Clinical trial NCT02588950
Conditions: Diabetes Mellitus, Type 2
Sponsor: Eli Lilly and Company
Start date: 2016-01-12; Completion date: 2017-05-25
Enrollment: 11 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this two-part study is to measure how much of the study drug gets into the blood stream and how long it takes the body to get rid of it. In Part A, each participant will receive two treatments, a single dose and a single dose with continuous infusion of U-500R insulin, both administered just under the skin. Participants who complete Part A will continue into Part B where they will be assigned to 1 of 2 treatments with U-500R insulin, injected either twice or three times daily under the skin for 5-10 days. This study can last from 7-14 weeks including initial screening and follow up.

Detailed description:

Arms: arm 1: Bolus of U-500R administered via single subcutaneous (SC) injection. arm 2: Bolus of U-500R administered via continuous subcutaneous insulin infusion (CSII). arm 3: U-500R administered thrice-daily (TID) via SC injection under steady state conditions for 5 to 10 days arm 4: U-500R administered twice-daily (BID) via SC injection under steady state conditions for 5 to 10 days
Interventions: intervention 1: U-500R
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
 
Protocol B5K-EW-IBHG(b) 
 
 
Comparative Pharmacokinetics and Pharmacodynamics of Human Regular U-500 Insulin 
Administered Subcutaneously as a Bolus via Syringe versus Continuous Subcutaneous Insulin 
Infusion and Characterization of TID and BID Dosing at Steady State in High-Dose Insulin-Treated 
Subjects with Type 2 Diabetes Mellitus 
 
NCT02588950 
 
Approval Date: 07-Jun-2016 
 
 


B5K-EW-IBHG(b) Protocol
Page 1
Human regular U-500 insulin (LY041001)
1. Protocol B5K-EW-IBHG(b)
Comparative Pharmacokinetics and Pharmacodynamics of 
Human Regular U-500 Insulin Administered 
Subcutaneously as a Bolus via Syringe versus Continuous 
Subcutaneous Insulin Infusion and Characterization of TID
and BID Dosing at Steady State in High-Dose 
Insulin-Treated Subjects with 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 
human regular U-500 insulin (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 -Exemption 4.
Human Regular U-500 Insulin (LY041001)
A Phase 1 (postmarketing), single-center, 2-part, randomized, open-label, 3-period, 
4-sequence, crossover-design euglycemic clamp study in high-dose insulin-treated 
subjects with type 2 diabetes mellitus to compare the pharmacokinetics (PK) and 
pharmacodynamics (PD) of a bolus of 100 U human regular U-500 insulin (U-500 R)
administered by single subcutaneous injection compared to continuous subcutaneous 
insulin infusion (Part A).  Part B will describe the PK and PD of U-500 R at steady state 
administered by multiple daily injections either TID or BID.  
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly: 29 April 2015
Amendment (a) Electronically Signed and Approved by Lilly: 24 August 2015
Amendment (b) Electronically Signed and Approved on approval date provided below:  
Approval Date: 07-Jun-2016 GMT


B5K-EW-IBHG(b) Protocol
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Human regular U-500 insulin (LY041001)
2. Synopsis
Clinical Pharmacology Protocol Synopsis:  Study B5K-EW-IBHG
Name of Investigational Product:  Human regular U-500 insulin (LY041001)
Title of Study:  Comparative Pharmacokinetics and Pharmacodynamics of Human Regular U-500 Insulin 
Administered Subcutaneously as a Bolus via Syringe versus Continuous Subcutaneous Insulin Infusion and 
Characterization of TID and BID Dosing at Steady State in High-Dose Insulin-Treated Subjects with Type 2 
Diabetes Mellitus
Number of Planned Subjects:  Up to 32 subjects 
may be enrolled to ensure approximately 24 complete 
the study
Phase of Development:  1 (postmarketing)
Length of Study:  Ranging from approximately 7 to 13.5 weeks (first screening visit to last follow-up visit)
Objectives:  The primary objective of Part A is to compare the time of maximum drug concentration (tmax) of a 
100-U bolus of human regular U-500 insulin (U-500R) (500 U/mL) administered via single subcutaneous (SC) 
injection versus a 100-U bolus of U-500R administered via continuous SC insulin infusion (CSII) in high-dose 
insulin-treated subjects with type 2 diabetes mellitus (T2DM).
The primary objective of Part B is to evaluate the area under the concentration versus time curve (AUC) from time 
zero to 24 hours postdose (AUC[0-24 hr]), maximum drug concentration (Cmax), and maximum glucose infusion 
rate (GIR) (Rmax) of U-500R at steady state following thrice- (TID) or twice- (BID) daily SC dosing in the study 
population.
The secondary objective of Part A is to compare the time to maximum glucose infusion rate (tRmax) and exposure 
(AUC from time zero to time t, where t is the last time point with a measurable concentration [AUC(0-tlast)]) of a 
100-U bolus of U-500R administered via single SC injection versus CSII in the study population.
The secondary objective of Part B is to evaluate tmax, total amount of glucose infused (Gtot), and the time of 
maximum GIR (tRmax) of U-500R at steady state following TID and BID SC dosing in the study population.  
Exploratory objectives are to evaluate other pharmacokinetic (PK) and pharmacodynamic (PD) parameters 
including, but not limited to half-life associated with the terminal rate constant in noncompartmental analysis (t1/2), 
apparent total body clearance of drug calculated after extra-vascular administration (CL/F), and apparent volume of 
distribution during the terminal phase after extra-vascular administration (Vz/F), the time of last GIR measurement 
(tRlast), the time of first change of GIR postdose (tRonset), the time of 50% of maximum GIR before Rmax (early 
tRmax50) , and the time of 50% of maximum GIR after Rmax (late tRmax50) in the study population in Part A, and
AUC of U-500R over each dosing interval and over each meal at steady state following TID or BID SC dosing in 
the study population in Part B.
Study Design:  This is a Phase 1 (postmarketing), single-center, 2-part, 3-period, 4-sequence, randomized, 
open-label, crossover design study.  In Part A, subjects will receive 100-U bolus of U-500R by SC injection in 
1 period and by CSII with basal infusion in another period (with sequence specified by the randomization 
schedule), prior to undergoing a euglycemic clamp procedure with a maximum duration of 24 hours.  In Part B, 
subjects will be randomized to receive U-500R either TID or BID for 5 to 10 days prior to undergoing a 24-hour 
euglycemic clamp procedure.  
Diagnosis and Main Criteria for Inclusion and Exclusion:  High-dose insulin-treated (U-100, U-200, and/or 
U-300 insulin total daily dose [TDD] ≥150 U/day OR at least 1 dose >100 U as part of a multiple daily injection 
(MDI) regimen AND have TDD ≤3.0 U/kg) males or females with T2DM, ≥18 to <75 years old, with a body mass 
index of ≥27.0 kg/m2, and HbA1c 7.5% to 11.5%, inclusive, at screening.  
Test Product, Dosage, and Mode of Administration:  Human regular U-500 insulin.  Part A: 100 U, given as 
bolus once by single SC injection in 1 period and once by CSII in another period (following a 12-hour 4.25-U/hour 
infusion started 12 hours prior to the CSII bolus and continuing throughout the clamp).  Part B: Individually 
tailored doses given either TID or BID by SC injection in the 5 to 10 days prior to and during Period 3.  
Randomized sequences will be followed for Parts A and B.
Comparator, Dose, and Mode of Administration:  None.  


B5K-EW-IBHG(b) Protocol
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Human regular U-500 insulin (LY041001)
Planned Duration of Treatment:  Screening to occur up to 28 days prior to Period 1.  Part A: 100 U bolus of 
U-500R will be administered once in each of 2 periods with 7 to 21 days between doses.  Part B: U-500R will be 
administered TID or BID for up to 12 days.  Each period will take approximately 2 days. Follow-up will occur 
7 to 28 days after the end of the Period 3 clamp.  Total maximum study duration approximately 13.5 weeks.  
Criteria for Evaluation:  
Safety:  Safety data will include recording of adverse events, hypoglycemic events, self-monitored plasma glucose, 
clinical laboratory evaluations, vital signs, 12-lead electrocardiograms, body weight, and physical examinations.  
Bioanalytical:  Whole blood samples will be collected and analyzed immediately for blood glucose (BG) 
concentration by the euglycemic clamp device/method.  Blood samples will be collected for the determination of 
serum immunoreactive insulin and C-peptide concentrations for up to 24 hours after dose administration in Part A 
and for 24 hours in Part B.  
Pharmacokinetic/Pharmacodynamic:  Pharmacokinetic parameters will be evaluated by standard 
noncompartmental methods of PK analysis.  The primary PK parameter in Part A will be tmax.  Other 
noncompartmental parameters such as Cmax, AUC from time zero to infinity (AUC[0-∞]), AUC(0-tlast), t1/2, CL/F, 
and Vz/F may be reported, as appropriate.  The primary PK parameters for Part B will be AUC(0-24) and Cmax;
other parameters such as tmax and AUC of U-500R over each dosing interval and over each meal at steady state 
may also be reported, as appropriate.  
Pharmacodynamic parameters will be derived from the glucose clamp data. Blood samples will be obtained during 
the euglycemic glucose clamp procedure for analysis of whole BG. Glucose infusion rates will be adjusted to 
maintain euglycemia with the documented GIRs over time, providing the primary PD measure of insulin action. 
Glucose infusion rates will be used to calculate several PD parameters in each part of the study, including Gtot, 
Rmax, tRmax, and tRlast.  Other parameters, such as tRonset, early tRmax50, and late tRmax50, may be reported.  
Parameters will be individually calculated for each subject and presented by summary statistics.  
Statistical Evaluation Methods:  
Safety:  The parameters will be listed and summarized using standard descriptive statistics as appropriate.  
Additional analysis will be performed if warranted upon review of the data.  
Pharmacokinetic/Pharmacodynamic:  For Part A, the primary parameter for statistical analysis will be tmax.  The 
values for tmax will be log-transformed and evaluated in a linear mixed-effects model with fixed effects for 
administration method, period and sequence (sequences 1 and 3, versus 2 and 4), and a random effect for subject.  
The difference in least squares means along with the 90% confidence interval (CI) will be back-transformed to 
present the ratios of geometric means and the CI for comparison of the administration methods (single SC injection 
and CSII).  This same analysis will be repeated for AUC(0-tlast), AUC(0-∞), and Cmax, and the PD parameters 
(Rmax and Gtot).  
The values for tmax will also be analyzed non-parametrically using a Wilcoxon signed-rank test. Median 
differences and approximate 90% CIs for the difference will be calculated for comparison of the administration 
methods (single SC injection and CSII).  
For Part A, the values of tRmax will be analyzed non-parametrically using a Wilcoxon signed-rank test as described 
above.  Other PD time parameters will be analyzed non-parametrically.  
Exploratory analyses may be performed for other PK and PD parameters as deemed appropriate.  
Descriptive statistics will be reported for other PK and PD parameters in Part A and all PK and PD parameters in 
Part B.  


B5K-EW-IBHG(b) Protocol
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Human regular U-500 insulin (LY041001)
3. Table of Contents
Comparative Pharmacokinetics and Pharmacodynamics of 
Human Regular U-500 Insulin Administered Subcutaneously 
as a Bolus via Syringe versus Continuous Subcutaneous 
Insulin Infusion and Characterization of TID and BID Dosing 
at Steady State in High-Dose Insulin-Treated Subjects with 
Type 2 Diabetes Mellitus
Section
Page
1.
Protocol B5K-EW-IBHG(b) Comparative Pharmacokinetics and 
Pharmacodynamics of Human Regular U-500 Insulin Administered 
Subcutaneously as a Bolus via Syringe versus Continuous 
Subcutaneous Insulin Infusion and Characterization of TID and BID 
Dosing at Steady State in High-Dose Insulin-Treated Subjects with 
Type 2 Diabetes Mellitus ....................................................................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................4
4.
Abbreviations and Definitions...........................................................................................10
5.
Introduction ......................................................................................................................14
5.1.
General Introduction ....................................................................................................14
5.2.
Rationale and Justification for the Study ......................................................................16
6.
Objectives.........................................................................................................................17
6.1.
Primary Objective ........................................................................................................17
6.2.
Secondary Objective ....................................................................................................17
6.3.
Exploratory Objective ..................................................................................................17
7.
Investigational Plan...........................................................................................................18
7.1.
Summary of Study Design............................................................................................18
7.1.1.
Screening Visit.....................................................................................................19
7.1.2.
Part A (Study Periods 1 and 2) .............................................................................19
7.1.3.
Part B (Study Period 3) ........................................................................................20
7.1.4.
Blood Glucose Monitoring...................................................................................20
7.2.
Discussion of Design and Control ................................................................................21
8.
Study Population...............................................................................................................22
8.1.
Criteria for Enrollment .................................................................................................22
8.1.1.
Inclusion Criteria .................................................................................................22
8.1.2.
Exclusion Criteria ................................................................................................23
8.1.3.
Rationale for Exclusion of Certain Study Candidates ...........................................25


B5K-EW-IBHG(b) Protocol
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Human regular U-500 insulin (LY041001)
8.2.
Discontinuation............................................................................................................26
8.2.1.
Discontinuation of Subjects..................................................................................26
8.2.1.1.
Subjects Inadvertently Enrolled ......................................................................26
8.2.1.2.
Discontinuations from Investigational Product and from 
the Study ........................................................................................................26
8.2.1.3.
Subjects Lost to Follow-up .............................................................................27
8.2.2.
Discontinuation of Study Sites .............................................................................27
8.2.3.
Discontinuation of the Study................................................................................28
9.
Treatment..........................................................................................................................29
9.1.
Treatment Materials and Supplies.................................................................................29
9.2.
Treatment Administration ............................................................................................29
9.3.
Rationale for Selection of Dose....................................................................................31
9.4.
Dose Conversion from Prestudy Insulin in Part B.........................................................32
9.4.1.
TID Treatment Group Titrations...........................................................................33
9.4.2.
BID Treatment Group Titrations ..........................................................................36
9.5.
Specific Restrictions/Requirements ..............................................................................37
9.6.
Blinding .......................................................................................................................38
9.7.
Concomitant Therapy...................................................................................................38
10.
Sample Collection and Safety Data Collection ..................................................................40
10.1. Laboratory Samples .....................................................................................................40
10.2. Samples for Pharmacokinetic and Pharmacodynamic Evaluations................................40
10.2.1.
Pharmacokinetic Samples.....................................................................................40
10.2.2.
Bioanalysis...........................................................................................................40
10.2.3.
Pharmacodynamic Evaluations (Glucose Clamp Procedure).................................41
10.3. Samples for Biomarker Research..................................................................................41
10.4. Safety Evaluations........................................................................................................41
10.4.1.
Safety Measures...................................................................................................42
10.4.2.
Adverse Events ....................................................................................................42
10.4.3.
Serious Adverse Events........................................................................................43
10.4.3.1.
Suspected Unexpected Serious Adverse Reactions..........................................44
10.4.4.
Hypoglycemia......................................................................................................44
10.4.5.
Other Safety Measures .........................................................................................45
10.4.5.1.
Physical Examination .....................................................................................45
10.4.5.2.
Vital Signs......................................................................................................45
10.4.5.3.
Body Weight ..................................................................................................46
10.4.5.4.
Electrocardiograms.........................................................................................46
10.4.6.
Safety Monitoring ................................................................................................46
10.4.7.
Complaint Handling.............................................................................................47


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Human regular U-500 insulin (LY041001)
10.5. Appropriateness and Consistency of Measurements......................................................47
10.6. Compliance..................................................................................................................47
11.
Sample Size and Data Analyses ........................................................................................48
11.1. Determination of Sample Size ......................................................................................48
11.2. Data Analysis Plans......................................................................................................48
11.2.1.
General Considerations ........................................................................................48
11.2.2.
Study Participant Disposition ...............................................................................48
11.2.3.
Study Participant Characteristics ..........................................................................48
11.2.4.
Pharmacokinetic Analyses....................................................................................49
11.2.4.1.
Pharmacokinetic Parameter Estimation...........................................................49
11.2.4.2.
Pharmacokinetic Statistical Inference .............................................................49
11.2.5.
Pharmacodynamic Analyses.................................................................................49
11.2.5.1.
Pharmacodynamic Parameter Estimation ........................................................49
11.2.5.2.
Pharmacodynamic Statistical Inference...........................................................49
11.2.6.
Safety Analyses....................................................................................................50
11.2.6.1.
Clinical Evaluation of Safety..........................................................................50
11.2.6.2.
Statistical Evaluation of Safety.......................................................................50
11.3. Interim Analyses ..........................................................................................................50
12.
Data Management Methods...............................................................................................51
12.1. Data Quality Assurance................................................................................................51
12.2. Data Capture Systems ..................................................................................................51
12.2.1.
Source Data and Case Report Form......................................................................51
12.2.2.
Ancillary Data......................................................................................................52
13.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................53
13.1. Informed Consent.........................................................................................................53
13.2. Ethical Review.............................................................................................................53
13.3. Regulatory Considerations ...........................................................................................53
13.3.1.
Investigator Information.......................................................................................54
13.3.2.
Protocol Signatures ..............................................................................................55
13.3.3.
Final Report Signature .........................................................................................55
14.
References ........................................................................................................................56


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Human regular U-500 insulin (LY041001)
List of Tables
Table
Page
Table IBHG.7.1.
Dosing Schedule.....................................................................................18
Table IBHG.9.1.
Investigational Product Regimens...........................................................29
Table IBHG.9.2.
TID and BID Dosing Algorithms for U-500R Using 
Plasma-Equivalent Glucose Values.........................................................33


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Human regular U-500 insulin (LY041001)
List of Figures
Figure
Page
Figure IBHG.7.1.
IBHG study design .................................................................................19


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Human regular U-500 insulin (LY041001)
List of Attachments
Attachment
Page
Attachment 1.
Protocol IBHG Study Schedule ..............................................................58
Attachment 2.
Protocol IBHG Clinical Laboratory Tests ...............................................64
Attachment 3.
Protocol IBHG Blood Sampling Summary .............................................65
Attachment 4.
World Health Organization (WHO) Classification Of Diabetes...............66
Attachment 5.
Protocol Amendment B5K-EW-IBHG(b) Summary Comparative 
Pharmacokinetics and Pharmacodynamics of Human Regular 
U-500 Insulin Administered Subcutaneously as a Bolus via 
Syringe versus Continuous Subcutaneous Insulin Infusion and 
Characterization of TID and BID Dosing at Steady State in 
High-Dose Insulin-Treated Subjects with Type 2 Diabetes Mellitus........67


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Human regular U-500 insulin (LY041001)
4. Abbreviations and Definitions
Term
Definition
ADA
American Diabetes Association
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 AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.
AHA
antihyperglycemic agent
AUC
area under the concentration versus time curve
AUC(0-∞)
area under the concentration versus time curve from time zero to infinity
AUC(0-24)
area under the concentration versus time curve from time zero to 24 hours postdose
AUC(0-tlast)
area under the concentration versus time curve from time zero to time t, where t is the last 
time point with a measurable concentration
BG
blood glucose
BID
twice daily
BMI
body mass index
CI
confidence interval
CL/F
apparent total body clearance of drug calculated after extra-vascular administration
Cmax
maximum drug concentration
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.
CRF/eCRF
case report form/electronic case report form:  Sometimes referred to as clinical report form.  
A printed or electronic form for recording study participants’ data during a clinical study, as 
required by the protocol.
CRP
clinical research physician:  Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research scientist, 
global safety physician, or other medical officer.
CRU
clinical research unit


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Human regular U-500 insulin (LY041001)
CSE
clinically significant event:  A moderate to severe adverse event (AE), abnormal clinical 
sign, or clinical laboratory finding that may pose a risk to the well-being of the subject.
CSII
continuous subcutaneous insulin infusion
early tRmax50
time of 50% of maximum glucose infusion rate (GIR) before maximum GIR (Rmax)
ECG
electrocardiogram
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 subject.
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.
ERB/IRB
ethical review board/institutional review board:  A board or committee (institutional, 
regional, or national) composed of medical professionals and nonmedical members whose 
responsibility is to verify that the safety, welfare, and human rights of the subjects
participating in a clinical trial are protected.
FSH
follicle-stimulating hormone
GCP
good clinical practice:  A standard for the design, conduct, performance, monitoring, 
auditing, recording, analyses, and reporting of clinical trials that provides assurance that the 
data and reported results are credible and accurate, and that the rights, integrity, and 
confidentiality of trial subjects are protected.
GIR
glucose infusion rate
Gtot
total amount of glucose infused
HbA1c
hemoglobin A1c
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Conference on Harmonisation
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.  
interim analysis
An interim analysis is an analysis of clinical trial data, separated into treatment groups, that 
is conducted before the final reporting database is created/locked.


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Human regular U-500 insulin (LY041001)
IP
investigational product:  A pharmaceutical form of an active ingredient or placebo being 
tested or used as a reference in a clinical trial, including products already on the market 
when used or assembled (formulated or packaged) in a way different from the authorized 
form, or marketed products used for an unauthorized indication, or marketed products used 
to gain further information about the authorized form.
investigator
A person responsible for the conduct of the clinical trial at a trial site.  If a trial is conducted 
by a team of individuals at a trial site, the investigator is the responsible leader of the team 
and may be called the principal investigator.
IRI
immunoreactive insulin
late tRmax50
time of 50% of maximum glucose infusion rate (GIR) after Rmax
legal 
representative
An individual or judicial or other body authorized under applicable law to consent, on 
behalf of a prospective subject, to the subject’s participation in the clinical trial.
MET
metformin
MDI
multiple daily injection
open-label
A study in which there are no restrictions on knowledge of treatment allocation, therefore 
the investigator and the study participant are aware of the drug therapy received during the 
study.
PD
pharmacodynamic(s)
PG
plasma glucose
PK
pharmacokinetic(s)
QTc
corrected QT interval
randomize
The process of assigning subjects to an experimental group according to the randomization 
schedule for the trial.
re-screen
To screen a subject who was previously declared a screen failure for the same study.  
Rmax
maximum GIR
SAE
serious adverse event:  Any untoward medical occurrence that at any dose results in death, 
is life-threatening, requires inpatient hospitalization or prolongation of existing 
hospitalization, results in persistent or significant disability/incapacity, or is a congenital 
anomaly/birth defect.
SC
subcutaneous(ly)
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 trial.  In this study, screening 
involves invasive or diagnostic procedures and/or tests (such as 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.


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Human regular U-500 insulin (LY041001)
SGLT2
sodium-glucose co-transporter-2
SMPG
self-monitored plasma glucose
subject
A study participant who has the disease or condition for which the investigational product is 
targeted.
SUSAR
suspected unexpected serious adverse reaction
t1/2
half-life associated with the terminal rate constant in noncompartmental analysis
T1DM
type 1 diabetes mellitus
T2DM
type 2 diabetes mellitus
TDD
total daily dose
TID
thrice daily
tmax
time of Cmax
TPO
third party organization
tRlast
time of last glucose infusion rate (GIR) measurement
tRmax
time of maximum glucose infusion rate (GIR)
tRonset
time of first change of glucose infusion rate (GIR) postdose
U-100R
human regular U-100 insulin
U-500R
human regular U-500 insulin
U-500 OmniPod
U-500 OmniPod Insulin Management System
USPI
United States package insert
Vz/F
apparent volume of distribution during the terminal phase after extra-vascular 
administration  
WHO
World Health Organization


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Human regular U-500 insulin (LY041001)
Comparative Pharmacokinetics and Pharmacodynamics of 
Human Regular U-500 Insulin Administered Subcutaneously 
as a Bolus via Syringe versus Continuous Subcutaneous 
Insulin Infusion and Characterization of TID and BID Dosing 
at Steady State in High-Dose Insulin-Treated Subjects with 
Type 2 Diabetes Mellitus
5. Introduction
5.1.
General Introduction
As obesity and insulin resistance become more prevalent, insulin dose requirements in diabetes 
mellitus patients are rising (Segal et al. 2010). Patients treated with high doses (and therefore 
high volumes) of U-100 insulin may require up to 8 or more daily injections. The use of 
concentrated human regular U-500 insulin (U-500R; 500 U/mL) allows a large dose to be 
administered in one-fifth the volume as compared to the U-100 concentration (100 U/mL) 
(Humulin-R U-500 Package Insert, 2014). Accordingly, there has been a steady increase in the 
number of U-500R prescriptions written per month in recent years (Lane et al. 2009; Segal et al. 
2010; de la Peña et al. 2011).
Human regular U-500 insulin is indicated for use in the treatment of severely insulin-resistant 
patients with diabetes requiring insulin daily doses >200 U. The United States package insert 
(USPI) advises administration via subcutaneous (SC) injection and states that Humulin-R U-500 
is usually given 2 or 3 times daily before meals.  However, a recent real-world large U.S. 
database study reported that over a quarter of patients treated with U-500R receive it via 
off-label continuous SC insulin infusion (CSII) (Eby et al. 2014).  A review and meta-analysis of 
case series of patients treated with U-500R by Reutrakul et al. (2012) reported on outcomes in 
55 patients who used U-500R via CSII. In the mean follow-up time of 3 to 30 months after 
initiation of U-500R via CSII, hemoglobin A1c (HbA1c) significantly decreased by a mean of 
1.64%, which was similar to the findings with U-500R administered by multiple daily injections 
(MDIs) (mean decrease in HbA1c of 1.59%). Patients treated with U-500R CSII achieved 
glycemic improvement with a nonsignificant decrease in total daily dose (TDD) of 13.6 U from 
U-100 insulin dose at baseline, in contrast to the MDI patients who had a statistically significant 
mean increase in TDD of 51.9 U from baseline U-100 insulin dose. 
Clinical experience has shown that a single SC dose of U-500R frequently has time-action 
characteristics reflecting both prandial and basal activity.  It takes effect 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.  
This effect has been attributed to the high concentration of the preparation (Humulin-R U-500 
package insert, 2014).
In healthy obese subjects with mean body mass index (BMI) 34.4 ± 2.6 kg/m2
(Study B5K-EW-IBHA; de la Peña et al. 2011), U-500R administered by single SC injection as 


B5K-EW-IBHG(b) Protocol
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Human regular U-500 insulin (LY041001)
50- or 100-U doses (0.4 to 0.6 and 0.8 to 1.3 U/kg, respectively) resulted in similar overall 
exposure (area under the concentration versus time curve [AUC] from time zero to return to 
baseline) to that observed after administration of equal doses of U-100R, although maximum 
observed drug concentrations (Cmax) were lower.  Findings in the pharmacodynamic (PD)
parameters generally reflected the pharmacokinetic (PK) findings, with similar overall effect 
(total amount of glucose infused [Gtot]) and lower maximum effect (maximum glucose infusion 
rate [Rmax]).  Time of maximum drug concentration (tmax) and the time of maximum effect (time 
of maximum glucose infusion rate [tRmax]) were significantly longer for U-500R compared to 
U-100R at only the 100-U dose.  Duration of action (time of last glucose infusion rate
measurement [tRlast]) and effect after the peak (time of 50% of maximum glucose infusion rate 
after Rmax [late tRmax50]) were significantly prolonged for U-500R versus U-100R at both doses.  
The only published PK study of U-500R in obese patients with type 2 diabetes mellitus (T2DM)
with severe insulin resistance was a small non-clamp study conducted by Davidson et al. (2010). 
Nine severely insulin-resistant obese patients with T2DM and poor glycemic control were given 
SC boluses of 100 U of U-500R.  Onset of action took place in 30 minutes or less with peak 
insulin levels at 5 hours and persistent elevation of insulin concentration was observed 7 hours 
postdose. The minimum time to reach a target plasma glucose (PG) level of less than 100 mg/dL 
(5.6 mmol/L) ranged from 3 to more than 7 hours (Davidson et al. 2010).
Recently, in order to predict steady-state PK/PD of high-dose U-500R, de la Peña et al. (2014) 
conducted a modeling and simulation study.  The model was built from 3 single-dose, crossover, 
euglycemic clamp PK/PD studies with human regular insulin.  Healthy obese (de la Peña et al. 
2011) and healthy normal-weight subjects, and patients of normal weight with type 1 diabetes 
mellitus (T1DM) participated in the studies.  A 1-compartment, first-order absorption and 
elimination PK model was used and provided independent absorption rate constants for both 
U-500R and U-100R.  An effect compartment model was used to describe the PD parameters 
(maximum pharmacologic effect [Emax] and concentration to achieve 50% Emax).  Human 
regular U-500 insulin PK/PD simulation profiles were performed for once-daily, twice-daily 
(BID), and thrice-daily (TID) dosing regimens (de la Peña et al. 2014).  
All 3 dosing regimens were predicted to achieve steady state PK by 24 hours after the initial 
insulin dose.  At steady state, the greatest fluctuations in PK/PD parameters were observed with 
once-daily dosing.  Conversely, BID dosing resulted in an increase in insulin concentration and 
effect with each dose and a stable basal effect while TID dosing resulted in sustained effects 
between doses.  Similar to the findings of de la Peña et al. (2011), the U-500R PK/PD simulation 
modeling study indicated the steady state basal PD effect from both BID and TID dosing appears 
to support use of U-500R as insulin monotherapy, without the need for concomitant U-100 basal 
insulin (de la Peña et al. 2014).  
Information on serious adverse events (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 study, may be found in the USPI.


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Human regular U-500 insulin (LY041001)
5.2.
Rationale and Justification for the Study
There have been no state-of-the-art euglycemic clamp PK/PD studies performed on U-500R in 
the target population of high-dose insulin-treated subjects with T2DM, in whom U-500R is most 
often used (Lane et al. 2009; Reutrakul et al. 2012; Jones and Idris 2013; Eby et al. 2013; Eby et 
al. 2014; Cochran et al. 2014).  Likewise, there have been no PK/PD studies conducted on steady
state time-concentration and time-action characteristics of U-500R on any population of subjects.
Rigorous study in both of these settings will address major gaps in scientific knowledge and will
further inform clinicians regarding appropriate use of U-500R in insulin-resistant patients with 
diabetes requiring high doses of insulin.  
Although the findings of studies describing clinical outcomes of off-label treatment with U-500R 
by CSII in patients appear favorable (Lane 2006; Lane et al. 2009; Lane et al. 2010; Reutrakul et 
al. 2012; Jones and Idris 2013; Lane et al. 2013), there are no PK/PD data available regarding
bolus dosing via this method of administration.  Dramatic improvements in continuous glucose 
monitoring patterns and flattening of postprandial PG excursions have been observed after 13 to 
52 weeks of high-dose U-500R therapy (Lane et al. 2010). This raises the possibility that 
U-500R via CSII may have a more rapid onset and perhaps greater prandial effects as compared 
to that observed by de la Peña et al. (2011) for SC bolus injections of U-500R, and by Hood et al. 
(2015) in the recent 24-week randomized clinical trial of U-500R comparing TID with BID 
dosing algorithms in severely insulin-resistant patients with poorly controlled T2DM.
Part A of this study seeks to evaluate and compare the PK and PD characteristics of a 100-U 
insulin dose using U-500R insulin administered via standard SC injection versus bolus 
administration delivered via CSII, with the primary measure being tmax.  Part B of the study will 
evaluate the steady state PK/PD of U-500R administered TID and BID in the target population, 
thus supplementing current PK/PD data obtained from studies in healthy and obese subjects and
enabling validation of predictions made through PK/PD modeling.  


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Human regular U-500 insulin (LY041001)
6. Objectives
6.1.
Primary Objective
Part A:  to compare the tmax of a 100-U bolus of U-500R (500 U/mL) administered via single SC 
injection versus a 100-U bolus of U-500R administered via CSII in high-dose insulin-treated
subjects with T2DM.
Part B: to evaluate the AUC from time zero to 24 hours postdose (AUC[0-24]), Cmax, and Rmax
of U-500R at steady state following TID or BID SC dosing in the study population.
6.2.
Secondary Objective
Part A:  to compare the tRmax and exposure (AUC from time zero to time t, where t is the last 
time point with a measurable concentration [AUC(0-tlast)]) of a 100-U bolus of U-500R 
administered via single SC injection versus CSII in the study population.  
Part B:  to evaluate the tmax, Gtot, and tRmax of U-500R at steady state following TID or BID SC 
dosing in the study population.  
6.3.
Exploratory Objective
Other PK and PD parameters may be evaluated including but not limited to:
Part A: half-life associated with the terminal rate constant in noncompartmental analysis (t1/2), 
apparent total body clearance of drug calculated after extra-vascular administration (CL/F), and 
apparent volume of distribution during the terminal phase after extra-vascular administration 
(Vz/F), tRlast, the time of first change of GIR postdose (tRonset), the time of 50% of maximum 
GIR before Rmax (early tRmax50), and late tRmax50 in the study population.
Part B:  AUC of U-500R over each dosing interval and over each meal at steady state following 
TID or BID SC dosing in the study population.


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Human regular U-500 insulin (LY041001)
7. Investigational Plan
7.1.
Summary of Study Design
This is a 2-part, Phase 1 (postmarketing), single-center, 3-period, 4-sequence, randomized, 
open-label, crossover euglycemic clamp study in high-dose insulin-treated subjects with T2DM.  
Part A (Periods 1 and 2) will compare the PK and PD of a 100-U bolus of U-500R administered 
via single SC injection versus a 100-U bolus of U-500R administered via CSII.  Subjects 
completing Part A will transition to Part B (Period 3), which will evaluate the PK and PD 
characteristics of U-500R administered by TID and BID MDIs under steady-state conditions.  
Up to 32 subjects may be enrolled to achieve a target of approximately 24 completing all 
3 periods of the study.  
Subjects will be randomly assigned to 1 of 4 dosing sequences (Table IBHG.7.1).  Each subject 
will be administered 100 U of U-500R by single SC injection, and 100 U of U-500R by CSII in 
Part A and either TID U-500R or BID U-500R in Part B.  
Table IBHG.7.1.
Dosing Schedule
Part A
Part B
Sequence
Period 1
Period 2
Period 3
1
SC
CSII
TID
2
CSII
SC
BID
3
SC
CSII
BID
4
CSII
SC
TID
Abbreviations:  BID = twice-daily administration of U-500R; CSII = 100 U U-500R administered via continuous 
subcutaneous insulin infusion; SC = 100 U U-500R administered via single subcutaneous injection; 
TID = thrice-daily administration of U-500R.
The study design is illustrated in Figure IBHG.7.1.  


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Human regular U-500 insulin (LY041001)
Figure IBHG.7.1.
IBHG study design
7.1.1.
Screening Visit
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will be enrolled 
into the study.  The screening visit may occur up to 28 days before Day 1 of Period 1.
7.1.2. Part A (Study Periods 1 and 2)
Subjects will be admitted to the clinical research unit (CRU) on Day -1 of each period and be 
fasted from 12 hours prior to clamp initiation until completion of the clamp procedure.  
All subjects will stop their prestudy U-100, U-200, and/or U-300 insulin dosing at least 15 hours 
prior to U-500R bolus dosing.  Subjects randomized to receive U-500R by SC injection will 
receive a 100-U U-500R bolus administration by SC injection prior to initiation of the clamp.  
Subjects randomized to receive U-500R by CSII will have a U-500 OmniPod Insulin 
Management System (U-500 OmniPod) fitted by a qualified member of CRU staff, which will 
administer a 12-hour infusion of 4.25 U/h of U-500R, prior to bolus administration of 100 U of 
U-500R (via the same pump) and initiation of the clamp.  The 4.25-U/h U-500R infusion will 
continue throughout the duration of the clamp following bolus administration by the U-500 
OmniPod.  
Overnight, between Day -1 and Day 1, all subjects will have their PG stabilized, using an insulin 
lispro and/or glucose drip, to a target fasting PG concentration of 120 mg/dL (6.7 mmol/L) (with 
an acceptable range of 100 to 130 mg/dL [5.6 to 7.2 mmol/L]).  
Following bolus dose administration (or initiation of bolus dose administration for CSII),
subjects will undergo a euglycemic clamp with a maximum duration of 24 hours. Following 
completion of the clamp procedures, subjects will be provided a meal and will be medically 
assessed and discharged from the CRU, unless the investigator has any safety concerns.  If 
glucose is still being infused at the time of clamp discontinuation, the subject will be monitored 
for safety and will remain in the CRU until stable according to investigator judgment (see 
Section 10.4.1).  
Blood samples will be collected prior to and during the clamp procedure (see Attachment 1) to 
determine serum immunoreactive insulin (IRI) and C-peptide concentrations for PK and PD 
analysis. 


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Human regular U-500 insulin (LY041001)
Following termination of the clamp procedure in Period 1, subjects will resume their prestudy 
treatment regimen (which may include basal; premixed; and/or basal/bolus U-100, U-200, and/or 
U-300 insulin regimens with or without antihyperglycemic agents [AHAs] as listed in Inclusion 
Criterion [5], Section 8.1.1) until their admission to the CRU on Day -1 of Period 2.  There will 
be a washout period of 7 to 21 days between U-500R bolus doses in Periods 1 and 2.  
Following termination of the clamp procedure in Period 2, subjects will be instructed on 
administration of U-500R either by TID or BID MDIs as described in Section 7.1.3 and 
Section 9.4.  There will be a period of 5 to 10 days between the end of the clamp in Period 2 and 
the clamp procedure in Period 3 to allow U-500R concentrations to reach steady state.
7.1.3. Part B (Study Period 3)
Following termination of the clamp procedure in Period 2, subjects will transition, as randomized,
to TID or BID MDIs of U-500R.  Human regular U-500 insulin will be self-administered by the 
subjects at home under telephone guidance from CRU staff during a telephone visit 2 to 3 days 
after the end of Period 2 (additional telephone or office visits may be added at the investigator’s 
discretion).  Initial U-500R doses will be based on each subject’s insulin TDD prior to admission 
for Period 2, with titration for safety, if necessary, using the formulas given in Section 9.4.  
There will be 5 to 10 days between the end of Period 2 and the clamp in Period 3 (that is, dosing 
will begin on up to Day -10 and no later than Day -5 of Period 3) to allow steady state of the 
U-500R dosing regimen to be achieved. Mean self-monitored plasma glucose (SMPG) will be 
recorded from Day -5 until admission to the CRU.  
Subjects will be admitted to the CRU on Day -1 of Period 3, prior to their pre-evening meal dose,
which will be administered by CRU staff, and undergo fasting, PG stabilization, and a 24-hour 
euglycemic clamp as detailed in Section 7.1.2, with PK sampling as detailed in the Study 
Schedule (Attachment 1).  
Following termination of the clamp procedure in Period 3 (Day 2), subjects will resume their 
prestudy insulin treatment regime.  Discharge from the CRU will be subject to the same 
postclamp safety assessments as detailed in Section 7.1.2 and Section 10.4.1.  Follow-up will 
occur 7 to 28 days after the end of Period 3 when safety procedures will be conducted and insulin 
use and dose will be recorded as detailed in the Study Schedule (Attachment 1).  
7.1.4. Blood Glucose Monitoring
Following Period 2 and prior to the Period 3 clamp, MDI study drug doses will be titrated 
according to subjects’ individual needs, as assessed by SMPG results obtained from monitoring 
at home (subjects will be supplied with the equipment required and trained to conduct SMPG).  
Site personnel may request additional PG monitoring from subjects and/or assess PG values at 
other times in order to make dose adjustment decisions.  
Subjects should record 4-point SMPG measurements and all insulin doses in the subject diary 
provided.  The mean SMPG measurements for the 5 days prior to Day 1 of Period 3 will be 
recorded in the electronic case report form (eCRF).  


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Human regular U-500 insulin (LY041001)
Subjects should be instructed to record 4-point SMPG daily.  The 4-point SMPG consists of PG 
measurements at:

Pre-morning meal (fasting)

Pre-midday meal 

Pre-evening meal

Bedtime (at least 2 hours after the evening meal)
Subjects should also record their 03:00 hours PG readings within 48 hours of any increase in 
insulin dose titration at telephone or office visits.  
During telephone visits, the investigator or site personnel will ask the subject about these PG 
measurements and recommend dosage titrations based on glucose targets within the TID and 
BID algorithms in Section 9.4.  
Missing values in 4-point SMPG profiles that do not reflect noncompliance with the protocol, in 
the opinion of the investigator, will not be considered a protocol deviation.  
7.2.
Discussion of Design and Control
In Part A of this study, a 2-period, randomized, crossover design has been chosen to allow each 
subject to act as his/her own control.  Prestudy U-100, U-200, and/or U-300 insulin will be taken 
at the same dose and at approximately the same time each day prior to Period 1 and between 
Periods 1 and 2, and stopped at least 15 hours prior to U-500R bolus administration in Part A in 
order to reduce variation in insulin carryover (as the bioanalytical methodology is not specific to 
U-500R).  
The use of a euglycemic clamp technique will provide data on the glucodynamic activity of
U-500R.  This is standard methodology routinely used to safely measure insulin action in clinical 
studies.  
High-dose insulin-treated subjects with T2DM are representative of the population that is 
prescribed the U-500R formulation.  An open-label design is considered appropriate as the 
PK/PD parameters being investigated in this study are objective endpoints. 
Fasting and pre-meal plasma-equivalent glucose target ranges in Period 3 are 71 to 130 mg/dL
(3.9 to 7.2 mmol/L), consistent with American Diabetes Association (ADA) standards of care 
(ADA 2012).  
Recommended administration of U-500R bolus doses at least 30 minutes before meals by TID or 
BID dosing is based on USPI advice and PK/PD study results in obese, healthy subjects, which 
demonstrate both prandial and basal activity of U-500R (de la Peña et al. 2011).  
The 5 to 10 days between Period 2 of Part A and the clamp procedure in Part B is expected to 
allow for subject recovery between clamps, for titration of doses, and for steady state to be 
achieved, given the findings of simulation modeling in which either TID or BID dosing steady
state was predicted to be achieved by 24 hours (de la Peña et al. 2014).


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Human regular U-500 insulin (LY041001)
8. Study Population
8.1.
Criteria for Enrollment
Eligibility of subjects for study enrollment will be based on the results of a screening medical 
history, physical examination, vital signs, clinical laboratory tests, and electrocardiogram (ECG). 
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented.
Screening may occur up to 28 days prior to enrollment.  Subjects who are not enrolled within 
28 days of screening may be subjected to an additional medical assessment and/or clinical 
measurements to confirm their eligibility.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
re-screened.  Individuals may be re-screened 1 time.  The interval between screen and re-screen 
should be at least 2 weeks.  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
8.1.1. Inclusion Criteria
Subjects are eligible for enrollment in the study only if they meet all of the following criteria:
[1]
males or females with T2DM (World Health Organization [WHO]
Classification of Diabetes [Attachment 4]; ADA, 2015).
[1a]
female subjects
are women of child-bearing potential who test negative for pregnancy at the time 
of screening based on a serum pregnancy test, and who agree to use a reliable 
method of birth control during the study 
or
are women not of child-bearing potential due to surgical sterilization (at least 6 weeks 
after surgical bilateral oophorectomy with or without hysterectomy or at least 6 weeks 
after tubal ligation) confirmed by medical history, or menopause
menopausal women include women with either
1) spontaneous amenorrhea for at least 12 months, not induced by a medical condition 
such as anorexia nervosa and not taking medications during the amenorrhea that induced 
the amenorrhea (for example oral contraceptives, hormones, gonadotropin releasing 
hormone, anti-estrogens, selective estrogen receptor modulators, or chemotherapy)
or
2) spontaneous amenorrhea for 6 to 12 months and a follicle-stimulating hormone (FSH) 
level greater than 40 mIU/mL


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Human regular U-500 insulin (LY041001)
[2]
are ≥18 to <75 years old at the time of screening
[3]
have a BMI of ≥27.0 kg/m2 at screening
[4]
are current users of U-100, U-200, and/or U-300 insulin/analog as basal, 
premixed, and/or basal/bolus delivered with any injection device (pens and/or 
syringe/vial but excluding CSII/insulin pump use in the preceding 3 months), 
taking:
a TDD of ≥150 U
OR 
at least one dose >100 U as part of an MDI regimen
AND 
TDD ≤3.0 U/kg
[5]
Concomitant AHA therapy may include: 

metformin (MET) 

dipeptidyl peptidase-4 inhibitors

pioglitazone (doses ≤30 mg/day) 

GLP-1 receptor agonists

sodium-glucose co-transporter-2 (SGLT2) inhibitors, except in combination 
with GLP-1 receptor agonists (see Exclusion Criterion [31] for excluded 
AHA therapy).
Subjects’ AHA therapy must have been stable for ≥3 months (except for 
weekly GLP-1 receptor agonists which must have been stable for ≥4 
months).  
[6]
have HbA1c 7.5% to 11.5%, inclusive, as measured at screening  
[7]
have venous access sufficient to allow for blood sampling and intravenous 
administration as per the protocol
[8]
are reliable and willing to make themselves available for the duration of the 
study and are willing and able to follow study procedures
[9]
must be able to safely withhold administration of U-100, U-200, and/or U-300
insulins from ≥15 hours prior to clamp procedures in Periods 1 and 2 as 
applicable, in the judgment of the investigator
[10] have given written informed consent approved by Lilly and the ethical review 
board (ERB) governing the site
8.1.2. Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria:


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Human regular U-500 insulin (LY041001)
[11] are investigator site personnel directly affiliated with this study and their 
immediate families.  Immediate family is defined as a spouse, parent, child, or 
sibling, whether biological or legally adopted.
[12] are Lilly employees 
[13] are currently enrolled in a clinical trial involving an investigational product or 
off-label use of a drug or device, or are concurrently enrolled in any other type 
of medical research judged not to be scientifically or medically compatible 
with this study
[14] have participated, within the last 30 days, in a clinical trial involving an 
investigational product. If the previous investigational product has a long 
half-life, 3 months or 5 half-lives (whichever is longer) should have passed.  
[15] are persons who have withdrawn from this study
[16] have T1DM or other types of diabetes mellitus apart from T2DM (WHO 
Classification of Diabetes [Attachment 4]; ADA 2015)
[17] have known hypersensitivities or allergies to insulin, excipients contained in 
insulin products, or related compounds
[18] have corrected QT interval (QTc) prolongation >500 ms or have any other
abnormality in the 12-lead ECG that, in the opinion of the investigator, 
increases the risks associated with participating in the study
[19] have an abnormal blood pressure for the study population, as determined by 
the investigator
[20] have a significant history of or current cardiovascular, respiratory, hepatic, 
renal, gastrointestinal, endocrine (apart from diabetes), hematological, or 
neurological disorders capable of significantly altering the absorption, 
metabolism, or elimination of drugs; of constituting a risk when taking the 
study medication; or of interfering with the interpretation of data
[21] have known or ongoing psychiatric disorders which in the opinion of the 
investigator might interfere with subject completion of the study or following 
of study procedures
[22] regularly use known drugs of abuse and/or show positive findings on urinary 
drug screening
[23] show evidence of human immunodeficiency virus (HIV) infection and/or 
positive human HIV antibodies
[24] show evidence of hepatitis C and/or positive hepatitis C antibody
[25] show evidence of hepatitis B and/or positive hepatitis B surface antigen
[26] are women who are pregnant
[27] are women who are lactating


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Human regular U-500 insulin (LY041001)
[28] are currently treated with prescription medication (other than those allowed in 
Inclusion Criteria [4] and [5]), herbal medications, or nutritional supplements 
that affect PG or insulin sensitivity, or promote weight loss within 4 weeks 
prior to dosing (Day 1 of Period 1).  Initiation of new over-the-counter 
medication within 7 days prior to dosing, or prescription medications or herbal 
medication within 14 days prior to dosing may be permitted following 
discussion with the Lilly clinical pharmacologist.  Occasional intake of 
acetaminophen or vitamin/mineral supplements will be allowed.  Ongoing 
medications (such as hormonal contraceptives, thyroid replacement therapy, 
anti-hypertensives, low-dose aspirin, or cholesterol-lowering agents) may be 
permitted at unchanged doses (Section 9.7).  
[29] have used systemic glucocorticoids within 4 weeks prior to screening  
[30] have used U-500R within 3 months prior to screening  
[31] have used rosiglitazone, pramlintide, once-weekly or BID exenatide, or other 
injectable or oral AHA not listed in Inclusion Criterion [5] in the 3 months 
prior to screening; or are taking oral antidiabetic medications at doses 
exceeding the respective product labels; or have a contraindication to current 
oral antidiabetic medication usage per the respective product labels (for 
example, MET:  serum creatinine ≥1.4 mg/dL in women or ≥1.5 mg/dL in 
men).  
[32] have donated blood of more than 500 mL within the last month
[33] have an average weekly alcohol intake that exceeds 21 units per week (males 
up to age 65) and 14 units per week (males over 65 and females), or are 
unwilling to stop alcohol consumption for 24 hours prior to each clamp 
procedure and while resident in the CRU (1 unit = 12 oz or 360 mL of beer; 
5 oz or 150 mL of wine; 1.5 oz or 45 mL of distilled spirits)
[34] are smokers who smoke >10 cigarettes or equivalent per day and/or are not 
able or willing to refrain from smoking, using electronic cigarettes or the 
using nicotine replacement therapy (for example, nicotine gum or patches) 
while resident in the CRU
[35] are excessive consumers of xanthines (more than 5 cups of tea, coffee, cola, or 
hot chocolate per day)
[36] have had a blood transfusion or severe blood loss within 3 months prior to 
screening or have known hemoglobinopathy, hemolytic anemia, or sickle cell 
anemia that may affect reliability of HbA1c measurements
[37] in the opinion of the investigator or sponsor, are unsuitable for inclusion in the 
study
8.1.3. Rationale for Exclusion of Certain Study Candidates
Exclusion Criteria 11 and 12 prevent conflict of interest in study participants.  Criteria 13
through 35 and 37 exclude medical conditions, medication intolerance, and concomitant 


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Human regular U-500 insulin (LY041001)
medication use that may constitute a risk for the subject and/or may confound the assessment of 
study endpoints. Criterion 36 addresses issues that could have an impact on HbA1c values that 
are not related to glycemic control. 
8.2.
Discontinuation
The reason for and date of discontinuation will be collected for all subjects.  All enrolled subjects
who discontinue, regardless of whether they received investigational product, will have 
procedures performed as shown in the Study Schedule (Attachment 1).
8.2.1. Discontinuation of Subjects
8.2.1.1.
Subjects Inadvertently Enrolled
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 Lilly clinical pharmacologist or clinical research physician (CRP) and the 
investigator to determine whether the subject may continue in the study, with or without 
investigational product.  Inadvertently enrolled subjects may be maintained in the study and on 
investigational product when the investigator and Lilly clinical pharmacologist or CRP agree it is 
medically appropriate for that subject to continue.  The subject may not continue in the study 
with or without investigational product if the Lilly clinical pharmacologist or CRP does not agree 
with the investigator’s determination it is medically appropriate for the sub ject to continue.  The 
investigator must obtain documented approval from the Lilly clinical pharmacologist or CRP to 
allow the inadvertently enrolled subject to continue in the study with or without investigational 
product.
8.2.1.2.
Discontinuations from Investigational Product and from the Study
Subjects will be discontinued from the investigational product and from the study in the 
following circumstances:

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.

If the subject’s body weight varies by more than 5 kg between the clamp procedures in 
Periods 1 and 2.  

Investigator Decision.
o
The investigator or attending physician decides that the subject should be 
discontinued from the study.
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 other agent.


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Human regular U-500 insulin (LY041001)
o
If the investigator determines that the subject is significantly noncompliant with 
study drug, glucose monitoring, completion of the subject diary, or other study 
procedures, and should be discontinued.

Subject Decision
o
the subject requests to be discontinued from the study

Sponsor Decision
o
Lilly 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 a clinically significant event (CSE) occurs, the investigational product is to be 
discontinued and appropriate measures taken.  Lilly or its designee should be 
alerted immediately.  A CSE will be defined as a moderate to severe adverse 
event (AE), abnormal clinical sign, or clinical laboratory finding that may pose a 
risk to the well-being of the subject.  Refer to Safety Evaluations Section
(Section 10.4).
o
A clinically significant systemic hypersensitivity reaction occurs follow ing 
administration of the investigational product (for example, drug-related 
symptomatic bronchospasm, allergy-related edema/angioedema, or hypotension), 
that requires parenteral medication, does not respond to symptomatic medication, 
or results in clinical sequelae or an anaphylactic reaction.
Following the investigator’s determination that CSE criteria have been met and the investigator’s 
judgment of relatedness to the investigational product is documented, a decision will be made 
between the investigator and Lilly or its designee regarding subject discontinuation.
The nature of any conditions, clinical signs or symptoms, or abnormal laboratory values present 
at the time of discontinuation and any applicable follow-up procedures will be documented.  
Refer to the Study Schedule (Attachment 1) for data collected at the time of discontinuation and 
follow-up.
8.2.1.3.
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.
8.2.2. Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ERB of the study 
site judges it necessary for any reason consistent with applicable laws, regulations, and GCP.


B5K-EW-IBHG(b) Protocol
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Human regular U-500 insulin (LY041001)
8.2.3. 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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Human regular U-500 insulin (LY041001)
9. Treatment
9.1.
Treatment Materials and Supplies
This study involves a comparison of a 100-U bolus of U-500R administered by single SC 
injection versus administration via CSII and evaluation of U-500R administered SC TID and 
BID.  Table IBHG.9.1 shows the treatment regimens.  
Table IBHG.9.1.
Investigational Product Regimens 
Regimen
Dose
Administration route
Time of 
administration
Part A
U-500R SC bolus
100-U
Single SC injection
Prior to initiation of 
euglycemic clamp
U-500R basal infusion plus 
U-500R CSII bolus
4.25 U/h basal and 
100-U bolus
CSII
12 hour infusion of 
4.25 U/h U-500R 
prior to 100-U bolus 
dose and initiation 
of euglycemic
clamp (with 
continued 4.25-U/h 
U-500R infusion)
Part B
U-500R TID 
Per titration algorithm 
(TID, injectable 
solution)
Multiple daily SC 
injection
Recommended 
07:00, 12:00, and 
18:00 hours, 
approximately 
30 minutes prior to 
morning meal, 
midday meal, and 
evening meal, 
respectivelya  
U-500R BID
Per titration algorithm 
(BID, injectable 
solution)
Multiple daily SC 
injection
Recommended 
07:00 and 
18:00 hours, 
approximately
30 minutes prior to 
morning meal and 
evening meal, 
respectivelya
Abbreviations:  BID = twice daily; CSII = continuous subcutaneous insulin infusion; SC = subcutaneous; 
TID = thrice daily; U-500R = human regular U-500 insulin.  
a
If a meal is skipped, insulin dose should be reduced by 50%.
9.2.
Treatment Administration
The investigator or designee is responsible for:

explaining the correct use of the investigational product to the subjects and site personnel, 

verifying that instructions are followed properly,


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Human regular U-500 insulin (LY041001)

maintaining accurate records of investigational product dispensing and collection,

and returning all unused medication 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 clinical trial materials.  
Subjects will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product or drug delivery system so that the 
situation can be assessed.
All clinical trial material provided to the investigator will be stored in a secure place and 
allocated and dispensed by appropriately trained persons.  The allocation and dispensing of the 
investigational products will be fully documented and verified by a second person.  Detailed 
records of the amounts of the investigational product received, dispensed, and remaining at the 
end of the study will be maintained.  Not in-use or unopened Humulin R U-500 vials should be 
stored in a refrigerator, (2°C to 8°C [36° F 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, even if they still 
contain U-500R (Humulin R U-500 Package Insert, 2014). Clinical trial materials will be 
labeled according to the respective country’s regulatory requirements.
During periods of prestudy U-100, U-200, and/or U-300 insulin treatment, subjects will 
self-administer their insulin at home, at approximately the same time each day.  The last dose 
prior to assessment should be taken at approximately the same time in each period and will be at 
least 15 hours before the U-500R bolus dose and clamp procedure in Part A.  The insulin TDD 
should remain approximately the same throughout Part A of the study (except while subjects are 
resident in the CRU when it will not be taken).  
The insulin preparation will be allowed to come to approximately room temperature prior to 
administration.  The qualified site personnel will be instructed on proper preparation and 
administration techniques for all insulin used in this study.  All insulin will be administered by 
an appropriately qualified member of the CRU staff while the subject is resident in the CRU.
All SC insulin injections will be given by means of a conventional U-100 insulin syringe (6 mm, 
31-gauge needle; 0.5 or 1.0 mL).  The same brand and model of syringe will be used throughout 
the study.  The needle will be applied at approximately 90 degrees into a raised skin fold to 
ensure consistent SC administration.  The injection site will be alternated between the 
4 quadrants of the abdominal wall, approximately 10 cm from the umbilicus.  
In Part A, 100 U of U-500R will be administered by single SC injection or CSII according to the 
randomization schedule.  
For CSII administration, U-500R will be administered via a U-500 OmniPod (currently not 
available commercially), which will be fitted by qualified staff upon subjects’ admission to the 
CRU.  The device will be programmed by CRU staff to administer a 12-hour 4.25-U/h infusion 


B5K-EW-IBHG(b) Protocol
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Human regular U-500 insulin (LY041001)
of U-500R, prior to the 100-U bolus and to continue the 4.25-U/h infusion throughout the clamp 
procedure. The insulin-on-board function on the U-500 OmniPod will be set at 6 hours.  The 
Pod will be filled from the 20-mL vial of U-500R using only the syringe and needle provided 
with the U-500 OmniPod by the vendor.  
The unit markings on a U-100 insulin syringe do not accurately reflect the unit dose of U-500R 
because U-500R is 5-times more concentrated than U-100 insulin, and thus only 1/5 the volume 
is needed to give an equivalent dose to U-100 insulin.  
In Part A, for subjects randomized to SC administration, a qualified member of CRU staff will 
administer 100 U of U-500R, equivalent to 20 unit markings on a 0.5-mL U-100 syringe.  
In Part B, CRU staff should instruct subjects on the dose conversion of calculated U-500R to the 
U-100 syringe unit markings (detailed instruction for which will be provided separately to the 
site).  
All U-500R doses ≤250 U should be administered using 0.5-mL U-100 insulin syringes.  All 
U-500R doses >250 U should be administered using 1.0-mL U-100 insulin syringes.  
For example:

155 U of U-500R have a volume equivalent to 31 U markings on a 0.5 mL U-100 syringe 
(155 divided by 5=31).

100 U of U-500R have a volume equivalent to 20 U markings on a 0.5 mL U-100 syringe 
(100 divided by 5=20).

300 U of U-500R have a volume equivalent to 60 U markings on a 1.0 mL U-100 syringe 
(300 divided by 5=60).
In Part B, U-500R doses determined as described in Section 9.4 will be administered either TID 
or BID according to the randomization schedule. The doses will be administered at 
approximately the same times on each day.  The actual time of all dose administrations will be 
recorded in the subject’s eCRF.
9.3.
Rationale for Selection of Dose
A dose of 100 U of U-500R was chosen for Part A of this study as this is within the range 
commonly encountered in high-dose insulin-treated patients whose T2DM is managed with 
U-500R either by MDI or off-label via CSII (Lane et al. 2009; de la Peña et al. 2011; Reutrakul 
et al. 2012; Cochran et al. 2014; and Lane et al. 2013).  
Study dosing and conversion and titration regimens for the TID and BID treatment groups in 
Part B, both guided by pre-Period 2 U-100, U-200, and/or U-300 insulin TDD (based on the 
highest TDD recorded in the 3 days prior to Period 2 which should be approximately unchanged 
from pre-Period 1) and baseline HbA1c (screening), and subsequent glucose monitoring, 
respectively, are based on literature expert reviews (Lane et al. 2009; Segal et al. 2010; Reutrakul, 
et al. 2012) and on the results from simulations performed using a systems physiology model of 
diabetes (in Physiolab®; de la Peña et al. 2014) based on data from previous PK/PD studies of 


B5K-EW-IBHG(b) Protocol
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Human regular U-500 insulin (LY041001)
U-500R and U-100 human regular insulin (de la Peña et al. 2011; Studies F3Z-LC-IMAC and 
H7U-MC-IDBM).
9.4.
Dose Conversion from Prestudy Insulin in Part B
Subjects will record their insulin doses throughout the study.  Baseline U-100, U-200, and/or 
U-300 insulin TDD will be defined as the highest TDD recorded in the 3 days prior to Period 2.  
All U-100, U-200, and/or U-300 insulin therapy will be discontinued upon initiation of study 
drug, but permitted prestudy AHA therapy should continue to be taken at prestudy doses, except 
on clamp assessment days.  For all subjects with HbA1c >8.0% at screening, initial U-500R
TDD will be the same (in units) as U-100, U-200, and/or U-300 insulin TDD at screening.  
For all subjects with baseline HbA1c ≤8.0% at screening, initial U-500R TDD dose will be 
reduced by 20% from the U-100, U-200, and/or U-300 insulin TDD at screening.  
Initial TID dosing will use a 40:30:30 proportion of calculated U-500R TDD for the respective 
pre-meal doses at 07:00 hours, 12:00 hours, and 18:00 hours, approximately 30 minutes prior to 
the morning meal, midday meal, and evening meal, respectively.  
Initial BID dosing will use a 60:40 proportion of calculated U-500R TDD for the respective 
pre-meal doses at 07:00 hours and 18:00 hours, approximately 30 minutes prior to the morning 
meal and evening meal, respectively.  
During dose conversion, bolus doses will be rounded down to the nearest 5 U as was done in 
Study B5K-US-IBHC (Hood et al. 2015).  If subjects are using 0.5-mL U-100 insulin syringes, 
this will be to the closest unit marking (0.01 mL) on the syringe; for those using 1.0-mL U-100 
insulin syringes, this will be half way between unit markings (0.02 mL).
Subjects will record SMPG throughout Period 3.  During telephone visits (conducted 2 days after 
the end of Period 2 at a minimum) the investigator or designee will titrate subjects’ U-500R dose 
for each meal according to the algorithms presented in Table IBHG.9.2.  
During dose titration (as opposed to initial dosage conversion), conventional rounding to the 
nearest 5 U will be applied, so that, for instance, values between 120.1 and 122.4 would be 
rounded down to 120 U while values between 122.5 and 124.9 would be rounded up to 125 U.
Subjects should perform a 03:00 hours SMPG within 48 hours of any dose increase and should 
telephone the CRU the next morning if their 03:00 hours SMPG value is ≤70 mg/dL
(≤3.9 mmol/L).  The investigator may deviate from the algorithms, if deemed necessary, for the 
safety or well-being of the subject (for example due to illness, unusual SMPG patterns, or other 
safety concerns).  Deviations from the algorithm should be discussed with Lilly, in a dvance if 
possible without compromising subject safety.
In the event of a subject reporting a severe hypoglycemic episode or any SMPG value is 
<50 mg/dL (<2.8 mmol/L), the investigator will make appropriate insulin adjustment per his/her 
judgment (this may be a 15% reduction in the appropriate U-500R mealtime dosage).  
If a meal is skipped during the treatment period, the U-500R dose should be reduced by 50%.  


B5K-EW-IBHG(b) Protocol
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Human regular U-500 insulin (LY041001)
Table IBHG.9.2.
TID and BID Dosing Algorithms for U-500R Using 
Plasma-Equivalent Glucose Values
Algorithm
Insulin Dose to 
Adjust
Plasma-Equivalent 
Glucose Value
Value (mg/dL)
Action 
TID
Initial Dose 
Proportion 
40:30:30
Pre-morning 
meal
Median pre-midday meal 
≤70 
71-130 
131-180 
181-220 
>220 
Reduce dose by 10%
No change in dose
Increase dose by 5%
Increase dose by 10%
Increase dose by 15%
Pre-midday 
meal
Median pre-evening meal 
SMPG
≤70
71-130
131-180
181-220
>220
Reduce dose by 10%
No change in dose
Increase dose by 5%
Increase dose by 10%
Increase dose by 15%
Pre-evening 
meal
Median pre-morning meal, 
median bedtime, or 
03:00 hours SMPG
≤70
Reduce dose by 10%
Median pre-morning meal 
SMPG
71-130
131-180
181-220
>220
No change in dose
Increase dose by 5%
Increase dose by 10%
Increase dose by 15%
BID
Initial Dose 
Proportion 
60:40
Pre-morning 
meal
Median pre-evening meal 
or median pre-midday 
meal SMPG
≤70
Reduce dose by 10%
Median pre-evening meal 
SMPG
71-130
131-180
181-220
>220
No change in dose
Increase dose by 5%
Increase dose by 10%
Increase dose by 15%
Pre-evening 
meal
Median pre-morning meal, 
median bedtime, or 
03:00 hours SMPG
≤70
Reduce dose by 10%
Median pre-morning meal 
SMPG
71-130
131-180
181-220
>220
No change in dose
Increase dose by 5%
Increase dose by 10%
Increase dose by 15%
Abbreviations:  BID = twice daily; SMPG = self-monitored plasma glucose; TID = thrice daily.  
9.4.1. TID Treatment Group Titrations
Subjects in the TID treatment group will have their insulin doses adjusted at a telephone visit 
2 to 3 days after the end of Period 2 (at a minimum, additional telephone or office visits may be 
added for safety as necessary) by the investigator or site designee according to the TID titration 
algorithm (Table IBHG.9.2).  
The U-500R doses will be changed according to corresponding median plasma-equivalent 
glucose readings from the most recent 3 values at respective times (also see examples below) 
prior to the telephone or office visit or for any add-on telephone calls or office visits.  If even 


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Human regular U-500 insulin (LY041001)
1 SMPG reading for a given time point is ≤70 mg/dL (≤3.9 mmol/L), no dosage increase will be 
applied to the corresponding dose.  These adjustments will be applied only to the 2 of the 3 doses 
(pre-morning meal, pre-midday meal, pre-evening meal) that most need adjustment (that is, the 
ones with the most out-of-range corresponding median plasma-equivalent glucose readings) at 
each study visit/interaction.  
For subjects receiving U-500R TID, median pre-morning meal and bedtime SMPG values and 
03:00 hours SMPG values (if performed) will inform adjustment of the pre-evening meal 
U-500R insulin dose.  When these 3 sets of values provide conflicting guidance, the investigator 
should base the dose adjustment on the lowest of these results, and prioritize adjustments for 
hypoglycemic readings ≤70 mg/dL (≤3.9 mmol/L) over dosage increases.  
In all instances, the 10% dosage reduction for values ≤70 mg/dL (≤3.9 mmol/L) and negation of 
respective dosage increases for single pre-meal or bedtime hypoglycemic readings should be 
prioritized over other titration options.  
Example 1
A subject assigned to the TID treatment group is taking 300 U TDD with a pre-morning meal 
dose of 120 U, pre-midday meal dose of 90 U and a pre-evening meal dose of 90 U.  
Over the last 3 days, the subject’s SMPG values were:
Date
Day 1
Day 2
Day 3
SMPG pre-morning meal, mg/dL (mmol/L)
102 (5.7)
110 (6.1)
135 (7.5)
SMPG pre-midday meal, mg/dL (mmol/L)
163 (9.1)
180 (10.0)
200 (11.1)
SMPG pre-evening meal, mg/dL (mmol/L)
240 (13.3)
221 (12.3)
238 (13.2)
SMPG at bedtime, mg/dL (mmol/L)
130 (7.2)
160 (8.9)
125 (6.9)
SMPG at 03:00 hours, mg/dL (mmol/L)
92 (5.1)
Abbreviation:  SMPG = self-monitored plasma glucose.
The 2 doses that most need adjustment are pre-midday meal and pre-morning meal because the 
median glucose values at pre-evening meal and pre-midday meal are the most outside of the 
target range.  The subject’s median pre-evening meal SMPG is 238 mg/dL (13.2 mmol/L); 
therefore, the pre-midday meal dose should be increased by 15% to 103.5 U, rounded up to 
105 U.  The subject’s median pre-midday meal SMPG is 180 mg/dL (10.0 mmol/L); therefore, 
the pre-morning meal dose should be increased by 5% to 126 U, rounded down to 125 U.
Example 2:
A subject assigned to the TID treatment group is taking 210 U TDD with a pre-morning meal 
dose of 90 U, pre-midday meal dose of 60 U, and pre-evening meal dose of 60 U.
Over the last 3 days, the subject’s SMPG values were:


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Human regular U-500 insulin (LY041001)
Date
Day 1
Day 2
Day 3
SMPG pre-morning meal, mg/dL (mmol/L)
160 (8.9)
145 (8.1)
110 (6.1)
SMPG pre-midday meal, mg/dL (mmol/L)
181 (10.1)
185 (10.3)
120 (6.7)
SMPG pre-evening meal, mg/dL (mmol/L)
140 (7.8)
120 (6.7)
170 (9.4)
SMPG at bedtime, mg/dL (mmol/L)
68 (3.8)
120 (6.7)
140 (7.8)
SMPG at 03:00 hours, mg/dL (mmol/L)
60 (3.3)
Abbreviation:  SMPG = self-monitored plasma glucose.
The 2 doses that appear to most need adjustment are pre-morning meal and pre-evening meal
because the median glucose values at pre-midday meal and pre-morning meal are the most 
outside of the target range (181 and 145 mg/dL (10.1 and 8.1 mmol/L), respectively).  However, 
due to the 03:00 hours SMPG being ≤70 mg/dL (≤3.9 mmol/L), the first prioritized dose change 
would be the subject’s pre-evening meal dose which should be reduced by 10% to 54 U, rounded 
up to 55 U.  After that first dose adjustment, the next adjustment most needed would be a 10% 
increase in the subject’s pre-morning meal dose to 99 U, rounded up to 100 U on the basis of the 
pre-midday median glucose value of 181 mg/dL (10.1 mmol/L).  Since only 2 of 3 TID doses 
can be adjusted, no change would be applied to the pre-midday meal dose.  
Example 3:
A subject assigned to the TID treatment group is taking 300 U TDD with a pre-morning meal 
dose of 120 U, pre-midday meal dose of 90 U, and pre-evening meal dose of 90 U.
Over the last 4 days, the subject’s SMPG values were:
Date
Day 1
Day 2
Day 3
Day 4
SMPG pre-morning meal, mg/dL (mmol/L)
66 (3.7)
148 (8.2)
160 (8.9)
SMPG pre-midday meal, mg/dL (mmol/L)
120 (6.7)
142 (7.9)
180 (10.0)
SMPG pre-evening meal, mg/dL (mmol/L) 
68 (3.8)
64 (3.6)
135 (7.5)
SMPG at bedtime, mg/dL (mmol/L)
102 (5.7)
135 (7.5)
165 (9.2)
SMPG at 03:00 hours, mg/dL (mmol/L)
100 (5.6)
Abbreviation:  SMPG = self-monitored plasma glucose.
The investigator should consider changing only the 2 doses that most need adjustment.  In this 
instance, the 2 doses that appear to most need adjustment are pre-evening meal and pre-morning
meal because the median glucose values at pre-morning meal and pre-evening meal are the most 
outside of the target range.  The median pre-morning meal SMPG (148 mg/dL [8.2 mmol/L]) is 
within the range of 131 to 180 mg/dL (7.3 to 10.0 mmol/L) calling for a 5% dose increase of 
pre-evening meal dosage. However, the unexplained hypoglycemia (66 mg/dL [3.7 mmol/L]) 
takes precedence and accordingly, there should be no upward evening meal dosage adjustment.  
The median of the last 3 readings for pre-evening meal SMPG (68 mg/dL [3.8 mmol/L]) is ≤70 
mg/dL (≤3.9 mmol/L); therefore, the investigator would reduce the pre-midday meal dose by 
10% to 81 U, which is rounded to 80 U, the nearest 5 U.


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Human regular U-500 insulin (LY041001)
9.4.2. BID Treatment Group Titrations
Subjects in the BID treatment group will have their insulin dosages adjusted at each study visit 
(office and telephone or for add-on visits) by the investigator or site designee according to the 
BID titration algorithm (Table IBHG.9.2).
Human regular U-500 insulin doses will be changed according to corresponding median 
plasma-equivalent glucose readings from the most recent 3 values at respective times (also see 
examples below) prior to the scheduled telephone or office visit or for any add-on visits.  If even 
1 of the SMPG readings for a given time point is ≤70 mg/dL (≤3.9 mmol/L), no dosage increase 
will be applied to the corresponding dose.  These adjustments will be applied to both doses as 
indicated (pre-morning meal and pre-evening meal) at each study visit/interaction.
For subjects receiving U-500R BID, median pre-morning and bedtime SMPG values and 
03:00 hours SMPG values (if performed) will inform adjustment of the pre-evening meal 
U-500R insulin dose, and both median pre-evening meal and pre-midday meal SMPG values will 
inform adjustment of the pre-morning meal U-500R insulin dose.  When these sets of values 
provide conflicting guidance, investigators should base the dose adjustment on the lowest of 
these results, and prioritize adjustments for hypoglycemic readings ≤70 mg/dL (≤3.9 mmol/L) 
over dosage increases.  
In all instances, the 10% dosage reduction for median pre-meal/bedtime values or single 03:00
hours glucose values ≤70 mg/dL (≤3.9 mmol/L) and negation of respective dosage increases for 
single pre-meal or bedtime hypoglycemic readings should be prioritized over other titration 
options.
Example 1:
A subject assigned to the BID treatment group is taking 300 U TDD, with a pre-morning meal 
dose of 180 U and a pre-evening meal dose of 120 U.
Over the last 4 days, the subject’s SMPG values were:
Date
Day 1
Day 2
Day 3
Day 4
SMPG pre-morning meal, mg/dL (mmol/L)
180 (10.0)
160 (8.9)
200 (11.1)
SMPG pre-midday meal, mg/dL (mmol/L)
120 (6.7)
170 (9.4)
132 (7.3)
SMPG pre-evening meal, mg/dL (mmol/L)
200 (11.1)
225 (12.5)
260 (14.4)
SMPG at bedtime, mg/dL (mmol/L)
142 (7.9)
128 (7.1)
110 (6.1)
SMPG at 03:00 hours, mg/dL (mmol/L)
101 (5.6)
Abbreviation:  SMPG = self-monitored plasma glucose
The median pre-evening meal SMPG value is 225 mg/dL (12.5 mmol/L); therefore, the subject’s 
pre-morning meal dose should be increased by 15% to 207 U, rounded down to 205 U.  The 
median pre-morning meal SMPG value is 180 mg/dL (10.0 mmol/L); therefore, the subject’s 
pre-evening meal dose should be increased by 5% to 126 U, rounded down to 125 U.


B5K-EW-IBHG(b) Protocol
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Human regular U-500 insulin (LY041001)
Example 2:
A subject assigned to the BID treatment group is taking 250 U TDD, with a pre-morning meal 
dose of 150 U and a pre-evening meal dose of 100 U.
Over the last 4 days, the subject’s SMPG values were:
Date
Day 1
Day 2
Day 3
Day 4
SMPG pre-morning meal, mg/dL (mmol/L)
138 (7.7)
130 (7.2)
110 (6.1)
SMPG pre-midday meal, mg/dL (mmol/L)
80 (4.4)
71 (3.9)
58 (3.2)
SMPG pre-evening meal, mg/dL (mmol/L) 
160 (8.9)
200 (11.1)
182 (10.1)
SMPG at bedtime, mg/dL (mmol/L)
140 (7.8)
132 (7.3)
110 (6.1)
SMPG at 03:00 hours, mg/dL (mmol/L)
142 (7.9)
Abbreviation:  SMPG = self-monitored plasma glucose.
The median pre-evening meal SMPG is 182 mg/dL (10.1 mmol/L); thus, the subject’s 
pre-morning meal dose would normally be increased by 10%.  However, there is a single 
pre-midday meal hypoglycemic reading (58 mg/dL [3.2 mmol/L]); therefore, the pre-morning 
meal dose should not be increased.  The median pre-morning meal SMPG value is 130 mg/dL
(7.2 mmol/L); therefore, the subject’s pre-evening meal dose should not change.
Example 3:
A subject assigned to the BID treatment group is taking 275 U TDD with a pre-morning meal 
dose of 165 U and a pre-evening meal dose of 110 U.
Over the last 3 days, the subject’s SMPG values were:
Date
Day 1
Day 2
Day 3
SMPG pre-morning meal, mg/dL (mmol/L)
66 (3.7)
141 (7.8)
160 (8.9)
SMPG pre-midday meal, mg/dL (mmol/L)
131 (7.3)
128 (7.1)
105 (5.8)
SMPG pre-evening meal, mg/dL (mmol/L)
66 (3.7)
70 (3.9)
110 (6.1)
SMPG at bedtime, mg/dL (mmol/L)
100 (5.6)
112 (6.2)
108 (6.0)
SMPG at 03:00 hours, mg/dL (mmol/L)
70 (3.9)
Abbreviation:  SMPG = self-monitored plasma glucose.
The median pre-evening meal SMPG is 70 mg/dL (3.9 mmol/L); therefore, the pre-morning meal 
dose should be reduced by 10% to 148.5 U, rounded up to 150 U.  The median pre-morning meal 
SMPG is 141 mg/dL (7.8 mmol/L), but the subject’s pre-evening meal dose should not be 
titrated upward due to the 03:00 hours value being ≤70 mg/dL (≤3.9 mmol/L) (70 mg/dL
[3.9 mmol/L]) which also necessitates a 10% reduction, in the pre-evening meal dose to 99 U, 
rounded up to 100 U. 
9.5.
Specific Restrictions/Requirements
Prior to beginning the study, the subjects will complete informed consent and baseline tests.  


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Throughout the study, subjects may undergo medical assessments and review of compliance with 
restrictions before continuing in the study.  
Meals/Diet – For all treatment periods, subjects will be fasted from approximately 12 hours prior 
to clamp initiation until after the clamp procedure is completed.  Water can be consumed freely 
during this period.  
When at home, subjects will be encouraged to maintain their body weight and consume their 
normal diets.
Alcohol – No alcohol will be allowed from at least 24 hours prior to clamp initiation and while
resident in the CRU.  
Smoking – Subjects will refrain from smoking, using electronic cigarettes, or using nicotine 
replacement therapy while resident in the CRU.  
Exercise – Subjects will be encouraged to maintain their regular exercise; however, they should 
not undertake vigorous or prolonged exercise within 48 hours prior to each clamp day.  
After dosing, and during the clamp procedure, subjects should remain recumbent or sitting in the 
CRU.  Movement will be restricted to retain integrity of connections to infusion and study 
procedures.  
Authorization to leave the CRU must be given by a physician.  
9.6.
Blinding
This is an open-label study.
9.7.
Concomitant Therapy
Subjects on stable concomitant medication at the time of study entry should continue their 
regular, unchanged dose throughout the study; for example, hormonal contraceptives, thyroid 
replacement therapy, anti-hypertensives, low-dose aspirin, and cholesterol lowering agents.  
Prescription medications (other than those allowed in Inclusion Criteria [4] and [5]), herbal 
medications, or nutritional supplements that affect PG or insulin sensitivity, or promote weight 
loss will not be allowed within 4 weeks prior to dosing.  Initiation of new over-the-counter 
medication within 7 days prior to dosing, or prescription medication or herbal medication within 
14 days prior to dosing may be permitted following discussion with the Lilly clinical 
pharmacologist.  Vitamin/mineral supplements and/or occasional use of acetaminophen will be 
allowed.  
Subjects may continue to take their stable prestudy AHA dose (MET, dipeptidyl peptidase-4 
inhibitors, pioglitazone [doses ≤30 mg/day], GLP-1 receptor agonists, and/or SGLT2 inhibitors
[not in combination with GLP-1 receptor agonists]), unchanged, throughout the study, except on 
clamp assessment days.  


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Rosiglitazone, pramlintide, once weekly or BID exenatide, other injectable or oral AHAs not 
listed in Inclusion Criterion [5], or permitted AHAs taken at doses other than that prescribed by 
the product label will not be allowed.  
If the need for concomitant medication arises, inclusion or continuation of the subject may be at 
the discretion of the investigator after consultation with a Lilly clinical pharmacologist or 
CRP/clinical research scientist.  Any additional medication used during the course of the study 
must be documented.


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10.
Sample Collection and Safety Data Collection
Attachment 1 lists the schedule for sample collections in this study.
Attachment 2 lists the clinical laboratory tests that will be performed for this study.
Attachment 3 summarizes the blood volumes for all blood sampling during the study.  
10.1. Laboratory Samples
Blood samples will be collected to determine whether subjects meet inclusion/exclusion criteria 
and to monitor subject health.  
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.
10.2. Samples for Pharmacokinetic and Pharmacodynamic 
Evaluations
10.2.1. Pharmacokinetic Samples
At the visits and times specified in the Study Schedule, venous blood samples of approximately
3.5 mL and 2.5 mL each will be collected to determine the serum IRI and C-peptide
concentrations, respectively.  Instructions for the collection and handling of blood samples will 
be provided by the sponsor.  The actual date and time (24-hour clock time) of each sampling will 
be recorded.  
10.2.2. Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.  
Concentrations of IRI will be assayed using a validated enzyme linked immunosorbent assay 
(ELISA) method for the quantitative determination of IRI.  This method measures endogenous 
insulin, as well as exogenous biosynthetic insulin, after a pretreatment of the sample with 
polyethylene glycol to remove anti-insulin antibodies.  C-peptide measurements will be used to 
correct for endogenous insulin production.  
Bioanalytical samples collected to measure investigational product concentrations will be 
retained for a maximum of 1 year following last subject visit for the study.  


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10.2.3. Pharmacodynamic Evaluations (Glucose Clamp Procedure)
The aim of the euglycemic glucose clamp is to maintain euglycemia through glucose infusion 
after the administration of a dose of insulin. During the glucose clamp, the GIR will be adjusted 
to maintain a predetermined target blood glucose (BG) concentration for the individual subject.  
The BG concentration will be maintained within approximately ±5% of the predose target value, 
which will be defined as 120 mg/dL (6.7 mmol/L).  
Thus BG concentrations will be kept constant while GIR varies.  The varying GIR will reflect 
the PD activity of insulin.  
Subjects will participate in euglycemic clamps on 3 separate visits.  Clamp procedures in Part A 
will last up to 24 hours after dosing, and clamp procedures in Part B will last 24 hours.  The 
GIRs required to maintain euglycemia and BG concentrations will be documented throughout the 
procedure.  If a clamp cannot be completed due to logistical reasons (for example, lack of venous 
access), the subject may return on 1 additional occasion for the clamp assessment.  
10.3. Samples for Biomarker Research
There is growing evidence that genetic variation may impact a patient’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 the investigational product.  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 the investigational 
product.
Samples will be destroyed according to a process consistent with local regulation.
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.


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The investigator is responsible for the appropriate medical care of subjects during the study.  
Planned safety assessments and measures are detailed in Section 10.4.5, but additional 
assessments and safety tests may be performed at the investigator’s discretion.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious, considered related to study treatment or the study, 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.
In addition to records of observations made at specific times, unexpected signs and symptoms 
and concomitant medications will be recorded in the clinical trial records throughout the study.
10.4.1. Safety Measures
At the end of the glucose clamp, the subject will receive a meal and undergo medical assessment
before discharge.  If glucose is still being infused at the time of clamp discontinuation, the 
subject will be monitored for safety.  This may consist of hourly PG determinations and 
monitoring for continuing signs or symptoms of hypoglycemia.  The subject will be observed 
until stable according to investigator judgment.  Per investigator judgment, appropriate measures 
for symptomatic hypoglycemia and/or PG ≤70 mg/dL (≤3.9 mmol/L) will be applied.  These 
measures may include oral glucose or glucose-containing food or drink, glucagon, or parenteral 
glucose, with follow-up testing, also according to investigator judgment.  
10.4.2. Adverse Events
Lilly has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent.
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.
Cases of pregnancy that occur during maternal or paternal exposures to the investigational 
product and/or drug delivery system should be reported.  Data on fetal outcome and 
breast-feeding are collected for regulatory reporting and drug safety evaluation.
After the informed consent form (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.
Any clinically significant findings from ECGs, labs, vital sign measurements, or other 
procedures, should be reported as an AE to Lilly or its designee.
In addition, all AEs occurring after the subject receives the first dose of the investigational 
product must be reported to Lilly or its designee via eCRF.


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Investigators will be instructed to report to Lilly or its designee their assessment of the potential 
relatedness of each AE to protocol procedure, studied disease state, investigational product, 
and/or drug delivery system via eCRF.
The investigator will decide whether he or she interprets the observed AEs as either related to 
disease, to the study medication, study procedure, drug delivery system, or other concomitant 
treatment or pathologies.  To assess the relationship of the AE to the investigational product, 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 the investigational product.
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.
10.4.3. Serious Adverse Events
All episodes of hypoglycemia that are determined by the investigator to constitute severe 
hypoglycemia according to the definition in Section 10.4.4 should be reported as SAEs.  
An SAE is any AE from this study that results in one of the following outcomes:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

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 SAEs 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.


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When a condition related to the insulin pump 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.
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.  
Serious adverse event collection begins after the subject has signed the ICF and has received 
investigational product.  If a subject experiences an SAE after signing informed consent, but 
prior to receiving investigational product, the event will NOT be reported as serious unless the 
investigator feels the event may have been caused by a protocol procedure.
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 specified 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 
them to the sponsor, regardless of the investigator’s opinion of causation, and the SAEs will be 
entered in the pharmacovigilance system at 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.  
10.4.3.1. 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 investigational product or procedure.  
United States 21 CFR 312.32 and European Union Clinical Trial Directive 2001/20/EC and the 
associated detailed guidances or national regulatory requirements in participating countries 
require the reporting of SUSARs.  Lilly has procedures that will be followed for the recording 
and expedited reporting of SUSARs that are consistent with global regulations and the associated 
detailed guidances.
10.4.4. Hypoglycemia
Subjects will be encouraged to perform SMPG 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 an 


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Human regular U-500 insulin (LY041001)
SMPG ≤70 mg/dL (≤3.9 mmol/L) as hypoglycemia.  All subjects will be advised to contact the 
study site if they experience severe hypoglycemia or SMPG <50 mg/dL (<2.8 mmol/L).  
Hypoglycemic events should be appropriately recorded in the eCRF.  The following 
hypoglycemia definition should be applied for reporting in the eCRF and evaluating 
hypoglycemic events;
Severe hypoglycemia:  an event requiring assistance of another person to actively administer 
carbohydrate, glucagon, or other resuscitative actions.  During these episodes, the subject 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 gluc ose 
measurements may not be available during such an event, but neurological recovery attributable 
to the restoration of PG to normal is considered sufficient evidence that the event was induced by 
a low PG (≤70 mg/dL [≤3.9 mmol/L]).  
Documented symptomatic hypoglycemia:  an event during which typical symptoms of 
hypoglycemia are accompanied by a measured PG concentration ≤70 mg/dL (≤3.9 mmol/L).
Asymptomatic hypoglycemia:  an event not accompanied by typical symptoms of 
hypoglycemia but with a measured PG concentration ≤70 mg/dL (≤3.9 mmol/L).
Nocturnal hypoglycemia:  is defined as any documented symptomatic hypoglycemic event that 
occurs between bedtime and waking.
Hypoglycemic events recorded by the euglycemic clamp device during the evaluation will not be 
documented.  In the case of a hypoglycemic event (other than severe), the actual PG value, if 
measured, should be recorded in the eCRF alongside one of the above terms, together with any 
treatments administered and should not be recorded as an AE.  Cases of hypoglycemia may be 
treated with foods or beverages rich in carbohydrate such as fruit, juice, skimmed milk, or energy 
bars.
All episodes of hypoglycemia that are determined by the investigator to constitute severe 
hypoglycemia according to the definition provided should be reported as SAEs.
10.4.5. Other Safety Measures
10.4.5.1. Physical Examination
Physical examinations and routine medical assessments will be conducted as specified in the 
Study Schedule and as clinically indicated (Attachment 1).
10.4.5.2. Vital Signs
Blood pressure and pulse rate will be measured as specified in the Study Schedule and as 
clinically indicated (Attachment 1).
Blood pressure and pulse rate should be measured after the subject has been supine for at least 
5 minutes.


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If orthostatic measurements are required, subjects should be supine for at least 5 minutes and 
stand for at least 3 minutes.
If the subject feels unable to stand, supine vital signs only will be recorded.  
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms.  Additional vital signs may be measured during each study period if 
warranted and agreed upon between the sponsor and investigator.
10.4.5.3. Body Weight
Body weight will be recorded as specified in the Study Schedule and as clinically indicated 
(Attachment 1).
Subjects should be weighed twice. The scale should be zeroed before each time 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.  Both weight values 
should be recorded in the source documentation and the eCRF.  
10.4.5.4. Electrocardiograms
For each subject, a single 12-lead digital ECG will be collected according to the Study Schedule 
(Attachment 1).  Electrocardiograms must be recorded before collecting any blood for safety or 
PK tests.  Subjects must be supine for approximately 5 to 10 minutes before ECG collection and 
remain supine but awake during ECG collection.  Electrocardiograms may be obtained at 
additional times, when deemed clinically necessary.  Collection of additional ECGs at a 
particular time point is allowed to ensure high quality records. All ECGs recorded should be 
stored at the investigator site.
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
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.  
If a clinically significant finding is identified (including, but not limited to changes in QT/QTc 
interval from baseline) after enrollment, the investigator will determine if the subject can 
continue in the study.  The investigator or qualified designee is responsible for determining if 
any change in subject management is needed and must document his/her review of the ECG 
printed at the time of collection.  Any new clinically relevant finding should be reported as an 
AE.
10.4.6. Safety Monitoring
The Lilly clinical pharmacologist or CRP/scientist will monitor safety data throughout the course 
of the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly clinical 
pharmacologist or CRP will consult with the functionally independent Global Patient Safety 


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therapeutic area physician or clinical research scientist when appropriate, and periodically 
review:

trends in safety data

laboratory analytes

AEs
10.4.7. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical trials in order to ensure the safety of study participants, monitor quality, and to facilitate 
process and product improvements.
Complaints related to unblinded comparator drugs or concomitant drugs/drug delivery systems 
(with the exception of the U-500 OmniPod) 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

faxing the completed product complaint form 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. Appropriateness and Consistency of Measurements
All assessments made in this study are standard, widely used, and generally recognized as 
reliable, accurate, and relevant.
10.6. Compliance
Every attempt will be made to select subjects who have the ability to understand and comply 
with instructions.  Noncompliant subjects may be discontinued from the study.  The time and day 
of drug administration will be recorded.  Drug accountability records will be maintained by the 
study site.
The specifications in this protocol for the timings of safety, PK, and PD sampling are given as 
targets, to be achieved within reasonable limits.  Modifications may be made to the time points 
based upon the safety and PK information obtained.  The scheduled time points may be subject 
to minor alterations; however, the actual time must be correctly recorded in the eCRF.
Any major modifications that might affect the conduct of the study, subject safety, and/or data 
integrity will be detailed in a protocol amendment.


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11.
Sample Size and Data Analyses
11.1. Determination of Sample Size
The primary objective of Part A of the study is to compare the tmax of U-500R administered by 
single SC injection or CSII.  Up to 32 subjects may be enrolled to ensure that approximately
24 subjects complete the study.
The sample size is based on a calculation of precision of the tmax. Intra-subject variability for 
tmax has not been assessed previously. Based on an assumption of an intra-subject variability 
estimate of 20% for tmax, a sample size of 24 completed subjects in Part A will provide 
approximately 90% coverage probability that the half-width of the 90% confidence interval (CI)
for the ratio of geometric means for tmax will be within 0.116 in the log scale, which corresponds 
to approximately 12% of the geometric mean ratio estimate in the natural scale.  
If any subjects discontinue the study prior to completion of the 3 periods, the replacement 
subjects who are enrolled will assume the discontinued subjects’ randomization schedule and 
will complete all 3 periods.  
11.2. Data Analysis Plans
11.2.1. General Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.
Pharmacokinetic and PD analyses will be conducted on the full analysis set.  This set includes all 
data from all randomized subjects receiving at least 1 dose of the investigational product and 
having evaluable PK/PD data according to the treatment the subjects actually received.  Safety 
analyses will be conducted for all enrolled subjects, regardless of whether they completed all 
protocol requirements.
Additional exploratory analyses of the data will be conducted as deemed appropriate.  Analyses 
will be fully detailed in the statistical analysis plan.  Study results may be pooled with the results 
of other studies for population PK analysis purposes to avoid issues with post-hoc analyses and 
incomplete disclosures of analyses.  
11.2.2. Study Participant Disposition
All subjects who discontinue from the study will be identified, and the extent of their 
participation in the study will be reported.  If known, a reason for their discontinuation will be 
given.
11.2.3. Study Participant Characteristics
The subject’s age, sex, weight, BMI, height, race/sub-race, smoking habits, and/or other 
demographic characteristics will be recorded.


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11.2.4. Pharmacokinetic Analyses
11.2.4.1. Pharmacokinetic Parameter Estimation
Pharmacokinetic parameter estimates will be calculated by standard noncompartmental methods 
of analysis. C-peptide may be used to correct serum IRI concentrations for endogenous insulin.  
The primary parameter for analysis in Part A will be tmax.  Other noncompartmental parameters 
such as Cmax, AUC from time zero to infinity (AUC[0-∞]), AUC(0-tlast), t1/2, CL/F, and Vz/F
may be reported, as appropriate.
The primary PK parameters for Part B will be AUC(0-24) and Cmax; other PK parameters such 
as tmax and AUC of U-500R over each dosing interval and over each meal at steady state may 
also be reported, as appropriate.  
Parameters will be individually calculated for each subject based on actual collection times.  
11.2.4.2. Pharmacokinetic Statistical Inference
For Part A, the primary parameter for statistical analysis will be t max. The values for tmax will be 
log-transformed and evaluated in a linear mixed-effects model with fixed effects for 
administration method, period and sequence (sequences 1 and 3, versus 2 and 4), and a random 
effect for subject.  The difference in least squares (LS) means along with the 90% CI will be 
back-transformed to present the ratios of geometric means and the CI for comparison of the
administration methods (single SC injection and CSII).  This same analysis will be repeated for 
AUC(0-tlast), AUC(0-∞), and Cmax.  
The values of tmax will also be analyzed non-parametrically using a Wilcoxon signed-rank test.  
Median differences and approximate 90% CIs for the difference will be calculated for the 
comparisons of the administration methods (single SC injection and CSII).
No formal statistical analysis will be conducted for Part B; PK parameters will be listed and 
summarized.  
Exploratory analyses may be performed for other PK parameters as deemed appropriate.
11.2.5. Pharmacodynamic Analyses
11.2.5.1. Pharmacodynamic Parameter Estimation
Glucose infusion rate and PG values will be recorded.  Glucose infusion rates will be used to 
calculate PD parameters, including Gtot, Rmax, tRmax, and tRlast.  Other parameters, such as 
tRonset, early tRmax50, and late tRmax50, may be reported.  Parameters will be individually 
calculated for each subject and presented by summary statistics.  
11.2.5.2. Pharmacodynamic Statistical Inference
For Part A, the values of tRmax will be analyzed non-parametrically using a Wilcoxon 
signed-rank test. Median differences and approximate 90% CIs for the difference will be 
calculated for the comparisons of the administration methods (single SC injection and CSII).


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The PD parameters (Rmax and Gtot) will be log-transformed prior to analysis and a linear 
mixed-effects model fitted to the data, with administration method, period, and sequence 
(sequences 1 and 3, versus 2 and 4) as fixed effects and subject as a random effect.  For each 
parameter, the difference in LS means along with the 90% CI will be back-transformed to 
present the ratios of geometric means and the CI for comparison of the administration methods.  
Other time parameters will be analyzed non-parametrically.  
No formal statistical analysis will be conducted for Part B; PD parameters will be listed and 
summarized.
Exploratory analyses may be performed for other PD parameters as deemed appropriate.
11.2.6. Safety Analyses
11.2.6.1. Clinical Evaluation of Safety
All investigational product and protocol procedure AEs will be listed, and if the frequency of 
events allows, safety data will be summarized using descriptive methodology.
The incidence of symptoms for each treatment will be presented by severity and by association 
with investigational product, study procedure, or drug delivery device, as perceived by the 
investigator.  Symptoms reported to occur prior to the first dose will be distinguished from those 
reported as new or increased in severity during the study.  Each symptom will be classified by 
the most suitable term from the medical regulatory dictionary.
The number of investigational product-related SAEs will be reported.
11.2.6.2. Statistical Evaluation of Safety
Safety parameters that will be assessed include safety laboratory parameters, vital signs, and 
ECG parameters.  The parameters will be listed and summarized using standard descriptive 
statistics.  Additional analysis will be performed if warranted upon review of the data.
11.3. Interim Analyses
An interim analysis will be conducted after approximately 12 subjects have completed both 
periods of Part A of the study.  An interim analysis of safety, PK and PD will be carried out and 
will be used to inform ongoing analysis of a Phase 3b trial, as appropriate.  


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12.
Data Management Methods
12.1. Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate.

sponsor start-up training to instruct the investigators and study coordinators.  This 
training will give instruction on the protocol, the completion of the 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/or use standard computer edits to detect errors in data 
collection.

conduct a quality review of the database.
In addition, Lilly or its representatives will periodically check a sample of the subject data 
recorded against source documents at the study site.  The study may be audited by Lilly and/or 
regulatory agencies at any time.  Investigators will be given notice before an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to the original source
documents.
12.2. Data Capture Systems
12.2.1. Source Data and Case Report Form
A source document is the first record of data.  These can be paper (for example, ECG tracing or 
subject diary), a paper CRF on which the data is initially recorded, or data captured directly on 
an investigator site electronic system (for example, Holter Monitor record data files or electronic 
health record).  The site must retain all source records and must maintain a record of any data 
where source data are directly entered into the paper CRF.
Data may then be entered into either an electronic or paper CRF and the process will be 
documented and communicated by the sponsor to the investigator site before first subject visit.
Some investigator site data may be collected directly in the paper CRF whereas other data that 
are collected by the site on paper or electronic records may be transferred to the paper CRF.
Lilly does not allow direct source data entry into Lilly computer systems, with the exception of 
the investigator site systems at the Lilly CRU.


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Human regular U-500 insulin (LY041001)
For data handled by a data management third party organization (TPO), CRF data and some or 
all data that are related will be managed and stored electronically in the TPO system. 
Subsequent to the final database lock, validated data will be transferred to the sponsor.
For data handled internally, CRF data and some or all data that are related will be managed by 
the sponsor and stored electronically in the sponsor’s system.
12.2.2. Ancillary Data
Data managed by a central vendor will be stored electronically in the central laboratory’s 
database system.  Data will subsequently be transferred from the central vendor to the Lilly 
generic labs system / TPO’s system.
Bioanalytical data will be stored electronically in the bioanalytical laboratory’s database.  Data 
will subsequently be transferred from the bioanalytical laboratory to the Lilly generic labs 
system / TPO’s system.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.


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Human regular U-500 insulin (LY041001)
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 potential risks and benefits of 
participating in the study and desires to participate in the study.
The investigator is ultimately responsible for ensuring that informed consent is given by each 
subject before the study is started.  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 
the investigational product.
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(s).  
All ICFs must be compliant with the International Conference on Harmonization (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 site(s).  The ERB(s) will review the protocol as required.
The study site’s ERB(s) should be provided with the following:

the current USPI and updates during the course of the study

ICF

relevant curricula vitae
13.3. Regulatory Considerations
This study will be conducted in accordance with:
1) consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences
(CIOMS) International Ethical Guidelines 


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Human regular U-500 insulin (LY041001)
2) ICH GCP Guideline [E6]
3) 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 by the investigator 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
Site-specific contact information may be provided in a separate document.


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Human regular U-500 insulin (LY041001)
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 investigator or designee will sign the clinical study report for this study, indicating 
agreement with the analyses, results, and conclusions of the report.
The sponsor’s responsible medical officer and statistician will sign/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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Human regular U-500 insulin (LY041001)
14.
References
[ADA] American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 
2012;35(Suppl 1): S11-S63.
[ADA] American Diabetes Association. Classification and diagnosis of diabetes. Diabetes Care. 
2015;38(Suppl 1): S8-S16.
Cochran EK, Valentine V, Samaan K, Corey IB, Jackson JA. Practice tips and tools for the 
successful use of U-500 regular human insulin: the diabetes is key. Diabetes Educ. 2014;40
(2):153-165.
Davidson MB, Navar MD, Echeverry D, Duran P. U-500 regular insulin: clinical experience and 
pharmacokinetics in obese, severely insulin-resistant type 2 diabetic patients. Diabetes Care. 
2010;33(2):281-283.
de la Peña A, Riddle M, Morrow LA, Jiang HH, Linnebjerg H, Scott A, Win KM, Hompesch M, 
Mace KF, Jacobson JG, 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, 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;8(4):821-829.  
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.
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 Econ. 2013;16(4):529-538.
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 U100 insulin therapy with or without oral agents: a randomized 
titration-to-target clinical trial. Endocr Pract. 2015;21(7):782-793.
Humulin R U-500 [package insert]. Indianapolis, IN: Eli Lilly and Company 2014.
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.
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].


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Human regular U-500 insulin (LY041001)
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.
Reutrakul S, Wroblewski K, Brown RL. Clinical use of U-500 regular insulin: review and 
meta-analysis. J Diabetes Sci Technol. 2012;6(2):412–420. 
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.  


B5K-EW-IBHG(b) Protocol
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Human regular U-500 insulin (LY041001)
Attachment 1.Protocol IBHG Study Schedule


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Human regular U-500 insulin (LY041001)
Study Schedule Protocol B5K-EW-IBHG
Periods 1 and 2a
Period 3
Screening
Days
Days
Follow-up
Comments
Procedure
Up to 28 
days prior 
to Period 1
-1
1
2
-10b
to -2
-1
1
2
7 to 28 days 
after discharge 
or early 
discontinuation
Informed consent
X
Subject 
admission to 
CRU
X
X
U-100, U-200, 
and/or U-300
insulin dosing
X
X
X
X
U-100, U-200, and/or U-300
dosing on Day -1 of Period 
1 and 2 to end ≥15 h prior to 
U-500R bolus dosing.  
Transition to U-100, U-200, 
and/or U-300 insulin after 
Period 3 is per investigator 
judgment.  
Subject discharge 
from CRU
X
X
Subjects will remain at the 
CRU until BG is stable 
according to investigator 
judgment.  
Recording of 
U-100, U-200, 
and/or U-300
insulin TDD
X
X
X
X
Subjects will record their 
U-100, U-200, and/or U-300
insulin TDD throughout the 
study apart from during 
dosing with U-500R.
Type and dose of 
insulin use 
recorded
X


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Human regular U-500 insulin (LY041001)
Periods 1 and 2a
Period 3
Screening
Days
Days
Follow-up
Comments
Procedure
Up to 28 
days prior 
to Period 1
-1
1
2
-10b
to -2
-1
1
2
7 to 28 days 
after discharge 
or early 
discontinuation
Telephone visit
for U-500R dose 
titration
X
Telephone visit for review 
of SMPG 2 to 3 days after 
end of Period 2.  Additional 
visits may be conducted at 
the investigator’s discretion.  
Recording of 
U-500R doses
X
Start of 
4.25-U/hour 
U-500R infusion
X
Infusion to start 12 hours 
prior to bolus administration 
by CSII and continue 
throughout the clamp 
procedures.  
Bolus U-500R 
administration
X
TID or BID 
administration of 
U-500R
X
Dosing will begin following 
Period 2 and will stop at the 
end of the Period 3 clamp 
procedure.  
Height
X
Weight
X
X
X
X
Body weight should be 
recorded on Day -1 of all 
study periods.  


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Human regular U-500 insulin (LY041001)
Periods 1 and 2a
Period 3
Screening
Days
Days
Follow-up
Comments
Procedure
Up to 28 
days prior 
to Period 1
-1
1
2
-10b
to -2
-1
1
2
7 to 28 days 
after discharge 
or early 
discontinuation
Vital signs 
(supine) (hours 
relative to 
bolus/morning 
dose)
X
-12 h 
(predose)d
Predose, 1, 2, 
4, 8, 12, 16 h
24 hc
Predose, 1, 
2, 4, 8, 12, 
16 h
24 h
X
Supine blood pressure 
and/or pulse rate may be 
measured as clinically 
indicated.  Additional vital 
signs may be measured 
during each study period, if 
warranted and agreed upon 
between Lilly and the 
investigator.  
Clinical 
laboratory tests
X
X (Period 
1 only)
X
See Attachment 2, Clinical 
Laboratory Tests, for 
details.
Pregnancy test
X
X
X
X
Serum pregnancy test will 
be performed at screening.  
Urine pregnancy test will be 
performed at every 
admission period and at 
poststudy, if applicable.
Physical exam
X
After screening, medical 
assessment only performed 
to include medical review 
and targeted examination, as 
appropriate.
12-lead ECG
X
Predose
24 hc
Predose
24 h
X


B5K-EW-IBHG(b) Protocol
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Human regular U-500 insulin (LY041001)
Periods 1 and 2a
Period 3
Screening
Days
Days
Follow-up
Comments
Procedure
Up to 28 
days prior 
to Period 1
-1
1
2
-10b
to -2
-1
1
2
7 to 28 days 
after discharge 
or early 
discontinuation
SMPG
X
4-point SMPG to be 
conducted daily throughout 
the study, except whilst 
resident in the CRU.  Mean 
SMPG for the 5 days prior 
to Period 3 will be collected 
in the eCRF.
Overnight PG 
stabilization
X
X
PG stabilized using an 
insulin lispro and/or glucose 
drip.
Euglycemic 
clamp
X
X
Pharmacogenetic 
sample
X 
(predose)
Single sample for 
pharmacogenetic analysis 
taken on Day -1 of Period 1.
PK and C-peptide 
samples 
-12,         
-8, -4 h
-0.5, 
0 (predose), 
0.5, 1, 2, 3, 4, 
5, 6, 7, 8, 12, 
16 h
24 h
-0.5, 
0 (predose), 
0.5, 1, 2, 3, 
4, 5
(predose 
for TID), 6, 
7, 9, 11
(predose),
12, 13, 15,
18 h
24 h,
Sampling times are relative 
to the time of the start of 
study treatment morning 
bolus administration (0 h).  
Sampling times for Period 3 
are relative to the time of 
breakfast (0 hr), lunch (5 hr) 
and dinner (11 hr).


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Human regular U-500 insulin (LY041001)
Abbreviations:  BG = blood glucose; BID = twice daily; CRU = clinical research unit; CSII = continuous subcutaneous insulin infusion; ECG = 
electrocardiogram; PG = plasma glucose; PK = pharmacokinetics; SMPG = self-monitored plasma glucose; TDD = total daily dose; TID = thrice daily; 
U-500R = human regular U-500 insulin.  
a
There may be 7 to 21 days between bolus doses in Period 1 and Period 2.  
b
There may be 5 to 10 days between the end of Period 2 and clamp initiation in Period 3 (Day 1), that is BID or TID dosing may begin on Day -10 through 
Day -5.
c
Clamp procedure in Periods 1 and 2 are of a maximum duration of 24 hours. Vital signs and ECGs will be conducted at the end of the clamp procedure.
d
CSII period only, taken prior to initiation of 12-hour U-500R infusion.  


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Human regular U-500 insulin (LY041001)
Attachment 2.Protocol IBHG Clinical Laboratory Tests
Laboratory Tests 
Hematology:a
Clinical Chemistrya
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count
Bicarbonate 
Mean cell volume 
Chloride 
Mean cell hemoglobin 
Calcium 
Mean cell hemoglobin concentration 
Phosphorus 
Leukocytes 
Glucose fasting
Cell Morphology
Blood urea nitrogen 
Absolute counts of:
Uric acid 
Neutrophils
Total cholesterol 
Lymphocytes
Triglycerides
Monocytes
High-density lipoprotein cholesterol
Eosinophils
Total protein
Basophils
Albumin
Platelets
Total bilirubin
Urinalysisa
Alkaline phosphatase
Specific gravity
Aspartate aminotransferase (AST)
pH
Alanine aminotransferase  (ALT)
Protein
Creatinine
Glucose
Gamma-glutamyl transferase (GGT)
Ketones
PT/INRb
Bilirubin
Urobilinogen
Ethanol testingb,c
Blood
Urine drug screenb,c
Nitrite
Hepatitis B surface antigenb
Microscopic examination of sedimentd
Hepatitis C antibodyb
HIVb
Pregnancy testc
FSHb
HbA1c
Abbreviations:  CRU = clinical research unit; FSH = follicle-stimulating hormone; HbA1c = hemoglobin A1c; 
HIV = human immunodeficiency virus; INR = international normalized ratio; PT = prothrombin time.  
a
Laboratory tests will be performed at a local laboratory and results will be validated at the time of initial testing.
b
Performed at screening only.
c
A serum pregnancy test will be performed at screening and urine pregnancy tests will be conducted at each CRU 
admission for women of child-bearing potential.  Urine drug screen and ethanol level may be repeated prior to 
admission to the CRU.  These tests will not be required at the follow-up visit.
d
Test only if dipstick result is abnormal.  


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Human regular U-500 insulin (LY041001)
Attachment 3.Protocol IBHG Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.  Fewer 
venipunctures and blood draws may actually occur, but this will not require a protocol 
amendment.
Protocol B5K-EW-IBHG Sampling Summary
Purpose
Maximum Blood Volume 
per Sample (mL)
Maximum Number 
of Blood Samples
Maximum Total 
Volume (mL)
Screening testsa
22.2
1
22.2
Clinical laboratory testsa
12.5
2
25
Self-monitored plasma glucose
0.05
372b
18.6
Pharmacokinetics
3.5
51
178.5
C-peptide
2.5
51
127.5
Euglycemic clamp
3 mL per hour
24 hours x 3 periods
216
Pharmacogenetics
10
1
10
Total
597.8
Total for clinical purposes [rounded up to nearest 10 mL]
600
a
Additional samples may be drawn if needed for safety purposes.
b
Includes 4 point self-monitored plasma glucose throughout study and 8 possible 03:00 hours measurements 
during titration.  


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Human regular U-500 insulin (LY041001)
Attachment 4.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.
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.
References:
Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its 
complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a 
WHO consultation. Diabetic Med. 1998;15(7):539-553.
Bennett P. Classification and diagnosis of diabetes mellitus and impaired glucose tolerance. In: 
Pickup J, Williams G, editors. Textbook of diabetes. Vol. 1. Oxford: Blackwell Scientific 
Publications, 1991: p 37-44.
Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. 
Diabetes Care. 1999;22(Suppl 1):S5-S19.


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Human regular U-500 insulin (LY041001)
Attachment 5.Protocol Amendment B5K-EW-IBHG(b) 
Summary Comparative Pharmacokinetics and 
Pharmacodynamics of Human Regular U-500 Insulin 
Administered Subcutaneously as a Bolus via Syringe 
versus Continuous Subcutaneous Insulin Infusion and 
Characterization of TID and BID Dosing at Steady State in 
High-Dose Insulin-Treated Subjects with Type 2 Diabetes 
Mellitus
Overview
Protocol B5K-EW-IBHG Comparative Pharmacokinetics and Pharmacodynamics of Human 
Regular U-500 Insulin Administered Subcutaneously as a Bolus via Syringe versus Continuous 
Subcutaneous Insulin Infusion and Characterization of TID and BID Dosing at Steady State in 
High-Dose Insulin-Treated Subjects with Type 2 Diabetes Mellitus has been amended.  The new 
protocol is indicated by Amendment (b) and will be used to conduct the study in place of any 
preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:

The inclusion criteria for BMI has been changed to ≥27.0 as the majority of subjects with 
T2DM are overweight or obese and this will aid recruitment whilst retaining a clinically 
relevant study population.  

The inclusion criteria for prestudy insulin has been amended to include U-200 and/or
U-300 insulins (as these formulations are used by insulin resistant subjects with T2DM 
and formulations of different strength may be used in basal/bolus combinations) and 
acceptable prestudy insulin use has been amended to TDD ≥150 U OR single doses 
>100 U as part of an MDI regimen AND TDD ≤3.0 U/kg in order to aid recruitment,
whilst still including subjects who are considered insulin resistant.

Acceptable concomitant medication has been amended to include SGLT2 inhibitors in 
order to aid recruitment as these agents are used by insulin resistant patients with T2DM.

The Abbreviations and Definitions section has been amended to include a definition for 
SGLT2.

Several editorial updates have been made to take into account the allowance of U-200 
and/or U-300 prestudy insulins and the removal of the requirements for subjects to be 
obese and for insulin resistance to be severe.


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Human regular U-500 insulin (LY041001)
Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
1. Protocol B5K-EW-IBHG(b)
Comparative Pharmacokinetics and Pharmacodynamics of 
Human Regular U-500 Insulin Administered Subcutaneously 
as a Bolus via Syringe versus Continuous Subcutaneous 
Insulin Infusion and Characterization of TID and BID Dosing 
at Steady State in High-Dose Insulin-Treated, Obese Subjects 
with Type 2 Diabetes Mellitus
2. Synopsis
Title of study:  Comparative Pharmacokinetics and Pharmacodynamics of Human Regular U-500 Insulin 
Administered Subcutaneously as a Bolus via Syringe versus Continuous Subcutaneous Insulin Infusion and 
Characterization of TID and BID Dosing at Steady State in High-Dose Insulin-Treated, Obese Subjects with Type 2 
Diabetes Mellitus
Objectives:  The primary objective of Part A is to compare the time of maximum drug concentration (tmax) of a 
100-U bolus of human regular U-500 insulin (U-500R) (500 U/mL) administered via single subcutaneous (SC) 
injection versus a 100-U bolus of U-500R administered via continuous SC insulin infusion (CSII) in high-dose 
insulin-treated, obese subjects with type 2 diabetes mellitus (T2DM).
The primary objective of Part B is to evaluate the area under the concentration versus time curve (AUC) from time 
zero to 24 hours postdose (AUC[0-24 hr]), maximum drug concentration (Cmax), and maximum glucose infusion 
rate (GIR) (Rmax) of U-500R at steady state following thrice- (TID) or twice- (BID) daily SC dosing in the study 
population.
Diagnosis and Main Criteria for Inclusion and Exclusion:  High-dose insulin-treated (U-100, U-200, and/or 
U-300 insulin total daily dose [TDD] ≥>200150 U/day OR at least 1 dose >100 U as part of a multiple daily 
injection (MDI) regimen AND have TDD ≤3.0 U/Kg) males or females with T2DM, ≥18 to <75 years old, with a 
body mass index of ≥3027.0 kg/m2, and HbA1c 7.5% to 11.5%, inclusive, at screening.  
3. Table of Contents
Comparative Pharmacokinetics and Pharmacodynamics of 
Human Regular U-500 Insulin Administered Subcutaneously 
as a Bolus via Syringe versus Continuous Subcutaneous 
Insulin Infusion and Characterization of TID and BID Dosing 
at Steady State in High-Dose Insulin-Treated, Obese Subjects 
with Type 2 Diabetes Mellitus


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Human regular U-500 insulin (LY041001)
4. Abbreviations and Definitions
Comparative Pharmacokinetics and Pharmacodynamics of 
Human Regular U-500 Insulin Administered Subcutaneously 
as a Bolus via Syringe versus Continuous Subcutaneous 
Insulin Infusion and Characterization of TID and BID Dosing 
at Steady State in High-Dose Insulin-Treated, Obese Subjects 
with Type 2 Diabetes Mellitus
5. Introduction
5.2 Rationale and Justification for the Study
There have been no state-of-the-art euglycemic clamp PK/PD studies performed on U-500R in 
the target population of high-dose insulin-treated obese subjects with T2DM, in whom U-500R is 
most often used (Lane et al. 2009; Reutrakul et al. 2012; Jones and Idris 2013; Eby et al. 2013; 
Eby et al. 2014; Cochran et al. 2014).  Likewise, there have been no PK/PD studies conducted on 
steady state time-concentration and time-action characteristics of U-500R on any population of 
subjects.  Rigorous study in both of these settings will address major gaps in scientific 
knowledge and will further inform clinicians regarding appropriate use of U-500R in severely 
insulin-resistant patients with diabetes requiring high doses of insulin.  
6.1 Primary Objective
Part A:  to compare the tmax of a 100-U bolus of U-500R (500 U/mL) administered via single SC 
injection versus a 100-U bolus of U-500R administered via CSII in high-dose insulin-treated, 
obese subjects with T2DM.
7.1 Summary of Study Design
This is a 2-part, Phase 1 (postmarketing), single-center, 3-period, 4-sequence, randomized, 
open-label, crossover euglycemic clamp study in high-dose insulin-treated, obese subjects with 
T2DM.  Part A (Periods 1 and 2) will compare the PK and PD of a 100-U bolus of U-500R 
administered via single SC injection versus a 100-U bolus of U-500R administered via CSII.  
SGLT2
sodium-glucose co-transporter-2


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Human regular U-500 insulin (LY041001)
Subjects completing Part A will transition to Part B (Period 3), which will evaluate the PK and 
PD characteristics of U-500R administered by TID and BID MDIs under steady-state conditions.  
7.1.2 Part A (Study Periods 1 and 2)
Subjects will be admitted to the clinical research unit (CRU) on Day -1 of each period and be 
fasted from 12 hours prior to clamp initiation until completion of the clamp procedure.  
All subjects will stop their prestudy U-100, U-200, and/or U-300 insulin dosing at least 15 hours 
prior to U-500R bolus dosing.  Subjects randomized to receive U-500R by SC injection will 
receive a 100-U U-500R bolus administration by SC injection prior to initiation of the clamp.  
Subjects randomized to receive U-500R by CSII will have a U-500 OmniPod Insulin 
Management System (U-500 OmniPod) fitted by a qualified member of CRU staff, which will 
administer a 12-hour infusion of 4.25 U/h of U-500R, prior to bolus administration of 100 U of 
U-500R (via the same pump) and initiation of the clamp.  The 4.25-U/h U-500R infusion will 
continue throughout the duration of the clamp following bolus administration by the U-500 
OmniPod.  
Overnight, between Day -1 and Day 1, all subjects will have their PG stabilized, using an insulin 
lispro and/or glucose drip, to a target fasting PG concentration of 120 mg/dL (6.7 mmol/L) (with 
an acceptable range of 100 to 130 mg/dL [5.6 to 7.2 mmol/L]).  
Following bolus dose administration (or initiation of bolus dose administration for CSII), 
subjects will undergo a euglycemic clamp with a maximum duration of 24 hours.  Following 
completion of the clamp procedures, subjects will be provided a meal and will be medically 
assessed and discharged from the CRU, unless the investigator has any safety concerns.  If 
glucose is still being infused at the time of clamp discontinuation, the subject will be monitored 
for safety and will remain in the CRU until stable according to investigator judgment (see 
Section 10.4.1).  
Blood samples will be collected prior to and during the clamp procedure (see Attachment 1) to 
determine serum immunoreactive insulin (IRI) and C-peptide concentrations for PK and PD 
analysis. 
Following termination of the clamp procedure in Period 1, subjects will resume their prestudy 
treatment regimen (which may include basal; premixed; and/or basal/bolus U-100, U-200, and/or 
U-300 insulin regimens with or without antihyperglycemic agents [AHAs] as listed in Inclusion 
Criterion [5], Section 8.1.1) until their admission to the CRU on Day -1 of Period 2.  There will 
be a washout period of 7 to 21 days between U-500R bolus doses in Periods 1 and 2.  
Following termination of the clamp procedure in Period 2, subjects will be instructed on 
administration of U-500R either by TID or BID MDIs as described in Section 7.1.3 and 
Section 9.4.  There will be a period of 5 to 10 days between the end of the clamp in Period 2 and 
the clamp procedure in Period 3 to allow U-500R concentrations to reach steady state.
7.1.3 Part B (Study Period 3)


B5K-EW-IBHG(b) Protocol
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Human regular U-500 insulin (LY041001)
Following termination of the clamp procedure in Period 2, subjects will transition, as randomized, 
to TID or BID MDIs of U-500R.  Human regular U-500 insulin will be self-administered by the 
subjects at home under telephone guidance from CRU staff during a telephone visit 2 to 3 days 
after the end of Period 2 (additional telephone or office visits may be added at the investigator’s 
discretion).  Initial U-500R doses will be based on each subject’s U-100 insulin TDD prior to 
admission for Period 2, with titration for safety, if necessary, using the formulas given in 
Section 9.4.  There will be 5 to 10 days between the end of Period 2 and the clamp in Period 3 
(that is, dosing will begin on up to Day -10 and no later than Day -5 of Period 3) to allow steady 
state of the U-500R dosing regimen to be achieved.  Mean self-monitored plasma glucose 
(SMPG) will be recorded from Day -5 until admission to the CRU.  
Subjects will be admitted to the CRU on Day -1 of Period 3, prior to their pre-evening meal dose, 
which will be administered by CRU staff, and undergo fasting, PG stabilization, and a 24-hour 
euglycemic clamp as detailed in Section 7.1.2, with PK sampling as detailed in the Study 
Schedule (Attachment 1).  
Following termination of the clamp procedure in Period 3 (Day 2), subjects will resume their 
prestudy U-100 insulin treatment regime.  Discharge from the CRU will be subject to the same 
postclamp safety assessments as detailed in Section 7.1.2 and Section 10.4.1.  Follow-up will 
occur 7 to 28 days after the end of Period 3 when safety procedures will be conducted and insulin 
use and dose will be recorded as detailed in the Study Schedule (Attachment 1).  
7.2 Discussion of Design and Control
In Part A of this study, a 2-period, randomized, crossover design has been chosen to allow each 
subject to act as his/her own control.  Prestudy U-100, U-200, and/or U-300 insulin will be taken 
at the same dose and at approximately the same time each day prior to Period 1 and between 
Periods 1 and 2, and stopped at least 15 hours prior to U-500R bolus administration in Part A in 
order to reduce variation in insulin carryover (as the bioanalytical methodology is not specific to 
U-500R).  
The use of a euglycemic clamp technique will provide data on the glucodynamic activity of 
U-500R.  This is standard methodology routinely used to safely measure insulin action in clinical 
studies.  
High-dose insulin-treated, obese subjects with T2DM are representative of the population that is 
prescribed the U-500R formulation.  An open-label design is considered appropriate as the 
PK/PD parameters being investigated in this study are objective endpoints.  
Fasting and pre-meal plasma-equivalent glucose target ranges in Period 3 are 71 to 130 mg/dL 
(3.9 to 7.2 mmol/L), consistent with American Diabetes Association (ADA) standards of care 
(ADA 2012).  
8.1.1 Inclusion Criteria
[3]
have a BMI of ≥3027.0 kg/m2 at screening


B5K-EW-IBHG(b) Protocol
Page 72
Human regular U-500 insulin (LY041001)
[4]
are current users of U-100, U-200, and/or U-300 insulin/analog as basal, 
premixed, and/or basal/bolus delivered with any injection device (pens and/or 
syringe/vial but excluding CSII/insulin pump use in the preceding 3 months), 
taking:
with a TDD of ≥>200 150 U AND
OR have TDD ≤3.0 U/Kg
at least 1 dose >100 U as part of an MDI regimen, basal, premixed, or 
basal/bolus by any injection device (pens and/or syringe/vial but excluding 
CSII/insulin pump use in the preceding 3 months)
AND 
TDD ≤3.0 U/kg
[5]
Concomitant AHA therapy may include:

metformin (MET),

dipeptidyl peptidase-4 inhibitors,

pioglitazone (doses ≤30 mg/day), and/or

GLP-1 receptor agonists

sodium-glucose co-transporter-2 (SGLT2) inhibitors, except in combination 
with GLP-1 receptor agonists (see Exclusion Criterion [31] for excluded 
AHA therapy).
Subjects’ AHA therapy must have been stable for ≥3 months (except for 
weekly GLP-1 receptor agonists which must have been stable for ≥4 
months).  
[9]
must be able to safely withhold administration of U-100, U-200, and/or U-300
insulins from ≥15 hours prior to clamp procedures in Periods 1 and 2 as 
applicable, in the judgment of the investigator
8.1.2. Exclusion Criteria
[31] have used sodium-glucose co-transporters inhibitors, rosiglitazone, 
pramlintide, once-weekly or BID exenatide, or other injectable or oral AHA 
not listed in Inclusion Criterion [5] in the 3 months prior to screening; or are 
taking oral antidiabetic medications at doses exceeding the respective product 
labels; or have a contraindication to current oral antidiabetic medication usage 
per the respective product labels (for example, MET:  serum creatinine 
≥1.4 mg/dL in women or ≥1.5 mg/dL in men).  
9.2. Treatment Administration
The investigator or designee is responsible for:

explaining the correct use of the investigational product to the subjects and site personnel, 


B5K-EW-IBHG(b) Protocol
Page 73
Human regular U-500 insulin (LY041001)

verifying that instructions are followed properly,

maintaining accurate records of investigational product dispensing and collection,

and returning all unused medication 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 clinical trial materials.  
Subjects will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product or drug delivery system so that the 
situation can be assessed.
All clinical trial material provided to the investigator will be stored in a secure place and 
allocated and dispensed by appropriately trained persons.  The allocation and dispensing of the 
investigational products will be fully documented and verified by a second person.  Detailed 
records of the amounts of the investigational product received, dispensed, and remaining at the 
end of the study will be maintained.  Not in-use or unopened Humulin R U-500 vials should be 
stored in a refrigerator, (2°C to 8°C [36° F 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, even if they still 
contain U-500R (Humulin R U-500 Package Insert, 2014). Clinical trial materials will be 
labeled according to the respective country’s regulatory requirements.
During periods of prestudy U-100, U-200, and/or U-300 insulin treatment, subjects will 
self-administer their U-100 insulin at home, at approximately the same time each day.  The last 
dose prior to assessment should be taken at approximately the same time in each period and will 
be at least 15 hours before the U-500R bolus dose and clamp procedure in Part A.  The U-100 
insulin TDD should remain approximately the same throughout Part A of the study (except while 
subjects are resident in the CRU when it will not be taken).  
9.3 Rationale for Selection of Dose
A dose of 100 U of U-500R was chosen for Part A of this study as this is within the range 
commonly encountered in high-dose insulin-treated patients whose T2DM is managed with 
U-500R either by MDI or off-label via CSII (Lane et al. 2009; de la Peña et al. 2011; Reutrakul 
et al. 2012; Cochran et al. 2014; and Lane et al. 2013).  
Study dosing and conversion and titration regimens for the TID and BID treatment groups in 
Part B, both guided by pre-Period 2 U-100, U-200, and/or U-300 insulin TDD (based on the 
highest TDD recorded in the 3 days prior to Period 2 which should be approximately unchanged 
from pre-Period 1) and baseline HbA1c (screening), and subsequent glucose monitoring, 
respectively, are based on literature expert reviews (Lane et al. 2009; Segal et al. 2010; Reutrakul, 
et al. 2012) and on the results from simulations performed using a systems physiology model of 
diabetes (in Physiolab®; de la Peña et al. 2014) based on data from previous PK/PD studies of 


B5K-EW-IBHG(b) Protocol
Page 74
Human regular U-500 insulin (LY041001)
U-500R and U-100 human regular insulin (de la Peña et al. 2011; Studies F3Z-LC-IMAC and 
H7U-MC-IDBM).
9.4 Dose Conversion from Prestudy Insulin in Part B
Subjects will record their U-100 insulin doses throughout the study.  Baseline U-100, U-200, 
and/or U-300 insulin TDD will be defined as the highest TDD recorded in the 3 days prior to 
Period 2.  All U-100, U-200, and/or U-300 insulin therapy will be discontinued upon initiation of 
study drug, but permitted prestudy AHA therapy should continue to be taken at prestudy doses, 
except on clamp assessment days.  For all subjects with HbA1c >8.0% at screening, initial 
U-500R TDD will be the same (in units) as U-100, U-200, and/or U-300 insulin TDD at 
screening.  
For all subjects with baseline HbA1c ≤8.0% at screening, initial U-500R TDD dose will be 
reduced by 20% from the U-100, U-200, and/or U-300 insulin TDD at screening.  
9.7 Concomitant Therapy
Subjects on stable concomitant medication at the time of study entry should continue their 
regular, unchanged dose throughout the study; for example, hormonal contraceptives, thyroid 
replacement therapy, anti-hypertensives, low-dose aspirin, and cholesterol lowering agents.  
Prescription medications (other than those allowed in Inclusion Criteria [4] and [5]), herbal 
medications, or nutritional supplements that affect PG or insulin sensitivity, or promote weight 
loss will not be allowed within 4 weeks prior to dosing.  Initiation of new over-the-counter 
medication within 7 days prior to dosing, or prescription medication or herbal medication within 
14 days prior to dosing may be permitted following discussion with the Lilly clinical 
pharmacologist.  Vitamin/mineral supplements and/or occasional use of acetaminophen will be 
allowed.  
Subjects may continue to take their stable prestudy AHA dose (MET, dipeptidyl peptidase-4 
inhibitors, pioglitazone [doses ≤30 mg/day], and/or GLP-1 receptor agonists, and/or SGLT2 
inhibitors [not in combination with GLP-1 receptor agonists]), unchanged, throughout the study, 
except on clamp assessment days.  
Rosiglitazone, pramlintide, once weekly or BID exenatide, sodium-glucose co-transport 
inhibitors, other injectable or oral AHAs not listed in Inclusion Criterion [5], or permitted AHAs 
taken at doses other than that prescribed by the product label will not be allowed.  


B5K-EW-IBHG(b) Protocol
Page 75
Human regular U-500 insulin (LY041001)
Attachment 1. Protocol IBHG Study Schedule


B5K-EW-IBHG(b) Protocol
Page 76
Human regular U-500 insulin (LY041001)
Periods 1 and 2a
Period 3
Screening
Days
Days
Follow-up
Comments
Procedure
Up to 28 
days prior 
to Period 1
-1
1
2
-10b
to -2
-1
1
2
7 to 28 days 
after discharge 
or early 
discontinuation
Informed consent
X
Subject 
admission to 
CRU
X
X
U-100, U-200, 
and/or U-300
insulin dosing
X
X
X
X
U-100, U-200, and/or U-300
dosing on Day -1 of Period 
1 and 2 to end ≥15 h prior to 
U-500R bolus dosing.  
Transition to 
U-100, U-200, and/or U-300  
insulin after Period 3 is per 
investigator judgment.  
Subject discharge 
from CRU
X
X
Subjects will remain at the 
CRU until BG is stable 
according to investigator 
judgment.  
Recording of 
U-100, U-200, 
and/or U-300
insulin TDD
X
X
X
X
Subjects will record their 
U-100, U-200, and/or U-300
insulin TDD throughout the 
study apart from during 
dosing with U-500R.
Type and dose of 
insulin use 
recorded
X


B5K-EW-IBHG(b) Protocol
Page 77
Human regular U-500 insulin (LY041001)
Periods 1 and 2a
Period 3
Screening
Days
Days
Follow-up
Comments
Procedure
Up to 28 
days prior 
to Period 1
-1
1
2
-10b
to -2
-1
1
2
7 to 28 days 
after discharge 
or early 
discontinuation
Telephone visit 
for U-500R dose 
titration
X
Telephone visit for review 
of SMPG 2 to 3 days after 
end of Period 2.  Additional 
visits may be conducted at 
the investigator’s discretion.  
Recording of 
U-500R doses
X
Start of 
4.25-U/hour 
U-500R infusion
X
Infusion to start 12 hours 
prior to bolus administration 
by CSII and continue 
throughout the clamp 
procedures.  
Bolus U-500R 
administration
X
TID or BID 
administration of 
U-500R
X
Dosing will begin following 
Period 2 and will stop at the 
end of the Period 3 clamp 
procedure.  
Height
X
Weight
X
X
X
X
Body weight should be 
recorded on Day -1 of all 
study periods.  


B5K-EW-IBHG(b) Protocol
Page 78
Human regular U-500 insulin (LY041001)
Periods 1 and 2a
Period 3
Screening
Days
Days
Follow-up
Comments
Procedure
Up to 28 
days prior 
to Period 1
-1
1
2
-10b
to -2
-1
1
2
7 to 28 days 
after discharge 
or early 
discontinuation
Vital signs 
(supine) (hours 
relative to 
bolus/morning
dose)
X
-12 h 
(predose)d
Predose, 1, 2, 
4, 8, 12, 16 h
24 hc
Predose, 1, 
2, 4, 8, 12, 
16 h
24 h
X
Supine blood pressure 
and/or pulse rate may be 
measured as clinically 
indicated.  Additional vital 
signs may be measured 
during each study period, if 
warranted and agreed upon 
between Lilly and the 
investigator.  
Clinical 
laboratory tests
X
X (Period 
1 only)
X
See Attachment 2, Clinical 
Laboratory Tests, for 
details.
Pregnancy test
X
X
X
X
Serum pregnancy test will 
be performed at screening.  
Urine pregnancy test will be 
performed at every 
admission period and at 
poststudy, if applicable.
Physical exam
X
After screening, medical 
assessment only performed 
to include medical review 
and targeted examination, as 
appropriate.
12-lead ECG
X
Predose
24 hc
Predose
24 h
X


B5K-EW-IBHG(b) Protocol
Page 79
Human regular U-500 insulin (LY041001)
Periods 1 and 2a
Period 3
Screening
Days
Days
Follow-up
Comments
Procedure
Up to 28 
days prior 
to Period 1
-1
1
2
-10b
to -2
-1
1
2
7 to 28 days 
after discharge 
or early 
discontinuation
SMPG
X
4-point SMPG to be 
conducted daily throughout 
the study, except whilst 
resident in the CRU.  Mean 
SMPG for the 5 days prior 
to Period 3 will be collected 
in the eCRF.
Overnight PG 
stabilization
X
X
PG stabilized using an 
insulin lispro and/or glucose 
drip.
Euglycemic 
clamp
X
X
Pharmacogenetic 
sample
X 
(predose)
Single sample for 
pharmacogenetic analysis 
taken on Day -1 of Period 1.
PK and C-peptide 
samples 
-12,         
-8, -4 h
-0.5, 
0 (predose), 
0.5, 1, 2, 3, 4, 
5, 6, 7, 8, 12, 
16 h
24 h
-0.5, 
0 (predose), 
0.5, 1, 2, 3, 
4, 5 
(predose 
for TID), 6, 
7, 9, 11 
(predose), 
12, 13, 15, 
18 h
24 h,
Sampling times are relative 
to the time of the start of 
study treatment morning 
bolus administration (0 h).  
Sampling times for Period 3 
are relative to the time of 
breakfast (0 hr), lunch (5 hr) 
and dinner (11 hr).


B5K-EW-IBHG(b) Protocol
Page 80
Human regular U-500 insulin (LY041001)
Abbreviations:  BG = blood glucose; BID = twice daily; CRU = clinical research unit; CSII = continuous subcutaneous insulin infusion; ECG = 
electrocardiogram; PG = plasma glucose; PK = pharmacokinetics; SMPG = self-monitored plasma glucose; TDD = total daily dose; TID = thrice daily; 
U-500R = human regular U-500 insulin.  
a
There may be 7 to 21 days between bolus doses in Period 1 and Period 2.  
b
There may be 5 to 10 days between the end of Period 2 and clamp initiation in Period 3 (Day 1), that is BID or TID dosing may begin on Day -10 through 
Day -5.
c
Clamp procedure in Periods 1 and 2 are of a maximum duration of 24 hours.  Vital signs and ECGs will be conducted at the end of the clamp procedure.  
d
CSII period only, taken prior to initiation of 12-hour U-500R infusion.  

SAP_001.pdf: 
 
Statistical Analysis Plan B5K-EW-IBHG 
 
 
Comparative Pharmacokinetics and Pharmacodynamics of Human Regular U-500 Insulin 
Administered Subcutaneously as a Bolus via Syringe versus Continuous Subcutaneous Insulin 
Infusion and Characterization of TID and BID Dosing at Steady State in High-Dose Insulin-Treated 
Subjects with Type 2 Diabetes Mellitus 
 
NCT02588950 
 
Approval Date: 21-Sep-2015 
 
 


Final, 15 September 2015
             Page 1 of 13
STATISTICAL ANALYSIS PLAN
Comparative Pharmacokinetics and Pharmacodynamics of Human Regular U-500 Insulin 
Administered Subcutaneously as a Bolus via Syringe versus Continuous Subcutaneous 
Insulin Infusion and Characterization of TID and BID Dosing at Steady State in High-Dose 
Insulin-Treated, Obese Subjects with Type 2 Diabetes Mellitus
Statistical Analysis Plan Status:  Final
Statistical Analysis Plan Date:  15-September-2015
Study Drug: LY041001
Sponsor Reference:  B5K-EW-IBHG
Covance CRU Study: 1000071-8316164
Clinical Phase I
Approval Date: 21-Sep-2015 GMT


Final, 15 September 2015
             Page 2 of 13
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8316164
Sponsor Reference B5K-EW-IBHG
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS .....................................................................................................2
2.
ABBREVIATIONS..............................................................................................................3
3.
INTRODUCTION ...............................................................................................................5
4.
STUDY OBJECTIVES........................................................................................................5
Primary Objectives.................................................................................................................5
Secondary Objectives .............................................................................................................6
Exploratory Objectives...........................................................................................................6
5.
STUDY DESIGN.................................................................................................................6
6.
TREATMENTS ...................................................................................................................7
7.
SAMPLE SIZE JUSTIFICATION .......................................................................................7
8.
DEFINITION OF ANALYSIS POPULATIONS..................................................................8
9.
STATISTICAL METHODOLOGY .....................................................................................8
9.1
General..........................................................................................................................8
9.2
Demographics and Subject Disposition..........................................................................8
9.3
Pharmacokinetic Assessment.........................................................................................9
9.3.1 Pharmacokinetic Analysis..............................................................................................9
9.3.2 Pharmacokinetic Statistical Methodology ....................................................................10
9.4
Pharmacodynamic Assessment ....................................................................................10
9.4.1 Pharmacodynamic Analysis.........................................................................................10
9.4.2 Pharmacodynamic Statistical Methodology .................................................................11
9.5
Safety and Tolerability Assessments ............................................................................11
9.5.1 Adverse events ............................................................................................................11
9.5.2 Concomitant medication..............................................................................................12
9.5.3 Clinical laboratory parameters .....................................................................................12
9.5.4 Vital signs ...................................................................................................................12
9.5.5 Blood Glucose Monitoring and Hypoglycemia ............................................................12
9.5.6 Other assessments........................................................................................................12
9.5.7 Safety and Tolerability Statistical Methodology ...........................................................12
10. INTERIM ANALYSES .....................................................................................................13
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ............13
12. REFERENCES ..................................................................................................................13
13. DATA PRESENTATION ..................................................................................................13
13.1 Derived Parameters .....................................................................................................13
13.2 Missing Data ...............................................................................................................13
13.3 Insufficient Data for Presentation ................................................................................13


Final, 15 September 2015
             Page 3 of 13
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8316164
Sponsor Reference B5K-EW-IBHG
2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
AE
Adverse event
AUC
Area under the concentration versus time curve
AUC(0-tlast)
Area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable concentration
BID
Twice daily
BQL
Below the quantifiable lower limit of the assay
Cmax
Maximum observed drug concentration
CI
Confidence interval
CL/F
Apparent total body clearance of drug calculated after extra-vascular
administration
CRF
Case Report Form
CSR
Clinical Study Report
CSII
Continuous subcutaneous insulin infusion
CRU
Clinical Research Unit
CV
Coefficient of variation
Early tRmax50
Time of 50% of maximum GIR before Rmax
ECB
Early clinical biometrics
ECG
Electrocardiogram
e.g.
For example (Latin: exempli gratia)
GIR
Glucose infusion rate
ICH
International Conference on Harmonisation
Late tRmax50
Time of 50% of maximum GIR after Rmax
LLOQ
Lower limit of quantitation
LS
Least square
MDI
Multiple daily injections
MedDRA
Medical Dictionary for Regulatory Activities
NA
Not applicable
PD
Pharmacodynamic


Final, 15 September 2015
             Page 4 of 13
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8316164
Sponsor Reference B5K-EW-IBHG
PK
Pharmacokinetic
QTcB
QT interval corrected using Bazett’s formula
QTcF
QT interval corrected using Fridericia’s formula
Rmax
Maximum glucose infusion rate
SAP
Statistical Analysis Plan
SC
Subcutaneous
SD
Standard deviation 
SMPG
Self-monitored plasma glucose
TDD
Total daily dose
T2DM
Type 2 diabetes mellitus
TID
Thrice daily
TFLs
Tables, Figures, and Listings
t1/2
Half-life associated with the terminal rate constant (λz) in non-
compartmental analysis
tmax
Time of maximum observed drug concentration
tRmax
Time of maximum glucose infusion rate
Vz/F
Apparent volume of distribution during the terminal phase after 
extra-vascular administration
WHO
World Health Organization


Final, 15 September 2015
             Page 5 of 13
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8316164
Sponsor Reference B5K-EW-IBHG
3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 29 
April 2015 and amendment (a) dated 24 August 2015).
This SAP describes the planned analysis of the safety, tolerability and pharmacokinetic (PK) and 
pharmacodynamic (PD) data from this study. A detailed description of the planned TFLs to be 
presented in the clinical study report (CSR) is provided in the accompanying TFL shell 
document.
The intent of this document is to provide guidance for the statistical and PK analyses of data. In 
general, the analyses are based on information from the protocol, unless they have been modified 
by agreement between Eli Lilly and Company and Covance Early Clinical Biometrics (ECB). A 
limited amount of information concerning this study (e.g., objectives, study design) is given to 
help the reader’s interpretation. This SAP must be signed off prior to first subject administration
for this study. When the SAP and TFL shells are agreed upon and finalized, they will serve as the 
template for this study’s CSR.
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon 
between Eli Lilly and Company and Covance ECB and identified in the CSR. Any minor 
deviations from the TFLs may not be documented in the CSR.
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials1 and the ICH E3 Guideline entitled Guidance for Industry: Structure 
and Content of Clinical Study Reports2.
4. STUDY OBJECTIVES
Primary Objectives
Part A: to compare the t max of a 100-U bolus of U-500R (500 U/mL) administered via single 
subcutaneous (SC) injection versus a 100-U bolus of U-500R administered via continuous 
subcutaneous insulin infusion (CSII) in high-dose insulin-treated, obese subjects with type 2 
diabetes mellitus (T2DM). 
Part B: to evaluate the area under the concentration versus time curve ( AUC) from time zero to 
24 hours postdose (AUC[0-24]), maximum drug concentration (Cmax), and maximum glucose 
infusion rate (Rmax) of U-500R at steady state following thrice daily (TID) or twice daily (BID)
SC dosing in the study population.


Final, 15 September 2015
             Page 6 of 13
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8316164
Sponsor Reference B5K-EW-IBHG
Secondary Objectives
Part A: to compare the time of maximum glucose infusion rate (GIR) (tRmax) and exposure (AUC 
from time zero to time t, where t is the last time point with a measurable concentration 
[AUC(0-tlast)]) of a 100-U bolus of U-500R administered via single SC injection versus CSII in 
the study population.
Part B: to evaluate the time of Cmax (tmax), total amount of glucose infused (Gtot) and tRmax of 
U-500R at steady state following TID or BID SC dosing in the study population.
Exploratory Objectives
Other PK and PD parameters may be evaluated including but not limited to:
Part A: half-life associated with the terminal rate constant in no ncompartmental analysis (t 1/2), 
apparent total body clearance of drug calculated after extra -vascular administration (CL/F), and
apparent volume of distribution during the terminal phase after extra -vascular administration
(Vz/F), time of last GIR measurement (tRlast), the time of first change of GIR postdose (tR onset), 
the time of 50% of maximum GIR before Rmax (early tRmax50), and the time of 50% of maximum 
GIR after Rmax (late tRmax50) in the study population.
Part B: AUC of U-500R over each dosing interval and over each meal at steady state following
TID or BID SC dosing in the study population.
5. STUDY DESIGN
This is a 2-part, Phase 1 (postmarketing), single-center, 3-period, 4-sequence, randomized, 
open-label, crossover euglycemic clamp study in high-dose insulin-treated, obese subjects with 
T2DM. Part A (Periods 1 and 2) will compare the PK and PD of a 100-U bolus of U-500R 
administered via single SC injection versus a 100-U bolus of U-500R administered via CSII. 
Subjects completing Part A will transition to Part B (Period 3), which will evaluate the PK and 
PD characteristics of U-500R administered by TID and BID multiple daily injections (MDIs)
under steady-state conditions. 
Up to 32 subjects may be enrolled to achieve a target of approximately 24 completing all 3 
periods of the study. 
Subjects will be randomly assigned to 1 of 4 dosing sequences (Table 1.). Each subject will be 
administered 100 U of U-500R by single SC injection, and 100 U of U-500R by CSII in Part A 
and either TID U-500R or BID U-500R in Part B.


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Table 1. Dosing Schedule
Part A
Part B
Sequence
Period 1
Period 2
Period 3
1
SC
CSII
TID
2
CSII
SC
BID
3
SC
CSII
BID
4
CSII
SC
TID
Abbreviations: BID=twice-daily administration of U-500R; CSII=100 U U-500R administered via continuous 
subcutaneous insulin infusion; SC=100 U U-500R administered via single subcutaneous injection; TID=thrice-daily 
administration of U-500R
Figure 1. Study Design
6. TREATMENTS
The following is a list of the study treatment abbreviations that will be used in the TFLs.
Study Treatment Name
Treatment order in TFL
100-U bolus U-500R (SC)
1
100-U bolus U-500R (CSII) 
2
U-500R (BID)
3
U-500R (TID)
4
7. SAMPLE SIZE JUSTIFICATION
The primary objective of Part A of the study is to compare the t max of U-500R administered by
single SC injection or CSII. Up to 32 subjects may be enrolled to ensure that approximately 24 
subjects complete the study.
The sample size is based on a calculation of precision of the t max. Intra-subject variability for tmax
has not been assessed previously. Based on an assumption of an intra-subject variability estimate 
of 20% for tmax, a sample size of 24 completed subjects in Part A will provide approximately 
90% coverage probability that the half-width of the 90% confidence interval (CI) for the ratio of 


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geometric means for t max will be within 0.116 in the log scale, which corresponds
to 
approximately 12% of the geometric mean ratio estimate in the natural scale.
If any subjects discontinue the study prior to completion of the 3 periods, the replacement
subjects who are enrolled will assume the discontinued subjects ’ randomization schedule and
will complete all 3 periods.
8. DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all subjects who received at least one dose of study drug, 
and have at least one postdose safety assessment.
The “Pharmacokinetic” population will consist of all subjects who received at least one dose of 
study drug and have evaluable PK data.  
The “Pharmacodynamic” population will consist of all subjects who received at least one dose of 
study drug and have evaluable PD data.
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when subjects are assigned to analysis populations.
9. STATISTICAL METHODOLOGY
9.1
General
Data listings will be provided for all data that is databased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include the arithmetic mean, arithmetic standard deviation (SD), median, 
min, max and N; for log-normal data (e.g. the PK parameters: AUCs and Cmax) the geometric 
mean and geometric coefficient of variation (CV%) will also be presented. For categorical data, 
frequency count and percentages will be presented. Data listings will be provided for all subjects 
up to the point of withdrawal, with any subjects excluded from the relevant population 
highlighted. Summary statistics and statistical analyses will generally only be performed for 
subjects included in the relevant analysis population. 
Mean change from baseline is the mean of all individual subjects’ change from baseline values. 
Each individual change from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint. The individual subject’s change from baseline 
values will be used to calculate the mean change from baseline using a SAS procedure such as 
Proc Univariate.
The TFLs will be programmed using SAS® Version 9.3 or greater.
9.2
Demographics and Subject Disposition
Subject disposition will be listed. The demographic variables age, sex, race, ethnicity, country of
enrollment, site ID, body weight, height and body mass index will be summarized and listed.


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Screening HbA1c, HbA1c >8.0%, HbA1c ≤8.0% , fasting blood glucose, duration of T2DM and 
prestudy insulin treatment will be summarized and listed.
9.3
Pharmacokinetic Assessment
9.3.1 Pharmacokinetic Analysis
For the primary analysis, serum immunoreactive concentrations of insulin will be corrected using 
C-peptide data. Specifically, drug insulin concentrations will be calculated as the difference 
between total insulin and endogenous insulin, which in turn will be estimated with the C-peptide 
concentration data using Owens method (Owens 1986) with the following equation:
Drug insulin = Total insulin – F*C-peptide
where F is the average of the ratios of insulin to C-peptide at baselines (-0.5, and 0 hour) and will
be calculated for the subject per the following rule:
1. If there is BQL values for insulin or C-peptide, set them to ½ LLOQ.
2. Take the mean of the ratios of insulin to C-peptide at the two pre-dose time points (-0.5h,
and 0h) during the single SC injection period as the F for the subject.
Pharmacokinetic parameter estimates will be calculated using non-compartmental methods of 
analysis in validated software (Phoenix WinNonlin Version 6.3, Pharsight Corporation, USA or 
later). The analyses will be performed according to the Lilly Global Pharmacokinetics, 
Pharmacodynamics, and Pharmacometrics Divisional Standard Operating Procedures. The actual 
validated software version used when actual analyses are conducted will be specified in the 
clinical study report. C-peptide may be used to correct serum immunoreactive insulin
concentrations for endogenous insulin.
The primary parameter for analysis in Part A will be tmax. Other noncompartmental parameters 
such as Cmax, AUC from time zero to infinity (AUC[0-∞]), AUC(0-tlast), half-life associated with 
the terminal rate constant in noncompartmental analysis (t1/2), the last time point with a 
measurable concentration (tlast), apparent total body clearance of drug calculated after extra-
vascular administration (CL/F), and apparent volume of distribution during the terminal phase 
after extra-vascular administration (Vz/F) may be reported, as appropriate.
In the treatment of CSII, the PK profile of insulin via SC injection can be corrected by 
subtracting baseline concentration, given steady-state of infused basal insulin via CSII will be 
reached after 12hrs.
The primary PK parameters for Part B will be AUC(0-24) and Cmax; other PK parameters such as 
tmax and AUC of U-500R over each dosing interval and over each assumed meal time period at 
steady state may also be reported, as appropriate.
Parameters will be individually calculated by Eli Lilly and Company and sent to Covance for
statistical analysis.


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9.3.2 Pharmacokinetic Statistical Methodology
For Part A, the primary parameter for statistical analysis will be tmax. The values for tmax will be 
log-transformed and evaluated in a linear mixed-effects model with fixed effects for 
administration method, period and sequence order (order 1 is derived based on sequences 1 and 
3, and order 2 is derived based on sequences 2 and 4), and a random effect for subject. The 
difference in least squares (LS) means along with the 90% CI will be back-transformed to 
present the ratios of geometric means and the 90% CI for the comparison of the administration 
methods (single SC injection [test] and CSII [reference]). This same analysis will be repeated for 
AUC(0-tlast), AUC(0-∞), and Cmax.
Example SAS code:
proc mixed data= ; 
class seqorder period method subject;
model l_pk = seqorder period method / outpred=resids ddfm=kr;
random subject;
lsmeans method / pdiff alpha=0.1;
ods output lsmeans=lsm;
ods output diffs=diff;
run; quit;
The values of tmax will also be analyzed non-parametrically using a Wilcoxon signed-rank test
using the SAS procedure PROC UNIVARIATE. Median differences and approximate 90% CIs 
for the difference will be calculated for the comparisons of the administration methods (single 
SC injection and CSII).
No formal statistical analysis will be conducted for Part B.
PK parameters will be listed and summarized for both parts of the study.
9.4
Pharmacodynamic Assessment
9.4.1 Pharmacodynamic Analysis
The PD measurements will be derived from the euglycemic clamp procedure, where the glucose 
infusion rate (GIR) over time is used as a measure of insulin effect. The analyses will be
performed according to the Lilly Global PK, PD, and Pharmacometrics Divisional Standard
Operating Procedures. 
A locally weighted scatterplot smoothing (LOESS) function will be applied to all individual GIR 
versus time profiles in each treatment group using S Plus® software (Version 8.2 or higher, 
TIBCO, USA). The fitted data for each subject will be used to calculate the PD parameters: the 
maximum GIR (Rmax), the total amount of glucose infused (Gtot) over the duration of the clamp 
procedure, the time of maximum GIR (tRmax). Raw (that is, observed) GIR values from each 
clamp procedure will be used to calculate other PD parameters, such as the time of first change 
of GIR postdose (tRonset), the time of last measurable GIR (tRlast). Other parameters, such as early 
tRmax50, and late tRmax50, may also be reported. Parameters will be individually calculated by Eli 
Lilly and Company and sent to Covance for statistical analysis.


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9.4.2 Pharmacodynamic Statistical Methodology
For Part A, the values of tRmax will be analyzed non-parametrically using a Wilcoxon
signed-rank test using the SAS procedure PROC UNIVARIATE. Median differences and 
approximate 90% CIs for the difference will be calculated for the comparisons of the 
administration methods (single SC injection [test] and CSII [reference]).
The PD parameters (Rmax and Gtot) will be log-transformed prior to analysis and a linear
mixed-effects model fitted to the data, with administration method, period, and sequence order
(order 1 is derived based on sequences 1 and 3, and order 2 is derived based on sequences 2 and 
4), as fixed effects and subject as a random effect. For each parameter, the difference in LS 
means along with the 90% CI will be back-transformed to present the ratios of geometric means 
and the CI for comparison of the administration methods.
See the PK statistical methodology for example SAS code.
Other time parameters (tRlast, tRonset, early tRmax50, and late tRmax50) will be analyzed 
non-parametrically if reported.
No formal statistical analysis will be conducted for Part B.
PD parameters will be listed and summarized for both parts of the study.
Mean daily 4-point self-monitored plasma glucose (SMPG) data will be listed and also 
summarised for the 5 days prior to period 1, 2 and 3. Figures of mean SMPG prior to periods 1, 2 
and 3 will be produced. Profiles prior to meals, bedtime and at 3am will also be produced as 
appropriate.
Exploratory analyses may be performed for other PD parameters as deemed appropriate.
9.5
Safety and Tolerability Assessments
9.5.1 Adverse events
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the adverse event (AE) will be reported in the listings, only the most severe will be used in the 
summary tables. A pre-existing condition is defined as an AE that starts before the subject has 
provided written informed consent and is ongoing at consent. A non-treatment emergent AE is 
defined as an AE which starts after informed consent but prior to dosing. A treatment-emergent 
AE is defined as an AE which occurs postdose or which is present prior to dosing and becomes 
more severe postdose.
All AEs will be listed.  Treatment-emergent AEs will be summarized by treatment, severity and 
relationship to the study drug. The frequency (the number of adverse events, the number of 
subjects experiencing an adverse event and the percentage of subjects experiencing an adverse 
event) of treatment-emergent adverse events will be summarized by treatment, Medical 
Dictionary for Regulatory Activities ( MedDRA) version 18.0 system organ class and preferred 


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Covance Clinical Study No. 8316164
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term. The summary and frequency adverse event tables will be presented for all causalities and 
those considered related to the study drug. Any serious adverse events will be tabulated.
9.5.2 Concomitant medication
Concomitant medication will be coded using the WHO drug dictionary (Version March 2015). 
Concomitant medication and anti-hyperglycemic concomitant medication will be listed.
9.5.3 Clinical laboratory parameters
All clinical chemistry, hematology and urinalysis data will be listed. Additionally, clinical 
chemistry, hematology and urinalysis data outside the reference ranges will be listed.
Values for any clinical chemistry, hematology and urinalysis values outside the reference ranges 
will be flagged on the individual subject data listings.
9.5.4 Vital signs
Vital signs data will be summarized by treatment together with changes from baseline, where 
baseline is defined as Day 1 predose of the relevant period. Figures of mean vital signs and 
change from baseline profiles will be presented. Furthermore, values for individual subjects will 
be listed.
9.5.5 Blood Glucose Monitoring and Hypoglycemia
Hypoglycemic events will be appropriately recorded in the CRF.
In the case of a hypoglycemic event, the actual blood glucose value, if measured, will be 
recorded in the CRF, together with any treatments administered.
Hypoglycemic events will be listed, and summarised if appropriate. Severe hypoglycemic events 
will be reported as SAEs.
9.5.6 Other assessments
Body weight will be listed. Change in weight and BMI from period 1 to period 2, and from 
period 2 to period 3 will be listed and summarized.
Change in total daily dose (Units and Units/kg) from pre-Period 3 U-100 to Period 3 U-500R 
will be listed.
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed. 
9.5.7 Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.


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10.
INTERIM ANALYSES
An interim analysis will be conducted after approximately 12 subjects have completed both 
periods of Part A of the study. An interim analysis of safety, PK and PD will be carried out and 
will be used to inform ongoing analysis of a Phase 3b trial, as appropriate.
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
There were no changes from the protocol specified statistical analyses.
12.
REFERENCES
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998.
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.
3. DR Owens, ed. Human Insulin: Clinical pharmacological studies in normal man. Lancaster, 
UK: MTP Press; 1986.
13.
DATA PRESENTATION
13.1
Derived Parameters
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be 
reported to three significant figures. Observed concentration data, e.g. Cmax, should be reported 
as received. Observed time data, e.g. tmax, should be reported as received. N and percentage 
values should be reported as whole numbers. Median values should be treated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values.
13.2
Missing Data
Missing data will not be displayed in listings.
13.3
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of subjects or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the centre of the table, 
such as, “No serious adverse events occurred for this study.”


Leo Document ID = e2cae2d2-b284-432e-b2c9-747f48e1b68b
Approver: 
Approval Date & Time: 18-Sep-2015 08:44:08 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 18-Sep-2015 14:07:07 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 21-Sep-2015 08:47:33 GMT
Signature meaning: Approved
PPD
PPD
PPD