Clinical trial NCT03555305
Conditions: Healthy
Sponsor: Eli Lilly and Company
Start date: 2018-09-26; Completion date: 2019-11-04
Enrollment: 58 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to compare a study drug known as Insulin glargine with Lantus in healthy Chinese participants. Blood samples will be taken to compare how the body handles the drugs and how they affect blood sugar levels. Side effects and tolerability will be documented. The study will last at least 18 days, not including screening. Screening is required within 4 weeks prior to the start of the study.

Detailed description:

Arms: arm 1: Participants received 0.5 units per kilogram (U/kg) of Insulin Glargine subcutaneously (SC). arm 2: Participants received 0.5 U/Kg of Lantus subcutaneously.
Interventions: intervention 1: Insulin Glargine intervention 2: Lantus
Intervention descriptions: intervention 1: Administered SC intervention 2: Administered SC

Protocol documents:
Prot_000.pdf: 
Protocol I4L-MC-ABEF(c)
Relative Bioavailability of LY2963016 to LANTUS® After Single-Dose Subcutaneous 
Administration in Healthy Chinese Subjects  
NCT03555305
Approval Date: 18-Dec-2018


I4L-MC-ABEF(c) Protocol
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LY2963016
1.
Protocol I4L-MC-ABEF(c)
Relative Bioavailability of LY2963016 to LANTUS® after 
Single-Dose Subcutaneous Administration in Healthy 
Chinese Subjects
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 
LY2963016, 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 US Freedom of Information Act (FOIA) Exemption 4.
LY2963016
This is a randomised, open-label, single-dose (0.5 U/kg), 2-treatment, 2-period, crossover 
study to compare the bioavailability of LY2963016 relative to that of LANTUS®.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly: 15 April 2013
Amendment (a) Electronically Signed and Approved by Lilly:  24 May 2017
Amendment (b) Electronically Signed and Approved by Lilly:  14  June 2018
Protocol Amendment (c) Electronically Signed and Approved by Lilly on date provided 
below.
Approval Date: 18-Dec-2018 GMT


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LY2963016
2.
Synopsis
Clinical Pharmacology Protocol Synopsis:  Study I4L-MC-ABEF
Name of Investigational Product:
LY2963016
Title of Study:  Relative Bioavailability of LY2963016 to LANTUS® after Single-Dose Subcutaneous 
Administration in Healthy Chinese Subjects
Number of Planned Subjects:  Up to 60 subjects may be 
enrolled in order for 40 subjects to complete the study.
Phase of Development:  1
Length of Study:  Approximately 1 month
Objectives:  
Primary:  To evaluate the relative bioavailability of LY2963016 compared to LANTUS following subcutaneous 
(SC) single-dose administrations (0.5 U/kg) in healthy Chinese subjects.
Secondary Objectives:  

To evaluate safety and tolerability of LY2963016 when administered to healthy Chinese subjects.

To compare other pharmacokinetic (PK) parameters of LY2963016 with those of LANTUS after 
0.5-U/kg SC administration.

To compare the pharmacodynamic (PD) responses of LY2963016 with those of LANTUS after 
0.5-U/kg SC administration.
Study Design:  This is a randomised, inpatient, open-label, single-dose (0.5 U/kg), 2-treatment, 2-period crossover 
euglycaemic clamp study to evaluate the relative bioavailability of LY2963016 to LANTUS.
Diagnosis and Main Criteria for Inclusion and Exclusion:  Male and female, native healthy Chinese subjects
aged 18 to 40 years, inclusive, with a body mass index between 18 and 28 kg/m2 (inclusive), and who agree to use 
a reliable form of birth control during the study.
Investigational Product, Dosage, and Mode of Administration:  LY2963016 100-U/mL solution, as 0.5-U/kg
dose, given SC once, alternating between the lower 2 quadrants of the abdominal wall, approximately 5 cm from 
the umbilicus.  
Comparator, Dose, and Mode of Administration:  LANTUS 100-U/mL solution, as 0.5-U/kg dose, given SC 
once, alternating between the lower 2 quadrants of the abdominal wall, approximately 5 cm from the umbilicus.  
Planned Duration of Treatment:  
During each treatment period, subjects will receive a single dose of LY2963016 or LANTUS.  Washout between 
the periods will be at least 7 days.  Total study duration is approximately 1 month. 


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Criteria for Evaluation:  
Safety:  Adverse events (AEs), vital signs, electrocardiograms (ECGs), clinical laboratory tests, and medical 
assessments.
Bioanalytical:  Blood glucose concentrations will be collected and analysed immediately from whole blood 
samples by an automated glucose oxidase technique or other appropriate analytical method.  Human serum 
samples will be collected and analysed for serum insulin glargine or C-peptide concentrations by a validated 
method.
Pharmacokinetic/Pharmacodynamic:  PK and PD parameters will be determined using noncompartmental methods 
of analysis.  The primary PK parameters are area under the serum study drug concentration versus time curve 
(AUC) from zero to 24 hours [AUC(0-24)] and maximum serum study drug concentration (Cmax).  Secondary PK 
parameters include AUC from time zero to the last measurable time [AUC(0-tlast)] and AUC from time zero to 
infinity [AUC(0-)], time to Cmax (tmax), apparent clearance (CL/F), apparent terminal half-life (t1/2), and the 
apparent volume of distribution (Vz/F). PD parameters include the maximum glucose infusion rate (Rmax), total 
glucose infused during the clamp procedure (Gtot), time of Rmax (tRmax). 
Statistical Evaluation Methods:  
Safety:  Safety laboratory parameters, vital signs, ECG parameters, and AEs will be listed and summarised using 
standard descriptive statistics.
Statistical:  The primary and secondary PK and PD parameters will be log-transformed prior to analysis.  The 
model will include subject as a random effect, with period, sequence, and treatment as fixed effects.  For each PK 
and PD parameter, the comparison will be evaluated as the ratio of the least-squares geometric means of test 
formulation (LY2963016) to reference formulation (LANTUS).  The estimate of the ratio of means between the 
2 treatments and the corresponding 90% confidence interval will be provided.  Descriptive statistics will be 
reported for all PK and PD parameters.


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3.
Table of Contents
Relative Bioavailability of LY2963016 to LANTUS® after 
Single-Dose Subcutaneous Administration in Healthy 
Chinese Subjects
Section
Page
1.
Protocol I4L-MC-ABEF(b) Relative Bioavailability of LY2963016 
to LANTUS® after Single-Dose Subcutaneous Administration in 
Healthy Chinese Subjects....................................................................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................4
4.
Abbreviations and Definitions.............................................................................................9
5.
Introduction ......................................................................................................................12
5.1.
General Introduction ....................................................................................................12
5.2.
Rationale and Justification for the Study ......................................................................14
6.
Objectives.........................................................................................................................15
6.1.
Primary Objective ........................................................................................................15
6.2.
Secondary Objectives...................................................................................................15
7.
Investigational Plan...........................................................................................................16
7.1.
Summary of Study Design............................................................................................16
7.1.1.
Screening Visit.....................................................................................................16
7.1.2.
Study Periods 1 and 2...........................................................................................16
7.1.3.
Follow-up Visit ....................................................................................................17
7.2.
Discussion of Design and Control ................................................................................17
7.3.
Determination of Sample Size ......................................................................................17
8.
Study Population...............................................................................................................19
8.1.
Criteria for Enrolment ..................................................................................................19
8.1.1.
Inclusion Criteria .................................................................................................19
8.1.2.
Exclusion Criteria ................................................................................................20
8.2.
Discontinuation............................................................................................................21
8.2.1.
Discontinuation of Subjects..................................................................................21
8.2.2.
Discontinuation of Study Sites .............................................................................22
8.2.3.
Discontinuation of the Study................................................................................22
9.
Treatment..........................................................................................................................23
9.1.
Rationale for Selection of Dose....................................................................................23
9.2.
Investigational Product Formulations ...........................................................................23


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9.3.
Investigational Product Administration.........................................................................23
9.4.
Specific Restrictions/Requirements ..............................................................................24
9.5.
Blinding .......................................................................................................................25
9.6.
Concomitant Therapy...................................................................................................25
10.
Pharmacokinetic, Pharmacodynamic, and Safety Data Collection......................................26
10.1. Pharmacokinetic and Pharmacodynamic Evaluations....................................................26
10.1.1.
Samples for Pharmacokinetic and Pharmacodynamic 
Measurements......................................................................................................26
10.1.2.
Bioanalysis...........................................................................................................26
10.1.3.
Pharmacodynamic Evaluations (Glucose Clamp Procedure).................................26
10.2. Samples for Standard Laboratory Testing.....................................................................27
10.3. Safety Evaluations........................................................................................................28
10.3.1.
Safety Measures...................................................................................................28
10.3.1.1.
Physical Examination .....................................................................................28
10.3.1.2.
Vital Signs......................................................................................................28
10.3.1.3.
Body Weight/Height.......................................................................................28
10.3.1.4.
Electrocardiograms.........................................................................................28
10.3.2.
Adverse Events ....................................................................................................28
10.3.2.1.
Hypoglycaemia...............................................................................................29
10.3.3.
Serious Adverse Events........................................................................................31
10.3.4.
Safety Monitoring ................................................................................................32
10.3.5.
Complaint Handling.............................................................................................32
10.4. Appropriateness and Consistency of Measurements......................................................32
10.5. Compliance..................................................................................................................32
11.
Data Management Methods...............................................................................................34
11.1. Data Quality Assurance................................................................................................34
11.2. Data Capture Systems ..................................................................................................34
11.2.1.
Case Report Form ................................................................................................34
11.2.2.
Ancillary Data......................................................................................................34
12.
Pharmacokinetic, Pharmacodynamic, and Safety Data Analyses .......................................36
12.1. Data Analysis Plans......................................................................................................36
12.1.1.
General Considerations ........................................................................................36
12.1.2.
Study Participant Disposition ...............................................................................36
12.1.3.
Study Participant Characteristics ..........................................................................36
12.1.4.
Pharmacokinetic Analyses....................................................................................36
12.1.4.1.
Pharmacokinetic Parameter Estimation...........................................................36
12.1.4.2.
Pharmacokinetic Statistical Inference .............................................................37
12.1.5.
Pharmacodynamic Analyses.................................................................................37


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12.1.5.1.
Pharmacodynamic Parameter Estimation ........................................................37
12.1.5.2.
Pharmacodynamic Statistical Inference...........................................................37
12.1.6.
Pharmacokinetic/Pharmacodynamic Analyses......................................................37
12.1.7.
Safety Analyses....................................................................................................37
12.1.7.1.
Clinical Evaluation of Safety..........................................................................37
12.1.7.2.
Statistical Evaluation of Safety.......................................................................38
12.2. Interim Analyses ..........................................................................................................38
13.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................39
13.1. Informed Consent.........................................................................................................39
13.2. Ethical Review.............................................................................................................39
13.3. Regulatory Considerations ...........................................................................................39
13.3.1.
Investigator Information.......................................................................................40
13.3.2.
Protocol Signatures ..............................................................................................40
13.3.3.
Final Report Signature .........................................................................................40
14.
References ........................................................................................................................41


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List of Figures
Figure
Page
Figure ABEF.7.1.
Study ABEF study design...........................................................................17


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List of Attachments
Attachment
Page
Attachment 1.
Protocol ABEF Study Schedule .........................................................................42
Attachment 2.
Protocol ABEF Clinical Laboratory Tests ..........................................................45
Attachment 3.
Protocol ABEF Blood Sampling Summary ........................................................46
Attachment 4.
Protocol Amendment I4L-MC-ABEF(b) Summary Relative 
Bioavailability of LY2963016 to LANTUS® after Single-Dose 
Subcutaneous Administration in Healthy Chinese Subjects ................................47


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4.
Abbreviations and Definitions
Term
Definition
adverse event (AE)
Any untoward medical occurrence in a subject or clinical investigation subject administered 
a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment.  An adverse event (AE) can therefore be any unfavourable 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.
AUC
area under the serum study drug concentration versus time curve
AUC(0-)
area under the serum study drug concentration curve from time zero to infinity 
AUC(0-24)
area under the serum study drug concentration-time curve from zero to 24 hours
AUC(0-tlast)
area under the serum study drug concentration curve from time zero to last measured 
concentration value 
audit
A systematic and independent examination of the trial-related activities and documents to 
determine whether the evaluated trial-related activities were conducted, and the data were 
recorded, analysed, and accurately reported according to the protocol, sponsor’s standard 
operating procedures (SOPs), good clinical practice (GCP), and the applicable regulatory 
requirement(s).
BMI
body mass index 
case report form 
(CRF) 
sometimes referred to as clinical report form:  A printed form for recording study 
participants’ data during a clinical study, as required by the protocol.
CI
confidence interval 
CL/F
apparent systemic clearance 
CLRM
Clinical Laboratory Results Modernization
Cmax
maximum serum study 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.
confirmation
A process used to confirm that laboratory test results meet the quality requirements defined 
by the laboratory generating the data and that Lilly is confident that results are accurate.  
Confirmation will either occur immediately after initial testing or will require that samples 
be held to be retested at some defined time point, depending on the steps required to obtain 
confirmed results.


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consent
The act of obtaining informed consent for participation in a clinical trial from subjects 
deemed eligible or potentially eligible to participate in the clinical trial.  Subjects entered 
into a trial are those who sign the informed consent document directly or through their 
legally acceptable representatives.
CRO
contract research organisation:  A person or organisation (commercial, academic, or other) 
contracted by the sponsor to perform one or more of the sponsor’s trial-related duties and 
functions.
CRU
clinical research unit
CSE
clinically significant event:  A moderate to severe adverse event, abnormal clinical sign, or 
clinical laboratory finding that may pose a risk to the well-being of the subject.
ECG
electrocardiogram
end of study 
End of study (trial) is the date of the last visit or last scheduled procedure shown in the 
Study Schedule for the last active subject in the study.
enrol
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.
ERB
ethical 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.
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 
HIV
human immunodeficiency virus 
IB
Investigator’s Brochure:  A compilation of the clinical and nonclinical data on the 
investigational product that is relevant to the study of the investigational product in human 
subjects.
ICF
informed consent form:  A Lilly term used to describe (1) information regarding the trial for 
the subject, and (2) the document that the subject signs to indicate consent to participate in 
the clinical trial
ICH
International Conference on Harmonisation
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.
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.


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PD
pharmacodynamic(s)
PG
plasma glucose
PK
pharmacokinetic(s)
QD
once daily
Rmax
maximum glucose infusion rate 
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 
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 (for example, 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.
subject
An individual who is or becomes a participant in clinical research, either as a recipient of 
the investigational product(s) or as a control.  A subject may be either a healthy human or a 
patient.
t1/2
apparent terminal half-life 
tmax
time of maximum serum study drug concentration 
TPO
third-party organisation
tRmax
time of maximum glucose infusion rate 
Vz/F
apparent volume of distribution 


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Relative Bioavailability of LY2963016 to LANTUS® after 
Single-Dose Subcutaneous Administration in Healthy 
Chinese Subjects
5.
Introduction
5.1.
General Introduction
LY2963016 (Basaglar®) is a long-acting human insulin analogue, having the same primary 
amino acid sequence as LANTUS® (insulin glargine) and similar in qualitative and quantitative 
composition to LANTUS.  
LANTUS is a recombinant human insulin analogue administered as a subcutaneous (SC) 
injection that is indicated for once-daily (QD) SC administration for the treatment of patients 
with diabetes mellitus for the control of hyperglycaemia (LANTUS package insert, 2015).  
Insulin glargine differs from human insulin in that the amino acid asparagine at position A21 is 
replaced by glycine, and 2 arginines are added to the C-terminus of the B-chain.  These structural 
modifications effectively shift the isoelectric point of the molecule, which decreases solubility of 
the insulin glargine at the physiologic pH of SC tissues.  Upon injection of the insulin glargine 
solution into the SC tissue, the acidic solution is neutralised, microprecipitates form, and small 
amounts of insulin glargine are slowly released.  This results in a relatively constant plasma 
concentration of insulin glargine over 24 hours with no pronounced peak.  
In a 4-week repeat-dose toxicology study, rats were administered QD SC doses of 0, 0.3, 1.0, and 
3.0/2.0 mg/kg of LY2963016 or LANTUS.  The dose-limiting toxicity was severe 
hypoglycaemia for both LY2963016 and LANTUS; based on this, the no-observed-adverse-
effect level, and maximum tolerated dose was 0.3 mg/kg for both LY2963016 and LANTUS.  
Findings common to insulin analogues, including neuropathy, lipohypertrophy, and islet cell 
atrophy, were produced in rats by LY2963016 and LANTUS at identical doses and were related 
to hyperinsulinaemia or hypoglycaemia.  While the margins of safety for hypoglycaemia are 
moderate in rats (15.9-fold), this is not unusual in the development of insulin analogues.
Chemical and biological activity testing demonstrated the similarity of LY2963016 drug product 
to LANTUS.  LY2963016 and LANTUS have comparable binding affinity to human insulin 
receptor, isoform A (IR-A), human insulin receptor, isoform B (IR-B), and human insulin-like 
growth factor 1 receptor (IGF-1R), highly similar in vitro functional activity, and highly similar 
in vitro mitogenic potential.  
In 2 Phase 1 clinical studies, conducted in predominantly Caucasian healthy subjects, 
LY2963016 serum concentrations increased gradually following single SC doses of 0.5 U/kg, 
indicating a slow, prolonged absorption with median time to maximum serum study drug 
concentration (tmax) of 12 hours.  The serum concentration-time profile was relatively flat and 
constant over 24 hours, with the geometric mean value for apparent terminal half-life (t1/2) being 
approximately 10 hours.  


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The pharmacokinetic (PK) parameters area under the serum study drug concentration versus time 
curve (AUC) from zero to 24 hours (AUC[0-24]) and maximum serum concentration (Cmax) of 
LY2963016, and the pharmacodynamic (PD) parameters total amount of glucose infused (Gtot) 
and maximum glucose infusion rate (GIR) (Rmax) during a euglycaemic glucose clamp were 
similar to LANTUS and similar durations of action were observed.  
Across 5 completed clinical pharmacology studies, conducted in predominantly Caucasian 
subjects, 209 healthy subjects received at least 1 dose of LY2963016 and 247 healthy subjects 
received at least 1 dose of LANTUS.  When data were combined for all 5 studies, a total of 215 
treatment-emergent adverse events (TEAEs; all causalities) were reported by 112 (53.6%) 
LY2963016-treated subjects and 327 TEAEs were reported by 149 (60.3%) LANTUS-treated 
subjects.  The TEAEs that occurred in ≥5% of subjects with either treatment were: headache, 
procedural site reaction, catheter site swelling, catheter site pain, and catheter site hematoma.  
The TEAEs that were judged by the investigator to be related to study drug that occurred in ≥1% 
of subjects with either treatment were:  injection site pain, injection site erythema, 
hypoglycaemia, vomiting, and headache.  One clinical pharmacology study was conducted in 
20 subjects with T1DM, each of whom received single doses of LY2963016 and LANTUS; a 
total of 9 TEAEs were reported by 5 subjects, none of which were considered to be related to 
study drug.  
A total of 268 and 276 patients with T1DM and 376 and 380 patients with T2DM were 
randomized to receive at least 1 dose of LY2963016 or LANTUS, respectively, in the 2 Phase 3 
clinical studies.  During the 52-week study comparing efficacy and safety of LY2963016 and 
LANTUS in patients with T1DM, the incidence of TEAEs reported was similar among treatment 
groups; 167/268 (62.3%) of patients in the LY2963016 group and 166/267 (62.2%) of patients in 
the LANTUS group reported TEAEs.  Overall, the most frequently reported TEAEs were: 
nasopharyngitis (experienced by 16.0% and 16.9% of patients treated with LY2963016 and 
LANTUS, respectively), upper respiratory tract infection (8.2% and 7.9% of patients, 
respectively), hypoglycaemia (4.9% and 4.5% of patients, respectively), and diarrhoea (4.5% and 
3.7% of patients, respectively).  
During the 24-week study comparing LY2963016 and LANTUS in patients with T2DM,
196/376 (52.1%) of patients in the LY2963016 group and 184/380 (48.4%) of patients in the 
LANTUS group reported TEAEs.  Overall, the most frequently reported TEAEs were:
nasopharyngitis (5.7%); upper respiratory tract infection (4.5%); and diarrhoea (3.0%).
More detailed information about the known benefits and risks of LANTUS and LY2963016 may 
be found in the package insert (LANTUS package insert, 2015) and LY2963016 Investigator’s 
Brochure (IB) and package insert (Basaglar Package Insert 2015), respectively.
The sponsor, monitor, and investigators will perform this study in compliance with the protocol, 
good clinical practice (GCP), International Conference on Harmonisation (ICH) guidelines, and 
applicable regulatory requirements.


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5.2.
Rationale and Justification for the Study
This study is being conducted to support the submission of LY2963016 in China. LY2963016 is 
being developed as an insulin glargine similar to LANTUS.  This study will evaluate the 
bioavailability and PD of LY2963016 relative to LANTUS after single 0.5-U/kg SC doses when 
administered to healthy Chinese subjects.  This study is designed in accordance with 
requirements in the “Technical Guidance of Human Bioavailability and Bioequivalence Studies 
of Chemical Drugs” (China Food and Drug Administration [CFDA], 2005). 


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6.
Objectives
6.1.
Primary Objective
To evaluate the relative bioavailability of LY2963016 compared to LANTUS following SC 
single-dose administrations (0.5 U/kg) in healthy Chinese subjects.  
6.2.
Secondary Objectives

To evaluate the safety and tolerability of LY2963016 when administered to healthy 
Chinese subjects.

To compare other PK parameters of LY2963016 with those of LANTUS after 
0.5-U/kg SC administration.

To compare the PD responses of LY2963016 with those of LANTUS after 0.5-U/kg 
SC administration.


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7.
Investigational Plan
7.1.
Summary of Study Design
This is a randomised, open-label, single-dose (0.5 U/kg), 2-treatment, 2-period, crossover, 
single-site, euglycaemic clamp study to evaluate the relative bioavailability of LY2963016 to 
LANTUS in healthy subjects.  The study will have 2 treatment periods, with subjects randomly 
assigned in a 1:1 fashion to a treatment sequence of either LY2963016 (Period 1) followed by 
LANTUS (Period 2), or LANTUS (Period 1) followed by LY2963016 (Period 2)
(Figure ABEF.7.1).  Study drug will be administered once per period as an SC dose.  Up to 
60 healthy men and women will be enrolled in order to ensure that 40 subjects complete the 
study. 
7.1.1. Screening Visit
Subjects meeting all the inclusion criteria and none of the exclusion criteria may be enrolled into 
the study.  The screening visit will occur within 4 weeks prior to enrolment (occurring on 
Period 1, Day -1).
7.1.2. Study Periods 1 and 2
Subjects will be admitted to the clinical research unit (CRU) on Day -1 of each period.  On 
Period 1, Day -1, subjects will be randomly assigned in a 1:1 fashion to the treatment sequence 
of either LY2963016 followed by LANTUS or LANTUS followed by LY2963016.  On Day -1
of each period, a clinical laboratory blood sample (local laboratory) will be collected in order to 
check for the subject’s continued eligibility.  Subjects who are no longer eligible will be 
withdrawn and replaced.  
On Day 1 of each period, subjects will begin the preclamp procedure up to 120 minutes prior to 
dosing, and following dosing the euglycaemic clamp procedure will continue up to 24 hours.  
Blood samples will be collected over the 24-hour clamp procedure to determine serum 
concentrations of insulin glargine for PK evaluations; for blood glucose measurements for PD 
(see Section 10.1.3 for details of the clamp procedure), and for measurement of C-peptide.  
Following completion of the clamp procedure on Day 2, subjects will remain in the CRU until a 
post-clamp safety evaluation is performed.  The interval between treatment administrations will 
be at least 7 days.  
Safety will be assessed throughout the study by adverse event (AE) and concomitant medication 
monitoring, physical examinations, clinical laboratory tests, electrocardiograms (ECGs), weight, 
and vital sign measurements.  Protocol Attachment 1 presents a schedule of events for this study.


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Abbreviation:  SC = subcutaneous.
Figure ABEF.7.1.
Study ABEF study design.
7.1.3. Follow-up Visit
In case of early discontinuation, subjects will return to the CRU between 7 and 14 days for a 
follow-up visit.  Subjects who have completed the study should return between 7 and 14 days of 
the end of the last study period for the follow-up visit.
7.2.
Discussion of Design and Control
An open-label design is appropriate because the study endpoints of PK and PD key parameters 
are not subject to bias. A single-dose euglycaemic clamp study design in healthy subjects is 
appropriate to evaluate the relative bioavailability of LANTUS to LY2963016. Lastly, the 
crossover design allows each subject to serve as his/her own control, thus reducing variability.  
7.3.
Determination of Sample Size
Up to 60 healthy subjects may be enrolled to ensure that at least 40 subjects complete the study. 
With 40 subjects completing, there is 80% coverage probability that the half-width of the 90% 
confidence interval (CI) of the difference of means for AUC will be within 0.223 in the log scale, 
which corresponds to approximately 20% in the ratio scale. This precision estimate was based 
on the intrasubject variability for AUC of 39.26% observed in completed studies in healthy 


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subjects. Drop-outs may be replaced and the replacement subject would assume the withdrawn 
subject’s treatment sequence (receiving both allocated treatments).


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8.
Study Population
8.1.
Criteria for Enrolment
Eligibility of subjects for study enrolment will be based on the results of a screening medical 
history, physical examination, clinical laboratory tests, and 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 4 weeks prior to enrolment.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
re-screened. Individuals may be re-screened once. The interval between re-screenings should be
at least 2 weeks. If re-screening is performed, the individual must sign a new informed consent 
form (ICF) and will be assigned a new identification number.
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, are not permitted.
8.1.1. Inclusion Criteria
Subjects are eligible for enrolment in the study only if they meet all of the following criteria:
[1]
Are native Chinese men or women.  Native Chinese is defined as a subject who 
has both parents and all 4 grandparents of Chinese origin.
[2]
Are overtly healthy males or females, as determined by medical history and 
physical examination.  
[3a] For females of childbearing potential (defined as not surgically sterilised and 
between menarche and 1-year postmenopause) only:
o
Negative serum pregnancy test at the time of screening.
o
Are not lactating.
o
Intend not to become pregnant during the study.
o
Are sexually inactive or have practiced a reliable method of birth control 
(for example, use of oral contraceptives or levonorgestrel; diaphragms with 
contraceptive jelly; cervical caps with contraceptive jelly; condoms with 
contraceptive foam; intrauterine devices; partner with vasectomy; or 
abstinence) for at least 6 weeks prior to screening.
o
Agree to continue to use a reliable method of birth control (as determined by 
the investigator) during the study.
[3b] For females not of childbearing potential, must be:  
o
Surgically sterile, defined as having had a hysterectomy or bilateral 
oophorectomy or tubal ligation, and/or 


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o
Menopausal, defined as having had no menses for at least 1 year, or a 
plasma follicular stimulating hormone value of >40 mIU/mL and no menses 
for at least 6 months, unless the subject is taking hormone-replacement 
therapy.
[4]
Are between the ages of 18 and 40 years, inclusive, at screening.
[5]
Having fasting plasma glucose <110 mg/dL (<6.1 mmol/L) and 2-hour glucose 
level <140 mg/dL (<7.8 mmol/L) on the 75 g oral glucose tolerance test. 
[6]
Have a body mass index (BMI) between 18 and 28 kg/m2, inclusive, at 
screening.
[7]
Are nonsmokers, have not smoked for at least 6 months prior to entering the 
study, and agree not to smoke (cigars, cigarettes, or pipes) or use smokeless 
tobacco for the duration of the study.
[8]
Have normal blood pressure and pulse rate at screening, as determined by the 
investigator.
[9]
Have an ECG, at screening, considered as within normal limits by the 
investigator.
[10] Have clinical laboratory test results within normal reference range for the 
population or investigator site, or results with acceptable deviations that are 
judged to be not clinically significant by the investigator.
[11] Have venous access sufficient to allow for blood sampling as per the protocol.
[12] Are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures.
[13] 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 enrolment if they meet any of the following criteria:
[14] 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.
[15] Are Lilly or Boehringer Ingelheim employees.
[16] Have a history of first-degree relatives known to have diabetes mellitus.
[17] Are persons who have previously completed or withdrawn from this study.
[18] Are currently enrolled in, have completed or discontinued within the last 
30 days from a clinical trial involving an investigational product; or are 
concurrently enrolled in any other type of medical research judged not to be 
scientifically or medically compatible with this study.


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[19] Have known allergies to insulin glargine or its excipients, or related drugs, or 
heparin, or have a history of relevant allergic reactions of any origin.
[20] Have a significant history of or current cardiovascular, respiratory, hepatic, 
renal, gastrointestinal, endocrine, haematological, 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] Show evidence of current significant active neuropsychiatric disease.
[22] Show evidence of current use of known drugs of abuse or a history of use within 
the past year.
[23] Show evidence of human immunodeficiency virus infection (HIV) and/or
positive human HIV antibodies.
[24] Have positive hepatitis B surface antigen.
[25] Have donated >400 mL of blood in the last 6 months or donated >100 mL 
within the last 30 days.
[26] Have an average weekly alcohol intake that exceeds 21 units per week (males) 
and 14 units per week (females), or are unwilling to stop alcohol consumption 
while resident in the CRU (1 unit = 12 ounces or 360 mL of beer; 5 ounces or 
150 mL of wine; 1.5 ounces or 45 mL of distilled spirits).
[27] Intend to use: prescription medication or over-the-counter medication or 
Chinese traditional medicine within 14 days before dosing (apart from 
vitamin/mineral supplements, occasional paracetamol, thyroid replacement, or 
birth control methods).  If this situation arises, an otherwise suitable subject 
may be included at the discretion of the investigator.
[28] Are persons determined by the investigator to be unsuitable for any other 
reason.
8.2.
Discontinuation
8.2.1. Discontinuation of Subjects
If the Sponsor or investigator identifies a subject who did not meet enrolment criteria and was 
inadvertently enrolled, a discussion must occur between the Lilly clinical pharmacologist/clinical 
research physician and the investigator to determine if the subject may continue in the study.  If 
both agree it is medically appropriate to continue, the investigator must obtain documented 
approval from the Lilly clinical pharmacologist/clinical research physician to allow the 
inadvertently enrolled subject to continue in the study with or without continued treatment with 
investigational product.  
Some possible reasons for early discontinuation of study participation:


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
Enrolment in any other clinical trial involving an investigational product or 
enrolment in any other type of medical research judged not to be scientifically or 
medically compatible with this study.

Investigator/Physician Decision
o
the investigator/physician decides that the subject should be withdrawn 
from the study

Subject Decision 
o
the subject requests to be withdrawn from the study

Sponsor Decision
o
the investigator or 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 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 AE, abnormal clinical sign, or clinical laboratory finding that may 
pose a risk to the well-being of the subject.  Refer to Section 10.3.
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.  
Discontinuation procedures are outlined in the Study Schedule (Attachment 1).
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.
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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9.
Treatment
9.1.
Rationale for Selection of Dose
A dose of 0.5 U/kg has been selected for this study as it was used in the previous studies that 
evaluated the similarity in the PK and PD properties between LY2963016 and LANTUS. This 
dose yields measurable serum immunoreactive LY2963016 and insulin glargine concentrations
and evaluable PD data for the comparison between LY2963016 and LANTUS. Previous studies 
have shown this dose to be safe in healthy subjects. 
9.2.
Investigational Product Formulations
LY2963016 will be supplied as a 100-U/mL solution.
LANTUS is available as a 100-U/mL solution.
LY2963016 and LANTUS should be stored refrigerated at 2°C to 8°C and should not be allowed 
to freeze.  Discard LY2963016 or LANTUS if product has been frozen.  Both agents should be 
stored in a locked and secured location.
9.3.
Investigational Product Administration
LY2963016 U-100 will be administered by the site as one 0.5-U/kg dose SC. 
LANTUS U-100 will be administered by the site as one 0.5-U/kg dose SC.
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.
The investigator or designee is responsible for:

explaining the correct use of the investigational agent(s) to the site personnel, 

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.
The study insulin preparation to be injected during a given study period will be determined by a 
randomisation schedule.  Where possible, the same site personnel will administer the study drug 
to the same subject on each dosing occasion.
The study insulin preparation will be allowed to come to approximately room temperature prior 
to injection.  The qualified site personnel will be instructed on proper preparation, mixing, and 
administration techniques for all insulin used in this study.  All insulin injections will be given 
by an appropriately qualified member of the CRU designated by the investigator. If possible the 
same individual should give the injection to the same subject for both administrations.


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Doses used in each study period will be based upon subject’s weight taken on Day-1 of Period 1.  
A calculated dose of n.00 to n.49 IU will be rounded down to n IU, whereas a calculated dose of 
n.50 IU to n.99 IU will be rounded up to n + 1 IU.  The actual dose administered will be recorded 
on the case report form (CRF).  All insulin injections will be given in the CRU subcutaneously.  
The appropriate needle will be applied at approximately 90 degrees into a raised skinfold to 
ensure consistent SC administration.  The injection site shall be alternated between the lower 
2 quadrants of the abdominal wall, approximately 5 cm from the umbilicus.
A dispensing record detailing the formulation and the amount received and dispensed will be 
kept by the CRU personnel.  Unused medications will remain in the CRU until a determination 
has been made for their destruction.
Subjects will be instructed to contact the investigator as soon as possible if they have a complaint 
or problem with the investigational product so that the situation can be assessed.
For both periods, the doses will be administered at approximately the same time each morning on 
the dosing day.  The actual time of dose administrations will be recorded in the subject’s CRF.
9.4.
Specific Restrictions/Requirements
Prior to beginning the study, the subjects will complete informed consent.
Throughout the study, subjects may be subject to medical assessment and review of compliance 
with restrictions before continuing in the study.  Subjects should continue to meet the inclusion 
and exclusion criteria at the start of each study period, including restrictions related to 
contraception and medication use.
Dietary Restriction
Subjects will be fasted from approximately 8 hours prior to start of each clamp until after the 
glucose clamp procedure is completed.  Water can be consumed freely during this time.
When at home, subjects will be encouraged to follow their normal diet.
Alcohol
No alcohol will be allowed at least 1 day prior to admission to the CRU and while resident in the 
CRU.  
Sleep/Activity
Subjects are encouraged to maintain their regular exercise; however, they should not undertake 
vigorous or prolonged exercise at least 48 hours prior to each dosing day.
During the clamp procedure, subjects should remain recumbent or sitting in the CRU.  
Movement will be restricted to ensure subject safety and retain integrity of connections to 
infusion and study procedures.
Authorisation to leave the CRU must be given by a physician.


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9.5.
Blinding
This is an open-label study.
9.6.
Concomitant Therapy
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 clinical 
research physician.  Any additional medication used during the course of the study must be 
documented.
Subjects should not use over-the-counter or prescription medication or Chinese traditional 
medicines within 14 days before dosing (apart from vitamin/mineral supplements, occasional 
paracetamol, thyroid replacement, or birth control methods).  If a subject does use these 
medications, inclusion of the subject may be at the discretion of the investigator.  
Subjects may not use traditional Chinese medicines during this study.


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10. Pharmacokinetic, Pharmacodynamic, and Safety Data 
Collection
10.1. Pharmacokinetic and Pharmacodynamic Evaluations
10.1.1. Samples for Pharmacokinetic and Pharmacodynamic
Measurements
During each clamp, venous blood collection (approximately 4 mL) for the determination of the 
serum concentrations of insulin glargine will begin prior to and continue for up to 24 hours after 
administration of LY2963016 or LANTUS.  Samples (approximately 2.5 mL) will also be taken 
for the analysis of C-peptide concentrations.  Timing of sample collection may be found in 
Attachment 1; an estimate of total blood volume to be collected during the study may be found in 
Attachment 3.  
The timing of scheduled samples may be adjusted according to clinical needs.  The actual 
collection times will be recorded.  Blood samples will be collected via a venous cannula or direct 
venipuncture.  Instructions for the collection and handling of blood samples will be provided by 
the sponsor.  Serum will be obtained by centrifugation and stored at -20°C or below.
10.1.2. Bioanalysis
Serum samples will be analysed for concentrations of LY2963016 or LANTUS using a validated 
radioimmunoassay method.  This insulin assay does not differentiate between LY2963016 or 
LANTUS and other insulins (endogenous or exogenous).  
In addition, serum samples will be analysed for concentrations of C-peptide using a validated 
method.  
Samples will be analysed at a laboratory approved by the sponsor.  Instructions for the collection 
and handling of blood samples will be provided.
Bioanalytical samples collected to measure immunoreactive insulin glargine concentration only 
will be retained for a maximum of 2 years following last subject visit for the study.  During this 
time, samples remaining after the bioanalyses may be used for exploratory analyses such as 
metabolism.
10.1.3. Pharmacodynamic Evaluations (Glucose Clamp Procedure)
The aim of the euglycaemic glucose clamp is to maintain euglycaemia 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 concentration for the individual subject. The 
intent is to maintain blood glucose concentrations approximately at the predose target value,
which is defined as 5 mg/dL below the mean predose fasting blood glucose (mean of predose 
values recorded at approximately -30, -20, and -10 minutes).


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Thus, blood glucose concentrations are kept constant while the GIR varies.  The varying GIR 
will reflect the PD activity of insulin.
The subjects will participate in a total of 2 euglycaemic clamps on 2 separate study periods.  
Glucose clamp studies will be performed after an overnight fast of approximately 8 hours.  The 
GIRs required to maintain euglycaemia and blood glucose concentrations will be documented 
throughout the procedure. On the morning of the study, a small catheter will be placed into a 
forearm vein, ideally at the elbow, for infusion of glucose.  Another catheter will be placed at the 
wrist or back of the hand, or in the case of difficult venous access, in the forearm as close to the 
wrist as possible, for blood sampling.  Blood samples will be obtained at the bedside for 
immediate determination of whole blood glucose concentrations using an automated glucose 
oxidase technique or other appropriate analytical method.  The glucose is infused as a 20% 
dextrose solution.
The time of study insulin dosing will be defined as time zero.  Following the dosing, in 
conjunction with frequent blood sampling for measurement of blood glucose, glucose will be 
infused intravenously at a variable rate in order to maintain euglycaemia for approximately 
24 hours.  If the GIR falls to zero for at least 30 minutes after the clamp has been underway for at 
least 8 hours, the clamp will be discontinued.
At the end of the clamp (approximately 24 hours after study drug administration) and following 
collection of the 24 hour study samples, the subject will be fed and medically assessed before 
discharge.
10.2. Samples for Standard Laboratory Testing 
Blood and urine samples will be collected at the times specified in the Study Schedule 
(Attachment 1). Standard laboratory tests, including chemistry, haematology, and urinalysis 
panels, will be performed.  For women of childbearing potential, a serum pregnancy test will be 
performed.  Standard clinical laboratory tests for safety will be analysed by a central or local 
laboratory (see Attachment 1).  Attachment 2 lists the specific tests that will be performed for 
this study.  Attachment 3 summarises the blood volumes for all blood sampling (screening, 
safety laboratories, and bioanalytical assays) during the study.
Investigators must document their review of each safety laboratory 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.


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10.3. Safety Evaluations
10.3.1. Safety Measures
10.3.1.1. Physical Examination
Physical examinations and routine medical assessments will be conducted as specified in the
Study Schedule and as clinically indicated (Attachment 1).
10.3.1.2. Vital Signs
Body temperature, blood pressure, and pulse rate will be measured as specified in the Study 
Schedule and as clinically indicated (Attachment 1).
Additional vital signs may be measured during each study period if warranted and agreed upon 
between the sponsor and investigator.
10.3.1.3. Body Weight/Height
Body weight and height will be recorded as specified in the Study Schedule and as clinically 
indicated (Attachment 1).  The screening weight will be used to satisfy the inclusion/exclusion 
criteria.  The weight measured at Period 1 will be used for insulin glargine dosage calculation.
10.3.1.4. Electrocardiograms
For each subject, a 12-lead digital ECG will be collected according to the Study Schedule 
(Attachment 1).  Subjects must be supine for approximately 5 to 10 minutes before ECG 
collection and remain supine but awake during ECG collection.  
ECGs may be obtained at additional times when deemed clinically necessary.  Collection of 
more ECGs than expected at a particular time point is allowed to ensure high-quality records. 
ECGs will be interpreted by a qualified physician (the investigator or qualified designee) at the 
site as soon after the time of ECG collection as possible, and ideally while the subject is still 
present, to determine whether the subject meets entry criteria at the relevant visit(s) and for 
immediate subject management, should any clinically relevant findings be identified.  
10.3.2. Adverse Events
Lilly has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent.
Investigators are responsible for monitoring the safety of subjects who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the subject.
The investigator is responsible for the appropriate medical care of subjects during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 


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product or the study, or that caused the subject to discontinue the investigational product before 
completing the study.  The subject should be followed until the event resolves, stabilizes with 
appropriate diagnostic evaluation, or is reasonably explained.  The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator.
After the ICF is signed, study site personnel will record, via CRF, the occurrence and nature of 
each subject’s preexisting conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study. Additionally, site personnel will record any change in the 
condition(s) and the occurrence and nature of any AEs.  
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account the 
disease, concomitant treatment or pathologies.  
Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study.
Any clinically significant findings from ECGs, laboratory tests, vital sign measurements, other 
procedures, etc that result in a diagnosis should be reported 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 electronic data entry.
Investigators will be instructed to report to Lilly or its designee their assessment of the potential 
relatedness of each AE to protocol procedure, investigational product, and/or drug-delivery 
system via CRF.
If a subject’s investigational product is discontinued as a result of an AE, study site personnel 
must clearly report this to Lilly or its designee via CRF.
10.3.2.1. Hypoglycaemia
Hypoglycaemia will be described using the following definitions:
Documented Glucose Alert Level (Level 1), plasma glucose (PG) ≤70 mg/dL (3.9 mmol/L)

Documented symptomatic hypoglycaemia: with typical symptoms of hypoglycaemia.

Documented asymptomatic hypoglycaemia: without typical symptoms of
hypoglycaemia.

Documented unspecified hypoglycaemia: with no information about symptoms of 
hypoglycaemia available. (This has also been called unclassifiable hypoglycaemia.)
Documented Clinically Significant Hypoglycaemia (Level 2) with similar criterion as above 
except for threshold PG <54 mg/dL (3.0 mmol/L)

Level 2 Documented symptomatic hypoglycaemia 

Level 2 Documented asymptomatic hypoglycaemia

Level 2 Documented unspecified hypoglycaemia
Severe hypoglycaemia (Level 3)

Severe hypoglycaemia: Patients had altered mental status, and could not assist in their own 


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care, or were semiconscious or unconscious, or experienced coma with or without seizures,
and the assistance of another person was to actively administer carbohydrate, glucagon, or 
other resuscitative actions. Plasma glucose measurements may not be available during such 
an event, but neurological recovery attributable to the restoration of PG concentration to
normal is considered sufficient evidence that the event was induced by a low PG
concentration (PG ≤70 mg/dL [3.9 mmol/L]).  
Other hypoglycaemia:

Nocturnal hypoglycaemia: Any documented hypoglycaemic event (including severe 
hypoglycaemia) that occurs at night and presumably during sleep.  This is captured as 
hypoglycaemia that occurs between bedtime and waking.  This definition is more useful 
than the commonly used ~midnight to ~6 AM definition which does not take patients’ 
individual sleep times into consideration, and is consistent with the ADA 
recommendations of reporting events that occur during sleep (ADA 2005).  It is also 
important to collect the actual time when a hypoglycaemic event occurred to allow further 
characterization of hypoglycaemia timing (e.g., to allow analysis of frequency of events 
occurring across a 24-hr clock).  Nocturnal hypoglycaemia may occur at severity Levels 1, 
2, or 3.

Relative hypoglycaemia (also referred to as Pseudohypoglycaemia [Seaquist et al.
2013]): An event during which typical symptoms of hypoglycaemia occur, that does not 
require the assistance of another person and is accompanied by PG >70 mg/dL
(3.9 mmol/L). The PG value of patients with chronically poor glycaemic control can 
decrease so rapidly that patients may report symptoms of hypoglyacemia before their PG 
concentration falls below 70 mg/dL (3.9 mmol/L). Events with PG ≤70 mg/dL should 
not be categorized as relative hypoglycaemia.  Evaluation and statistical analysis of this 
category is optional. However, if a patient reports a relative hypoglycaemia event where
assistance from another person was received or the patient experienced significant 
symptoms, the study team should clarify the circumstances to ensure the event is not a
severe hypoglycaemia event, and report it appropriately. 

Probable symptomatic hypoglycaemia: Symptoms of hypoglycaemia were present, but 
PG measurement was not reported.
Only severe hypoglycaemic episodes will be reported separately as AEs. All episodes of severe
hypoglycaemia will be reported as serious adverse events (SAEs).
The goal of the euglycaemic clamp is to maintain blood glucose concentrations at 
normoglycaemic levels close to a predefined target. Therefore, PG concentrations below 
70 mg/dL (equivalent to blood glucose of approximately 63 mg/dL) will not routinely be 
recorded as hypoglycaemic events during the glucose clamp procedure. However, at the 
discretion of the investigator, a decrease in glucose concentrations may be recorded as a 
hypoglycaemic event based on clinical concern, or related to technical issues resulting in 
hypoglycaemia.


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10.3.3. Serious Adverse Events
An SAE is any AE from this study that results in one of the following:

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 be immediately life-threatening or result in 
death or require hospitalization but may jeopardise the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above.

when a condition related to the investigational device 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.
Study site personnel must alert the Lilly clinical pharmacologist/clinical research physician, or 
its designee, of any SAE as soon as practically possible.
Additionally, study site personnel must alert Lilly Global Patient Safety, 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.
Although all AEs are recorded in the CRF after signing informed consent, SAE reporting to the 
sponsor begins after the subject has signed informed consent and has received investigational 
product.  However, if an SAE occurs after signing informed consent, but prior to receiving 
investigational product, AND is considered reasonably possibly related to a study procedure then 
it MUST be reported.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued from and/or completed the study (the subject summary CRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly. 
Pregnancy (maternal or paternal exposure to investigational product) does not meet the definition 
of an AE.  However, to fulfill regulatory requirements any pregnancy should be reported 
following the SAE process to collect data on the outcome for both mother and fetus.


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10.3.4. Safety Monitoring
The Lilly clinical pharmacologist or clinical research physician 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 research physician will consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical scientist when appropriate, and will 
periodically review:

trends in safety data,

laboratory analytes, and

AEs. 
10.3.5. 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 comparator drugs or concomitant drugs/drug-delivery systems 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.
10.4. Appropriateness and Consistency of Measurements
All assessments made in this study are standard, widely used, and generally recognised as 
reliable, accurate, and relevant.
10.5. 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 


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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 CRF.
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. Data Management Methods
11.1. 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 a start-up training session to instruct the investigators and study 
coordinators.  This session will give instruction on the protocol, the completion of 
the CRFs, and study procedures.

make periodic visits to the study site.

be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax.

review and evaluate CRF data and/or use standard computer edits to detect errors 
in data collection.

conduct a quality review of the database.
In addition, Lilly or its representatives may 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.
11.2. Data Capture Systems
11.2.1. Case Report Form
An electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
For data handled by a data management third-party organisation (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.
11.2.2. Ancillary Data
Central laboratory data will be stored electronically in the central laboratory’s database system.
Data will subsequently be transferred from the contract laboratory to the Lilly Clinical 
Laboratory Results Modernization (CLRM) system and/or TPO’s system.


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Bioanalytical data will be stored electronically in the bioanalytical laboratory’s database.  Data 
will subsequently be transferred from the bioanalytical laboratory to the Lilly CLRM system and 
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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12. Pharmacokinetic, Pharmacodynamic, and Safety Data 
Analyses
12.1. Data Analysis Plans
12.1.1. General Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or designee.
PK and PD analyses will be conducted on the full analysis set.  This set includes all data from all 
subjects randomly assigned to a treatment sequence who receive at least 1 dose of study drug 
(according to the treatment actually received), and who have evaluable data.  Safety analyses will 
be conducted for all enrolled subjects, whether or not they completed all protocol requirements.
Additional exploratory analyses of the data will be conducted as deemed appropriate.  
12.1.2. 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.
12.1.3. Study Participant Characteristics
The subject’s age, sex, weight, height, or other demographic characteristics will be recorded.
12.1.4. Pharmacokinetic Analyses
12.1.4.1. Pharmacokinetic Parameter Estimation
PK parameter estimates for LY2963016 and LANTUS will be calculated by standard 
noncompartmental methods of analysis.  PK analyses will be conducted on those subjects with 
evaluable data.
The analyses will be performed according to the Lilly Global Pharmacokinetics, 
Pharmacodynamics, and Trial Simulation Divisional Standards.  For each profile, concentration 
values that are below the quantifiable limit of the assay will be treated as missing data. Actual 
sampling times in individual subjects will be used in the analysis.  The serum concentration of 
immunoreactive LY2963016 and LANTUS will be corrected for endogenous insulin using the 
C-peptide data.  The primary parameters for PK analysis will be:  AUC(0-24) and Cmax.  Other 
PK parameters that will be reported include:  AUC from time zero to last measured concentration 
value [AUC(0-tlast)], AUC from time zero to infinity [AUC(0-∞)], tmax, apparent clearance 
(CL/F), t1/2, and the apparent volume of distribution (Vz/F).  The AUC values will be calculated 
by the linear/log trapezoidal method, where the linear trapezoidal method will be employed up to 
tmax, and the log trapezoidal rule will be used for concentrations beyond tmax.  


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12.1.4.2. Pharmacokinetic Statistical Inference
The primary PK parameters, AUC(0-24) and Cmax, will be log-transformed prior to analysis. A 
linear mixed effects model will be fitted to the data.  The model will include subject as a random 
effect, with period, sequence, and treatment as fixed effects.  For each PK parameter, the 
comparison will be evaluated as the ratio of the least-squares geometric means of LY2963016 to 
LANTUS.  The estimate of the ratio of geometric means between the 2 treatments and the 
corresponding 90% CI will be provided.  A similar statistical analysis may be performed for the 
log-transformed secondary PK parameters AUC(0-∞) and AUC(0-tlast). A nonparametric 
approach will be taken to evaluate tmax. Descriptive statistics may be reported for other PK 
parameters as deemed appropriate (eg, CL/F, Vz/F, t1/2).  
Exploratory analyses may be performed for other PK parameters as deemed appropriate.
12.1.5. Pharmacodynamic Analyses
12.1.5.1. Pharmacodynamic Parameter Estimation
The GIRs and blood glucose values will be recorded on Day 1.  Glucose infusion rates will be 
used to calculate several PD parameters, including Rmax, time of Rmax (tRmax), and Gtot.  Other 
parameters may be calculated as appropriate.  The PD parameters will be calculated using 
S-PLUS® software (v8.2).
12.1.5.2. Pharmacodynamic Statistical Inference
The PD parameters (Rmax and Gtot) will be log-transformed prior to analysis.  A linear mixed 
effects model will be fitted to the data.  The model will include subject as a random effect, with 
period, sequence, and treatment as fixed effects.  From the models, the difference in least-squares 
mean estimates between the 2 treatments and the corresponding 90% CIs for the difference will 
be estimated and back-transformed from the log scale to provide estimates of the ratios of 
geometric means and 90% CI for the ratio of these means.  A nonparametric approach will be 
taken to evaluate tRmax.
Exploratory analyses of the PD time parameters may be performed as deemed appropriate.
12.1.6. Pharmacokinetic/Pharmacodynamic Analyses
Not applicable.
12.1.7. Safety Analyses
12.1.7.1. 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 summarised using descriptive methodology.
The incidence of symptoms for each treatment will be presented by severity and by association 
with investigational product as perceived by the investigator.  Symptoms reported to occur prior 
to study enrolment will be distinguished from those reported as new or increased in severity


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during the study.  Each symptom will be classified by the most suitable term from the medical 
regulatory dictionary.
12.1.7.2. Statistical Evaluation of Safety
Safety parameters that will be assessed include safety laboratory parameters, vital signs, and 
ECGs.  The parameters will be listed, and summarised using standard descriptive statistics.  
Additional analysis will be performed if warranted upon review of the data.
12.2. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the Lilly clinical pharmacologist, clinical research physician/investigator, or designee 
will consult with the appropriate medical director or designee to determine if it is necessary to 
amend the protocol.


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13. Informed Consent, Ethical Review, and 
Regulatory Considerations
13.1. Informed Consent
The investigator is responsible for ensuring that the subject understands the potential risks and 
benefits of participating in the study, including answering any questions the subject may have 
throughout the study and sharing any new information that may be relevant to the subject’s 
willingness to continue his or her participation in the trial in a timely manner.
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.
13.2. Ethical Review
Lilly or its representatives must approve all ICFs before they are submitted to the ERB and are 
used at investigative sites(s).  All ICFs must be compliant with the ICH guideline on GCP.  
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.
Any member of the ERB who is directly affiliated with this study as an investigator or as site 
personnel must abstain from the ERB’s vote on the approval of the protocol.
The study site’s ERB(s) should be provided with the following:

the current IB and updates during the course of the study,

ICF, and

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
International Ethical Guidelines,
2) the ICH GCP Guideline [E6], and
3) applicable laws and regulations.
The investigator or designee will promptly submit the protocol to applicable ERB(s).


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All or some of the obligations of the sponsor will be assigned to a contract research 
organisation (CRO).
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.
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 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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14. References
[ADA] American Diabetes Association; Workgroup on Hypoglycemia. Defining and reporting
hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on
Hypoglycemia. Diabetes Care. 2005;28(5):1245-1249.
Basaglar [Package Insert]. Indianapolis, IN: Eli Lilly and Company; 2015. Available at: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/205692lbl.pdf. Accessed 
September 06, 2016.  
[CFDA] China Food and Drug Administration. Technical Guidance of Human Bioavailability 
and Bioequivalence Studies of Chemical Drugs. March 2005; [H]GCL2-1.
LANTUS® (insulin glargine [rDNA origin] injection) [package insert]. Sanofi-Aventis web site, 
2015. Available at: http://products.sanofi-aventis.us/lantus/lantus.html. Accessed
September 06, 2016.  
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, Heller SR, Rodriguez H,
Rosenzweig J, Vigersky R. Hypoglycemia and diabetes: a report of a workgroup of the
American Diabetes Association and the Endocrine Society. Diabetes Care. 2013;36(5):1384-
1395.


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Attachment 1.Protocol ABEF Study Schedule


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Study Schedule Protocol I4L-MC-ABEF
Screena
Euglycaemic Clamp Procedure Periods 1 and 2b
Discharge
Procedure
Within 
4 weeks 
prior to 
Day -1
Day -1
Pre-
Clamp
Day 1
Pre-
Clamp
Begin Day 1, 
End on Day 2
Day 2
Post-
Clamp
Between 7 and 
14 Days of End of 
Period 2 or Early 
Discontinuation
Informed consent
X
Medical history
X
Height
X
Serum pregnancy test
X
Xc
X
Urine ethanol and drug screen
X
Hepatitis B and HIV test
X
FSH (if applicable)
X
OGTT
X
ECG
X
X
X
X
Randomization
Period 1
Physical examination
X
Xd
Xd
X
Vital signse (supine)
X
X
X
X
Clinical laboratory testsf
X
X
X
Subject admission to CRU
X
Weight
X
Xg
Glucose clamp procedures
Xh
Blood sampling for PKi
-0.5 (predose), 0 
(predose), 0.5, 1, 
2, 3, 4, 6, 9, 12, 
15, 18, 21 hr
24 hr
C-peptide samplingi
-0.5 (predose), 0 
(predose), 0.5, 1, 
2, 3, 4, 6, 9, 12, 
15, 18, 21 hr
24 hr
LANTUS or LY2963016 
administration (0.5 U/kg single 
dose SC)
X
Subject Discharge from CRU
X
Abbreviations:  CRU = clinical research unit; ECG = electrocardiogram; FSH = follicle-stimulating hormone; 
HIV = human immunodeficiency virus; hr = hour(s); PK = pharmacokinetics; SC = subcutaneous; OGTT = oral 
glucose tolerance test.  
a
Subjects who are not enrolled within 4 weeks of screening may be subjected to additional medical assessments 
and clinical laboratory tests prior to study entry.
b The interval between treatment administrations (washout) will be at least 7 days.
c
Women of childbearing potential must have a negative serum pregnancy test ≤3 days prior to Day 1 of each 
period.  
d Abbreviated physical examinations may be performed pre- and post-clamp at each period.
e
Vital signs of supine pulse rate and supine blood pressure will be routinely measured.  Body temperature will be 
measured on Day 1 of each period.  During the clamp procedure, supine blood pressure and/or pulse rate may be 
measured as clinically indicated.  Additional vital signs may be measured during each study visit, if warranted 
and agreed upon between Lilly and the investigator.  


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f
Screening and follow-up clinical laboratory tests to be performed at a central laboratory.  On Day -1 of each 
period, clinical laboratory sample should be collected and sent to a local laboratory and results should be 
reviewed to check subject’s eligibility before dosing.  See Attachment 2 for list of clinical laboratory tests 
performed.  
g Weight will be recorded for all periods.  Weight recorded at the first period only will be used for dose 
calculation, and the subjects will receive the same exact dose at each period.
h Blood sampling will occur per institutional procedures, but approximately every 10 minutes for approximately 
30 minutes prior to dosing, and will continue approximately every 5 to 10 minutes for the first 2 hours after 
dosing, and may be reduced to 10- to 30-minute intervals up to the end of clamp.  Repeat samples for spurious 
results or safety management may be taken where indicated.
i
Sampling times are relative to the time of study drug administration.


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Attachment 2.Protocol ABEF Clinical Laboratory Tests
Laboratory Tests 
Haematologya:
Clinical Chemistrya:
Haematocrit
Sodium
Haemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume (MCV)
Chloride
Mean cell haemoglobin (MCH)
Calcium
Mean cell haemoglobin concentration (MCHC)
Phosphorus 
Leukocytes (WBC)
Glucose (fasting)
Absolute counts of: 
Blood urea
Neutrophils
Uric acid
Lymphocytes
Total cholesterol
Monocytes
Total protein 
Eosinophils
Albumin
Basophils
Total bilirubin
Platelets
Alkaline phosphatase
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Urinalysisa:
Creatinine
Specific gravity
Gamma-glutamyl transferase (GGT)
pH
Protein
Glucose
Ketones
Serum pregnancy test (women of childbearing 
potential)a
Bilirubin
Hepatitis B surface antigenb
Urobilinogen
HIVc
Blood
OGTT b
FSH (if applicable)b
Urine ethanol testingb
Urine drug screenb
Abbreviations:  FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; OGTT = oral glucose 
tolerance test; RBC = red blood cells; WBC = white blood cells.
a
Performed at screening and follow-up at a central laboratory and at a local laboratory on Day -1 of each Period.  
b
Performed at screening only at a central laboratory.
c
Performed at screening only at a local laboratory.


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Attachment 3.Protocol ABEF Blood Sampling Summary
This table summarises the maximum 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 these will not require a protocol 
amendment.
Purpose
Maximum Blood 
Volume per Sample 
Maximum Number of 
Blood Samples
Maximum Total 
Volume (mL)
Screening clinical laboratory 
testsa
30 mL
1
30
Central laboratory follow-up 
clinical laboratory tests
7.5 mL
1
7.5
Local laboratory clinical 
laboratory tests (Day -1 of each 
period)
7 mL
2
14
PK samples
4 mL
14 samples/clamp x 2 clamps
112
C-peptide samples
2.5 mL
14 samples/clamp x 2 clamps
70
Glucose clamp samplesa,b
0.3 mL
27 hours/clamp x 2 clamps
(approx. 159 samples/clamp) 
95.4
Blood discard for cannula patency
0.2 mL/discard x
2 discards/hour
27 hours/clamp x 2 clamps
21.6
Total for study
-
-
approximately 351
a
Additional samples may be drawn if needed for safety purposes.
b
Blood sampling will occur per institutional procedures, but approximately every 10 minutes for approximately 
30 minutes prior to dosing, and will continue approximately every 5 to 10 minutes for the first 2 hours after 
dosing, and may be reduced to 10- to 30-minute intervals up to the end of clamp.


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Attachment 4.Protocol Amendment I4L-MC-ABEF(c) 
Summary Relative Bioavailability of LY2963016 to 
LANTUS® after Single-Dose Subcutaneous Administration 
in Healthy Chinese Subjects
Overview
Protocol I4L-MC-ABEF(b) [Relative Bioavailability of LY2963016 to LANTUS® after 
Single-Dose Subcutaneous Administration in Healthy Chinese Subjects] has been amended.  The 
new protocol is indicated by Amendment (c) and will be used to conduct the study in place of 
any preceding version of the protocol.
The change and rationale for the change made to this protocol are as follows:

Human Immunodeficiency Virus (HIV) testing will now be performed at a local 
laboratory instead of a central laboratory.


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Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
Attachment 2. Protocol ABEF Clinical Laboratory Tests
Laboratory Tests 
Haematologya:
Clinical Chemistrya:
Haematocrit
Sodium
Haemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume (MCV)
Chloride
Mean cell haemoglobin (MCH)
Calcium
Mean cell haemoglobin concentration (MCHC)
Phosphorus 
Leukocytes (WBC)
Glucose (fasting)
Absolute counts of: 
Blood urea
Neutrophils
Uric acid
Lymphocytes
Total cholesterol
Monocytes
Total protein 
Eosinophils
Albumin
Basophils
Total bilirubin
Platelets
Alkaline phosphatase
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Urinalysisa:
Creatinine
Specific gravity
Gamma-glutamyl transferase (GGT)
pH
Protein
Glucose
Ketones
Serum pregnancy test (women of childbearing 
potential)a
Bilirubin
Hepatitis B surface antigenb
Urobilinogen
HIVbc
Blood
OGTT b
FSH (if applicable)b
Urine ethanol testingb
Urine drug screenb
Abbreviations:  FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; OGTT = oral glucose 
tolerance test; RBC = red blood cells; WBC = white blood cells.
a
Performed at screening and follow-up at a central laboratory and at a local laboratory on Day -1 of each Period.  
b
Performed at screening only at a central laboratory.
c
Performed at screening only at a local laboratory.


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Attachment 3. Protocol ABEF Blood Sampling Summary
This table summarises the maximum 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 these will not require a protocol 
amendment.
Purpose
Maximum Blood 
Volume per Sample 
Maximum Number of 
Blood Samples
Maximum Total 
Volume (mL)
Central laboratory sScreening 
clinical laboratory testsa
30 mL
1
30
Central laboratory follow-up 
clinical laboratory tests
7.5 mL
1
7.5
Local laboratory clinical 
laboratory tests (Day -1 of each 
period)
7 mL
2
14
PK samples
4 mL
14 samples/clamp x 2 clamps
112
C-peptide samples
2.5 mL
14 samples/clamp x 2 clamps
70
Glucose clamp samplesa,b
0.3 mL
27 hours/clamp x 2 clamps
(approx. 159 samples/clamp) 
95.4
Blood discard for cannula patency
0.2 mL/discard x
2 discards/hour
27 hours/clamp x 2 clamps
21.6
Total for study
-
-
approximately 351
a
Additional samples may be drawn if needed for safety purposes.
b
Blood sampling will occur per institutional procedures, but approximately every 10 minutes for approximately 
30 minutes prior to dosing, and will continue approximately every 5 to 10 minutes for the first 2 hours after 
dosing, and may be reduced to 10- to 30-minute intervals up to the end of clamp.


Leo Document ID = c20772d9-b974-42bf-94e5-b6dbcf0c8e44
Approver: 
Approval Date & Time: 13-Dec-2018 14:26:19 GMT
Signature meaning: Approved
Approver:
Approval Date & Time: 18-Dec-2018 02:14:06 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
Statistical Analysis Plan I4L-MC-ABEF(V2)
Relative Bioavailability of LY2963016 to LANTUS® After Single-Dose Subcutaneous 
Administration in Healthy Chinese Subjects  
NCT03555305
Approval Date: 06-May-2019


Final V2, 29 April 2019
             Page 1 of 11
STATISTICAL ANALYSIS PLAN
Relative Bioavailability of LY2963016 to LANTUS® after Single-Dose Subcutaneous 
Administration in Healthy Chinese Subjects
Statistical Analysis Plan Status:  Final Version 2
Statistical Analysis Plan Date:  29-April-2019
Study Drug: LY2963016
Sponsor Reference:  I4L-MC-ABEF
Covance CRU Study: 1001215-8370489
Clinical Phase I
Approval Date: 06-May-2019 GMT


Final V2, 29 April 2019
             Page 2 of 11
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8370489
Sponsor Reference I4L-MC-ABEF
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS ............................................................................................... 2
2.
ABBREVIATIONS........................................................................................................ 3
3.
INTRODUCTION ......................................................................................................... 5
4.
STUDY OBJECTIVES.................................................................................................. 5
4.1
Primary Objective.................................................................................................... 5
4.2
Secondary Objectives .............................................................................................. 5
5.
STUDY DESIGN........................................................................................................... 6
6.
TREATMENTS............................................................................................................. 6
7.
SAMPLE SIZE JUSTIFICATION ................................................................................. 7
8.
DEFINITION OF ANALYSIS POPULATIONS............................................................ 7
9.
STATISTICAL METHODOLOGY ............................................................................... 7
9.1
General Considerations............................................................................................ 7
9.2
Demographics and Subject Disposition.................................................................... 8
9.3
Pharmacokinetic Analyses....................................................................................... 8
9.3.1
Pharmacokinetic Parameter Estimation........................................................... 8
9.3.2
Pharmacokinetic Statistical Inference ............................................................. 8
9.4
Pharmacodynamic Analyses .................................................................................... 9
9.4.1
Pharmacodynamic Parameter Estimation........................................................ 9
9.4.2
Pharmacodynamic Statistical Inference........................................................... 9
9.5
Safety and Tolerability Assessments........................................................................ 9
9.5.1
Adverse events ............................................................................................... 9
9.5.2
Concomitant medication............................................................................... 10
9.5.3
Clinical laboratory parameters...................................................................... 10
9.5.4
Vital signs .................................................................................................... 10
9.5.5
Electrocardiogram (ECG)............................................................................. 10
9.5.6
Glucose Monitoring and Hypoglycaemia Reporting...................................... 10
9.5.7
Other assessments......................................................................................... 11
9.5.8
Safety and Tolerability Statistical Methodology............................................ 11
10. INTERIM ANALYSES ............................................................................................... 11
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ...... 11
12. REFERENCES ............................................................................................................ 11
13. DATA PRESENTATION ............................................................................................ 11
13.1 Derived Parameters ............................................................................................... 11
13.2 Missing Data ......................................................................................................... 11
13.3 Insufficient Data for Presentation .......................................................................... 11


Final V2, 29 April 2019
             Page 3 of 11
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8370489
Sponsor Reference I4L-MC-ABEF
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
AUC(0-24)
Area under the serum study drug concentration-time curve from zero 
to 24 hours
AUC(0-∞)
Area under the serum study drug concentration curve from time zero 
to infinity
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
CRU
Clinical Research Unit
CV
Coefficient of variation
EC
Early Clinical 
ECG
Electrocardiogram
e.g.
For example (Latin: exempli gratia)
Gtot
Total amount of glucose infused
ICH
International Council on Harmonisation
MedDRA
Medical Dictionary for Regulatory Activities
PD
Pharmacodynamic
PK
Pharmacokinetic
Rmax
Maximum glucose infusion rate
SAP
Statistical Analysis Plan
SC
Subcutaneous 
SD
Standard deviation 
SOP
Standard Operating Procedure


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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


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3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 15 
April 2013) and Protocol Amendment (a) (final version dated 24 May 2017).
The SAP is being updated from Version 1 to Version 2 due to errors in the protocol and include 
updates to Section 7, Section 9.3.2.and Section 9.4.2.
This SAP describes the planned analysis of the safety, tolerability, 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 (EC) Biometrics. 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 EC Biometrics 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 
Council 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
4.1
Primary Objective

To evaluate the relative bioavailability of LY2963016 compared to LANTUS following 
subcutaneous (SC) single-dose administrations (0.5 U/kg) in healthy Chinese subjects.
4.2
Secondary Objectives

To evaluate the safety and tolerability of LY2963016 when administered to healthy
Chinese subjects.

To compare other PK parameters of LY2963016 with those of LANTUS after 0.5-U/kg 
SC administration.

To compare the PD responses of LY2963016 with those of LANTUS after 0.5-U/kg SC 
administration.


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5. STUDY DESIGN
This is a randomised, open-label, single-dose (0.5 U/kg), 2-treatment, 2-period, crossover, 
single-site, euglycaemic clamp study to evaluate the relative bioavailability of LY2963016 to 
LANTUS in healthy subjects. The study will have 2 treatment periods, with subjects randomly 
assigned in a 1:1 fashion to a treatment sequence of either LY2963016 (Period 1) followed by 
LANTUS (Period 2), or LANTUS (Period 1) followed by LY2963016 (Period 2) (Figure 1). 
Study drug will be administered once per period as an SC dose. Up to 60 healthy men and 
women will be enrolled in order to ensure that 40 subjects complete the study.
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


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LY2963016 0.5 U/kg SC
1
LANTUS 0.5 U/kg SC
2
7. SAMPLE SIZE JUSTIFICATION
Up to 60 healthy subjects may be enrolled to ensure that at least 52 subjects complete the study.
Assuming the ratio of AUC between test and reference product is 1, with 52 subjects completing, 
there is 80% coverage probability that the half-width of the 90% confidence interval (CI) of the 
difference of means for the area under the concentration time curve (AUC) will be within 0.223 
in the log scale, which corresponds to approximately 20% in the ratio scale. This precision 
estimate was based on the intrasubject variability for AUC of 39.26% observed in completed 
studies in healthy subjects. Drop-outs may be replaced and the replacement subject would 
assume the withdrawn subject’s treatment sequence (receiving both allocated treatments).
8. DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all subjects who received at least one dose of study drug.
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 Considerations
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 the maximum drug 
concentration [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. For 
the calculation of summary statistics and statistical analysis, unrounded data will be used. 
Data analysis will be performed using SAS® Version 9.4 or greater.


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9.2
Demographics and Subject Disposition
Subject disposition will be listed. The demographic variables age, sex, race, ethnicity, site ID,
body weight, height and body mass index will be summarized and listed.
9.3
Pharmacokinetic Analyses
PK analyses will be conducted on the Pharmacokinetic population.
9.3.1 Pharmacokinetic Parameter Estimation
PK parameter estimates for LY2963016 and LANTUS will be calculated by standard 
noncompartmental methods of analysis using WinNonlin Phoenix software. The version of any 
software used for the analysis will be documented, and the program will meet the Lilly 
requirements of software validation.
The analyses will be performed according to the Lilly Global Pharmacokinetics, 
Pharmacodynamics, and Pharmacometrics Divisional Standards. For each profile, concentration 
values that are below the quantifiable limit of the assay will be imputed as ½ LLOQ. Actual 
sampling times in individual subjects will be used in the analysis. The serum concentration of 
immunoreactive LY2963016 and LANTUS will be corrected for endogenous insulin using the C-
peptide data. The primary parameters for PK analysis will be: AUC from time zero to 24 hours 
[AUC(0-24)] and Cmax. Other PK parameters that will be reported include: AUC from time zero 
to last measured concentration value [AUC(0-tlast)], AUC from time zero to infinity [AUC(0-∞)], 
tmax, apparent clearance (CL/F), t1/2, and the apparent volume of distribution (Vz/F). The AUC 
values will be calculated by the linear/log trapezoidal method, where the linear trapezoidal 
method will be employed up to tmax, and the log trapezoidal rule will be used for concentrations 
beyond tmax.
9.3.2 Pharmacokinetic Statistical Inference
The primary PK parameters, AUC(0-24) and Cmax, will be log-transformed prior to analysis. A 
linear mixed effects model will be fitted to the data. The model will include subject as a random 
effect, with period, sequence, and treatment as fixed effects. For each PK parameter, the 
difference in least-square treatment means (LY2963016 – Lantus) along with the 90% 
confidence intervals (CIs) will be back-transformed to produce the ratio of geometric means and 
the CIs comparing LY2963016 to Lantus. Within subject coefficient of variation (CV) for each 
insulin may be reported if estimable. A similar statistical analysis will be performed for the log-
transformed secondary PK parameters AUC(0-∞) and AUC(0-tlast). 
Example SAS code:
proc mixed data=pk;
class subject period sequence treatment;
model log_pk = period sequence treatment /solution ddfm=kr residual;
random subject;
lsmeans treatment / pdiff alpha=0.1;
ods output lsmeans=lsm;
ods output diffs=diff;


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run;
Exploratory analyses may be performed for other PK parameters as deemed appropriate.
Descriptive statistics may be reported for other PK parameters as deemed appropriate (e.g, CL/F, 
Vz/F, t1/2). Median tmax will be calculated per treatment and a nonparametric approach will be 
taken to evaluate the difference in median tmax, using the Wilcoxon signed-rank test. The 
difference in median tmax  between treatments and the 95% CIs for the difference will be 
reported.
9.4
Pharmacodynamic Analyses
PD analyses will be conducted on Pharmacodynamic population.
9.4.1 Pharmacodynamic Parameter Estimation
The GIRs and blood glucose values will be recorded on Day 1. A locally weighted scatterplot 
smoothing (LOESS) function will be applied to all individual GIR versus time profiles in each 
treatment group and/or period using S-PLUS® software (v8.2). Glucose infusion rates will be
used to calculate several PD parameters, including maximum glucose infusion rate (Rmax), time 
of Rmax (tRmax), and total amount of glucose infused (Gtot). Other parameters namely, the time of 
first change of GIR postdose (tRonset), the time of last measurable GIR (tRlast), and the last 
measurable GIR (GIRlast) may be calculated as appropriate. 
9.4.2 Pharmacodynamic Statistical Inference
The PD parameters (Rmax and Gtot) will be log-transformed prior to analysis. A linear mixed
effects model will be fitted to the data. The model will include subject as a random effect, with
period, sequence, and treatment as fixed effects. From the models, the difference in least-squares
mean estimates between the 2 treatments and the corresponding 90% CIs for the difference will
be estimated and back-transformed from the log scale to provide estimates of the ratios of
geometric means and 90% CI for the ratio of these means. The SAS code will be similar to the 
SAS code used in the PK analysis. Within subject CV for each insulin may be reported if 
estimable. 
Exploratory analyses of other PD parameters may be performed as deemed appropriate, for 
example, time to Rmax (tRmax), time to first change of GIR postdose (tRonset), the time of last 
measurable GIR (tRlast), and the last measurable GIR (GIRlast) .
9.5
Safety and Tolerability Assessments
Safety Analyses will be conducted on Safety population.
9.5.1 Adverse events
Adverse events (AEs) will be coded based upon the latest version of the Medical Dictionary for 
Regulatory Activities (MedDRA). 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 


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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 AEs, the number of subjects 
experiencing an AE and the percentage of subjects experiencing an AE) of treatment-emergent 
AEs will be summarized by treatment, system organ class and preferred term. The summary and 
frequency AE tables will be presented for all causalities and those considered related to the study 
drug. Any serious AEs will be listed; this listing will include the reason the event was 
categorized as serious as well as relatedness.
9.5.2 Concomitant medication
Concomitant medication will be coded using the latest version of WHO drug dictionary. 
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 local 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 will be listed for individual subjects.
9.5.5 Electrocardiogram (ECG)
The ECG data will be listed for individual subjects.
9.5.6 Glucose Monitoring and Hypoglycaemia Reporting
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. Each category of hypoglycemic event (defined in Section 10.3.2.1 
of the Protocol) will be listed and summarized by treatment.
Blood glucose and C-peptide levels will be listed for individual patients and summarized by 
group.


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9.5.7
Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed. 
9.5.8
Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.
10.
INTERIM ANALYSES
No interim statistical analyses are planned.
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.
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 = 5fc9adfe-95d3-48d4-84f7-154d49bbfbd0
Approver:
Approval Date & Time: 03-May-2019 08:18:46 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 06-May-2019 08:37:20 GMT
Signature meaning: Approved
PPD
PPD