those patients requiring simpler interface, as well as those 
who would benefit from increased individualization.  For example, the CSII treatment arm will 
initially utilize 2 basal rates for simplicity but allow for individualization up to 4 basal rates if 
needed.  Additionally, a variety of bolus options will be available including boluses based on 
carbohydrate (CHO) counting, fixed meal doses, or doses based on meal sizes (small, medium,
or large). 
It is estimated that 10% to 18% of patients treated with U-500R are on concomitant noninsulin 
injectable therapy, including glucagon-like peptide-1 (GLP-1) receptor agonist therapy (Eby et 
al. 2013, 2014 and Data on File).  Although the percentage of U-500R used in combination with 
sodium-glucose co-transporter 2 (SGLT2) inhibitors is unknown, combination of SGLT2 
inhibitors with U-100 insulin has risen by 4-fold to 1.4% (July 2013 to April 2014 [IMS Data on 
File]).  GLP-1 receptor agonists and SGLT2 inhibitors have been used in insulin-sparing and 
weight attenuating strategies and have shown clinical utility in combination with U-500R or 
U-100 insulin (Lane et al. 2011; Rosenstock et al. 2014).  Two study population groups 
(Groups A and B) will be stratified by nonuse or use of these therapies.  Subjects in each group 
will be randomly assigned equally between treatment arms.  Study population Group A will 
include patients who are not using GLP-1 receptor agonists or SGLT2 inhibitors.  The study 
population Group B will include patients who are using GLP-1 receptor agonists or SGLT2
inhibitors.  Group A will be the primary analysis population.  Combined Groups A and B will be 
included in the key and other secondary objectives. The use of GLP-1 receptor agonists or
SGLT2 inhibitors is also intended for exploratory analyses.  
Appropriate testing supporting use of the U-500R in the OmniPod U-500 Insulin Management 
System in clinical trials has been completed.  More detailed information about the known and 
expected benefits and risks of U-500R may be found in the U-500R package insert.  More 


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detailed information regarding the use of the OmniPod U-500 system may be found in the 
OmniPod U-500 Insulin Management System User Guide.


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6. Objectives
6.1.
Primary Objective
The primary objective is to demonstrate the change in HbA1c of U-500R administered by CSII is 
noninferior to U-500R administered by MDI therapy from baseline to the 26-week in high-dose 
insulin-requiring patients with T2DM who have inadequate glycemic control on high-dose non 
U-500R (>200 and ≤600 units per day) insulins (CSII or MDI) and/or high-dose U-500R insulin 
(MDI) without use of GLP-1 receptor agonists or SGLT2 inhibitors and with or without other 
insulins/antihyperglycemic agents (AHAs).  This population is referred to as Group A. 
The following hypothesis will be tested for the primary objective:
H1: CSII is noninferior to MDI in change in HbA1c using a noninferiority margin (NIM)
of 0.4%.
The family-wise type I error rate for the primary objective and the following key secondary 
objectives will be controlled at a two-sided 5% level by the graphical approach, which will be 
discussed in detail in the Statistical Analysis Plan (SAP).
6.2.
Secondary Objectives
6.2.1. Key Secondary Objectives
The following 4 key (alternative hypotheses [H#]) secondary objectives at Week 26 are to 
demonstrate for the main study population (Group A [without use of GLP-1 receptor agonists or
SGLT2 inhibitors, Section 7.1]) that:
H2: CSII is superior to MDI in change in fasting plasma glucose (FPG).
H3: CSII is superior to MDI in proportions of subjects achieving HbA1c targets/values <7.0%.
H4: CSII is superior to MDI in change in HbA1c.
H5: CSII is superior to MDI in proportions of subjects achieving HbA1c targets/values <7.5%.
The following 5 key (alternative hypotheses [H#]) secondary objectives are to demonstrate the 
objectives at Week 26 for the total study population (Group A [without use of GLP-1 receptor 
agonists or SGLT2 inhibitors] and Group B [those who use GLP-1 receptor agonists or SGLT2 
inhibitors use, Section 7.1]) that:
H6: CSII is noninferior to MDI in change in HbA1c using NIM of 0.4%.
H7: CSII is superior to MDI in change in FPG.
H8: CSII is superior to MDI in proportions of subjects achieving HbA1c targets/values <7.0%.
H9: CSII is superior to MDI in change in HbA1c.
H10: CSII is superior to MDI in proportions of subjects achieving HbA1c targets/values <7.5%.


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6.2.2. Other Secondary Objectives
Additional secondary objectives of the study are to compare the efficacy and safety of U-500R
given by CSII versus MDI at Week 26 for the main study population Group A and the total study 
population (Groups A and B) respectively (separately), with respect to the following:

Proportions of subjects achieving HbA1c targets/values (≤6.5% and <8.0%).

Mean change in 7-point self-monitored blood glucose (SMBG) including mean 
SMBG for each time point measurement.

Change in TDD (unit and unit/kg).

Proportions of subjects achieving HbA1c targets/values (≤6.5%, <7.0%, <7.5%, 
and <8.0%) without documented symptomatic hypoglycemia (SMBG 
<50 mg/dL).

Rate and incidence of hypoglycemia (documented [documented symptomatic, 
asymptomatic, and unspecified], severe, and nocturnal).

Change in body weight between treatment groups and as a function of change in 
HbA1c.
6.3.
Exploratory Objectives

The change in patient reported outcomes including Treatment-Related Impact 
Measure for Diabetes (TRIM-D) and TRIM-D for Diabetes Device (TRIM-DD) 
surveys from baseline to 26-week value.

Assess subject-reported OmniPod pump experience via OmniPod U-500 System 
Exit Questionnaire.

Assess proportion of subjects with an HbA1c ≥9% and <9% at the 26-week value.

Postprandial contributions to total glycemic burden at baseline to 26-week values
using area under the curve (AUC) analysis of 7-point SMBG profiles.  

Glycemic variability using 7-point SMBG profiles (including within day and 
day-to-day standard deviation [SD], coefficient of variation, average daily risk 
range, and mean of daily differences).

Examine the relationship between gene variants including, but not limited to, 
insulin receptor, insulin like growth factor-1, melatonin receptor 1B1, 
adiponectin, transcription factor 7-like 2, phosphoinositide-3-kinase, regulatory 
subunit 1 and B-cell CLL/lymphoma 11A on clinical outcomes. 

Evaluate subgroups of baseline TDD >2 and ≤2 units/kg, TDD >200 units at 
baseline that fall below TDD 200 units during the study, baseline TDD >400 and 
≤400 units, users of GLP-1 receptor agonists or SGLT2 inhibitors, and geriatric 
subjects (age ≥65 years and ≥75 years) on each of the primary and secondary 
objectives.

Functionality and safe use of the OmniPod U-500 system.


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7. Investigational Plan
7.1.
Summary of Study Design
Study B5K-MC-IBHD is a Phase 3b, multicenter, randomized, open-label, parallel clinical trial 
comparing U-500R administered by CSII (OmniPod U-500 system) to U-500R administered
MDI in high-dose insulin-requiring patients with T2DM who have inadequate glycemic control
on high-dose non U-500R (>200 and ≤600 units per day) insulins (CSII or MDI) and/or U-500R 
insulin (MDI) with or without other insulins/AHAs.  The trial design includes: 1-week screening
period, 2-week lead-in period, and a 26-week treatment period (2 week transition to U-500R
MDI administered TID, 12 weeks titration and 12 weeks maintenance U-500R CSII or MDI).  
As shown in the following recruitment plan (Table IBHD.7.1), approximately 320 subjects 
requiring high-dose insulin without use of GLP-1 receptor agonists or SGLT2 inhibitors (Group 
A) and approximately 64 to 96 additional subjects who are using GLP-1 receptor agonists or
SGLT2 inhibitors (Group B) with or without other AHAs will be randomized based on a 1:1 
ratio to two treatment arms.  After Group A has been fully enrolled, Lilly may stop enrollment 
for Group B, even if the minimum recruitment goal for Group B has not been met.  
Approximately 240 (Group A) and 48 to 72 (Group B) subjects are expected to complete the 
26-week treatment period (assuming a 25% dropout rate).
Table IBHD.7.1.
Planned Subject Recruitment
Group A 
Group B GLP-1 or SGLT2 users
(Target range)
Entered
450
90 to 136
Enrolled/Randomized
320
64 to 96
Completed
240
48 to 72
Abbreviations:  GLP-1 = glucagon-like peptide-1; SGLT2 = sodium-glucose cotransporter 2.
The end of the study for each subject is Visit 17 or the early termination (ET) visit for subjects 
who discontinue early.  Figure IBHD.7.1 illustrates the study design.


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Abbreviations:  CSII = continuous subcutaneous insulin infusion; MDI = multiple daily injections.
a
Subjects will continue their pre-study insulin regimens.
b
Subjects will be stratified and randomly assigned equally between treatment arms by nonusers (Group A) versus 
users (Group B) of GLP-1 receptor agonists or SGLT2 inhibitors, entry HbA1c ≥8.5% or <8.5%, and U-500R at 
entry versus other insulins.
c
MDI or CSII and will be transitioned to U-500R by MDI.
d
Telephone visits.
Figure IBHD.7.1.
Illustration of study design for Clinical Protocol B5K-MC-IBHD.
7.1.1. Diaries
As indicated in the study schedule (Attachment 1), starting at Visit 1 (Week -3) subjects will be 
given a study diary at each office visit and instructed to record 4- point, and 7-point SMBG 
values, insulin doses, hypoglycemic episodes, adverse events (AEs), illnesses, concomitant 
medications, infusion site changes, and reasons for nonroutine infusion site changes (post-
randomization and transition to U-500R) through the end of participation in the study or at ET, if 
applicable.  Investigators should encourage subjects to measure BG values during the symptoms 
of hypoglycemia and record BG values in their study diaries.  Investigative staff will review the 
study diaries and transfer data to electronic case report forms (eCRFs) at each office visit 
beginning at Visit 2 (Week -2), with the exception of 4-point SMBG values. Investigative staff 
will also record any additional AEs and episodes of hypoglycemia that are reported by subjects 
and that have occurred since the previous entry on the eCRFs, even when the event was initially 
not entered into the study diary. Study diaries are considered source information and are to be 
returned to the investigator (or designee) at each office visit.


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7.1.2. Type 2 Diabetes Lifestyle Counseling
Per the study schedule (Attachment 1), qualified medical staff will provide diabetes management 
counseling including diet, exercise, and education about the signs, symptoms, and treatment of 
hypoglycemia, should it occur.  Subjects should continue their usual exercise habits and 
generally follow stable meal plans (consistent meal size and time of day) throughout the course 
of the study.  Instruction on how to assess CHO content and caloric content of meals may be 
incorporated into the counseling.  Dietary counseling may be reviewed throughout the study as 
needed.  Subjects are not to initiate a weight loss program during the trial.
7.1.3. Blood Glucose Monitoring
The U-500R dosage will be based on subjects’ individual needs, as assessed by SMBG results
obtained from monitoring at home.  Site personnel may request additional BG monitoring from 
subjects and/or assess BG values at other times during the study in order to make dose
adjustment decisions.  Subjects should record both 4- and 7-point SMBG measurements, as well 
as insulin doses, in the subject diary provided.
4-Point SMBG
7.1.3.1.
Subjects will be instructed to record 4-point SMBGs daily beginning with the screening period.  
The 4-point SMBG consists of BG measurements at:

Pre-morning meal (fasting)

Pre-midday meal

Pre-evening meal

Bedtime (at least 2 hours after the evening meal)
7-Point SMBG
7.1.3.2.
All subjects will be instructed to record 7-point SMBG profiles on any 2 nonconsecutive days in 
the 2 weeks prior to visits as outlined in the study schedule (Attachment 1); profiles should 
include weekend day(s), if possible.  The timing of the 7-point SMBG measurement over a 
24-hour period is as follows:

Pre-morning meal (fasting)

2 hours after the morning meal

Pre-midday meal

2 hours after the midday meal

Pre-evening meal

2 hours after the evening meal

0300 hours


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0300 Hours SMBG
7.1.3.3.
Subjects will also be instructed to record their 0300 hours BG within 48 hours of each increase in 
insulin dose titration at telephone and office visits (preferably the first night after the dosage 
adjustment).  The investigator or site personnel will ask the subjects about these BG 
measurements and the investigator will recommend dosage titrations based on glucose targets 
within the CSII (Section 9.8.1.1) and MDI (Section 9.8.2.1) algorithms during telephone and 
office visits.
7.1.4. Screening Period
This study contains a 1-week screening period between Visit 1 (Week -3) and Visit 2 (Week -2),
which allows for the evaluation and assessment of potential subjects’ eligibility against the 
inclusion and exclusion criteria (Sections 8.1 and 8.2, respectively).  Subjects may be 
prescreened for inclusion/exclusion criteria that are available from their subject files, including 
any laboratory values on file collected within the previous 30 days, in compliance with local 
privacy regulations.  Subjects will continue their pre-study insulin and AHA regimens and doses 
(per inclusion/exclusion criteria in Sections 8.1 and 8.2).  Refer to Attachment 1 for the study 
schedule of screening period activities.
7.1.5. Lead-In Period
Eligible subjects will begin a 2-week lead-in period at Visit 2 (Week -2) according to the Study 
Schedule (Attachment 1).  The lead-in period is intended to stabilize HbA1c related to study 
effect (Gale et al. 2007) and verify insulin dose.  Subjects entering the trial at Visit 1 will 
continue their pre-study insulin regimen.  Subjects will also continue taking pre-study AHA
regimens and doses (per inclusion/exclusion criteria in Sections 8.1 and 8.2) and should not 
discontinue or change doses during the study, apart from specific instructions provided in 
Section 9.11.
7.1.6. Randomization 
Study subjects who have completed all screening procedures will be randomized at a 1:1 ratio to 
the two treatment arms (U-500R CSII or MDI) using interactive web-response system (IWRS) at
Visit 4 (Section 9.6).
A review of subjects’ understanding of daily glucose monitoring and emphasis on adherence, 
4-point and 7-point SMBG profile, use of glucose meters, hypo- and hyperglycemia, and 
completion of subjects’ diary will be conducted.
7.1.7. Treatment Period
At Visit 4 through Visit 17 or ET, subjects will be treated with U-500R based on titration 
algorithms.  The total treatment period for this study will be 26 weeks (2 week transition to 
U-500R MDI administered TID, 12 weeks titration and 12 weeks maintenance U-500R CSII or 
MDI).  
During the Treatment Period, Visits 8, 9, 11, 12, 14, and 16 will be telephone visits only and 
subjects will not be required to return to the study site.  At office visits (Visits 5, 6, 7, 10, 13, 15,


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and 17), clinical assessments and required procedures should occur as outlined in the Study 
Schedule (Attachment 1).  Adverse event and product complaint collection should occur at each 
office and telephone visit.
Apart from scheduled telephone visits, per the Study Schedule (Attachment 1), subjects will be 
instructed to call the study site office if a serious adverse event (SAE) or device-related event 
occurs, or for any concern at any time.  Specific reasons may include but are not limited to:  
hospital admission for any reason, persistent or severe hypoglycemia, recommendations for 
changes of medication from another provider, injection device or study glucose meter 
malfunction, questions about study treatment and dose changes, or scheduled surgical or dental 
procedures.
Subjects will continue taking noninsulin pre-study AHAs (per inclusion/exclusion criteria in 
Sections 8.1 and 8.2 and allowed concomitant therapies in Section 9.11) and should not 
discontinue or change doses during the study. 
Transition to U-500R MDI
7.1.7.1.
A 2-week transition period is included in the 26-week treatment period and will follow 
randomization. The transition period is intended to transition all subjects safely from their 
current insulin regimen to U-500R TID 40:30:30 (Section 9.5), and to titrate U-500R according 
to the TID algorithm (Section 9.8.2.1). The highest 24-hour TDD from the past 3 days will be 
utilized for calculation of the U-500R TID dose and the dose split into the ratio of 40:30:30. 
Those subjects already on U-500R TID at entry can continue their pre-entry U-500R TID 
proportions at the discretion of the investigator.  At Visit 6 through Visit 17 or ET, subjects will 
be treated with either U-500R CSII (Section 9.8.1.1) or U-500R MDI delivered TID 
(Section 9.8.2.1) based on titration algorithms and the treatment to which they are randomized.  
U-100 Insulin Syringe for Administering U-500R MDI
7.1.7.2.
All subjects will receive training on the appropriate use of U-100 insulin syringes for drawing up 
and administering correct doses of U-500R, including the conversion of insulin units of U-500R 
to the unit markings (one-fifth of actual volume) on the U-100 insulin syringe (Section 9.7.1).
CSII Pump Training
7.1.7.3.
Subjects assigned to U-500R CSII treatment will receive training on the OmniPod U-500 system
at 2 visits (Visit 5 [Week 1] and Visit 6 (Week 2).  At Visit 5, subjects will be introduced to the 
basics of pump usage (ie, basal rates, boluses, and filling Pods).  At Visit 6, subjects will receive 
hands-on training on the U-500 OmniPod System.  Additional subject training can be considered 
at the investigator’s discretion after consulting with Lilly clinical research physician 
(CRP)/clinical research scientist (CRS) (Section 9.7.2).
7.2.
Discussion of Design and Control
This is a randomized, open-label, parallel study comparing U-500R administered by CSII 
(OmniPod U-500 system) to U-500R administered by MDI in high-dose insulin-requiring
patients with T2DM who have inadequate glycemic control on existing high-dose non U-500R 
(>200 and ≤600 units per day) insulins (CSII or MDI), and/or U-500R insulin MDI with or 


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without other insulins/AHAs.  Delivery of U-500R insulin by CSII in currently marketed insulin 
pumps requires dose conversion to “U-100 pump units” (one-fifth of U-500R insulin dose per 
volume), which potentially could result in dosing confusion.  The OmniPod Insulin Management 
System for use with U-500 insulin (OmniPod U-500 system) software has been developed so that 
1 unit of insulin is delivered with every 4 pulses of the drive mechanism (for example, the 
OmniPod U-500 system would deliver 0.25 units per pulse compared to 0.05 units per pulse in 
the conventional U-100 OmniPod insulin pump).  The volume delivered in 1 pulse is the same 
for the U-100 and U-500 insulin pumps; thus due to higher concentration, fewer pulses are 
required by the U-500 pump to deliver the same insulin dose (4 pulses for 1-unit for U-500 
insulin versus 20 pulses for 1-unit for U-100 insulin).  
The majority (86%) of patients currently using U-500R have T2DM (Eby et al. 2013).  Because 
patients with type 1 diabetes mellitus (T1DM) constitute a small proportion of U-500R users and 
could have a different response to the algorithms and/or CSII delivery system, they are excluded 
from this study.
The total treatment period for this study will be 26 weeks.  The 26-week duration of treatment in 
this study was selected because it allows enough time for insulin therapy to be intensified, and 
permits sufficient time to show glycemic improvement and stabilization as measured by HbA1c, 
FPG, SMBG values, and TDD.  
After Visit 1 (screening), subjects who meet all of the inclusion criteria (Section 8.1) and none of 
the exclusion criteria (Section 8.2) will remain on their pre-study treatment for a 2 week lead-in 
period at Visit 2 (Week -2).  This lead-in period is intended to stabilize HbA1c related to study 
effect (Gale et al. 2007) and verify actual insulin dose.  Following the lead-in, subjects will be 
randomized at Visit 4 (Week 0) in an open-label fashion based on a 1:1 ratio to U-500R 
treatment by MDI or U-500R treatment by CSII.  A 2-week transition to U-500R by MDI 
administered TID, regardless of insulin or combination thereof at Visit 2 (Week -2) (Section 9.5) 
will begin after randomization (Visit 4 [Week 0]) utilizing the TID algorithm with weekly 
titrations (Section 9.8.2.1).  The transition period is to ensure safe transition to U-500R insulin 
monotherapy from entry insulin (as applicable).  After completion of the 2-week transition 
period, 24-weeks of U-500R delivered by MDI versus CSII will begin.
The primary and key secondary objectives will be assessed in subjects from Group A (without 
use of GLP-1 receptor agonists or SGLT2 inhibitors) and combined for the total study population 
Group A and Group B (those who use GLP-1 receptor agonists or SGLT2 inhibitors). 
The study will be performed open-label since blinding of the investigators, subjects, and study 
site personnel could not be accomplished given the differing modes of delivery of U-500R (CSII 
versus MDI). To minimize bias, aggregate review of summary data by the study team (that is, 
CRP/CRS overseeing the global conduct of the study, statisticians, and statistical analysts) will 
remain blinded until after the final database is locked (Section 9.10).


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8. Study Population
Individuals who do not meet the inclusion criteria for participation in this study (screen failure) 
may be re-screened once.  The interval between screen and re-screen should be at least 2 weeks.  
When re-screening is performed, the individual must sign a new informed consent form (ICF) 
and will be assigned a new identification number.
Entered subjects who meet all inclusion criteria ([1] through [7]) and are not excluded by 
exclusion criteria ([8] through [28]) will initiate the lead-in period at Visit 2 (Week -2).
Prior to randomization at Visit 4, all subjects will be re-confirmed for inclusion criteria [1], [2]
and [7] and exclusion criteria [18].
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
8.1.
Inclusion Criteria
Subjects are eligible to be included in the study only if they meet all of the following criteria:
Diagnosed with T2DM (World Health Organization [WHO] Classification of 
[1]
Diabetes [Attachment 3]).
For 2 weeks prior to Visit 1, TDD >200 but ≤600 units of non U-500R 
[2]
insulin/analog (basal; premixed; or basal/bolus by any injection device [MDI; pens 
and/or syringe/vial or CSII]) and/or U-500R by MDI with syringe and vial.  Type 
of insulin must be stable for ≥3 months at entry. 
o
If TDD of U-500R and other insulins are combined, then insulin other than 
U-500R not to exceed 25% of TDD.
HbA1c ≥7.5% and ≤12.0% as measured by the central laboratory at Visit 1.
[3]
Aged ≥18 to ≤85 years.
[4]
Body mass index ≥25 but ≤50 kg/m2.
[5]
Have a history of stable body weight (not varying by greater than 5% for at least 
[6]
3 months prior to study entry).
Concomitant AHA therapy may include metformin (MET), dipeptidyl peptidase-4
[7]
inhibitors (sitagliptin, saxagliptin, linagliptin, and alogliptin), and/or pioglitazone 
(doses ≤30 mg/day). Subjects’ AHA therapy must have been stable for ≥3 months
See exclusion criteria [18] and [19] for excluded medications.


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o
Approximately 64 to 96 subjects using GLP-1 receptor agonists
(albiglutide, dulaglutide, or liraglutide) or SGLT2 inhibitors (canagliflozin, 
dapagliflozin, empagliflozin) will be enrolled in Study Group B.  (GLP-1 
receptor agonists must have been stable for ≥4 months). After the 
enrollment of this group is completed, subjects using GLP-1 receptor
agonists or SGLT2 inhibitors will no longer be enrolled in the study.  
After Group A has been fully enrolled, Lilly may stop enrollment for 
Group B, even if the minimum recruitment goal for Group B has not been 
met.
8.2.
Exclusion Criteria
Subjects will be excluded from study if they meet any of the following criteria:
Diagnosed with T1DM or other types of diabetes apart from T2DM (WHO 
[8]
Classification of Diabetes Attachment 3; ADA 2014).
Have obvious clinical or radiographic signs or symptoms of liver disease (except 
[9]
nonalcoholic fatty liver disease), cirrhosis, acute or chronic hepatitis, or alanine 
aminotransferase (ALT/SGPT) and/or aspartate aminotransferase (AST/SGOT) 
levels ≥2.5X upper limit of normal (ULN), alkaline phosphatase ≥2X ULN or total 
bilirubin ≥ 2X ULN (with the exception of known Gilbert syndrome) as defined by 
central laboratory.
Have chronic kidney disease Stage 4 and higher (estimated glomerular filtration 
[10]
rate <30 mL/minute/1.73m2 as measured by Modification of Diet in Renal Disease
[MDRD] formula) (NKF 2007) or history of renal transplantation.
Have history of more than 1 episode of severe hypoglycemia requiring assistance 
[11]
of another person, resulting in coma, seizures, or disorientation within the 
6 months prior to Visit 1.
Have received U-500R insulin by CSII in the 3 months prior to Visit 1.
[12]
Have had a blood transfusion or severe blood loss within 3 months prior to Visit 1 
[13]
or have known hemoglobinopathy, hemolytic anemia, or sickle cell anemia that is 
known to interfere with HbA1c measurement.
Have known allergy to human insulin preparations or excipients contained in these 
[14]
products or prior history of suspected antibodies to human insulin.
Are taking chronic (lasting longer than 14 consecutive days) systemic 
[15]
glucocorticoid therapy (excluding topical, intra-articular, intraocular, and inhaled 
prescriptions), or have received any systemic glucocorticoid therapy within the 
4 weeks immediately prior to Visit 1.
Have an irregular sleep/wake cycle (for example, subjects who sleep during the 
[16]
day and work during the night), in the investigator’s opinion.
Intend to participate in an extended period of fasting during the study period (for 
[17]
religious or other purposes).


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Have used rosiglitazone, sulfonylurea/glinides, pramlintide, once-weekly or twice-
[18]
daily exenatide, or other AHAs not listed in the inclusion criteria in the 3 months 
prior to Visit 1, are taking AHA doses exceeding the respective product labels, or 
have a contraindication to current AHA usage per respective product labels (for 
example, for MET:  serum creatinine ≥1.4 mg/dL in women or ≥1.5 mg/dL in 
men).  
Have used any weight loss drugs (for example, prescription drugs; lorcaserin, 
[19]
orlistat, phentermine, phentermine/topiramate, naltrexone/bupropion, or over-the-
counter weight loss medications or herbal supplements) in the 3 months prior to 
Visit 1.
Have a history of bariatric surgery including Roux-en-Y gastric bypass surgery, 
[20]
gastric banding, and/or gastric sleeve.
Have a history of an active or untreated malignancy, or in remission from a 
[21]
clinically significant malignancy (other than basal cell or squamous cell skin 
cancer, in situ carcinomas of the cervix, colon, or prostate that is considered cured) 
during the last 5 years before Visit 1 (if a malignancy occurred >5 years ago, 
subject is eligible with documentation of disease-free state since treatment).  
Significant hearing loss and/or vision impairment deemed by the investigator to 
[22]
interfere with the safe use of OmniPod U-500 system.
Have cardiac disease with functional status that is New York Heart Association 
[23]
(NYHA) Class III or IV per New York Heart Association Cardiac Disease 
Functional Classification [Attachment 4].
Are women breastfeeding or pregnant, or intend to become pregnant during the 
[24]
course of the study; are men who intend to impregnate their partners; or are 
sexually active of procreation potential not actively practicing birth control by a 
method determined by the investigator to be medically acceptable.
Are investigator site personnel directly affiliated with this study and/or their 
[25]
immediate families.  Immediate family is defined as a spouse, parent, child, or 
sibling, whether biological or legally adopted.
Are Lilly or Insulet employees, or are employees of third party organizations 
[26]
(TPOs) involved in study that require exclusion of their employees.
Are currently enrolled in, or discontinued within the last 30 days, from a clinical 
[27]
trial involving an investigational product or nonapproved use of a drug or device
(other than the study treatment used in this study), or concurrently enrolled in any 
other type of medical research judged not to be scientifically or medically 
compatible with this study, and any subjects who have previously completed or 
withdrawn from this study.


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Are unwilling or unable to independently perform study procedures, such as 
[28]
monitoring SMBG levels, recording diary data, and/or administering medication 
via syringe or CSII as applicable, or have any illness or condition (including 
known drug or alcohol abuse or psychiatric disorder) within the 6 months prior to 
Visit 1, that precludes subject from following and completing the protocol 
according to the investigator’s judgment.  Subjects may not use a proxy to perform 
collection procedures, administer medication, or record data.
8.2.1. Rationale for Exclusion of Certain Study Candidates
Exclusion criterion [8] ensures that subjects with T1DM or other types of diabetes (except 
T2DM) will be excluded from the study due to the potentially different response to the 
algorithms and/or device.  Exclusion criteria [9], [10], [13], [14], [16], [17], [21], and [23]
represent clinical situations that may prevent subjects from completing the protocol, or may 
influence the efficacy or safety of study regimens, or are serious conditions that pose a risk for 
morbidity and mortality.  Exclusion criterion [11] addresses the potential difficulty of 
distinguishing if severe hypoglycemia is related to study drugs, or to counter-regulatory 
deficiencies, or to the natural history of the disease in subjects with recurring episodes.  
Exclusion criterion [12] relates to the potential of sub-optimal glycemic control and possible
changes in quality of life when changing from U-500R CSII therapy.  Exclusion criterion [15] 
relates to the negative effect of steroid therapy on the management of diabetes and need for 
altered dosing titration of insulin.  Exclusion criterion [18] excludes medications that are 
restricted by product label (exenatide), may cause HbA1c-lowering not attributable to the study 
insulin regimens or the combination of AHAs being studied, or which could confound 
interpretation of the results, or may influence the safety of study regimens.  Exclusion criteria 
[19], [20] and [27] prevent a situation in which positive or negative outcomes may not be clearly 
attributable to the regimens in this study.  Exclusion criterion [22] would prevent the subject 
from safely using the OmniPod U-500 system.  Exclusion criterion [24] ensures the safety of 
unborn or newborn children.  Exclusion criteria [25] and [26] reduce potential bias due to 
conflict of interest.  Exclusion criterion [28] excludes subjects who may be unwilling or unable 
to perform study procedures per protocol instructions for their safety.
8.3.
Discontinuations
8.3.1. Discontinuation of Inadvertently Enrolled Subjects
The criteria for enrollment must be followed explicitly.  If the investigator site identifies a 
subject who did not meet enrollment criteria and who was inadvertently enrolled, the sponsor 
must be notified.  If the sponsor identifies a subject who did not meet enrollment criteria and 
who was inadvertently enrolled, the investigator site will be notified.  A discussion must occur 
between the sponsor CRP/CRS and the investigator to determine whether the subject may 
continue in the study, with or without study treatment.  Inadvertently enrolled subjects may be 
maintained in the study and on study treatment when the Lilly CRP/CRS agrees with the 
investigator that it is medically appropriate for that subject.  The subject may not continue in the 
study with or without study treatment if the Lilly CRP/CRS does not agree with the 


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investigator’s determination it is medically appropriate for the subject to continue.  The 
investigator must obtain documented approval from the Lilly CRP/CRS to allow the 
inadvertently enrolled subject to continue in the study with or without study treatment.
8.3.2. Discontinuation of Study Treatment
Subjects will be discontinued from the study treatment in the following circumstances:

If Exclusion Criteria [9] (with the exception of the hepatic laboratory values; 
Section 10.4.4), [11] to [15], [18] to [21], [23] and [24] are observed or 
develop after study enrollment, the subject will be discontinued from the study 
treatment at the next visit or sooner. 

If in the investigators judgment, the subject is not at least 80% compliant with 
study treatment (i.e.; investigator recommended dose adjustments based on 
algorithms)

If the subject is off study medication for more than 7 consecutive days during 
the study treatment period.
In the event that the subject is discontinued from the study treatment, the investigator should 
encourage the subject to remain in the study for continued safety monitoring. 
8.3.3. Subject Discontinuation from the Study
If exclusion criterion [25] through [28] is observed or develops after entry or enrollment, 
the subject will be discontinued from the study at the next site visit or sooner in the event 
of a safety exclusion criterion.  
Subjects who discontinue the study early will have ET procedures performed as shown in the 
Study Schedule (Attachment 1).  For information as to how efficacy and safety analyses will be 
conducted for subjects who are discontinued from study treatment, see Sections 12.2.3 and
12.2.10, respectively.
The subject may be discontinued from the study if:

Enrollment in any other clinical trial involving an investigational product or enrollment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study.

Investigator decision
o
The investigator decides that the subject should be discontinued from the study
(this can be for safety reasons, such as for recurrent hypoglycemia, or it can be for 
any reason).
o
If the subject, 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 subject requests to be withdrawn from the study.


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
Sponsor decision
o
Lilly or its designee stops the study or stops the subject’s participation in the 
study for medical, safety, regulatory, or other reasons consistent with applicable 
laws, regulations, and good clinical practice (GCP).

Adverse event 
o
If the investigator decides that the subject should be withdrawn because of a SAE, 
treatment emergent adverse event (TEAE), or a clinically significant laboratory 
value, study treatment is to be discontinued and appropriate measures are to be 
taken.  Lilly or its designee is to be alerted immediately.  Refer to Safety 
Evaluations Section 10.4.
8.3.4. Subjects Lost to Follow-Up
A subject 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 subjects who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.
Site personnel, or an independent third party, will attempt to collect the vital status of the subject
within legal and ethical boundaries for all subjects randomized, including those who did not get 
study treatment.  Public sources may be searched for vital status information.  If vital status is 
determined, this will be documented and the subject will not be considered lost to follow up.
Lilly personnel will not be involved in any attempts to collect vital status information.
8.3.5. Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ethical review board 
(ERB) of the study site judges it necessary for medical, safety, regulatory, or other reasons 
consistent with applicable laws, regulations, and GCP.
8.3.6. Discontinuation of the Study
The study will be discontinued if Lilly judges it necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP.


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9. Treatment
9.1.
Treatments Administered
This study involves a comparison of U-500R administered by CSII with U-500R administered by 
MDI.  Table IBHD.9.1 shows the treatment regimens.
Table IBHD.9.1.
Treatment Regimens
Regimen
Dose
U-500R CSII
Per titration algorithm
(continuous infusion, injectable solution)
U-500R MDI
Per titration algorithm
(TID, injectable solution)
Abbreviations:  CSII = continuous subcutaneous insulin infusion; MDI = multiple daily injections; TID = three 
times daily.
The investigator or his/her designee is responsible for the following:

explaining the correct use of the investigational agent(s) to the subject/site 
personnel,

verifying that subject clearly understands instructions and is able to demonstrate 
understanding, maintaining accurate records of study treatment dispensing and 
collection, and returning all unused medication or devices to Lilly or its designee 
at the end of the study.
Note:  In some cases, sites may destroy the material if, during the investigator site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical trial materials.  In all other cases, the site has to return used or 
unused material to Lilly or designee.
Subjects will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with study treatment or drug delivery system so that the situation can be 
assessed.
9.2.
Materials and Supplies
Subjects should continue taking their noninsulin pre-study AHA doses throughout the study, as 
applicable.  Pre-study AHAs must be used as described in their respective product labeling.  
Supplies and appropriate instructions for use will be provided for both treatment groups 
beginning at screening Visit 1 (Week -3). Study drug and additional supplies will be provided at 
Visits 4, 5, and as needed thereafter per the Study Schedule (Attachment 1).
Subjects will be assigned to treatment arm at randomization Visit 4 (Week 0).  Appropriate pump 
training will be provided for the CSII group (Section 9.7.2).  The OmniPod U-500 system


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supplies for infusion including PDM and Pod with fill syringe will be provided at Visit 6 
(Week -2) and as needed thereafter per the study schedule.  
U-500R will be provided in 20-mL vials (10,000 U) for use by CSII or MDI.  Unopened U-500R 
vials or U-500R vials not in-use should be stored in a refrigerator (2° to 8°C [36° to 46°F]), but 
not in the freezer. Once opened, the U-500R vial can be kept unrefrigerated as long as it is kept 
as cool as possible (below 30°C [86°F]) and away from heat and light.  In-use vials must be used 
within 40 days or be discarded, even if they still contain U-500R.  
The respective labeling information will be provided with the insulin pump and supplies, the 
disposable syringes, and the study drug as applicable.  In addition, a commercially available BG 
meter will be provided with necessary supplies and instructions at Visit 1 (Week -3).  Clinical 
trial materials will be labeled according to the respective country’s regulatory requirements.
Table IBHD.9.2.
Study Devices
Regimen
Device
Device Details
U-500R CSII
OmniPod U-500 systema
CSII
U-500R MDI
BD U-100 insulin syringe and needle
0.5 mL syringe for ≤250-U dose; or
1.0 mL syringe for >250-U dose; 
31 gauge; 6 mm length needle
Abbreviations:  BD = Becton Dickinson; CSII = continuous subcutaneous insulin infusion; MDI = multiple daily 
injections; U = unit.
a
The OmniPod U-500 system is an investigational device.
9.3.
Method of Assignment to Treatment
Subjects will continue on their pre-study insulin regimens until Visit 4 (Week 0). After re-
confirmation of eligibility, subjects who meet specific criteria (Section 8) for enrollment will be 
randomized at Visit 4 (Week 0) to open-label treatment with U-500R administered by one of two 
treatment regimens:  MDI or CSII. However, subjects randomized to CSII will not initiate U-
500R administered by CSII until transition to U-500R is complete (Section 9.7). Assignment to 
treatment arms will be determined by a computer-generated random sequence using an IWRS.  
9.4.
Rationale for Selection of Doses in the Study
Protocol IBHD dosing transition to U-500R MDI and titration regimens for the CSII and MDI
treatment groups are guided by initial insulin TDD (based on the highest TDD recorded in the 
3 days before Visit 4), screening HbA1c (Visit 1), subsequent glucose monitoring, literature 
expert reviews (Lane 2006; Lane et al. 2009; Hirsch 2010, Lane et al. 2010; Segal et al. 2010; 
Reutrakul et al. 2012), efficacy and safety results from one Phase 4 clinical study 
(B5K-US-IBHC [Hood et al, 2015]), results from simulations performed using a systems 
physiology model of diabetes (Entelos PhysioLab® Modeler) based on data from previous 
pharmacodynamics/pharmacokinetics studies (de la Peña et al. 2011) of U-500R and U-100 
Humulin regular insulin) and on expert protocol consultant advice.
Fasting and bolus for CSII and MDI therapy plasma-equivalent glucose target ranges are 80 to 
140 mg/dL. Recommended administration of U-500R bolus doses, within approximately


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30 minutes before meals by CSII or MDI dosing, is based on label advice and recent 
pharmacodynamics/pharmacokinetics study results in obese, healthy subjects that demonstrate 
both prandial and basal activity of U-500R (de la Peña et al. 2011).  Administration of U-500R 
bolus doses 15 minutes before meals will be assessed in a subset of subjects participating in the 
continuous glucose monitoring (CGM) addendum to demonstrate glycemic impact.  If the shorter 
bolus time period is found to be equally efficacious, there may be a potential benefit on
adherence.
9.5.
Lead-in Period 
The 2-week lead-in period of the trial includes the interval between Visit 2 and Visit 4.  
Subjects’ current diet (particularly caloric intake) and exercise levels will be reviewed during 
lead-in and at subsequent visits throughout the study, as needed, to assess adherence to the 
lifestyle advice discussed at Visit 2 (Week -2) as part of subject training and education.  Subjects 
should be encouraged to eat 3 meals a day plus a snack before bedtime (21 grams CHO Extend 
Bar®, Extend Nutrition, St. Louis, MO or equivalent) to support U-500R dosing per CSII or MDI 
during the study.  
Subjects will continue taking prestudy AHAs and doses (per inclusion/exclusion criteria in 
Sections 8.1 and 8.2 and allowed concomitant therapies in Section 9.11) and should not 
discontinue or change doses during the study. Refer to Study Schedule for details of events 
(Attachment 1).
9.6.
Randomization
At Visit 4 (Week 0), if subjects have been re-confirmed for trial eligibility (Section 8), they will 
be randomized at a 1:1 ratio to the two treatment arms (CSII or MDI) using IWRS (Section 9.3).  
Subjects will be stratified by entry HbA1c ≥8.5% or <8.5%, nonusers versus users of GLP-1
receptor agonists or SGLT2 inhibitors, and U-500R at entry versus other insulins.
Subjects in the study will continue taking noninsulin pre-study AHA regimens (per 
inclusion/exclusion criteria in Sections 8.1and 8.2) and allowed concomitant therapies. Subjects 
should not discontinue or change doses during the study (Section 9.11).  Subjects will transition 
to U-500R MDI for 2 weeks and then initiate 24 weeks of CSII or MDI treatment (Section 9.7).
Subjects who discontinue prior to randomization will be considered screen failures.  No ET 
activities will be applicable.
9.7.
Transition to U-500R MDI 
All subjects will administer U-500R MDI delivered TID (40:30:30 unless otherwise noted) 
during the transition period (Weeks 0-2).  Transition to U-500R MDI will follow the criteria 
below in Table IBHD.9.3.  Subjects will have their insulin adjusted weekly by the investigator 
using the algorithm from Section 9.8.2.1.


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Table IBHD.9.3. Transition from entry insulin to U-500R MDI
Insulin Regimen (Screening)
HbA1c
(Screening)
Mean SMBG
(Screening to Week 0)
Conversion from Screening 
TDD to U-500R TID Dose
Insulin with or without U-500R
>8%
>183 mg/dL
1:1
Insulin with or without U-500R
>8%
≤183 mg/dL
Reduce TDD by 20%
Insulin with or without U-500R
≤8%
--
Reduce TDD by 20%
U-500R only
--
--
1:1
Abbreviations: HbA1c = hemogloblin A1c; SMBG=self-monitored blood glucose; MDI = multiple daily injections; 
TID= three times daily; TDD=total daily dose.
Subjects treated with U-100 and/or other concentrated insulin (with or without U-500R) at 
screening Visit 1 (Week -3) with HbA1c levels >8% and a mean SMBG (recorded prior to 
Visit 4 [Week 0]) value >183 mg/dL (corresponding to HbA1c value of >8.0% [estimated 
average glucose; Nathan et al. 2008]) at Visit 4 should be transitioned to U-500R using 1:1 
dosage conversion.  
Subjects treated with U-100 and/or other concentrated insulin (with or without U-500R) at 
screening Visit 1 (Week -3) with HbA1c levels >8% and a mean SMBG (recorded prior to 
Visit 4 [Week 0]) value ≤183 mg/dL (corresponding to HbA1c value of ≤8.0%) at Visit 4, should 
transition by reducing their U-500R TDD by 20%.
Subjects treated with U-100 and/or other concentrated insulin (with or without U-500R) at 
screening Visit 1 (Week -3) with HbA1c ≤8% should transition to U-500R at Visit 4 (Week 0)
by reducing their U-500R TDD by 20%, regardless of SMBG value.
Subjects treated with U-500R insulin only at screening Visit 1 (Week -3) should transition to 
U-500R TID with proportion 40:30:30 using a 1:1 dosage conversion at Visit 4 (Week 0), 
regardless of HbA1c and/or SMBG.  Those subjects already on U-500R TID at entry can 
continue their pre-entry U-500R TID proportions at the discretion of the investigator. 
Investigators may also deviate from the proportion, if deemed necessary, for the safety or 
well-being of the subject (that is, due to a safety concern).  Any major deviation from the 
recommended proportion must be discussed with Lilly CRP/CRS.
9.7.1. Dosing Using U-100 Insulin Syringes
The units marked on a U-100 insulin syringe do not accurately reflect the unit dose of U-500R 
insulin because U-500R is 5 times more concentrated than U-100 insulin, and thus only one-fifth
of the volume is needed to give an equivalent dose to U-100 insulin.  Site personnel should 
instruct subjects on the dose conversion of calculated U-500R to the U-100 insulin syringe unit 
markings (examples below and conversion charts are also provided in the U-500R package insert
and Subject Information on U-500R).
The U-100 insulin 0.5 mL syringes should be used for administration for all U-500R doses 
≤250 U.  All U-500R doses >250 units should be administered using 1.0 mL U-100 insulin 
syringes. 


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For example:

155 units of U-500R has a volume equivalent to 31 units markings on a 0.5 mL 
U-100 insulin syringe (155 divided by 5=31).

100 units of U-500R has a volume equivalent to 20 units markings on a 0.5 mL 
U-100 insulin syringe (100 divided by 5=20).

300 units of U-500R has a volume equivalent to 60 units markings on a 1.0 mL 
U-100 insulin syringe (300 divided by 5=60).
9.7.2. CSII Training 
Subjects randomized to the CSII treatment arm will be trained on the use of the OmniPod U-500 
system after randomization at Visits 5 and 6 (Weeks 1 and 2). CSII training will include but not 
be limited to pre-pump training regarding basal rates and bolus dosing, initial PDM and Pod 
setup, setting basal rates (including temporary basal rate) and boluses (CHO counting, fixed 
dosages or meal sizes), and responding to hazard alarms. The OmniPod U-500 system basics of 
pump usage (ie, basal rates, boluses, and filling Pods) will be introduced to subjects at Visit 5 
(Week 1) and the hands on training will occur at Visit 6 (Week 2) (Section 7.1.7.3.).
9.7.3. Intensified Dose Titration Period
The 12-week intensified dose titration period of the trial will extend from Visit 6 (Week 2) to 
Visit 13 (Week 14) and will include investigator-driven dosage titration according to the 
titration algorithms (Sections 9.8.1.1 and 9.8.2.1) at weekly intervals starting on Visit 6 through 
8 (Weeks 2 through 4) and biweekly starting at Visit 9 through 13 (Weeks 6 through 14) 
(Attachment 1).  Additional dosage titrations per algorithms may be made more frequently if 
needed per investigator’s judgment during this period.
9.7.4. Maintenance Dose Titration Period
The 12-week maintenance dose titration period of the trial will extend from Visit 13 (Week 14) 
to the final visit, Visit 17 (Week 26) or ET visit.  Dose titrations by the investigator will be 
completed in an identical manner to those during the intensified dose titration period 
(Sections 9.8.1.1 and 9.8.2.1) but will be at 3-week intervals (Attachment 1).  Additional dosage 
titrations per algorithms may also be made more frequently if needed per investigator’s judgment 
during this period.
9.8.
Treatment Periods
9.8.1. CSII
The OmniPod U-500 system is designed to deliver U-500 insulin in insulin units without 
converting to U-100 insulin ‘pump units’ (Section 7.2).  Beginning at Visit 6 (Week 2), all CSII 
subjects will be instructed to change their OmniPod U-500 system Pod every 2 to 3 days 
(depending on TDD) during the treatment period.  Subjects will be instructed to inspect Pod 
cannula insertion sites for signs of redness, swelling, or leakage and to respond to any CSII 
alarms (Bolderman et al. 2013).


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For subjects randomized to CSII: 

The OmniPod U-500 system Pod should be filled in the clinic with U-500R 
during Visit 6.

The highest 24-hour TDD from the past 3 days will be utilized for calculation of 
the CSII doses.  

50% of the TDD will be basal split into 2 rates:
o
2100 to 0600 hours 10% basal rate reduction  
o
0600 to 2100 hours for the calculated basal rate 

50% of the TDD will be bolus split into the following ratio:
o
40:30:30 (Section 9.8.1.3) for fixed bolus doses.
o
Suggested initial setting for insulin:  CHO ratio should be programmed between
1:3 and 1:5.
CSII Treatment Group Algorithms
9.8.1.1.
Subjects in the CSII group will have their basal rates (Table IBHD.9.4) and bolus doses 
(Table IBHD.9.5) adjusted at each study visit (office and telephone) by the investigator
according to the CSII titration algorithms.  Investigators may deviate from the algorithms, if 
deemed necessary, for the safety or well-being of the subject (that is, due to illness or other 
safety concern).  Any major deviation from the algorithm must be discussed with Lilly.  The 
CSII bolus titration scheme (Table IBHD.9.5) will be divided into 2 dosing bins:  TDD 
<400 units and TDD ≥400 units.  Subjects will have their U-500R adjusted according to the TDD 
at the time of adjustment.
Subjects taking <400 units TDD at Visit 6 (Week 2) should use a 1:10 correction factor with a 
target of 100 mg/dL starting at 25 mg/dL above target for all mealtime boluses.  Subjects taking 
≥400 units TDD at Visit 6 (Week 2) should use a 1:5 correction factor with a target of 
100 mg/dL starting at 25 mg/dL above target for all mealtime boluses.  If, in the opinion of the 
investigator, the subject would benefit from a different correction factor, the investigator should 
discuss this with the Sponsor.  
Note:  Subjects should be instructed to hold their U-500R bolus dose if a meal is skipped.


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Table IBHD.9.4.
Basal Titration Scheme for CSII
Median SMBG
(mg/dL)
Titration of Corresponding
Basal Rate for All Dose Rangesa
<80
-5%
80-140
0
141-190
+5%
191-230
+10%
>230
+15%
3-day median SMBG measure
Dose adjusted
Pre-Morning Meal, 0300 hoursb
Overnight infusion
Pre-Evening Meal
Daytime infusion
Abbreviations:  CSII = continuous subcutaneous insulin infusion; SMBG = self-monitored blood glucose.
a
Any plasma glucose (SMBG or lab) measurement <50 mg/dL or ≤70 mg/dL at 0300 hours during the week, 
investigator should reduce corresponding basal dose by 10-20% as soon as it occurs or notification of the reading 
occurs. 
b
If subject acquires more than the 2 initial basal rates, adjusted basal doses will continue to be based on the pre-
morning meal and 0300 hours, and pre-evening meal SMBG.
Table IBHD.9.5.
Bolus Titration Scheme for CSII
Median SMBGa,b,c
(mg/dL)
Dosing Bin for TDD <400 U 
Titration (U)
Dosing Bin for TDD ≥400 U 
Titration (U)
<80
-5
-10
80-140
0
0
141-190
+2.5
+5
191-230
+5
+10
>230
+7.5
+15
3 Day Median SMBGd
Adjusted Dose
Pre-midday meal
Pre-morning meal
Pre-evening meal
Pre-midday meal
Bedtimee
Pre-evening meal
Abbreviations:  CSII = continuous subcutaneous insulin infusion; CHO = carbohydrate; SMBG = self-monitored 
blood glucose; TDD = total daily dose; U = units.
a
Each of the 3 bolus doses is adjusted independently based on the median of 3 corresponding SMBG values 
(preferably most recent 3 days).
b
Any plasma glucose (SMBG or lab) measurement <50 mg/dL, investigator should reduce corresponding bolus 
dose by 10-20% as soon as it occurs or notification of the reading occurs. 
c
If the algorithm adjustment leads to overlapping basal and bolus adjustments, the investigator has the discretion 
to reduce the bolus adjustment for safety.
d
If the subject is using CHO meal sizes or CHO counting for boluses and their SMBGs are not in the target range 
for the corresponding meal at the visits (telephone or office) for algorithm titrations, then the principal 
investigator should adjust (increase or decrease) the insulin CHO ratio by approximately 10% to 15%.
e
In the event that nocturnal hypoglycemia occurs requiring a reduction in the overnight basal rate, the investigator 
may reduce the pre-dinner dose even if the bedtime SMBG median is in the target range of 80-140 mg/dL.
Note:  All CSII basal and bolus doses will be rounded to the nearest 0.25 units.


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CSII Basal Rate
9.8.1.2.
The overnight basal rate from 2100 to 0600 hours is adjusted based on the median fasting pre-
breakfast SMBG from the past 3 values (most recent 3 days recommended) and the basal rate 
from 0600 to 2100 hours is adjusted based on pre-dinner SMBG (most recent 3 days 
recommended).  The principal investigator may increase the number of basal rates up to 4 basal 
rates during the trial, if in the investigator’s opinion the subject needs further individualization of 
basal rates based on blood sugar trends, such as nocturnal hypoglycemia or the dawn 
phenomenon indicating a need for the change(s).
9.8.1.2.1. Adding a Basal Rate for Nocturnal Hypoglycemia
If a subject has persistent nocturnal hypoglycemia, an additional basal rate reduction can be 
added.  For example, if a subject has persistent nocturnal hypoglycemia between 2100 hours and 
midnight after the initial 10% reduction in the basal rate between 2100 and 0600 hours, an 
additional basal rate reduction can be added in the time period from 2000 hours to midnight (that 
is, 20% reduction between 2000 hours and midnight with 10% reduction continuing between 
midnight and 0600 hours).  Alternatively, the investigator may decide to suspend the basal rate 
overnight.
9.8.1.2.2. Adding a Basal Rate for Dawn Phenomenon
If a subject has significant dawn phenomenon leading to persistent hyperglycemia, an additional 
basal rate increase can be added based on investigator discretion.  For example, if a subject has 
persistent hyperglycemia from 0600 to 1000 hours, an additional basal rate increase of 10% can 
be added from 0600 to 1000 hours.
CSII Bolus Dosing
9.8.1.3.
Subjects should bolus 30 minutes prior to meals except for a subset of the subjects in the CGM 
addendum who will be assigned to bolus 15 minutes prior to meals.  
Subjects should be encouraged to eat a bedtime snack (Extend Bar 21 gm CHO or equivalent) 
without administering a bolus for the snack.  Note:  If the subject has an allergy or intolerance to 
the Extend Bar, then the subject may substitute a bedtime snack between 15 and 25 grams CHO.
9.8.1.3.1. CSII Bolus Settings
The investigator has the option of prescribing 3 bolus options. Table IBHD.9.5 should be 
followed for dosage adjustments. The U500 OmniPod system bolus calculator should be set to 
one of the following bolus options (according to principal investigator discretion):

Use fixed bolus regimen based on previous mealtime insulin requirements.  Bolus 
dose will be imputed manually (that is, the user would enter their BG value and 
answer ‘use for bolus calcs?’ with ‘yes’; answer ‘are you going to eat now’ with
‘no’ and then override the suggested bolus based on the fixed bolus dose size). 

A mealtime bolus utilizing CHO meal sizes. Adjust dose based on a preset CHO meal 
size (for example:  small = 30 gram CHO; medium = 60 gram CHO; and large = 90 gram 
CHO).

A mealtime bolus for the corresponding meal if the subject is using CHO counting.


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Note: Subjects should be encouraged to maintain the bolus option throughout the study.
All subjects should have the insulin-on-board (IOB) setting programmed at 6 hours except for a 
subset of the subjects participating in the CGM Addendum who will have the IOB set at 8 hours. 
The clinical protocol addendum will assess alternative IOB based on U-500R time action profile.
9.8.2. MDI
For MDI subjects, initial doses of U-500R will be determined according to Section 9.7; dosage 
titrations per bolus titration schedule (Table IBHD.9.6) will occur at the same visits (telephone or 
office) as for CSII subjects.  
MDI subjects should also bolus U-500R 30 minutes prior to meals except for a subset of 
the subjects participating in the CGM addendum who will bolus 15 minutes prior to 
meals.  
Subjects should be instructed to eat a bedtime snack (Extend Bar 21 gm CHO or 
equivalent).
Subjects should be instructed to use a U-100 insulin syringe to draw up the U-500R dose 
(Section 9.7.1).  All bolus doses will be rounded to the nearest 5 units.
MDI Treatment Group Algorithms
9.8.2.1.
Subjects in the MDI group will have their insulin dosages adjusted at each study visit (office and 
telephone) by the investigator according to the TID titration algorithm (Table IBHD.9.6).  The 
MDI bolus titration scheme will be divided into 2 dosing bins; TDD <400 units and TDD 
≥400 units.  Subjects will have their U-500R adjusted according to the TDD at the time of 
adjustment.
Note:  Subjects should be instructed to reduce their U-500R dose by 50% if a meal is skipped.


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Table IBHD.9.6.
Bolus Titration Scheme for MDI Delivered TID
Median SMBGa,b
(mg/dL)
Dosing Bin for TDD <400 U Titration (U)
Dosing Bin for TDD ≥400 U Titration
(U)
<80
-10
-20
80-140
0
0
141-190
+5
+10
191-230
+10
+20
>230
+15
+30
3 Day Median SMBG
Dose Adjusted
Pre-midday meal
Pre-morning meal
Pre-evening meal
Pre-midday meal
Pre-morning meal, 0300 hours
Pre-evening meal
Abbreviations:  MDI = multiple daily injections; SMBG = self-monitored blood glucose; TDD = total daily dose; 
TID = three times daily; U = units.
a
Each of the 3 bolus doses are adjusted independently based on the median of 3 corresponding SMBG values 
(preferably most recent 3 days).
b
Any plasma glucose (SMBG or lab) measurement below 50 mg/dL or ≤70 mg/dL at 0300 hours, investigator 
should reduce corresponding bolus dose by 10%-20% as soon as it occurs or notification of the reading occurs.
9.9.
Special Treatment Considerations 
9.9.1. Rescue Therapy
Rescue therapy should be initiated in the following circumstances:

If median of 3 fasting SMBG >300 mg/dL over a 3-day period is unexplained from 
previous week, starting at Visit 10 through Visit 13 (Weeks 8 through 14).

If HbA1c value at Visit 13 (Week 14) is ≥10.0% and decreased by <0.4% compared to 
Visit 10 (Week 8) HbA1c.

If HbA1c value at Visit 15 (Week 20) is ≥10.0% and decreased by <0.4% compared to 
Visit 13 (Week 14) HbA1c.
Subjects receiving U-500R MDI will be rescued by the addition of a bedtime U-500R dose 
(increase injections to 4-times daily therapy).  A suggested starting dose for the rescue dose 
would be 10% of TDD, but this may be modified based on investigator judgment.
Subjects receiving CSII U-500R will be rescued by the addition of a bedtime U-500R dose 
delivered by CSII.  A suggested starting dose for the rescue dose would be 5% to 10% of TDD, 
but this may be modified based on investigator judgment. 
Subjects should be instructed to record their 0300-hour BG within 24 hours after adding a rescue 
dose and subjects should also be encouraged to record their 0300-hour BG 2 to 3 times the first 
2 weeks after adding a rescue dose.
Every attempt should be made to keep these subjects in the study.  Change in treatment regimen 
should be recorded in the eCRF.  


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9.9.2. Continued Access to Study Treatment
The U-500R insulin used in this study is commercially available in the US and is therefore 
available for subjects after the conclusion of this study.
9.10. Blinding
This is an open-label study.  Treatment blinding of the investigators, subjects, and study site 
personnel is not feasible due to differences in the appearance and functionality of the delivery 
devices.  To minimize bias, aggregate review of summary data by the study team (that is, 
CRP/CRS overseeing the global conduct of the study, statisticians, and statistical analysts) will 
remain blinded until after the final database is locked.  Unblinding of the subject study treatment 
assignment may occur in the course of individual subject consultation between the investigator 
and the study team (principally between the investigator and the CRP/CRS) or during review of 
SAEs.  No systematic unblinding of study treatment assignments will be solicited by the study 
team.  
9.11. Concomitant Therapy
All concomitant therapies that are part of routine care are allowed and may be used during the 
study with the exception of those specifically outlined in Sections 8.1 and 8.2.  Subjects who 
take any excluded concomitant therapy will be discontinued from the study treatment at the next 
visit or sooner.  In emergency/urgent situations, subjects may cease taking study medication for 
7 consecutive days and may be treated instead with nonstudy insulin during that time.  If a 
subject takes nonstudy insulin for more than 7 consecutive days, then discontinuation criteria 
apply (Section 8.3.2).
9.11.1. Concomitant Medications Including Antihyperglycemic Agents
Subjects will be allowed to continue to use any concomitant medications with the exception of
those listed in the exclusion criteria.  A list of selected concomitant medications that have an 
effect on glucose metabolism, and their conditions for use, is presented in Table IBHD.9.7.  The 
subject should be encouraged to report any new concomitant medications after initiating the 
medication.  Please check with the study team if you have any concerns or questions about a 
medication the subject is taking.  


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Table IBHD.9.7.
Concomitant Medications and Conditions for Use
Drug Class
As Needed
Chronic Use
Conditions for Use
Metformin
N
Y
DPP-4 inhibitors
N
Y
Pioglitazone
N
Y
Dosages ≤30 mg daily
SGLT2 inhibitors
N
Ya
Rosiglitazone
N
N
Alpha glucosidase inhibitors
N
N
Bromocriptine
N
N
Sulfonylureas/glinides
N
N
GLP-1 receptor agonists (except exenatide)
N
Ya
Pramlintide
N
N
Niacinb
N
Y/N
Bile acid resin bindersb
N
Y/N
Systemic glucocorticoids (excluding ocular topical, 
other topical, or inhaled preparations)
Y if ≤2 weeks 
N
Abbreviations:  DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1; N = No; SGLT2 = Sodium-
glucose transporter protein; Y = Yes.
a
Allowed for study population Group B only.
b
Low doses are acceptable.
9.12. Treatment Compliance
Subject compliance with study medication will be assessed at each applicable study visit.  
Compliance will be based on adherence to the Study Schedule (Attachment 1), compliance with 
appropriate assigned injection method (CSII versus MDI), completion of the subject’s diary, and 
any other parameters the investigator deems necessary.  Compliance will be assessed by direct 
questioning and returned study materials.  
Subjects who are deemed significantly noncompliant will be discontinued from the study
treatment.  A subject will be considered significantly noncompliant if he or she:

misses more than 7 consecutive days of study medication during the study. 

is judged by the investigator to have intentionally or repeatedly taken more than the 
prescribed amount of medication that may cause patient safety concerns. 

is not at least 80% compliant with study treatment (ie, PI recommended doses 
adjustments based on algorithms).


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10.
Efficacy, Patient Reported Outcomes, Safety 
Evaluations, Sample Collection and Testing, and 
Appropriateness of Measurements
Study procedures and their timing (including tolerance limits for timing) are summarized in the 
Study Schedule (Attachment 1).
10.1. Efficacy Measures 
10.1.1. Primary Efficacy Measure 
The primary efficacy measure for this study is change in HbA1c from baseline (last nonmissing 
value at or prior to the treatment starting Visit 4) to the 26-week value.
10.1.2. Secondary Efficacy Measures
The following secondary efficacy measures will be collected at the times shown in the Study 
Schedule (Attachment 1).  The secondary objectives are summarized in Section 6.2.
Fasting Plasma Glucose
10.1.2.1.
Change in mean FPG levels will be compared between treatments.
7-point SMBG
10.1.2.2.
Mean plasma glucose will be analyzed for each individual time point using the 7-point SMBG.  
The 7-point SMBG is a subject self-administered plasma glucose test that utilizes measurements 
at specific time points over a 24-hour period.  The timing of the 7-point SMBG measurement is 
described in Section 7.1.3.2.
Total Daily Insulin Dose
10.1.2.3.
Change in TDD (unit and unit/kg) as basal/bolus for the CSII arm and by bolus dosing for the 
MDI arm from baseline to 26-week value will be calculated and analyzed.
10.2. Patient Reported Outcomes
The self-reported questionnaires will be administered, according to the Study Schedule 
(Attachment 1).  
10.2.1. TRIM-D and TRIM-D Device
The TRIM-D and TRIM-DD scales are valid and reliable patient-reported outcome (PRO) 
measures, which capture the full range of impact of diabetes treatment on subject functioning 
and well-being across T1DM and T2DM subjects, as well as across all currently available 
delivery systems and treatments (oral agents, GLP-1 receptor agonist pens, inhaled- or pump-
delivered insulin, and insulin delivered with syringe/pens) (Brod et al. 2009).  The TRIM-D 
consists of 28 items, and the TRIM-DD consists of 8 items.  In both of these PROs, items are 
measured on a 5-point scale, where the higher score indicates a better health state.  In addition to 
an overall score, the TRIM-D items make up the 5 domains of impact:  Treatment Burden 
(6 items), Daily Life (5 items), Diabetes Management (5 items), Compliance (4 items), and 


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Psychological Health (8 items).  In addition to an overall score, the TRIM-DD items include the 
domain’s device function (5 items) and bother of device (3 items).
The TRIM-D and TRIM-DD will be administered at Visit 4 (Week 0, prior to randomization), at 
Visit 13 (Week 14) and at Visit 17 (Week 26) or ET if subjects do not complete the full 26 weeks 
of the study.
10.3. OmniPod U-500 System Exit Questionnaire
An OmniPod U-500 system exit questionnaire will be administered to subjects in the CSII group 
at Visit 17 (Week 26) or at ET if subjects terminate.
10.4. Safety Evaluations
Investigators are responsible for monitoring the safety of subjects who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the subject.
The investigator is responsible for the appropriate medical care of subjects during the study.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious, considered related to the study treatment or the study, related to the study 
device (U-500 OmniPod system), or that caused the subject to discontinue before completing the 
study.  The subject should be followed until the event is resolved or explained.  Frequency of 
follow-up evaluation is left to the discretion of the investigator.
Safety evaluations include the following:

Frequency and incidence of AEs and TEAEs

Incidence/rate of hypoglycemia (documented [documented symptomatic, 
asymptomatic, and unspecified], severe, and nocturnal)

Body weight

Vital signs

Study treatment exposure

Clinical laboratory tests abnormalities

Product complaints
10.4.1. Adverse Events
Lilly has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent.  
Lack of drug effect is not an AE in clinical studies because the purpose of the clinical study is to 
establish drug effect.


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Cases of pregnancy that occur during maternal or paternal exposures to study treatment or drug 
delivery system should be reported.  Data on fetal outcome and breastfeeding are collected for 
regulatory reporting and drug safety evaluation.
Study site personnel will record the occurrence and nature of each subject’s preexisting 
conditions, including clinically significant signs and symptoms of the disease under treatment in 
the study.
After the ICF is signed, site personnel will record any change in the condition(s) and the 
occurrence and nature of any AEs.  All AEs related to protocol procedures are reported to Lilly 
or designee.
In addition, all AEs occurring after the subject receives the first dose of study treatment must be 
reported to Lilly or its designee via the eCRF.
Any clinically significant findings (vital sign measurements, laboratory measures, and treatment 
exposure) that result in a diagnosis should be reported to Lilly or its designee.
Investigators will be instructed to report to Lilly or its designee their assessment of the potential 
relatedness of each AE to protocol procedure, study treatment, and/or drug delivery system via 
eCRF.  
The investigator decides whether he or she interprets the observed AEs as either related to 
disease, to the study medication, study procedure, study device, or other concomitant treatment 
or pathologies.  To assess the relationship of the AE to study treatment, the following 
terminologies are defined:
Related:  a direct cause and effect relationship between the study treatment and the AE is 
likely
Possibly related:  a cause and effect relationship between the study treatment and the AE 
has not been demonstrated at this time and is not probable, but is also not impossible
Unrelated:  without question, the AE is definitely not associated with the study 
treatment.
As per Lilly’s standard operating procedures, all “related” and “possibly related” AEs and SAEs 
will be defined as related to study treatment.
If a subject’s dosage is reduced, or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to Lilly or its designee via eCRF the circumstances and data 
leading to any such dosage reduction or discontinuation of treatment.
Serious Adverse Events
10.4.1.1.
Serious adverse event collection begins after the subject has signed informed consent and has
received study treatment.  If a subject experiences an SAE after signing informed consent, but 
prior to receiving study treatment, the event will NOT be reported as serious unless the 
investigator feels the event may have been caused by a protocol procedure.


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Planned surgeries should not be reported as SAEs unless the underlying medical condition has 
worsened during the course of the study.
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.  
An SAE is any AE from this study that results in one of the following outcomes:

Death 

Severe hypoglycemia (as defined in Section 10.4.2)

Initial or prolonged inpatient hospitalization

A life-threatening experience (that is, immediate risk of dying)

Persistent or significant disability/incapacity

Congenital anomaly/birth defect

Considered significant by the investigator for any other reason
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse drug events when, based upon appropriate 
medical judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.
When a condition related to the U-500 OmniPod system necessitates medical or surgical 
intervention to preclude either permanent impairment of a body function or permanent damage to 
a body structure, the serious outcome of “required intervention” will be assigned.
Serious adverse events occurring up to and including the subject’s last study visit will be 
collected, regardless of the investigator’s opinion of causation, in the clinical data collection 
database and the pharmacovigilance system at the sponsor.
The investigator does not need to actively monitor subjects for AEs once the trial has ended, 
unless provided otherwise in the protocol.  However, if an investigator becomes aware of SAEs
occurring to a subject after the subject’s participation in the trial has ended, the investigator 
should report the SAEs to the Sponsor, regardless of the investigator’s opinion of causation; the 
SAEs will be entered in the pharmacovigilance system by the sponsor.
Information on SAEs expected in the study population independent of drug exposure and that 
will be assessed by the Sponsor in aggregate periodically during the course of the trial may be 
found in the USPI.
10.4.1.1.1.Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the USPI and that the investigator identifies as related to study treatment or procedure.  United 


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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 recording 
and expedited reporting of SUSARs that are consistent with global regulations and the associated 
detailed guidance.
10.4.2. Hypoglycemia
As a secondary objective, the rate/incidence of hypoglycemia will be analyzed and compared 
between treatment groups.  Subjects are encouraged to perform SMBG whenever hypoglycemia 
may be suspected, either by symptoms experienced or perceived increased risk as related to 
dietary intake, physical activity, or inadvertent or atypical insulin dosing.  All subjects will be 
instructed to treat a SMBG ≤70 mg/dL as hypoglycemia by ingesting 15 gram of CHO (for 
example, 4 ounces of juice or 3 to 5 gram glucose tabs).  All subjects will be advised to contact 
the site if they experience severe hypoglycemia or SMBG <50 mg/dL.
Hypoglycemia is defined as ≤70 mg/dL (Seaquist et al. 2013) and categorized as follows:

Documented hypoglycemia
o
Documented symptomatic – an event that: 
1. is accompanied by signs/symptoms of hypoglycemia, and
2. is accompanied by a measured SMBG concentration of ≤70 mg/dL.  
o
Asymptomatic hypoglycemia an event that:
1. is not accompanied with signs/symptoms of hypoglycemia, and
2. is accompanied with a measured SMBG concentration of ≤70 mg/dL.
o
Unspecified hypoglycemia an event during that:
1. no relative signs/symptoms of hypoglycemia are recorded, and
2. is accompanied with a measured SMBG concentration of ≤70 mg/dL. 

Severe hypoglycemia: An event accompanied by neuroglycopenic symptoms 
that result in cognitive impairment such that the patient requires assistance of 
another person to actively administer CHO, glucagon, or perform other 
resuscitative actions.  During these episodes, the patient has an altered mental 
status, and cannot assist in their care, is semiconscious or unconscious, or 
experienced coma with or without seizures, and may require parenteral therapy.  
Plasma glucose measurements may not be available during such an event, but 
neurological recovery attributable to the restoration of SMBG concentration to 
normal is considered sufficient evidence that the event was induced by a low 
SMBG concentration (≤70 mg/dL).

Nocturnal hypoglycemia:  Any hypoglycemic event (documented hypoglycemia 
or severe hypoglycemia) that occurs between bedtime and waking. 


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10.4.3. Body Weight
The scale should be zeroed out before the subject is weighed.  Subjects should remove their 
shoes and any additional layers of clothing (such as sweaters or coats) and empty their pockets 
before being weighed.  If possible, subjects should also be given the opportunity to empty 
bladder/bowel before being weighed.  The weight value should be recorded in the source 
documentation and the eCRF.
10.4.4. Other Safety Measures
Vital signs
10.4.4.1.
Blood pressure and pulse, as well as height and weight, will be measured and recorded at the 
indicated visits per the Study Schedule (Attachment 1).  Blood pressure will be measured using a 
standard blood pressure meter to obtain the systolic and diastolic pressures with the subject 
sitting for at least 5 minutes prior to the measurement.
Physical Examinations
10.4.4.2.
Complete physical examinations will be performed at Visit 1 according to the Study Schedule 
(Attachment 1).
Electrocardiograms
10.4.4.3.
For each subject, 12-lead digital electrocardiograms (ECGs) will be performed locally at Visit 1 
according to the Study Schedule (Attachment 1).  Subjects must be supine for approximately 
5 to 10 minutes before ECG collection and remain supine but awake during ECG collection.  
The ECGs will be interpreted by a qualified physician (the investigator or qualified designee) at 
the site as soon after the time of ECG collection as possible, and ideally while the subject is still 
present, to determine whether the subject meets entry criteria at the relevant visit(s) and for 
immediate subject management, should any clinically relevant findings be identified.  
Investigators must document their review of ECG reports.
Clinical Laboratory Tests
10.4.4.4.
Clinical laboratory tests will be conducted at the indicated visits per the Study Schedule 
(Attachment 1) and Clinical Laboratory Tests (Attachment 2).
Concomitant Medications
10.4.4.5.
Concomitant medication usage will be assessed at office visits, per the Study Schedule 
(Attachment 1).  Concomitant medications allowed in this study are discussed in Section 9.11
and Table IBHD.9.7.
Functionality and Safe Use of OmniPod U-500 System
10.4.4.6.
The functionality issues, hazards alarms, and safe use of the OmniPod U-500 system will be 
evaluated at study visits and/or by an assessment of device complaint data. 
10.4.5. Safety Monitoring
The Lilly CRP or CRS will monitor safety data throughout the course of the study.


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Lilly will review SAEs within timeframes mandated by company procedures.  The Lilly 
CRP/CRS will, as is appropriate, consult with the functionally independent Global Patient Safety 
therapeutic area physician or clinical scientist, and periodically review:

Trends in safety data

Laboratory analytes 

AEs

Product complaints
If a study subject experiences elevated ALT or AST ≥3X ULN, elevated total bilirubin ≥2X 
ULN, or alkaline phosphatase ≥2X ULN, clinical and laboratory monitoring should be initiated 
by the investigator.  Details for hepatic monitoring depend upon the severity and persistence of 
observed laboratory test abnormalities.  To ensure subject safety and comply with regulatory 
guidance, the investigator is to consult with the Lilly designated medical monitor regarding 
collection of specific recommended clinical information and follow-up laboratory tests.
10.4.6. Complaint Handling
Lilly collects product complaints on study treatment and drug delivery systems used in clinical 
studies in order to ensure the safety of study participants, monitor quality, and to facilitate 
process and product improvements.
Complaints related to unblinded drug delivery systems (with exception of U-500 OmniPod 
system) are reported directly to the manufacturers of those drugs/devices in accordance with the 
package insert.
The investigator or his/her designee is responsible for handling the following aspects of the 
product complaint process in accordance with the instructions provided for this study:

Recording a complete description of the product complaint reported and any 
associated AEs using the study-specific complaint forms provided for this 
purpose.

The completed product complaint form must be faxed within 24 hours to Lilly or 
its designee.
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint form with the product.
10.5. Sample Collection and Testing
The Study Schedule (Attachment 1) lists the schedule for sample collections in this study.  The 
Clinical Laboratory Tests (Attachment 2) lists the laboratory tests that will be performed for this 
study.  


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10.5.1. Samples for Study Qualification and Health Monitoring
Standard laboratory tests including chemistry, hematology, and urinalysis panels will be 
performed. The Clinical Laboratory Tests (Attachment 2) lists the specific tests that will be 
performed for this study.  Clinical laboratory tests will be analyzed by a central laboratory 
selected by Lilly.  
Blood and urine samples will be collected per standard procedures at the times specified in the 
Study Schedule (Attachment 1).  Blood will be collected by venipuncture.
Investigators must document their review of each laboratory safety report.
Samples collected for specified laboratory tests will be destroyed within 60 days of receipt of 
confirmed test results.  Tests are run and confirmed promptly whenever scientifically 
appropriate.  When scientific circumstances warrant, however, it is acceptable to retain samples 
to batch the tests run, or to retain the samples until the end of the study to confirm that the results 
are valid.  Certain samples may be retained for a longer period, if necessary, to comply with 
applicable laws, regulations, or laboratory certification standards.
10.5.2. Pharmacogenetic Samples for Biomarker Research
Samples will be stored and analysis may be performed on genetic variants thought to play a role 
in insulin sensitivity, efficacy, beta cell function, hypoglycemia risk, and TDD requirements 
(Section 6.3) including, but not limited to, Insulin receptor, Insulin like Growth Factor-1, 
Melatonin Receptor 1B1, adiponectin and transcription factor 7-like 2, Phosphoinositide-3-
Kinase, Regulatory Subunit 1 and B-Cell CLL/Lymphoma 11A to evaluate their association with 
observed clinical outcomes to U-500R (a one-time collection, as noted in the Study Schedule 
[Attachment 1]).
There is growing evidence that genetic variation may impact a subject’s response to therapy.  
Variable response to therapy may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion, the mechanism of action of the drug, the disease 
etiology and/or the molecular subtype of the disease being treated.  Therefore, where local 
regulations and ERBs allow, a blood sample will be collected for pharmacogenetic analysis.  
In the event of an unexpected AE or the observation of unusual response, the pharmacogenetic 
samples may be genotyped and analysis may be performed to evaluate a genetic association with 
response to U-500R.  These investigations may be limited to a focused candidate gene study or, 
if appropriate, genome-wide analysis may be performed to identify regions of the genome 
associated with the variability observed in drug response.  The pharmacogenetic samples will 
only be used for investigations related to disease and drug or class of drugs under study in the 
context of this clinical program.  They will not be used for broad exploratory unspecified disease 
or population genetic analysis.
The samples will be coded with the subject number and stored for up to a maximum 15 years 
after the last subject visit for the study at a facility selected by the Sponsor.  The samples and any 
data generated from them can only be linked back to the subject by investigator site personnel.  
The duration allows the Sponsor to respond to regulatory requests related to study treatment.


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Pharmacogenetic data will not be provided to the investigators nor will it be shared with patients 
in the trial. Samples will be destroyed according to a process consistent with local regulation.
10.5.3. Nonpharmacogenetic Biomarker Stored Samples
Collection of samples for nonpharmacogenetic biomarker research is a required part of this 
study.  Urine and blood (serum and plasma) samples will be collected as specified in the Study 
Schedule (Attachment 1).
Samples may be used for research to understand the pathophysiology of T2DM or its 
complications, the mechanism of action, efficacy, and/or adverse effects related to U-500R.  In 
addition, samples may be used to develop research methods and/or validate diagnostic tools or 
assays.  Nonpharmacogenetic biomarker data from stored samples will not be provided to the 
investigators nor will it be shared with patients in the trial.
Samples will be identified by the subject number (coded) and stored for up for a maximum of 
15 years after the last subject visit for the study at a facility selected by the Sponsor.
10.6. Appropriateness of Measurements
All efficacy and safety assessments included in this study are generally regarded as reliable and 
accurate with respect to management of T2DM.


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11.
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.

Provide start-up training to instruct the investigators and study coordinators.  This 
training will give instruction on the protocol, the completion of the eCRFs, 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 eCRF data and use standard computer edits to detect errors 
in data collection.

Conduct a quality review of the database.
To reduce missing data in the study, subjects who are discontinued from study treatment before 
study completion will be encouraged to remain in the study for continued safety monitoring (see 
Section 8.3.2).  In addition, study site investigators will be trained on the importance of complete 
data collection.
Lilly or its representatives will periodically check a sample of the subject 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.
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the investigator will keep records of laboratory tests, clinical notes, and subject medical 
records in the subject files as original source documents for the study.  If requested, the 
investigator will provide the Sponsor, applicable regulatory agencies, and applicable ERBs with 
direct access to original source documents.
11.1. Data Capture System
An electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into the Sponsor-provided electronic data capture system.  Case
report form data will be encoded and stored in a clinical trial database.  Data managed by a 
central vendor, such as laboratory test data, will be stored electronically in the central vendor’s 
database system.  Data will subsequently be transferred from the central vendor to the Lilly 
generic labs system.
Any data for which paper documentation provided by the subject will serve as the source 
document will be identified and documented by each site in that site’s study file.  Paper 
documentation provided by the subject may include, for example, a paper diary to collect PRO 
measures (for example, a rating scale), a daily dosing schedule, or an event diary.


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Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.


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12.
Sample Size and Statistical Methods
12.1. Determination of Sample Size
Approximately 320 subjects requiring high-dose insulin without use of GLP-1 receptor agonists 
or SGLT2 inhibitors (Group A) and approximately 64 to 96 additional subjects with use of GLP-
1 receptor agonists or SGLT2 inhibitors (Group B) will be randomized based on a 1:1 ratio to 
two treatment arms.  Approximately 240 (Group A) and 48 to 72 (Group B) subjects are 
expected to complete the 26-week treatment period (assuming a 25% dropout rate).
The sample size was calculated based on the first primary objective for subjects without use of 
GLP-1 receptor agonists or SGLT2 inhibitors (Group A).  The 240 completers will provide 80% 
statistical power to demonstrate the noninferiority (NIM is 0.4%; SD=1.1%) of U-500R insulin 
CSII versus U-500R MDI in change in HbA1c at 26 weeks at 2-sided alpha = 0.05. 
12.2. Statistical and Analytical Plans
12.2.1. General Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.
Unless otherwise specified, both safety and efficacy analyses will be conducted on the ARS, 
including those who discontinued study treatment or were rescued.  This set includes all 
randomized patients and is defined based on the intention-to-treat (ITT) principle. Sensitivity 
analysis may be done for the Full Analysis Set (FAS) that includes ARS subjects who received at 
least 1 dose of the U-500R via the administration method to which they were assigned.
Separate efficacy analyses for primary and key secondary objectives will be conducted by either 
including or excluding post study treatment discontinuation/data based on different FDA
analyses (see Section 12.2.7). In general, missing data will not be imputed, unless otherwise 
specified (eg, where the multiple imputation method or the LOCF method is mentioned).
Baseline will be the last value obtained at or prior to the randomization, Visit 4 (Week 0), unless 
otherwise stated. 
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, unless otherwise 
stated.
Changes 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 changes to the data analysis methods 
described in the protocol, and the justifications, will be described in the clinical study report.  
Additional exploratory analyses of the data will be conducted as deemed appropriate.
12.2.2. Adjustment for Multiplicity
This section explains the graphical approach in detail and illustrates how the graphical approach 
works in practice.  As discussed in Bretz et al. 2009, this testing approach controls the 


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family-wise type I error rate at alpha=0.05.  More details of this method will be documented in 
the SAP.
Figure IBHD.12.1 illustrates the graphical approach to adjust multiplicity for the primary and 
key secondary objectives.  In Figure IBHD.12.1 and for the explanations of the scenarios, the 
alternative hypotheses H1 through H10 are defined as follows:
H1: CSII is noninferior to MDI in change in HbA1c using a NIM of 0.4%.
Key Secondary Objectives:
H2:  CSII is superior to MDI in change in FPG.
H3: CSII is superior to MDI in proportions of subjects achieving HbA1c targets/values 
<7.0%.
H4: CSII is superior to MDI in change in HbA1c. 
H5: CSII is superior to MDI in proportions of subjects achieving HbA1c targets/values 
<7.5%.
H6 through H10 are the same as H1 through H5 except that they are combined for the total study 
population Group A (without use of GLP-1 receptor agonists or SGLT2 inhibitors) and Group B 
(those who use GLP-1 receptor agonists or SGLT2 inhibitors). 
As shown by the Figure IBHD.12.1, the graphical approach begins with testing the noninferiority 
for the primary objective at alpha=0.05.  The numbers (weights) on the arrows depict the 
proportion of alpha which is propagated to the next test if a null hypothesis is rejected.  At each 
step, all hypotheses are tested based on the current alpha assigned to them by the approach.  If,
and only if one of the null hypotheses is rejected, then the alpha flows based on the graph, and 
the weights are updated based on the preset algorithms and rules as described in Bretz et al. 
2009.


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Figure IBHD.12.1.
Graphical approach to adjust multiplicity.
One of the possible scenarios for the graphical approach is given below (step by step) for 
illustration only: 

The null hypothesis for H1 is rejected at alpha=0.05, so H2 will be tested at 
alpha=0.01 and H3 will be tested at alpha=0.04.

The null hypothesis for H3 is rejected at alpha=0.04, so based on the graph 
(Figure IBHD.12.1), 99% of the alpha (0.0396) from H3 will flow to H2 and 1%
of the alpha (0.0004) from H3 will flow to H4.  Therefore, H2 will be tested at 
alpha=0.01+0.0396=0.0496 and H4 will be tested at alpha=0+0.0004=0.0004.  

The null hypothesis for H2 is rejected at alpha=0.0496, so based on the updated
graph and weights, 100% of its alpha will flow to H4 and H4 will be tested at 
alpha=0.0004+0.0496=0.05.

The null hypothesis for H4 cannot be rejected at alpha=0.05, so the graphical approach 
stops here.


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12.2.3. Subject Disposition
All subjects who discontinue from the study will be identified, and the extent of their 
participation in the study (discontinuation visit) will be reported.  The primary reasons for 
discontinuation will be listed for all subjects who have entered the study (signed informed 
consent). Reasons for discontinuation of study treatment and study will be summarized by 
treatment for the ARS, by visit and for overall study.  All of the summaries will be broken down 
by “discontinue study treatment and device but still remain in the study” and “discontinue the 
study”.  The treatment comparison will be based on Fisher’s exact test or Pearson’s chi-square 
test, as appropriate.  
12.2.4. Subject Characteristics
The subject characteristics and demographic variables will be recorded at Screening (Visit 1; 
Week -3) and will be listed and summarized by treatments.  The summaries will include 
descriptive statistics such as:  mean, SD, sample size, median, minimum, and maximum for 
continuous variables; and frequency, percentage, and number of subjects for categorical 
variables.  The treatment groups will be compared using an analysis of variance model for 
continuous measurements and Fisher’s exact test for categorical measurements.  In addition, 
these analyses will be conducted for baseline hypoglycemic episodes collected from Visit 2 to 
Visit 4.
12.2.5. Concomitant Therapy
Frequencies and percentages of concomitant medication used prior to and after randomization 
(by visit), will be summarized by treatments.  Antihyperglycemic agents will be summarized by 
treatment at entry, randomization, and the end of study.   
12.2.6. Treatment Compliance 
No specific study data will be collected for analysis for treatment compliance except as it is 
collected in Patient Reported Outcomes Questionnaires.
12.2.7. Primary Outcome and Methodology
The primary efficacy measure is change from baseline to the 26-week HbA1c value.  The 
primary analysis will be conducted for the All Randomized Set (ARS) population in Group A.  
There will be two primary analysis methods for different purposes as follows:
1. Per FDA’s request, the analysis method will use the copy reference approach to 
impute missing data based on multiple imputations with a pattern mixture model 
(later referred to as ‘copy reference multiple imputation analysis’). This analysis 
will include post study treatment discontinuation data.  The reference is all 
observed data from all randomized subjects in the same treatment arm who 
discontinued study treatment but completed the study without missing data. After 
imputation, an analysis of covariance (ANCOVA) with baseline HbA1c as a 
covariate, treatment (U-500R CSII, U-500R MDI) and the stratification factor 


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(U-500R at entry versus other insulins) as fixed effects will be used to analyze the 
26-week HbA1c including imputed values. 
If in the reference group mentioned above there is only a limited number of 
subjects and this leads to a failure in performing the proposed multiple imputation 
analysis, the reference will be changed to include all observed data from all 
randomized subjects in the same treatment arm who do not have missing data. 
2. For manuscripts and other non-FDA submission purposes, a MMRM model that 
does not include post study treatment discontinuation data and adjusts for missing 
data through an observed-data-likelihood-based approach will be used. The 
model will include the following fixed effects:  treatment (U-500R CSII, U-500R 
MDI), weeks on treatment, the interaction between treatment and weeks, and the 
stratification factor (U-500R at entry versus other insulins).  The model will also 
include baseline HbA1c as a covariate. 
As a sensitivity analysis to the missing at random assumption of MMRM model, a 
stress test will be performed.  The missing data are first imputed with the missing 
at random assumption.  Prior to multiple-imputation analysis, in the CSII arm the 
imputed values will be replaced by the imputed value plus delta.  Multiple values 
of delta within a clinically reasonable and meaningful range will be tested to 
assess if the conclusion from the MMRM primary analysis changes.
The test for the primary objective of noninferiority will be performed at the 0.05 significance 
level using the LS mean estimate of the difference in change in HbA1c between the two 
treatments at Week 26.  Noninferiority will be established if the upper limit of a 2-sided 95% 
confidence interval (CI) for the difference (U-500R CSII minus U-500R MDI) is below the NIM 
of 0.4%.
Using the LS mean estimate of the difference in change in HbA1c between the 2 treatments, 
superiority will be established if the upper limit of a two-sided 95% CI for the difference 
(U-500R CSII minus U-500R MDI) is below 0.
The following supportive and sensitivity analyses will also be conducted:

If the following sets are different from ARS, then similar copy reference multiple 
imputation and MMRM analyses will be done for the FAS (subjects who were 
randomized and received at least 1 dose of the study insulin through the administration 
method they were assigned to), all completer set (subjects who complete the study
treatment), and the per-protocol population (subjects included in the ARS who have 
completed the study without important protocol deviations that will impact the primary 
outcome).

An ANCOVA model with similar fixed effects as in the copy reference multiple 
imputation analysis using LOCF method for the ARS will also be performed.


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
For the analysis performed for the total study population (Groups A and B), the analysis 
model will include additional stratification factor (nonusers versus users of GLP-1 
receptor agonists or SGLT2 inhibitors) as fixed effect.
12.2.8. Secondary Efficacy Analyses
Similar to the primary analysis, two sets of analysis approaches (copy reference multiple 
imputation and MMRM) will be used to analyze the change from baseline for the following key 
secondary endpoints 1 and 2 at Week 26.  For endpoint 3, only MMRM analysis will be 
performed.
1) FPG (by laboratory measurement)
2) 7-point SMBG
3) Total Daily Insulin dose (TDD)
The MMRM or ANCOVA models will include terms similar to those in the primary analysis 
with the appropriate stratification factors as fixed effect, with the corresponding baseline 
measures included as a covariate.  
Similar to the primary analysis, two sets of analysis approaches (repeated-measure logistic 
regression excluding post study treatment discontinuation data and the multiple imputations 
based logistic regression including post study treatment discontinuation data) will be applied to 
assess the following secondary objectives in the following values at Week 26:

Proportions of subjects achieving HbA1c targets/values (≤6.5%, <7.0%, <7.5%, and 
<8.0%). 

Proportions of subjects achieving HbA1c targets/values (≤6.5%, <7.0%, <7.5%, and 
<8.0%) without documented symptomatic hypoglycemia (SMBG <50 mg/dL)
The logistic regression model will include similar fixed effects as in the above ANCOVA and 
MMRM models.  The proportion of subjects achieving HbA1c targets with no documented 
symptomatic hypoglycemia (from baseline to the corresponding visit) will be analyzed using 
similar logistic regression models including the baseline documented symptomatic hypoglycemia 
event rate as a covariate.
12.2.9. Exploratory Analyses 
Patient Reported Outcomes Analyses
12.2.9.1.
As an exploratory objective, the TRIM-D and TRIM-DD measures will be used to compare the 
change in diabetes treatment and diabetes treatment device on patient’s functioning, well-being,
and quality-of-life outcomes from baseline to the 26-week values between treatment groups.  
12.2.9.1.1.TRIM-D and TRIM-DD
The TRIM-D and TRIM-DD will be administered at Visit 4 (Week 0, prior to randomization), at 
Visit 13 (Week 14) and at Visit 17 (Week 26) or ET if subjects do not complete the full 26 weeks 
of the study.


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Summaries of the domain and overall scores will include sample size, mean, SD, median, 
minimum, maximum, LS mean and standard error (SE) of LS mean.  The changes from baseline 
in domain scores and total scores of TRIM-D and TRIM-DD will be analyzed using MMRM 
model (with terms similar to the primary/secondary analyses). For change from baseline, LS 
means and SE of LS means will be reported by treatment group.  For treatment difference of 
change, LS means, SE of LS means, 95% CI, and p-value will be reported.
OmniPod U-500 System Exit Questionnaire
12.2.9.2.
An OmniPod U-500 System Exit Questionnaire will be administered to CSII subjects at Visit 17 
(Week 26) or at ET if subjects do not complete the full 26 weeks of the study.
Descriptive statistics will be provided to summarize the results from the U-500 System Exit 
Questionnaire. 
Functionality and Safe Use of the OmniPod U-500 System
12.2.9.3.
The functionality and safe use of the OmniPod U-500 system will be evaluated by an assessment 
of device complaint data, subject-reported hazard alarms, and clinically relevant hyperglycemia 
possibly related to site occlusion.  Lilly should be contacted for CSII device complaints and will 
provide the data to be listed.  The reported hazard alarms as well as the “Infusion Site Change” 
from the diary will be listed also. 
12.2.10.
Safety Analyses 
As stated in Section 6.2, all of the secondary objectives will be analyzed for Group A and for the 
total study population (Groups A and B combined). Safety measures will include hypoglycemic 
events, body weight, AEs and TEAEs, vital signs (systolic and diastolic blood pressures and 
pulse), study treatment exposure, and laboratory measures.  As stated in Section 12.2.1, all safety 
measures will be summarized for ARS including the data after subjects discontinue study 
treatment and device but still remain in the study by treatment and by visit for the 26-week 
treatment period. Safety measures will also be listed for those patients who discontinue study 
treatment but still remain in the study for safety monitoring purpose. These listings will contain 
data after the patients discontinue the study treatment. For treatment comparisons of frequency 
and proportion of event variables (such as AEs and hypoglycemia events), the conventional 
Fisher’s exact test or Pearson’s chi-square test are appropriate to use.  Further details of analyses 
will be provided in the SAP.
Hypoglycemia
12.2.10.1.
The rate per 30 days calculated between 2 visits is defined as the total number of episodes for all 
subjects between the visits divided by the total actual number of exposure days between the 
visits, and then multiplied by 30 days.  A similar definition will be used to calculate the rate per 
subject per 365 days (year).
For documented (documented symptomatic, asymptomatic and unspecified), severe and 
nocturnal hypoglycemic episodes, the following analyses will be conducted.  The incidence and 
percentage of subjects with at least 1 hypoglycemic event will be analyzed using Fisher’s exact 
test or Pearson’s chi-square test, as appropriate.  The rate of hypoglycemic events per 30 days


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and per 365 days will be analyzed using a negative binomial regression model with similar fixed 
effects as in the primary MMRM analysis model.  Baseline hypoglycemic event rate for the 
corresponding category of the dependent hypoglycemia variable will be included as a covariate, 
as well as the stratification factors.  
Body Weight
12.2.10.2.
Baseline values used for the weight analysis will be obtained for each subject at or prior to 
randomization. The body weight change will be analyzed by MMRM models similar to that 
used in the primary analysis for the ARS population.  The model specifications will be adjusted 
as appropriate.
Treatment-Emergent Adverse Events and Serious Adverse Events
12.2.10.3.
Adverse events will be listed by subject, system organ class, preferred term, severity, and 
relationship to the study disease, drug, device, or procedure.  Adverse events will be summarized 
as TEAEs during treatment period (defined as events that are newly reported after randomization 
Visit 4 or reported to be worsened in severity from randomization Visit 4) for ARS by treatment
and visit. These listings will contain data after the patients discontinue the study treatment.
The frequency and proportion of subjects experiencing at least 1 of each reported TEAE will be 
summarized by system organ class, preferred term, and treatment group for treatment period.  
The frequency and proportion comparisons will be analyzed using Fisher’s exact test or 
Pearson’s chi-square test, as appropriate.  The frequency and proportion of subjects experiencing
at least 1 of each reported TEAE that are assessed as possibly related to the study disease, drug, 
device, or procedures will also be summarized. 
All SAEs (including severe hypoglycemic events) will be listed by subject with similar 
information as the AE listing.  If a sufficient number of SAEs are reported, then a frequency and 
proportion summary, similar to the summary for TEAEs, will be included for the ARS.  
Discontinuations due to TEAEs and SAEs will be listed separately, by subject (including 
information about whether they discontinue only the study treatment or study treatment and the 
study), and summarized (if a sufficient number of events are reported) by treatment. All of the 
summaries will be broken down by “discontinue study treatment and device but still remain in 
the study” and “discontinue the study.”
Vital Signs
12.2.10.4.
Systolic and diastolic blood pressures and pulse will be summarized by visit and additionally for 
endpoints (LOCF).  Additionally, change from baseline to the last visit of each period for actual 
value and endpoint (LOCF) will be summarized.
Study Treatment Exposure
12.2.10.5.
Exposure to each treatment will be calculated for each subject and summarized by treatment.  
Total subject-years will be included in the summaries.


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Laboratory Measures
12.2.10.6.
As applicable per protocol, measures within the following panels will be summarized at 
Screening (Visit 1), Visit 4 (Week 0), Visit 13 (Week 14), and Visit 17 (Week 26) or endpoint 
(LOCF):

Chemistry 

Hematology 

Lipids
Treatment-emergent high, low, and abnormal values will be summarized for each lab measure.
A treatment-emergent high value is defined as a value that was normal or low at baseline and 
subsequently found to be above the normal range at any post-baseline visit.  A treatment-
emergent low value is defined as a value that was normal or high at baseline and subsequently 
found to be below the normal range at any post-baseline visit.  A treatment-emergent abnormal 
value is defined as a value that was normal at baseline and subsequently found to be abnormal at 
any post-baseline visit.
12.2.11.
Safety Committee
Trial level safety reviews using selected blinded safety data will be conducted throughout the 
study by the study team.  
12.2.12.
Interim Analyses
A DMC (Data Monitoring Committee) will have access to unblinded data for their review(s).  
Only the DMC is authorized to evaluate unblinded interim safety analyses.  The DMC will be 
composed of individuals internal and external to Lilly who are not part of the study team and will 
monitor the safety of U-500R administered CSII or MDI and may recommend changes to the 
protocol, including termination.  Unblinding details are specified in the unblinding plan section 
of the SAP and/or DMC Charter.  The timing and frequency of these data reviews will be stated 
in the DMC charter.  In the event of any patient safety concerns, the DMC will communicate to 
the study team so that the CRP/CRS can inform the investigator of appropriate action.  Study 
sites will receive information about interim results ONLY if they need to know for the safety of 
their subjects.
If an unplanned interim analysis is deemed necessary, the appropriate Lilly regulatory scientist 
will be consulted to determine whether it is necessary to amend the protocol.


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13.
Informed Consent, Ethical Review, and Regulatory 
Considerations
13.1. Informed Consent
The investigator is responsible for ensuring that the subject understands the potential risks and 
benefits of participating in the study, including answering any questions the subject may have 
throughout the study and sharing in a timely manner any new information that may be relevant to 
the subject’s willingness to continue his or her participation in the trial.
The ICF will be used to explain the potential risks and benefits of study participation to the 
subject in simple terms before the subject is entered into the study, and to document that the
subject is satisfied with his or her understanding of the risks and benefits of participating in the 
study and desires to participate in the study.  
The investigator is responsible for ensuring that informed consent is given by each subject or 
legal representative.  This includes obtaining the appropriate signatures and dates on the ICF 
prior to the performance of any protocol procedures and prior to the administration of study 
treatment.
As used in this protocol, the term “informed consent” includes all consent and assent given by 
subjects or their legal representatives.
13.2. Ethical Review
Lilly or its representatives must approve all ICFs before they are used at investigative sites.  All 
ICFs must be compliant with the International Conference on Harmonisation (ICH) guideline on
GCP.  
The investigator must give assurance that the ERB was properly constituted and convened as 
required by 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 sites.  The ERB(s) will review the protocol as required.
The study site’s ERB(s) should be provided with the following:

IBHD Subject Information, Humulin R U-500 USPI, OmniPod U-500 Insulin 
Management System User Guide, and updates during the course of the study

ICF

Relevant curricula vitae
13.3. Regulatory Considerations
This study will be conducted in accordance with:

Consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International Organizations
of Medical Sciences International Ethical Guidelines.


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
The ICH GCP Guideline [E6].

Applicable laws and regulations.
The investigator or designee will promptly submit the protocol to applicable ERB(s).
Some of the obligations of the Sponsor will be assigned to a TPO.
An identification code assigned to each subject will be used in lieu of the subject’s name to 
protect the subject’s identity when reporting AEs and/or other trial-related data.
13.3.1. Investigator Information
Physicians with a specialty in internal medicine or endocrinology with extensive experience in 
intensive insulin therapy including CSII therapy may participate as investigators in this clinical 
trial.
13.3.2. 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.
13.3.3. Final Report Signature
The clinical study report-coordinating investigator will sign the final clinical study report for this 
study, indicating agreement that, to the best of his or her knowledge, the report accurately
describes the conduct and results of the study.  
The Sponsor’s responsible medical officer and statistician will approve the final clinical study 
report for this study, confirming that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.


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14.
References
[ADA] American Diabetes Association. Diagnosis and classification of diabetes mellitus. 
Diabetes Care. 2014;37(Suppl 1):S81-S90.
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. Diabetic Med. 1998;15(7):539-553.
Ballani P, Tran MT, Navar MD, Davidson MB. Clinical experience with U-500 regular insulin in 
obese, markedly insulin-resistant type 2 diabetic patients. Diabetes Care. 
2006;29(11):2504-2505. 
Bolderman KM. Infusion site and tubing concerns. In: Putting Your Patients on the Pump. 2nded.
United States: American Diabetes Association; 2013: 95.
Boldo A, Comi RJ. Clinical experience with U500: risks and benefits. Endocr Pract. 
2012;18(1):56-61. 
Bretz F, Maurer W, Brannath W, Posch M. A graphical approach to sequentially rejective 
multiple test procedures. Stat Med. 2009;28(4):586-604.
Brod M, Hammer D, Christensen T, Lessard S, Bushnell DM. Understanding and assessing the 
impact of treatment in diabetes: the treatment-related impact measures for diabetes and devices 
(TRIM-Diabetes and TRIM-Diabetes Device). Health Qual Life Outcomes. 2009;7:83.
Bulchandani DG, Konrady T, Hamburg MS. Clinical efficacy and patient satisfaction with 
U-500 insulin pump therapy in patients with type 2 diabetes. Endocr Pract. 
2007;13(7):721-725. 
[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.
Cochran E, Musso C, Gorden P. The use of U-500 in patients with extreme insulin resistance. 
Diabetes Care. 2005;28(5):1240-1244. 
Cochran EK, Valentine V, Samaan KH, Corey IB, Jackson JA. Practice tips and tools for the 
successful use of U-500 regular human insulin: the diabetes educator is key. Diabetes Educ.
2014;40(2):153-165.
Dailey AM, Williams S, Taneja D, Tannock LR. Clinical efficacy and patient satisfaction with 
U-500 insulin use. Diabetes Res Clin Pract. 2010;88(3):259-264. 
de la Peña A, Riddle M, Morrow LA, Jiang HH, Linnebjerg H, Scott A, Win KM, Hompesch M, 
Mace KF, Jacobson JG, and Jackson JA. Pharmacokinetics and pharmacodynamics of high-
dose human regular U-500 insulin versus human regular U-100 insulin in healthy obese 
subjects. Diabetes Care. 2011;34(12):2496-2501. 
de la Peña A, Ma X, Reddy S, Miller MA, Ovalle F, Bergenstal RM, Jackson JA. Application of 
PK/PD modeling and simulation to dosing regimen optimization of high-dose human regular 
U-500 insulin.  J Diabetes Sci Technol. 2014; May 12. pii: 1932296814532326. [Epub ahead 
of print].


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Distiller LA, Nortje H, Wellmann H, Amad A, Lombard L. Treatment of obese type 2 diabetes 
patient with severe insulin resistance: A 24-week, prospective, randomized, open-label, treat-
to-target study: A pilot study to compare the efficacy of U-500 regular insulin plus metformin 
with U-500 regular insulin, metformin and exenatide. Endocr Pract. 2014;16:1-26. Epub.
Eby EL, Wang P, Curtis BH,Xie J, Haldane DC, Idris I, Peters AL, Hood RC, Jackson JA. Cost, 
healthcare resource utilization, and adherence of individuals with diabetes using U-500 or 
U-100 insulin: a retrospective database analysis. J Med Economics 2013;16(4):529-538.
Eby EL, Zagar AJ, Wang P, Curtis BH, Xie J, Haldane DC, Idris I, Peters AL, Hood RC, 
Jackson JA. Healthcare costs and adherence associated with human regular U-500 versus high-
dose U-100 insulin in patients with diabetes. Endocr Pract. 2014;20(7):663-670.
Gale EA, Beattie SD, Hu J, Koivisto V, Tan MH. Recruitment to a clinical trial improves 
glycemic control in patients with diabetes. Diabetes Care. 2007;30(12):2989-2992. 
Hirsch BI, Practical pearls in insulin pump therapy. Diabetes Technol Ther. 2010;12 Suppl 
1:S23-S27.
Hood RC, Arakaki RF, Wysham C, Li YG, Settles JA, Jackson JA. Two treatment approaches 
for human regular U-500 insulin in patients with type 2 diabetes not achieving adequate 
glycemic control on high-dose U-100 insulin therapy with or without oral agents: A 
randomized, titration-to-target clinical trial. Endocr Pract. 2015;26:1-28.[Epub]. 
Humulin R U-500 [package insert]. Indianapolis, IN: Eli Lilly and Company;2011. 
Jones P, Idris I. The use of U-500 regular insulin in the management of patients with obesity and 
insulin resistance. Diabetes Obes Metab. 2013;15(10):882-887.
Knee TS, Seidensticker DF, Walton JL, Solberg LM, Lasseter DH. A novel use of U-500 insulin 
for continuous subcutaneous insulin infusion in patients with insulin resistance: a case series. 
Endocr Pract. 2003;9(3):181-186. 
Lane WS. Use of U-500 regular insulin by continuous subcutaneous insulin infusion in patients 
with type 2 diabetes and severe insulin resistance. Endocr Pract. 2006;12(3):251-256. 
Lane WS, Cochran EK, Jackson JA, Scism-Bacon JL, Corey IB, Hirsch IB, Skyler JS. High-dose 
insulin therapy: is it time for U-500 insulin? Endocr Pract. 2009;15(1):71-79.
Lane WS, Weinrib SL, Rappaport JM, Przestrzelski T. A prospective trial of U-500 insulin 
delivered by Omnipod in patients with type 2 diabetes and severe insulin resistance. Endocr 
Pract. 2010;16(5):778-784. [published correction appears in Endocr Pract. 2010;16(6):1082].
Lane WS, Weinrib S, Rappaport J. The effect of liraglutide added to U-500 insulin in patients
with type 2 diabetes and high insulin requirements. Diabetes Technol Ther. 
2011;13(5):592-596.
Lane WS, Weinrib SL, Rappaport JM, Hale CB, Farmer LK, Lane RS. The effect of long-term 
use of U-500 insulin via continuous subcutaneous infusion on durability of glycemic control 
and weight in obese, insulin-resistant patients with type 2 diabetes. Endocr Pract.
2013;19(2):196-201.


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Nathan DM, Kuenen J, Borg R, Zheng H, Schoenfeld D, Heine RJ; A1c-Derived Average 
Glucose Study Group. Translating the A1C assay into estimated average glucose values. 
Diabetes Care. 2008;31(8):1473-1478. Erratum in: Diabetes Care. 2009;32(1):207.
Nayyar V, Jarvis J, Lawrence I, Kong M-F, Gregory R, Hiles S, Jackson S, McNally P, Davies 
MJ. Long-term follow up of patients on U-500 insulin: a case series. Pract Diab Int. 
2010;27(5):194-197. 
Neal JM. Analysis of effectiveness of human U-500 insulin in patients unresponsive to 
conventional insulin therapy. Endocr Pract. 2005;11(5):305-307. 
Quinn SL, Lansang MC, Mina D. Safety and effectiveness of U-500 insulin therapy in patients 
with insulin-resistant type 2 diabetes mellitus. Pharmacotherapy. 2011;31(7):695-702. 
Reutrakul S, Brown RL, Koh CK, Hor TK, Baldwin D. Use of U-500 regular insulin via 
continuous subcutaneous insulin infusion: clinical practice experience. J Diabetes Sci Technol. 
2011;5(4):1025-1026. 
Reutrakul S, Wroblewski K, Brown R. Clinical use of U-500 regular insulin: review and meta-
analysis. J Diabetes Sci Technol. 2012;6(2):412-420.
Rosenstock J, Jelaska A, Frappin G, Salsali A, Kim G, Woerle HJ, Broedl UC; EMPA-REG 
MDI Trial Investigators. Improved glucose control with weight loss, lower insulin doses, and 
no increased hypoglycemia with empagliflozin added to titrated multiple daily injections of 
insulin in obese inadequately controlled type 2diabetes. Diabetes Care. 2014 
Jul;37(7):1815-1823.
Schwartz FL. A caution regarding U-500 insulin by continuous subcutaneous infusion. Endocr 
Pract. 2004;10(2):163-164.
Segal AR, Brunner JE, Burch FT, Jackson JA. Use of concentrated insulin human regular 
(U-500) for patients with diabetes. Am J Health Syst Pharm. 2010;67(18):1526-1535. 
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, Heller SR, Rodriguez H, 
Rosenzweig J, Vigersky R. Hypoglycemia and diabetes: a report of a workgroup of the 
American Diabetes Association and the Endocrine Society. Diabetes Care.
2013;36(5):1384-1395.
Ziesmer AE, Kelly KC, Guerra PA, George KG, Dunn FL. U-500 regular insulin use in insulin 
resistant type 2 diabetic veteran patients. Endocr Pract. 2012;18(1):34-38.


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Attachment 1.Protocol IBHD Study Schedule


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Study Schedule, Protocol B5K-MC-IBHD
Perform procedure as indicated. 
Visit 6:  CSII Treatment Arm Begins
S
Lead- In
R
Transition
Treatment Period
ETa
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Week of Study (week prior to visit)
-3
-2
-1
0
1
2
3
4
6
8
10
12
14
17
20
23
26
Allowable Range (± d=days, w=weeks)
-
1w
3d
1w
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
1w
Telephone (T) or Office (O) Visit
O
O
T
O
O
O
O
T
T
O
T
T
O
T
O
T
O
Informed consent 
X
Confirm eligibility
X
Xb
Demographic data
X
Randomization
X
IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessmentsc
Subjects fast prior to visit
X
X
X
X
Clinical chemistry/hematology
X
X
X
X
X
Estimated glomerular filtration rate 
(eGFR)
X
X
X
X
X
Lipid panel
X
X
X
X
Urinalysis
X
X
X
Pregnancy testd
X
HbA1c
X
X
X
X
X
X
X
Fasting plasma glucose
X
X
X
X
C-peptide
X
X
X
Pharmacogenetic sample for storage
X
Nonpharmacogenetic biomarkers sample 
storage (plasma, serum, urine)
X
X
X
X
X
X
X
Clinical Assessments
ECG
X
Medical history
X
Preexisting conditions
X
Physical examination
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Visit 6:  CSII Treatment Arm Begins
S
Lead- In
R
Transition
Treatment Period
ETa
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Week of Study (week prior to visit)
-3
-2
-1
0
1
2
3
4
6
8
10
12
14
17
20
23
26
Allowable Range (± d=days, w=weeks)
-
1w
3d
1w
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
1w
Telephone (T) or Office (O) Visit
O
O
T
O
O
O
O
T
T
O
T
T
O
T
O
T
O
Clinical Assessments, Cont.
Assess/record BG and hypoglycemic 
eventse
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Eventse
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
Height
X
Training on 7-point SMBG profiles
X
Subject records 7-point SMBG profilesf
X
X
X
Health Outcomes Questionnaires
TRIM-D
Xg
X
X
X
TRIM-DD
Xg
X
X
X
Pump Specific Endpoint Assessment
OmniPod U-500 Exit Questionnaire for 
CSII subjects
X
Xh
Study Drug/Devices/Diaries
Dispense and training of glucose meter
X
Education on diabetes lifestyle and diet
X
X
Training on OmniPod U-500
(CSII treatment arm only)
Xi
Xj
Dispense study diary
X
X
X
X
X
X
X
X
X
Collect study diary
X
X
X
X
X
X
X
X
X
X
Dispense study drug
X
Xk
Xk
Xk
Xk
Xk
Xk
Collect study drug
X
X
X
X
X
X
X
X
Dispense subject supplies
X
X
X
X
X
X
X
X
X
Dispense OmniPod U-500 supplies
(CSII treatment arm only)
X
X
X
X
X


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Study Schedule, Protocol B5K-MC-IBHD

Visit 6:  CSII Treatment Arm Begins
S
Lead- In
R
Transition
Treatment Period
ETa
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Week of Study (week prior to visit)
-3
-2
-1
0
1
2
3
4
6
8
10
12
14
17
20
23
26
Allowable Range (± d=days, w=weeks)
-
1w
3d
1w
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
1w
Telephone (T) or Office (O) Visit
O
O
T
O
O
O
O
T
T
O
T
T
O
T
O
T
O
Study Drug/Devices/Diaries, Cont
Dispense nutrition bars
X
X
X
X
X
X
X
X
Adjust/record insulin dose
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Product complaints
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviations:  AE = adverse event; BG = blood glucose; CRF = case report form; d = day; ET = early termination; HbA1c = Hemoglobin A1c; IWRS = 
interactive web response system; O = office, R = randomization, S = screening; SAE = serious adverse event; SMBG = self-monitored blood glucose; T = 
telephone; TRIM-D = treatment-related impact measure for diabetes; TRIM-DD = treatment-related impact measure for diabetes device; w = week.
a
Early termination visit only performed on subjects who did not complete the full 26 weeks of the study.
b
Prior to randomization at Visit 4, all subjects will be re-confirmed for inclusion criteria [1], [2], and [7] and exclusion criteria [18].
c
Central laboratory unless otherwise specified.  Laboratory tests may be performed at any time at the investigator’s discretion in the event of an adverse event.
d
Serum screening pregnancy test will be performed at Visit 1 for women of childbearing potential by a Lilly-designated central laboratory.  A urine pregnancy 
test may be repeated locally for any follow-up visits.
e
Hypoglycemic and AEs should be collected in the subject’s diary and will be discussed during telephone visits and at the next onsite visit for each subject 
unless a severe hypoglycemic event occurs (SAE that needs to be reported immediately).
f
Subjects will be instructed to record 7-point SMBG profiles on 2 nonconsecutive days (including a weekend day if possible) in the 2 weeks prior to Visits 4, 
13, and 17.
g
Health outcomes questionnaires will be administered prior to randomization during this office visit.
h
OmniPod U-500 System Exit Questionnaire will be administered to CSII subjects at ET if subjects terminate during treatment period.  
i
Subjects will be introduced to the basics of the OmniPod U-500 system at investigator site before beginning CSII treatment but will not be given the device.
j
Subjects will receive hands-on training of the OmniPod U-500 system at investigator site using study drug and will be given device to begin CSII treatment.
k
Study drug assessed and dispensed based on need and expiration.


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Attachment 2.Protocol IBHD Clinical Laboratory Tests
Clinical Laboratory Testsa
Hematology
Clinical Chemistry
Urinalysis
Hemoglobin
BUN
Bilirubin
Hematocrit
Creatinine
Blood
MCH
Uric acid
Glucose
MCHC
LDH
Ketones
MCV
Albumin
Urine leukocyte esterase
Platelets
Total Protein
Nitrite
Erythrocyte count (RBC)
Calcium
pH
RBC Morphology
Magnesium
Protein
Leukocytes (WBC)
Chloride
Specific gravity
WBC Differential
Potassium
Urobilinogen
     Neutrophils, segmented
Sodium
b Microscopic
     Lymphocytes
Phosphorus
     Monocytes
Bicarbonate
eGFR (MDRD equation)
     Eosinophils
CK
     Basophils
Total bilirubin
Direct bilirubin
HbA1c
Alkaline phosphatase
Glucose, fasting plasma
Alanine aminotransferase (ALT)
C-peptide
Aspartate aminotransferase (AST)
Gamma-Glutamyl Transferase 
(GGT)
CDC Lipid Panel
Pregnancy Test (females only)
     Cholesterol
     Triglycerides
Storage Samples
     HDL
Non-PGx Biomarkers: 
Urine, Serum, Plasma
     LDL (calculated)
PGx:  DNA Whole Blood
     FFA
Abbreviations:  BUN = blood urea nitrogen; CDC = Centers for Disease Control and Prevention; CK = creatine 
kinase; DNA = deoxyribonucleic acid; FFA= free fatty acids; HbA1c = hemoglobin A1c; HDL = high density 
lipoprotein; LDH = lactic acid dehydrogenase; LDL = low-density lipoprotein; MCH = mean cell hemoglobin; 
MCHC = mean cell hemoglobin concentration; MCV = mean corpuscular volume; PGx = pharmacogenetics; 
RBC = red blood cells; WBC = white blood cells; eGFR = estimated glomerular filtration rate; MDRD = 
Modification of Diet in Renal Disease.
a
Assayed by Lilly-designated central laboratory.
b
Microscopic evaluation if any listed urinalysis analyte is positive.


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Attachment 3.World Health Organization (WHO) 
Classification of Diabetes
Type 1 Diabetes Mellitus:  Type 1 diabetes mellitus is judged to be present when the classical 
symptoms of diabetes (thirst, polyuria, wasting and stupor, or coma) are associated with readily 
detectable concentrations of glucose and ketone bodies in the blood and urine.  Insulin treatment 
is necessary not only to control hyperglycemia but also to prevent spontaneous ketosis and death 
(Alberti and Zimmet 1998).
Type 2 Diabetes Mellitus:  Type 2 diabetes mellitus, although often asymptomatic, may also 
present with classical hyperglycemic symptoms (thirst, polyuria, weight loss), but despite 
hyperglycemia, ketone bodies are present in only low concentrations in the blood and urine.  
Coma is rare in type 2 diabetes but may result from extreme hyperglycemia and hyperosmolarity; 
lactic acidosis or ketoacidosis can also occur in fulminating illness (for example, severe infection 
or mesenteric artery thrombosis) due to an acute increase in insulin requirements, but 
spontaneous ketosis does not occur.  Some patients with type 2 diabetes later progress to a state 
of absolute insulin deficiency (Alberti and Zimmet 1998).


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Attachment 4.New York Heart Association (NYHA) Cardiac 
Disease Classifications
Functional Capacity (CCNYHA 1994):
Class I.
Patients with cardiac disease but without resulting limitation of physical activity.  Ordinary 
physical activity does not cause undue fatigue, palpitation, or dyspnea.
Class II.
Patients with cardiac disease resulting in slight limitation of physical activity.  They are 
comfortable at rest.  Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal 
pain.
Class III.
Patients with cardiac disease resulting in marked limitation of physical activity.  They are 
comfortable at rest.  Less than ordinary activity causes fatigue, palpitation, or dyspnea.
Class IV.
Patients with cardiac disease resulting in inability to carry on any physical activity without 
discomfort.  Symptoms of heart failure at rest.  If any physical activity is undertaken, discomfort 
increases.


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Attachment 5.Protocol Amendment B5K-MC-IBHD(a) 
Summary [Safety and Efficacy of Human Regular U-500 
Insulin Administered by Continuous Subcutaneous Insulin 
Infusion versus Multiple Daily Injections in Subjects with 
Type 2 Diabetes Mellitus:  A Randomized, Open-Label, 
Parallel Clinical Trial]
Overview
Protocol B5K-MC-IBHD [Safety and Efficacy of Human Regular U-500 Insulin Administered 
by Continuous Subcutaneous Insulin Infusion versus Multiple Daily Injections in Subjects with 
Type 2 Diabetes Mellitus:  A Randomized, Open-Label, Parallel Clinical Trial] has been 
amended.  The new protocol is indicated by amendment (a) and will be used to conduct the study 
in place of any preceding version of the protocol.
Some changes in the statistical section (“Statistical and Analytical Plans”) were made on request 
from the US Food and Drug Administration (FDA).
The overall changes and rationale for the changes made to this protocol are as follows:

Synopsis
o
In Study rationale, aligned the gaps in scientific and clinical knowledge with the 
pre-study insulin regimens allowed per the inclusion criteria.
o
Updated sections “Diagnosis and Main Criteria for Inclusion and Exclusions”, 
“Primary Efficacy,” “Secondary Efficacy,” and “Safety Analyses” to reflect 
changes made to the protocol throughout this amendment

Updated Section 8.1: Inclusion Criterion [2] to clarify the time period for a subject to 
have maintained the total daily insulin dose prior to study entry. The sentence was split 
for clarity that the type of insulin must have been stable for 3 months at study entry.

Updated Section 8.2: Exclusion Criterion [19] to clarify that use of weight loss herbal 
supplements is excluded.

Updated Section 8.2: Exclusion Criterion [23] to clarify that subjects with only New 
York Heart Association Class III and IV functional status of cardiac disease are excluded
from the trial.

Clarified in the “Discussion of Design and Control” (Section 7.2) that no insulin other 
than U-500R is allowed to start during the transition period.

Corrected a typographical error in visit number in the section ‘Rationale for Selection of 
Doses in the Study’ (Section 9.4).


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
Corrected typographical errors in table number and referencing to table number in section 
“Transition to U-500R MDI” (Section 9.7). 

Corrected study week in the column header for the mean SMBG duration of Table 
IBHD.9.3.

Made minor grammatical changes in “Hypoglycemia” (Section 10.4.2).

Elaborated on the safety and efficacy analyses and handling of missing data in “Statistical 
and Analytical Plans” (Sections 12.2.1, 12.2.7, 12.2.8).  The protocol now provides for 
multiple analysis methods of the primary and key secondary objectives to account for 
missing data. Based on US FDA request, the ITT estimand that accounts for all observed 
data, including those for subjects who have stopped study drug but continued in the 
study, will be used for the primary analysis of the ARS and will be analyzed using copy 
reference multiple imputation analyses with ANCOVA. For publications and regulatory 
purposes in other regions, the efficacy estimand that includes only data observed while 
subjects were receiving study drug (excludes data after subjects discontinued study drug 
but remained in study) will be used for the primary analysis using MMRM.  Two sets of 
similar analysis approaches (MMRM and multiple imputation based ANCOVA) models 
as those for the primary objective will be used for key secondary endpoints.

Edited “Concomitant Therapy” (Section 12.2.5) to remove analyses typically not 
included in parallel studies.

Revised “Safety Analyses” (Section 12.2.10) to specify that data listings will be 
combined for subjects who discontinue study treatment (but still remain in the study) 
with safety data listings for other subjects.  Therefore, the mention of “separate listings”
for these subjects has been deleted.

Made other minor changes (rephrasing/addition of words) in “Statistical and Analytical 
Plans” (Section 12.2) for clarification purposes only.


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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
2. Synopsis
Study Rationale
This prospective, randomized clinical trial will provide clinical information on the use of human
regular U-500 insulin (Humulin® R U-500; U-500R) in high-dose insulin-requiring patients with 
type 2 diabetes mellitus (T2DM).  Gaps in scientific and clinical knowledge for U-500R include 
initial dosing and transition from high-dose U-100 insulin CSII or from non-U-500R and/or U-
500R MDI insulin therapy; dose titration including use of multiple daily injections (MDI) 
delivered three times daily (TID), administration safety in combination with antihyperglycemic 
agents (AHAs),; and transition from U500 MDI to continuous subcutaneous insulin infusion 
(CSII).  
Diagnosis and Main Criteria for Inclusion and Exclusions:  
Planned subject population is men and women diagnosed with T2DM requiring high-dose insulin who have 
inadequate glycemic control.
Inclusion Criteria:  Aged ≥18 to ≤85 years; for 2 weeks prior to Visit 1, TDD >200 but ≤600 units of non U-500R 
insulin/analog (basal; premixed; or basal/bolus by any injection device [MDI; pens and/or syringe/vial or CSII]) 
and/or U-500R by MDI with syringe and vial.  Type of insulin must be stable for ≥3 months at entry. If TDD of U-
500R and other insulins are combined, then insulin other than U-500R not to exceed 25% of TDD are currently 
prescribed non U-500R insulin/analog by CSII or MDI or U-500R insulin by MDI with syringe and vial with or 
without AHAs for ≥3 months at a TDD >200 but ≤600 U; HbA1c ≥7.5% but ≤12.0%; body mass index ≥25 but ≤50 
kg/m2; history of stable body weight; concomitant AHA therapy may include metformin, dipeptidyl peptidase-4 
inhibitors (sitagliptin, saxagliptin, linagliptin, and alogliptin), pioglitazone (doses ≤30 mg/day), GLP-1 receptor 
agonists (albiglutide, dulaglutide, or liraglutide [Group B only]), and SGLT2 inhibitors (canagliflozin, dapagliflozin, 
empagliflozin [Group B only]).  Subjects’ AHA therapy must have been stable for ≥3 months (except GLP-1 
receptor agonists must have been stable for ≥4 months).
Exclusion Criteria:  Type 1 diabetes mellitus or other types of diabetes; or alanine aminotransferase and/or aspartate 
aminotransferase (ALT/AST) ≥2.5x the upper limit of normal; chronic kidney disease Stage 4 and higher (estimated 
glomerular filtration rate <30 mL/minute/1.73 m2 as measured by MDRD formula); history of >1 episode of severe 
hypoglycemia (defined as hypoglycemia requiring the assistance of a another person) within the prior 6 months; 
have received U-500R insulin by CSII in the 3 months prior to Visit 1; recent blood transfusion or severe blood loss 
within 3 months prior to Visit 1; known hemoglobinopathy, hemolytic anemia, sickle cell anemia; chronic systemic 
glucocorticoid therapy; use of weight loss drugs in 3 months prior to Visit 1; women who are pregnant, 
breastfeeding, or are sexually active and of childbearing potential but are not using appropriate contraception; men 
who intend to impregnate their partners; received sulfonylureas/glinides in the 3 months prior to Visit 1, or other 
injectable or oral AHA therapy not listed in the inclusion criteria in the prior 3 months; bariatric surgery; active or 
untreated malignancy; significant hearing loss or vision impairment; cardiac disease with functional status New 
York Heart Association Class III or IV; irregular sleep/wake cycle; use of nonapproved investigational drug within 1 
month prior to trial.
Primary Efficacy: The primary efficacy measure is change from baseline to the 26-week HbA1c value.  The primary 
analysis will be conducted for the All Randomized Set (ARS) population in Group A.  There will be two primary 


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analysis methods for different purposes as follows.
1.
Per FDA’s request, the analysis method will use the copy reference approach to impute missing 
data based on multiple imputations with a pattern mixture model (later referred to as ‘copy 
reference multiple imputation analysis’).  This analysis will include post study treatment 
discontinuation data.   The reference is all observed data from all randomized subjects in the same 
treatment arm who discontinued study treatment but completed the study without missing data.  
After imputation, an analysis of covariance (ANCOVA) with baseline HbA1c as a covariate, 
treatment (U-500R CSII, U-500R MDI) and the stratification factor (U-500R at entry versus other 
insulins) as fixed effects will be used to analyze the 26-week HbA1c including imputed values. 
If in the reference group mentioned above there is only a limited number of subjects and this leads 
to a failure in performing the proposed multiple imputation analysis, the reference will be changed 
to include all observed data from all randomized subjects in the same treatment arm who do not 
have missing data. 
2.
For manuscripts and other non-FDA submission purposes, a MMRM model that does not include 
post study treatment discontinuation data and adjusts for missing data through an observed-data-
likelihood-based approach will be used.  The model will include the following fixed effects:  
treatment (U-500R CSII, U-500R MDI), weeks on treatment, the interaction between treatment 
and weeks, and the stratification factor (U-500R at entry versus other insulins).  The model will 
also include baseline HbA1c as a covariate. 
As a sensitivity analysis to the missing at random assumption of MMRM model, a stress test will 
be performed.  The missing data are first imputed with the missing at random assumption.  Prior to 
multiple-imputation analysis, in the CSII arm the imputed values will be replaced by the imputed 
value plus delta.  Multiple values of delta within a clinically reasonable and meaningful range will 
be tested to assess if the conclusion from the MMRM primary analysis changes.
The primary efficacy measure is change from baseline (last nonmissing value at or prior to the treatment starting at 
Visit 4) to the 26-week HbA1c value, which will be summarized and analyzed using a mixed-model repeated 
measures (MMRM) approach for the All Randomized Set (ARS) population.  The baseline is selected to be the last 
value on or prior to the treatment starting visit:  Visit 4 (Week 0).  Neither last-observation-carried-forward (LOCF) 
method nor other imputation methods will be used for the outcome measures.  However, LOCF method will be used 
for sensitivity analysis.  The MMRM model adjusts for missing data through an observed-data-likelihood-based 
approach.  The model will include the following fixed effects:  treatment (U-500R CSII, U-500R MDI), weeks on 
treatment, the interaction between treatment and weeks, and the appropriate stratification factor (nonusers versus 
users of GLP-1 receptor agonists or SGLT2 inhibitors and U-500R at entry versus other insulins).  The model will 
also include baseline HbA1c as a covariate.  An unstructured covariance matrix will be first modeled for the 
repeated measures of each subject.  If the analysis fails to converge, the following variance-covariance matrix will 
be used (in order) until one converges:
1.
Heterogeneous compound symmetry;
2.
Compound symmetry;
3.
First-order autoregressive.
The test for the firstprimary objective of noninferiority will be performed at the 0.05 significance level using the 
least-squares (LS) mean estimate of the difference in change in HbA1c between the two treatments at Week 26.  
Noninferiority will be established if the upper limit of a 2-sided 95% confidence interval (CI) for the difference 
(U 500R CSII minus U-500R TID) is below the NIM of 0.4%.


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Using the LS mean estimate of the difference in change in HbA1c between the 2 treatments, superiority will be 
established if the upper limit of a two-sided 95% CI for the difference (U-500R CSII minus U-500R MDI) is 
below 0.
The following supportive and sensitivity analyses will also be conducted:

If the following sets are different from ARS, then similar copy reference multiple imputation and MMRM 
analyses will be done for the FAS (subjects who were randomized and received at least 1 dose of the study 
insulin through the administration method they were assigned to), all completer set (subjects who complete 
the study treatment), and the per-protocol population (subjects included in the ARS who have completed 
the study without important protocol deviations that will impact the primary outcome).

An ANCOVA model with similar fixed effects as in the copy reference multiple imputation analysis using 
LOCF method for the ARS will also be performed.

For the analysis performed for the total study population (Groups A and B), the analysis model will include 
additional stratification factor (nonusers versus users of GLP-1 receptor agonists or SGLT2 inhibitors) as 
fixed effect.

If the following sets are different from the ARS, then similar MMRM analyses will be done for the Full 
Analysis Set (subjects who were randomized and received at least 1 dose of the study insulin through the 
administration method they were assigned to), All Completer Set (subjects who complete the study 
treatment), and the Per-Protocol Population (subjects included in the ARS who have completed the study 
without significant protocol violations).

An ‘analysis of covariance’ model with similar fixed effects as in the MMRM analysis using LOCF method 
for the ARS population.
Secondary Efficacy:
Similar to the primary analysis, two sets of analysis approaches (copy reference multiple imputation and MMRM) 
will be used to analyze the change from baseline for the following key secondary endpoints 1 and 2 at Week 26.  For 
endpoint 3, only MMRM analysis will be performed.
1)
FPG (by laboratory measurement)
2)
7-point SMBG
3)
Total Daily Insulin dose (TDD)
The MMRM or ANCOVA models will include terms similar to those in the primary analysis with the appropriate 
stratification factors as fixed effect, with the corresponding baseline measures included as a covariate.  
Similar to the primary analysis, two sets of analysis approaches (repeated-measure logistic regression excluding post 
study treatment discontinuation data and the multiple imputations based logistic regression including post study 
treatment discontinuation data) will be applied to assess the following secondary objectives in the following values 
at Week 26:

Proportions of subjects achieving HbA1c targets/values (≤6.5%, <7.0%, <7.5%, and <8.0%) 

Proportions of subjects achieving HbA1c targets/values (≤6.5%, <7.0%, <7.5%, and <8.0%) without 
documented symptomatic hypoglycemia (SMBG <50 mg/dL)
The logistic regression model will include similar fixed effects as in the above ANCOVA and MMRM models.  The 
proportion of subjects achieving HbA1c targets with no documented symptomatic hypoglycemia (from baseline to 


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the corresponding visit) will be analyzed using similar logistic regression models including the baseline documented 
symptomatic hypoglycemia event rate as a covariate.
Similar MMRM models for the ARS population will be used to analyze the change from baseline for the following 
values at week 26:
1)
FPG (by laboratory measurement)
2)
7-point SMBG
3)
Total Daily Insulin dose (TDD)
Baseline values will be the last value obtained for each subject at or prior to the randomization visit: Visit 4, unless 
otherwise stated.  The MMRM model will include similar fixed effects as in the primary analysis, with the 
corresponding baseline measures included as a covariate.  The model specifications will be carefully adjusted as 
appropriate.
For the following values at week 26:

Proportions of subjects achieving HbA1c targets/values (≤6.5%; <7.0%; <7.5% and <8.0%). 

Proportions of subjects achieving HbA1c targets/values (≤6.5%; <7.0%; <7.5% and <8.0%) without 
documented symptomatic hypoglycemia (SMBG <50 mg/dL).
Treatment comparisons will be analyzed using a repeated-measure logistic regression model including subject to 
account for the repeated measurements and similar fixed effects as in the above MMRM models.  The proportion of 
subjects achieving HbA1c targets with no documented symptomatic hypoglycemia (from baseline to corresponding 
visit) will be analyzed using a similar repeated-measure logistic regression model including the baseline documented 
symptomatic hypoglycemia event rate as a covariate.
Safety Analyses:
All of the secondary objectives related to safety will be analyzed for Group A and for the total study population 
(Groups A and B combined). All safety measures will be summarized for ARS including the data after subjects 
discontinue study treatment and device but still remain in the study by treatment and by visit for the 26-week 
treatment period.  Safety measures will also be listed for those patients who discontinue study treatment but still 
remain in the study for safety monitoring purpose. These listings will contain data after the patients discontinue 
study treatment.  For treatment comparisons of frequency and proportion of event variables (such as AEs and 
hypoglycemia events), the conventional Fisher’s exact test or Pearson’s chi-square test are appropriate to use. 
Hypoglycemia:  (documented [documented symptomatic, asymptomatic, and unspecified], severe, and nocturnal 
episodes):  The rate per 30 days calculated between 2 visits is defined as the total number of episodes for all subjects 
between the visits divided by the total actual number of exposure days between the visits, and then multiplied by 
30 days.  A similar definition will be used to calculate the rate per subject per 365 days (year).  For documented 
(documented symptomatic, asymptomatic and unspecified), severe, and nocturnal hypoglycemic episodes, the 
following analyses will be conducted.  The incidence and percentage of subjects with at least 1 hypoglycemic event 
will be analyzed using Fisher’s exact test or Pearson’s chi-square test, as appropriate.  The rate of hypoglycemia 
events per 30 days and per 365 days will be analyzed using a repeated-measure negative binomial regression model 
with similar fixed effects as in the primary MMRM analysis model.  Baseline hypoglycemia event rate for the 
corresponding category of the dependent hypoglycemia variable will be included as a covariate, as well as the 
stratification factors. 
Body Weight:  The body weight change will be analyzed separately by MMRM models similar to that which will be
used in the primary analysis for the ARS population.  The model specifications will be adjusted as appropriate.


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7.2. Discussion of Design and Control
After Visit 1 (screening), subjects who meet all of the inclusion criteria (Section 8.1) and none of 
the exclusion criteria (Section 8.2) will remain on their pre-study treatment for a 2 week lead-in 
period at Visit 2 (Week -2).  This lead-in period is intended to stabilize HbA1c related to study 
effect (Gale et al. 2007) and verify actual insulin dose.  Following the lead-in, subjects will be 
randomized at Visit 4 (Week 0) in an open-label fashion based on a 1:1 ratio to U-500R 
treatment by MDI or U-500R treatment by CSII.  A 2-week transition to U-500R by MDI 
administered TID, regardless of insulin or combination thereof at Visit 2 (Week -2) (Section 9.5) 
will begin after randomization (Visit 4 [Week 0]) utilizing the TID algorithm with weekly 
titrations (Section 9.8.2.1).  The transition period is to ensure safe transition to U-500R insulin 
monotherapy from entry insulin (as applicable).  After completion of the 2-week transition 
period, 24-weeks of U-500R delivered by MDI versus CSII will begin.
8.1.
Inclusion Criteria
[2] Current For 2 weeks prior to Visit 1, TDD >200 but ≤600 units of non U-500R 
insulin/analog (basal; premixed; or basal/bolus by any injection device [MDI; 
pens and/or syringe/vial or CSII]) and/or U-500R by MDI with syringe and 
vial.  Type of insulin must be stable for ≥3 months at entry. 
o If TDD of U-500R and other insulins are combined, then insulin other than 
U-500R not to exceed 25% of TDD.
8.2.
Exclusion Criteria
[19] Have used any weight loss drugs (for example, prescription drugs; lorcaserin, 
orlistat, phentermine, phentermine/topiramate, naltrexone/bupropion, or over-
the-counter weight loss medications or herbal supplements) in the 3 months 
prior to Visit 1.
[23] Have cardiac disease with functional status that is New York Heart Association 
(NYHA) Class III or IV per New York Heart Association Cardiac Disease 
Functional Classification [Attachment 4] or have congestive heart failure 
requiring pharmacologic treatment.
9.4. Rationale for Selection of Doses in the Study
Protocol IBHD dosing transition to U-500R MDI and titration regimens for the CSII and MDI 
treatment groups are guided by initial insulin TDD (based on the highest TDD recorded in the 
3 days before Visit 2 4), screening HbA1c (Visit 1), subsequent glucose monitoring, literature 
expert reviews (Lane 2006; Lane et al. 2009; Hirsch 2010, Lane et al. 2010; Segal et al. 2010; 
Reutrakul et al. 2012), efficacy and safety results from one Phase 4 clinical study 
(B5K-US-IBHC [Hood et al, 2015]), results from simulations performed using a systems 
physiology model of diabetes (Entelos PhysioLab® Modeler) based on data from previous 
pharmacodynamics/pharmacokinetics studies (de la Peña et al. 2011) of U-500R and U-100 
Humulin regular insulin) and on expert protocol consultant advice. 


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9.7. Transition to U-500R MDI 
All subjects will administer U-500R MDI delivered TID (40:30:30 unless otherwise noted) 
during the transition period (Weeks 0-2).  Transition to U-500R MDI will follow the criteria 
below in Table IBHD.9.3Table IBHC9.3. Subjects will have their insulin adjusted weekly by the 
investigator using the algorithm from Section 9.8.2.1.
Table IBHCIBHD.9.3. Transition from entry insulin to U-500R MDI
Insulin Regimen (Screening)
HbA1c
(Screening)
Mean SMBG
(Screening to Week -2 0)
Conversion from Screening 
TDD to U-500R TID Dose
Insulin with or without U-500R
>8%
>183 mg/dL
1:1
Insulin with or without U-500R
>8%
≤183 mg/dL
Reduce TDD by 20%
Insulin with or without U-500R
≤8%
--
Reduce TDD by 20%
U-500R only
--
--
1:1
Abbreviations: HbA1c = hemogloblin A1c; SMBG=self-monitored blood glucose; MDI = multiple daily injections; 
TID= three times daily; TDD=total daily dose.
10.4.2. Hypoglycemia
As a secondary objective, the rate/incidence of hypoglycemia will be analyzed and compared 
between treatment groups.  Subjects are encouraged to perform SMBG whenever hypoglycemia 
may be suspected, either by symptoms experienced or perceived increased risk as related to 
dietary intake, physical activity, or inadvertent or atypical insulin dosing.  All subjects will be 
instructed to treat a SMBG ≤70 mg/dL as hypoglycemia by ingesting 15 gram of CHO (for 
example, 4 ounces of juice or 3 to 5 gram glucose tabs).  All subjects will be advised to contact 
the site if they experience severe hypoglycemia or SMBG <50 mg/dL.
Hypoglycemia is defined as ≤70 mg/dL (Seaquist et al. 2013) and categorized as follows:

Documented hypoglycemia
o
Documented symptomatic – an event that: 
1. is accompanied by with signs/symptoms of hypoglycemia, and
2. is accompanied by a measured SMBG concentrations of ≤70 mg/dL.  
12.2. Statistical and Analytical Plans
12.2.1 General Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.
Unless otherwise specified, both safety and efficacy analyses will be conducted on the ARS, 
including those who discontinued study treatment or were rescued.  This set includes all 
randomized patients and is defined based on the intention-to-treat (ITT) principle. Sensitivity 
analysis may be done for the Full Analysis Set (FAS) that includes ARS subjects who received at 
least 1 dose of the U-500R via the administration method to which they were assigned.


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Separate efficacy analyses for primary and key secondary objectives will be conducted by either 
including or excluding post study treatment discontinuation/data based on different FDA 
analyses (see Section 12.2.7). In general, missing data will not be imputed, unless otherwise 
specified (eg, where the multiple imputation method or the LOCF method is mentioned).
Baseline will be the last value obtained at or prior to the randomization, Visit 4 (Week 0), unless 
otherwise stated. 
Separate listings for safety data will also be done for those patients who discontinue study 
treatment but still remain in the study for safety monitoring purpose.  These listings will contain 
data after the patients discontinue the study treatment.
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, unless otherwise 
stated.
Changes 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 changes to the data analysis methods 
described in the protocol, and the justifications, will be described in the clinical study report.  
Additional exploratory analyses of the data will be conducted as deemed appropriate.
12.2.3 Subject Disposition
All subjects who discontinue from the study will be identified, and the extent of their 
participation in the study (discontinuation visit; whether remain in the study after discontinuation 
of study treatment for safety monitoring) will be reported.  If known, a reason for their 
discontinuation will be given.  The primary reasons for discontinuation will be listed for all 
subjects who have entered the study (signed informed consent) and will be summarized for the 
lead-in period.  Reasons for discontinuation of study treatment and study will also be 
summarized by treatment for the ARS, by visit and for overall study.  All of the summaries will 
be broken down by “discontinue study treatment and device but still remain in the study for 
safety monitoring” and “discontinue both study treatment and the study”.  The treatment 
comparison will be based on Fisher’s exact test or Pearson’s chi-square test, as appropriate.  
12.2.5 Concomitant Therapy
Frequencies and percentages of concomitant medication used prior to and after randomization 
(by visit), will be summarized by treatments.  Antihyperglycemic agents will be summarized by 
treatment at entry, randomization, and the end of study.  AHA usage change and AHA mean 
daily-dose change from baseline to the end of study will be summarized by treatment.  Treatment 
comparisons will be conducted.  
12.2.7 Primary Outcome and Methodology
The primary efficacy measure is change from baseline to the 26-week HbA1c value.  The 
primary analysis will be conducted for the All Randomized Set (ARS) population in Group A.  
There will be two primary analysis methods for different purposes as follows.
1. Per FDA’s request, the analysis method will use the copy reference approach to 
impute missing data based on multiple imputations with a pattern mixture model 


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(later referred to as ‘copy reference multiple imputation analysis’).  This analysis 
will include post study treatment discontinuation data.  The reference is all 
observed data from all randomized subjects in the same treatment arm who 
discontinued study treatment but completed the study without missing data.  After 
imputation, an analysis of covariance (ANCOVA) with baseline HbA1c as a 
covariate, treatment (U-500R CSII, U-500R MDI) and the stratification factor (U-
500R at entry versus other insulins) as fixed effects will be used to analyze the 
26-week HbA1c including imputed values. 
If in the reference group mentioned above there is only a limited number of 
subjects and this leads to a failure in performing the proposed multiple imputation 
analysis, the reference will be changed to include all observed data from all 
randomized subjects in the same treatment arm who do not have missing data. 
2. For manuscripts and other non-FDA submission purposes, a MMRM model that 
does not include post study treatment discontinuation data and adjusts for missing 
data through an observed-data-likelihood-based approach will be used.  The 
model will include the following fixed effects:  treatment (U-500R CSII, U-500R 
MDI), weeks on treatment, the interaction between treatment and weeks, and the 
stratification factor (U-500R at entry versus other insulins).  The model will also 
include baseline HbA1c as a covariate. 
As a sensitivity analysis to the missing at random assumption of MMRM model, a 
stress test will be performed.  The missing data are first imputed with the missing 
at random assumption.  Prior to multiple-imputation analysis, in the CSII arm the 
imputed values will be replaced by the imputed value plus delta.  Multiple values 
of delta within a clinically reasonable and meaningful range will be tested to 
assess if the conclusion from the MMRM primary analysis changes.
The primary efficacy measure is change from baseline (last nonmissing value at or prior to the 
treatment starting at randomization) to the 26-week HbA1c value, which will be summarized and 
analyzed using a MMRM approach for the ARS.  The baseline is selected to be the last value on 
or prior to the randomization visit:  Visit 4 (Week 0).  Neither LOCF method nor other 
imputation methods will be used for the outcome measures.  However, LOCF method will be 
used for sensitivity analysis.  The MMRM model adjusts for missing data through an observed-
data-likelihood-based approach.  The model will include the following fixed effects:  treatment 
(U-500R CSII, U-500R MDI), weeks on treatment, the interaction between treatment and weeks, 
and the appropriate stratification factor (nonusers versus users of GLP-1 receptor agonists or 
SGLT2 inhibitors and U-500R at entry versus other insulins).  The model will also include 
baseline HbA1c as a covariate.  An unstructured covariance matrix will be first modeled for the 
repeated measures of each subject.  If the analysis fails to converge, the following variance-
covariance matrix will be used (in order) until one converges:
1.
Heterogeneous compound symmetry;
2.
Compound symmetry;


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3.
First-order autoregressive.
The test for the first primary objective of noninferiority will be performed at the 0.05 
significance level using the LS mean estimate of the difference in change in HbA1c between the 
two treatments at Week 26.  Noninferiority will be established if the upper limit of a 2-sided 95% 
confidence interval (CI) for the difference (U-500R CSII minus U-500R MDI) is below the NIM 
of 0.4%.
Using the LS mean estimate of the difference in change in HbA1c between the 2 treatments, 
superiority will be established if the upper limit of a two-sided 95% CI for the difference 
(U-500R CSII minus U-500R MDI) is below 0.
The following supportive and sensitivity analyses will also be conducted:

If the following sets are different from ARS, then similar copy reference multiple 
imputation and MMRM analyses will be done for the FAS (subjects who were 
randomized and received at least 1 dose of the study insulin through the administration 
method they were assigned to), all completer set (subjects who complete the study 
treatment), and the per-protocol population (subjects included in the ARS who have 
completed the study without important protocol deviations that will impact the primary 
outcome).

An ANCOVA model with similar fixed effects as in the copy reference multiple 
imputation analysis using LOCF method for the ARS will also be performed.

If the following sets are different from ARS, then similar MMRM analyses will be done 
for the FAS (subjects who were randomized and received at least 1 dose of the study 
insulin through the administration method they were assigned to), all completer set 
(subjects who complete the study), and the per-protocol population (subjects included in 
the ARS who have completed the study without significant protocol violations).

An “analysis of covariance” model with similar fixed effects as in the MMRM analysis 
using LOCF method for the ARS.

For the analysis performed for the total study population (Groups A and B), the analysis 
model will include additional stratification factor (nonusers versus users of GLP-1 
receptor agonists or SGLT2 inhibitors) as fixed effect.
12.2.8 Secondary Efficacy Analyses
Similar to the primary analysis, two sets of analysis approaches (copy reference multiple 
imputation and MMRM) will be used to analyze the change from baseline for the following key 
secondary endpoints 1 and 2 at Week 26.  For endpoint 3, only MMRM analysis will be 
performed.
1) FPG (by laboratory measurement)
2) 7-point SMBG
3) Total Daily Insulin dose (TDD)


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The MMRM or ANCOVA models will include terms similar to those in the primary analysis 
with the appropriate stratification factors as fixed effect, with the corresponding baseline 
measures included as a covariate.  
Similar to the primary analysis, two sets of analysis approaches (repeated-measure logistic
regression excluding post study treatment discontinuation data and the multiple imputations 
based logistic regression including post study treatment discontinuation data) will be applied to 
assess the following secondary objectives in the following values at Week 26:

Proportions of subjects achieving HbA1c targets/values (≤6.5%, <7.0%, <7.5%, and 
<8.0%). 

Proportions of subjects achieving HbA1c targets/values (≤6.5%, <7.0%, <7.5%, and 
<8.0%) without documented symptomatic hypoglycemia (SMBG <50 mg/dL)
The logistic regression model will include similar fixed effects as in the above ANCOVA and 
MMRM models.  The proportion of subjects achieving HbA1c targets with no documented 
symptomatic hypoglycemia (from baseline to the corresponding visit) will be analyzed using 
similar logistic regression models including the baseline documented symptomatic hypoglycemia 
event rate as a covariate.
Similar MMRM models for the ARS will be used to analyze the change from baseline for the 
following values at week 26:
1)
FPG (by laboratory measurement)
2)
7-point SMBG
3)
Total Daily Insulin dose (TDD)
Baseline values will be the last value obtained for each subject at or prior to the randomization 
visit: Visit 4, unless otherwise stated.  The MMRM model will include similar fixed effects as in 
the primary analysis, with the corresponding baseline measures included as a covariate.  The 
model specifications will be carefully adjusted as appropriate.
For the following values at week 26:

Proportions of subjects achieving HbA1c targets/values (≤6.5%; <7.0%; <7.5% and 
<8.0%). 

Proportions of subjects achieving HbA1c targets/values (≤6.5%; <7.0%; <7.5% and 
<8.0%) without documented symptomatic hypoglycemia (SMBG <50 mg/dL).
Treatment comparisons will be analyzed using a repeated-measure logistic regression model 
including subject to account for the repeated measurements and similar fixed effects as in the 
above MMRM models.  The proportion of subjects achieving HbA1c targets with no 
documented symptomatic hypoglycemia (from baseline to the corresponding visit) will be 
analyzed using a similar repeated-measure logistic regression model including the baseline 
documented symptomatic hypoglycemia event rate as a covariate. 


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12.2.9.1.1 TRIM-D and TRIM-DD
The TRIM-D and TRIM-DD will be administered at Visit 4 (Week 0, prior to randomization), at 
Visit 13 (Week 14) and at Visit 17 (Week 26) or ET if subjects do not complete the full 26 weeks 
of the study.
Summaries of the domain and overall scores will include sample size, mean, SD, median, 
minimum, maximum, LS mean and standard error (SE) of LS mean.  The changes from baseline 
in domain scores and total scores of TRIM-D and TRIM-DD will be analyzed using MMRM 
model (with terms similar to the primary/secondary analyses).  For change from baseline, LS 
means and SE of LS means will be reported by treatment group.  For treatment difference of 
change, LS means, SE of LS means, 95% CI, and p-value will be reported.
12.2.9.3. Functionality and Safe Use of the OmniPod U-500 System
The functionality and safe use of the OmniPod U-500 system will be evaluated by an assessment 
of device complaint data, and subject-reported hazard alarms, and clinically relevant 
hyperglycemia possibly related to site occlusion.  Lilly should be contacted for CSII device 
complaints and will provide the data to be listed.  The reported hazard alarms as well as the 
“Infusion Site Change” from the diary will be listed also. 
12.2.10 Safety Analyses 
As stated in Section 6.2, all of the secondary objectives will be analyzed for Group A and for the 
total study population (Groups A and B combined). Safety measures will include hypoglycemic 
events, body weight, AEs and TEAEs, vital signs (systolic and diastolic blood pressures and 
pulse), study treatment exposure, and laboratory measures.  As stated in Section 12.2.1, all safety 
measures will be summarized for ARS including the data after subjects discontinue study 
treatment and device but still remain in the study by treatment and by visit for the 26-week 
treatment period.  Safety measures will also be listed for those patients who discontinue study 
treatment but still remain in the study for safety monitoring purpose.  These listings will contain 
data after the patients discontinue the study treatment.  For treatment comparisons of frequency 
and proportion of event variables (such as AEs and hypoglycemia events), the conventional 
Fisher’s exact test or Pearson’s chi-square test are appropriate to use.  Further details of analyses 
will be provided in the SAP. 
12.2.10.1. Hypoglycemia
The rate per 30 days calculated between 2 visits is defined as the total number of episodes for all 
subjects between the visits divided by the total actual number of exposure days between the 
visits, and then multiplied by 30 days.  A similar definition will be used to calculate the rate per 
subject per 365 days (year).
For documented (documented symptomatic, asymptomatic and unspecified), severe and 
nocturnal hypoglycemic episodes, the following analyses will be conducted.  The incidence and 
percentage of subjects with at least 1 hypoglycemic event will be analyzed using Fisher’s exact 
test or Pearson’s chi-square test, as appropriate.  The rate of hypoglycemic events per 30 days 
and per 365 days will be analyzed using a repeated-measure negative binomial regression model 


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with similar fixed effects as in the primary MMRM analysis model.  Baseline hypoglycemic 
event rate for the corresponding category of the dependent hypoglycemia variable will be 
included as a covariate, as well as the stratification factors.  
12.2.10.2. Body Weight
Baseline values used for the weight analysis will be obtained for each subject at or prior to 
randomization.  The body weight change will be analyzed by MMRM models similar to that 
which will be used in the primary analysis for the ARS population.  The MMRM model will 
include similar fixed and random effects, as in the primary analysis, with the corresponding 
baseline measures included as a covariate.  The model specifications will be adjusted as 
appropriate.
12.2.10.3. Treatment-Emergent Adverse Events and Serious Adverse Events
Adverse events will be listed by subject, system organ class, preferred term, severity, and 
relationship to the study disease, drug, device, or procedure.  Adverse events will be summarized 
as TEAEs during treatment period (defined as events that are newly reported after randomization 
Visit 4 or reported to be worsened in severity from randomization Visit 4) for ARS by treatment 
and visit.  Similar listings will be done for subjects who discontinued study treatment but still 
remain in the study for safety monitoring purpose.  These listings will contain data after the 
patients discontinue the study treatment.
The frequency and proportion of subjects experiencing at least 1 of each reported TEAE will be 
summarized by system organ class, preferred term, and treatment group for treatment period.  
The frequency and proportion comparisons will be analyzed using Fisher’s exact test or 
Pearson’s chi-square test, as appropriate.  The frequency and proportion of subjects experiencing 
at least 1 of each reported TEAE that are assessed as possibly related to the study disease, drug, 
device, or procedures will also be summarized. 
All SAEs (including severe hypoglycemic events) will be listed by subject with similar 
information as the AE listing.  If a sufficient number of SAEs are reported, then a frequency and 
proportion summary, similar to the summary for TEAEs, will be included for the ARS.  
Discontinuations due to TEAEs and SAEs will be listed separately, by subject (including 
information about whether they discontinue only the study treatment or study treatment and the 
study), and summarized (if a sufficient number of events are reported) by treatment.  All of the 
summaries will be broken down by “discontinue study treatment and device but still remain in 
the studyfor safety monitoring” and “discontinue both study treatment and the study.”


Leo Document ID = 1a47d3c8-800f-47f5-92c4-552025d09305
Approver: 
Approval Date & Time: 06-Dec-2016 19:02:18 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 07-Dec-2016 03:00:56 GMT
Signature meaning: Approved
PPD
PPD