A Prospective, Randomized, Open-Label Comparison of a Long-Acting Basal Insulin Analog, LY2963016, to Lantus® in Combination With Mealtime Insulin Lispro in Adult Chinese Patients With Type 1 Diabetes Mellitus
Phase: PHASE3
Conditions: Type 1 Diabetes
Sponsor: Eli Lilly and Company

Protocol I4L-GH-ABES(a) 
 
A Prospective, Randomized, Open-Label Comparison of a Long-Acting Basal Insulin Analog, 
LY2963016, to Lantus® in Combination with Mealtime Insulin Lispro in 
Adult Chinese Patients with Type 1 Diabetes Mellitus 
NCT03338023 
Approved Date: 02Mar2017 
 
 

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LY2963016
1. Protocol I4L-GH-ABES(a)
A Prospective, Randomized, Open-Label Comparison of a 
Long-Acting Basal Insulin Analog, LY2963016, to
Lantus
® in Combination with Mealtime Insulin Lispro in 
Adult Chinese Patients with Type 1 Diabetes Mellitus
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators. It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
LY2963016 unless such persons are bound by a confidentiality agreement with Eli Lilly and 
Company or its subsidiaries. This document and its associated attachments and 
appendices are subject to United States Freedom of Information Act (FOIA), Exemption 4.
LY2963016
Phase 3, randomized, multicenter, 2-arm, active-control, open label, parallel, 24-week 
treatment study to compare LY2963016 and Lantus
® with mealtime insulin lispro in adult
Chinese patients with type 1 diabetes mellitus, with 4-week post-treatment follow up.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly:  02 August 2016
Amendment (a) Electronically Signed and Approved by Lilly
on date provided below.
Approval Date: 02-Mar-2017 GMT

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2. Synopsis
Study Rationale
LY2963016 is a highly similar version of Lantus® (insulin glargine [recombinant 
deoxyribonucleic acid (rDNA) origin] injection), the reference medicinal product (also referred 
to as the innovator product) produced by Sanofi-Aventis (Lantus® is a registered trademark of 
Sanofi-Aventis).  The primary amino acid sequence of LY2963016 is the same as that of the 
active ingredient in Lantus®. Both LY2963016 and Lantus® have similar formulations. The 
current study is a randomized, multicenter, parallel study to compare LY2963016 and Lantus® in 
the presence of mealtime lispro in adult Chinese patients with type 1 diabetes mellitus (T1DM). 
This is a 24-week treatment study with a 4-week post-treatment follow up.

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Clinical Protocol Synopsis:  Study I4L-GH-ABES
Name of Investigational Product:
LY2963016
Title of Study:  A Prospective, Randomized, Open-Label Comparison of a Long-Acting Basal Insulin Analog,
LY2963016, to Lantus® in Combination with Mealtime Insulin Lispro in Adult Chinese Patients with Type 1 
Diabetes Mellitus
Number of Planned Patients/Subjects:
   Entered: 330
   Enrolled/Randomized: 258
   Completed: 218
Phase of Development:  Phase 3
Length of Study:  
Estimated first patient visit:  Mar 2018               Estimated last patient visit:  Sep 2020
Objectives:  The primary objective of this study is to test the hypothesis that LY2963016 administered once daily
(QD) is noninferior to Lantus® QD by a margin of 0.40%, as measured by change in hemoglobin A1c (HbA1c) 
from baseline to 24 weeks, when used in combination with premeal insulin lispro thrice a day (TID) in adult 
Chinese patients with T1DM.
The secondary objectives of the study are:

To test the hypothesis that Lantus® is noninferior to LY2963016, as measured by change in HbA1c from 
baseline to 24 weeks, when used in combination with premeal insulin lispro TID (this secondary 
objectives is tested with a gated approach)

To compare the safety of LY2963016 to Lantus® (proportion of patients with detectable anti-glargine
antibodies, hypoglycemia and injection site reaction) when used in combination with premeal insulin 
lispro

To compare change in HbA1c at 6, 12, and 18 weeks between LY2963016 and Lantus® when used in 
combination with premeal insulin lispro

To compare 7-point self-monitored blood glucose (SMBG) profiles at baseline, 2, 4, 6, 12, 18, and 
24 weeks between LY2963016 and Lantus® when used in combination with premeal insulin lispro

To compare percentage of patients with HbA1c <7% and percentage of patients with HbA1c ≤6.5% at 6, 
12, 18, and 24 weeks between LY2963016 and Lantus® when used in combination with premeal insulin 
lispro

To compare LY2963016 to Lantus® when used in combination with premeal insulin lispro with regard to 
the following measures
o
intrapatient blood glucose (BG) variability
o
basal and prandial insulin dose
o
weight change

To compare patient-reported outcomes (PRO), as measured by responses to the Insulin Treatment 
Satisfaction Questionnaire (ITSQ), between LY2963016 and Lantus®
Study Design:  A Phase 3, prospective, randomized, multicenter, 2-arm, active-control, open-label, parallel, 
24-week treatment study in patients with T1DM, with a 4-week post-treatment follow up.

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Diagnosis and Main Criteria for Inclusion and Exclusions:                                                                         
Patients with T1DM for ≥1 year, of ≥18 years of age, with a body mass index (BMI) ≤35 kg/m2 will be included in 
the study. Patients should have an HbA1c ≤11%. Patients must be administered with basal-bolus or premixed 
insulins before enrollment for at least 3 months (90 days) prior to Visit 1. For basal-bolus therapy, bolus insulin
includes mealtime injections of human regular insulin, or insulin analog lispro, or aspart, or glulisine; basal insulin
can be QD injection of Lantus®, or either QD or twice daily (BID) injection of human insulin isophane suspension 
[NPH] or detemir. For those patients with premixed therapy before the study, insulin regimens with any 
NPH/neutral protamine lispro [NPL] (basal) and bolus combination are administered at least BID.  
Patients with known hypersensitivity or allergy to the study insulin (Lantus® or insulin lispro) or their excipients, 
or with significant renal, cardiac, gastrointestinal, or liver disease, will be excluded. Patients with active cancer or 
cancer within the past 5 years will be excluded. Twice-daily insulin glargine within 6 months prior to Visit 1 will 
be excluded.
Investigational Product, Dosage, and Mode of Administration or Intervention:
In the patients who were administered with basal-bolus therapies before enrollment with QD basal insulin and 
mealtime insulins, QD LY2963016 will be started at the same dose as the QD prestudy basal insulin. For those 
patients with BID prestudy basal insulin as part of basal-bolus regimen, the total daily prestudy basal insulin dose 
will be reduced by 20% at randomization to LY2963016, therefore, the study basal insulin dose will be 80% of the 
prestudy basal insulin dose. Insulin lispro will be administered with meals at the same dose as the patient’s
prestudy mealtime insulin dose while avoiding hypoglycemia, as determined by unit-to-unit conversion. 
In the patients who were administered with pre-mixed insulin, the total daily dosage at randomization will be the 
average for the sum of all insulin doses taken in the 3 days prior to randomization. The total daily dosage will then 
be split between basal and bolus insulin doses at the discretion of the investigator. The initial basal insulin dose is 
recommended to be approximately 40% to 60% of the total daily dose. Then the initial bolus insulin dose (insulin 
lispro, 60% to 40% of the total daily dose) will be divided into 3 equal doses before 3 meals. The doses of initial 
bolus insulin can be adjusted at the discretion of investigators based on consideration of individual patient’s 
diet/physical activity/or insulin needs as reflected by SMBG pattern.
The basal and bolus insulin dose will be adjusted during the study to achieve glycemic targets (HbA1c <7%, 
preprandial capillary BGs 79 to 126 mg/dL [4.4 to 7.0 mmol/L], avoiding hypoglycemia). The mode of 
administration will be subcutaneous.
Planned Duration of Treatment:
Lead-in period:  None
Treatment period:  24 weeks when primary outcome will be measured by change in HbA1c from baseline.
Washout period:  None
Observation period:  4-week post-treatment follow up
Reference Therapy, Dose, and Mode of Administration or Comparative Intervention:  
The initial doses of insulin lispro and Lantus® will be based on the individual patient’s prestudy insulin 
dose/regimen and similarly determined as those for the bolus and basal insulins respectively of the investigational 
group.
Criteria for Evaluation:  
Efficacy:  
Primary Endpoint: 
Change in HbA1c from baseline to 24 weeks.
Secondary Endpoints:

7-point SMBG (expressed as plasma-equivalent glucose values obtained before each meal, after morning
meal, after midday meal, at bedtime, and at 3 am).

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
Intrapatient variability, as measured by the standard deviation of the 7-point SMBG.

Change in HbA1c from baseline to 6, 12, and 18 weeks or last observation carried forward (LOCF).

Percentage of patients with HbA1c <7%, percentage of patients with HbA1c ≤6.5%.

Total insulin, basal insulin, and mealtime insulin lispro doses in U/day and U/kg/day

Weight change.

Patient-reported outcomes, as reflected in responses to Insulin Treatment Satisfaction Questionnaire
(ITSQ).
Safety:
Anti-glargine antibodies, laboratory measures, adverse events (AEs; including injection-site reactions and 
neoplasms), and hypoglycemia will be collected, captured, and/or monitored for safety. Episodes of severe 
hypoglycemia will be captured as serious adverse events (SAEs). 
Hypoglycemia is defined as an event associated with signs or symptoms consistent with hypoglycemia, and/or a 
BG level ≤70 mg/dL (≤3.9 mmol/L) is noted even if it is not associated with signs or symptoms.  
Nocturnal hypoglycemia is defined as any hypoglycemic event that occurs between bedtime and waking.  
Severe hypoglycemia is defined as an event requiring assistance of another person to actively administer 
carbohydrate, glucagon, or other resuscitative actions.
Health Outcomes:  
Patient-reported outcomes, as reflected in responses to ITSQ. The ITSQ is a validated instrument containing 
22 items that assesses treatment satisfaction for persons with diabetes who are taking insulin.
Statistical Methods:
Sample Size:
Based on the primary objective, to show noninferiority of LY2963016 to Lantus® at the 0.40% noninferiority 
margin (NIM), 109 completers per arm (218 total) are needed at 24 weeks. This calculation assumes no treatment 
difference in HbA1c between LY2963016 and Lantus®, a common standard deviation (SD) of 1.05% for change 
from baseline in HbA1c, a two-sided significance level of 0.05, and over 80% power. Assuming a 15% dropout 
rate at 24 weeks, the required number of randomized patients is 129 per arm (258 total).  
Blinded sample-size reestimation may be performed when approximately 40% of the subjects have been enrolled 
in the study and finished 24-week of treatment, or about 6 months prior to the completion of enrollment, depending 
on which occur first by team assessment.
Statistical: 
The primary efficacy outcome is the change in HbA1c level from baseline to 24 weeks.  The primary analysis will 
be a likelihood-based, mixed model repeated measure (MMRM) approach, treating the data as missing at random 
(MAR) for the full analysis set (FAS) population.  The MMRM model will evaluate the change from baseline in 
HbA1c level as the dependent variable with treatment (LY2963016, Lantus®), stratification factors screening 
HbA1c Stratum, prestudy treatment, and prestudy metformin or acarbose usage (metformin only, acarbose only, or 
neither), visit, and interaction between visit and treatment as fixed effects; the baseline value of HbA1c as a 
covariate; and a random effect for patient.  Supportive analyses will be performed with the same MMRM model on 
per-protocol (PP) population and with an analysis of covariance (ANCOVA) model on FAS population.
The analysis of the continuous secondary efficacy and safety measurements will use the same MMRM model for 
the primary efficacy analyses with the baseline value of the response as a covariate with the FAS patient 
population. Continuous laboratory measures will be analyzed using an ANCOVA model. For categorical 

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LY2963016
measures, Fisher’s exact test or Pearson’s Chi-square test will be used.
A single interim analysis on both efficacy and safety data may be performed to allow interaction with regulatory 
authorities. Analyses on both interim and final data will be performed using the same statistical methods as 
described in this protocol and the statistical analysis plan. The study will not stop for early efficacy at the interim 
analysis therefore no adjustment of Type I error is needed. If there are significant safety concerns arising from the 
interim analyses, the study team may decide to stop the trial early for safety concerns. The study team will decide, 
based on the trial operation and blinded safety information, whether and when the interim analyses will be 
performed.
The final database lock for this study will be performed when all randomized patients have completed (or 
discontinued from) the study.
If any other unplanned interim analysis is deemed necessary, the appropriate Lilly regulatory scientist will be 
consulted to determine whether it is necessary to amend the protocol.

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3. Table of Contents
A Prospective, Randomized, Open-Label Comparison of a 
Long-Acting Basal Insulin Analog, LY2963016, to
Lantus
® in Combination with Mealtime Insulin Lispro in Adult 
Chinese Patients with Type 1 Diabetes Mellitus
Section
Page
1.
Protocol I4L-GH-ABES(a) A Prospective, Randomized, Open-Label 
Comparison of a Long-Acting Basal Insulin Analog, LY2963016, to 
Lantus
® in Combination with Mealtime Insulin Lispro in Adult 
Chinese Patients with Type 1 Diabetes Mellitus ..................................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................7
4.
Abbreviations and Definitions...........................................................................................12
5.
Introduction ......................................................................................................................16
6.
Objectives.........................................................................................................................18
6.1.
Primary Objective ........................................................................................................18
6.2.
Secondary Objectives...................................................................................................18
7.
Investigational Plan...........................................................................................................19
7.1.
Summary of Study Design............................................................................................19
7.2.
Discussion of Design and Control ................................................................................20
7.2.1.
Introduction .........................................................................................................20
7.2.2.
Study Visits..........................................................................................................21
7.2.2.1.
Screening (Visit 1)..........................................................................................21
7.2.2.2.
Randomization (Visit 2)..................................................................................22
7.2.2.2.1.
Patients Eligible for Randomization at Visit 2...........................................22
7.2.2.2.1.1.
Instructions for Insulin Self-administration .........................................22
7.2.2.3.
Telephone Visits.............................................................................................23
7.2.2.4.
Study Visits (Visit 3 to Visit 13 or Early 
Discontinuation) .............................................................................................23
7.2.2.5.
Follow-up Visit (Visit 801).............................................................................25
7.2.3.
Blood Glucose Monitoring Plan ...........................................................................25
8.
Study Population...............................................................................................................26
8.1.
Inclusion Criteria..........................................................................................................26
8.2.
Exclusion Criteria ........................................................................................................27

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8.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................28
8.3.
Discontinuations ..........................................................................................................30
8.3.1.
Discontinuation of Inadvertently Enrolled Patients...............................................30
8.3.2.
Discontinuation of Investigational Product...........................................................30
8.3.3.
Patient Discontinuation from the Study ................................................................30
8.3.4.
Patients Lost to Follow-Up...................................................................................31
8.3.5.
Discontinuation of Study Sites .............................................................................31
8.3.6.
Discontinuation of the Study................................................................................32
9.
Treatment..........................................................................................................................33
9.1.
Treatments Administered .............................................................................................33
9.2.
Materials and Supplies .................................................................................................34
9.3.
Method of Assignment to Treatment ............................................................................34
9.4.
Rationale for Selection of Doses in the Study...............................................................34
9.5.
Selection and Timing of Doses.....................................................................................35
9.5.1.
Special Treatment Considerations ........................................................................36
9.6.
Continued Access to Investigational Product................................................................36
9.7.
Blinding .......................................................................................................................36
9.8.
Concomitant Therapy...................................................................................................36
9.9.
Treatment Compliance .................................................................................................36
9.10. Hypoglycemic Episodes...............................................................................................37
10.
Efficacy, Health Outcome/Quality of Life Measures, Safety 
Evaluations, Sample Collection and Testing, and Appropriateness of 
Measurements...................................................................................................................39
10.1. Efficacy Measures........................................................................................................39
10.1.1.
Primary Efficacy Measure....................................................................................39
10.1.2.
Secondary Efficacy Measures...............................................................................39
10.2. Health Outcome/Quality of Life Measures ...................................................................39
10.3. Safety Evaluations........................................................................................................40
10.3.1.
Adverse Events ....................................................................................................40
10.3.1.1.
Serious Adverse Events ..................................................................................41
10.3.1.1.1.
Suspected Unexpected Serious Adverse Reactions....................................42
10.3.2.
Other Safety Measures .........................................................................................42
10.3.3.
Safety Monitoring ................................................................................................43
10.3.4.
Complaint Handling.............................................................................................43
10.4. Sample Collection and Testing.....................................................................................43
10.4.1.
Samples for Study Qualification and Health Monitoring.......................................43
10.4.2.
Samples for Biomarker Research..........................................................................44
10.4.2.1.
Nonpharmacogenetic Biomarker Evaluations..................................................44

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10.4.3.
Samples for Immunogenicity Research.................................................................44
10.5. Appropriateness of Measurements................................................................................44
11.
Data Quality Assurance.....................................................................................................45
11.1. Data Capture System....................................................................................................45
12.
Sample Size and Statistical Methods .................................................................................46
12.1. Determination of Sample Size ......................................................................................46
12.2. Statistical and Analytical Plans.....................................................................................46
12.2.1.
General Considerations ........................................................................................46
12.2.2.
Patient Disposition...............................................................................................47
12.2.3.
Patient Characteristics..........................................................................................48
12.2.4.
Concomitant Therapy...........................................................................................48
12.2.5.
Treatment Compliance .........................................................................................48
12.2.6.
Primary Efficacy Outcome and Methodology.......................................................48
12.2.7.
Secondary Efficacy Outcomes and Methodology .................................................49
12.2.8.
Health Outcome/Quality of Life Analyses............................................................50
12.2.9.
Safety Analyses....................................................................................................50
12.2.9.1.
Immunogenicity Test......................................................................................50
12.2.9.2.
Adverse Events...............................................................................................50
12.2.9.3.
Hypoglycemic Events.....................................................................................51
12.2.9.4.
Laboratory Measures ......................................................................................51
12.2.9.5.
Vital Signs......................................................................................................52
12.2.10. Subgroup Analyses ..............................................................................................52
12.2.11. Interim Analyses..................................................................................................52
13.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................54
13.1. Informed Consent.........................................................................................................54
13.2. Ethical Review.............................................................................................................54
13.3. Regulatory Considerations ...........................................................................................54
13.3.1.
Investigator Information.......................................................................................55
13.3.2.
Protocol Signatures ..............................................................................................55
13.3.3.
Final Report Signature .........................................................................................55
14.
References ........................................................................................................................56

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List of Figures
Figure
Page
Figure ABES.7.1.
Study design for Clinical Protocol I4L-GH-ABES. ...................................20

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List of Attachments
Attachment
Page
Attachment 1.Protocol ABES Study Schedule...........................................................................58
Attachment 2.Protocol ABES Clinical Laboratory Tests............................................................63
Attachment 3.Protocol ABES Estimated Sampling Summary....................................................64
Attachment 4.Protocol ABES Hepatic Monitoring Tests for Treatment Emergent 
Abnormality ..................................................................................................65
Attachment 5.ABES General Rules and Guidance for Intensive Insulin Therapy for 
ABES Study ..................................................................................................66
Attachment 6.Protocol ABES World Health Organization (WHO)
Classification of Diabetes ..............................................................................73
Attachment 7.Protocol Amendment I4L-GH-ABES(a) Summary:  A Prospective, 
Randomized, Open-Label Comparison of a Long-Acting Basal 
Insulin Analog, LY2963016, to Lantus® in Combination with 
Mealtime Insulin Lispro in Adult Chinese Patients with Type 1 
Diabetes Mellitus...........................................................................................74

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4. Abbreviations and Definitions
Term
Definition
ACS
American Cancer Society
ADA 
American Diabetes Association
AE (adverse event)
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
ALT 
alanine aminotransferase
ANCOVA
analysis of covariance
AST 
aspartate aminotransferase
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, analyzed, and accurately reported according to the protocol, applicable 
standard operating procedures (SOPs), good clinical practice (GCP), and the applicable 
regulatory requirement(s).
BG
blood glucose
BID
twice daily
BMI
body mass index
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the trial-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements.
consent
The act of obtaining informed consent for participation in a clinical trial from patients 
deemed eligible or potentially eligible to participate in the clinical trial.  Patients 
entered into a trial are those who sign the informed consent form directly or through 
their legally acceptable representatives.
CRF (case report form) 
and eCRF (electronic 
case report form)
Sometimes referred to as clinical report form:  A printed or electronic form for 
recording study participants’ data during a clinical study, as required by the protocol.
CRO
contract research organization

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CRP (clinical research 
physician)
Individual responsible for the medical conduct of the study.  Responsibilities of the 
CRP may be performed by a physician, clinical research scientist, global safety 
physician or other medical officer.
CSR
clinical study report
DCCT
The Diabetes Control and Complications Research Group
ECG
electrocardiogram
ED
early discontinuation
efficacy
Efficacy is the ability of a treatment to achieve a beneficial intended result.
EGFR
estimated glomerular filtration rate
end of study (trial)
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.
FAS
full analysis set
FBG 
fasting blood glucose
GCP 
Good Clinical Practice
GMP
Good Manufacturing Practices
HbA1c
hemoglobin A1c
HIV
human immunodeficiency virus
IB 
investigator’s brochure
ICF
informed consent form
ICH 
International Conference on Harmonisation
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form. 
investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible 
leader of the team and may be called the principal investigator.
IRB/ERB (institutional 
review board/ethical 
review board)
A board or committee (institutional, regional, or national) composed of medical and 
nonmedical members whose responsibility is to verify that the safety, welfare, and 
human rights of the patients participating in a clinical study are protected.
ITSQ
Insulin Treatment Satisfaction Questionnaire

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ITT (intent[ion] to 
treat)
The principle that asserts that the effect of a treatment policy can be best assessed by 
evaluating on the basis of the intention to treat a patient (that is, the planned treatment 
regimen) rather than the actual treatment given.  It has the consequence that patients 
allocated to a treatment group should be followed up, assessed, and analyzed as 
members of that group irrespective of their compliance to the planned course of 
treatment.
legal representative
An individual, judicial, or other body authorized under applicable law to consent on 
behalf of a prospective patient to the patient’s participation in the clinical study.
LOCF 
last-observation-carried-forward or last post-baseline observation carried forward
LSMean 
least-squares mean
MAR
missing at random
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed model repeated measure
NIM
noninferiority margin
NPH 
human insulin isophane suspension
NPL
neutral protamine lispro
OAM 
oral antihyperglycemic medication
OM
observed margins
patient
A study participant who has the disease or condition for which the investigational 
product is targeted.
PP
per-protocol
PRO/ePRO
(electronic) patient-reported outcomes
QD 
once daily
randomize
The act of assigning a patient to a treatment.  Patients who are randomized in the trial 
are those who have been assigned to a treatment.
rDNA
recombinant deoxyribonucleic acid
SAE 
serious adverse event
SD
standard deviation
SMBG 
self-monitored blood glucose or self-monitoring of blood glucose
Study entry
patients will be considered to have been entered into the study after they have signed 
the inform consent form
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.

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SUSARS (suspected 
unexpected serious 
adverse reactions)
Suspected unexpected serious adverse reactions are serious events that are not listed in 
the Investigator’s Brochure (IB) and that the investigator identifies as related to 
investigational product or procedure.
TID
thrice a day
T1DM
type 1 diabetes mellitus
TDID
total daily insulin dose
TEAE
Treatment-emergent adverse event:  An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment.
U 
unit(s)
ULN
upper limit of normal
WHO 
World Health Organization

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LY2963016
A Prospective, Randomized, Open-Label Comparison of a 
Long-Acting Basal Insulin Analog, LY2963016, to
Lantus
® in Combination with Mealtime Insulin Lispro in Adult 
Chinese Patients with Type 1 Diabetes Mellitus
5. Introduction
The Diabetes Control and Complications Trial (DCCT) has shown that intensive insulin therapy 
(3 or more insulin injections or continuous subcutaneous insulin infusion) is a key part of therapy 
for patients with type 1 diabetes mellitus (T1DM) to improve glycemia and achieve better 
outcomes (The DCCT Research Group 1993; Nathan et al. 2005). At the time of the DCCT, 
intermediate- and short-acting human insulins were used, and, despite improved microvascular 
outcomes, there was a high rate of severe hypoglycemia (62 episodes/100 patient-years) (ADA 
2011). Insulin analogs that better mimic the physiologic pattern of mealtime or basal insulin 
secretion have been developed and shown to be associated with less hypoglycemia with similar 
glycemic control in patients with T1DM (DeWitt and Hirsch 2003). The American Diabetes 
Association (ADA) recommends use of insulin analogs as a component of therapy for many 
patients with T1DM, especially if hypoglycemia is a problem (ADA 2011).
Lantus® (insulin glargine [recombinant deoxyribonucleic acid (rDNA) origin]; [Sanofi- Aventis,
Bridgewater, New Jersey, USA]) 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 changes shift the isoelectric point, producing a solution that is completely soluble at pH 4. 
When injected into the subcutaneous tissue, the acidic solution is neutralized. This leads to the 
formation of microprecipitates, from which small amounts of glargine are released. The slow 
dissolution of hexamers into dimers and, finally, monomers results in an extended duration of 
action without a pronounced peak (Lantus® US package insert, 2010). In patients with T1DM, 
insulin glargine has been shown to provide similar glycemic control to human insulin isophane 
suspension (NPH), with less or no difference in occurrence of hypoglycemia (Raskin et al. 2000;
Ratner et al. 2000).
LY2963016 is a highly similar version of Lantus® (insulin glargine [rDNA origin] injection), the 
reference medicinal product (also referred to as the innovator product) produced by Sanofi-
Aventis (Lantus® is a registered trademark of Sanofi-Aventis).  The primary amino acid 
sequence of LY2963016 is the same as that of the active ingredient in Lantus®. Both 
LY2963016 and Lantus® have similar formulations.
The clinical development program for LY2963016 has generated evidence substantiating the
similar nature, in terms of clinical pharmacokinetics and pharmacodynamics, safety, and efficacy 
of LY2963016 and LANTUS.

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Study I4L-MC-ABEB was a Phase 3, open-label, 52 weeks trial to compare LY2963016 to 
Lantus® in combination with mealtime insulin lispro in adult patients with T1DM. Severe 
hypoglycemia was the most frequently reported serious adverse event (SAE) in both groups 
(LY2963016: 13 patients [4.9%]; Lantus®: 12 patients [4.5%]). LY2963016 and Lantus® were 
considered to have equivalent efficacy. LY2963016 was safe and well tolerated. The safety 
profiles for LY2963016 and Lantus® were similar; there were no new safety findings in either 
treatment group. Both LY2963016 and Lantus®, when used in combination with lispro, 
provided effective (and similar) glucose control with similar safety profiles. The data from this 
trial demonstrate that LY2963016 provides a well-tolerated and effective once-daily (QD) basal 
insulin option for treatment of patients with T1DM in combination with insulin lispro, with an 
efficacy and safety profile similar to that of Lantus® (insulin glargine).
In this randomized, controlled trial, the efficacy and safety of LY2963016 will be compared to 
Lantus® when used as QD basal insulin in combination with mealtime lispro in adult Chinese
patients with T1DM. This study will expand the evaluation of the efficacy and safety of 
LY2963016 to a broader race/ethnic spectrum of patients with T1DM considering that the study 
population in Study ABEB was predominantly white (74.5%).
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.
More detailed information about the known and expected benefits, risks and reasonably 
anticipated adverse events (AEs) of LY2963016 may be found in the Investigator’s Brochure 
(IB). Information on AEs expected to be related to the investigational product may be found in 
Section 7 (Development Core Safety Information) of the IB. Information on SAEs expected in 
the study population independent of drug exposure will be assessed by the sponsor in aggregate 
periodically during the course of the study and may be found in Section 6 (Effects in Humans) of 
the IB.

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6. Objectives
6.1.
Primary Objective
The primary objective of this study is to test the hypothesis that LY2963016 QD is noninferior to 
Lantus
® QD by a margin of 0.40%, as measured by change in hemoglobin A1c (HbA1c) from 
baseline to 24 weeks, when used in combination with premeal insulin lispro administered thrice a 
day (TID).
6.2.
Secondary Objectives
The secondary objectives of the study are as follows: 

To test the hypothesis that Lantus® is noninferior to LY2963016, as measured by change 
in HbA1c from baseline to 24 weeks, when used in combination with premeal insulin 
lispro (TID) (this secondary objective is tested with a gated approach).

To compare the safety of LY2963016 to Lantus® (proportion of patients with detectable 
of anti-glargine antibodies, hypoglycemia and injection site reaction) when used in 
combination with premeal insulin lispro. 

To compare change in HbA1c at 6, 12, and 18 weeks between LY2963016 and Lantus®
when used in combination with premeal insulin lispro

To compare 7-point self-monitored blood glucose (SMBG) profiles at baseline, 2, 4, 6, 12, 
18, and 24 weeks between LY2963016 and Lantus® when used in combination with 
premeal insulin lispro

To compare percentage of patients with HbA1c <7% and percentage of patients with 
HbA1c ≤6.5% at 6, 12, 18, and 24 weeks between LY2963016 and Lantus® when used in 
combination with premeal insulin lispro

To compare LY2963016 to Lantus® when used in combination with premeal insulin 
lispro with regard to the following measures
o
intrapatient blood glucose (BG) variability
o
basal and prandial insulin dose
o
weight change

To compare patient-reported outcomes (PRO) between LY2963016 and Lantus® as 
measured by responses to the Insulin Treatment Satisfaction Questionnaire (ITSQ).

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7. Investigational Plan
7.1.
Summary of Study Design
Study I4L-GH-ABES (ABES) is a prospective, Phase 3, randomized, multicenter, 2-arm, active-
control, open-label, parallel, 24-week treatment study in patients with T1DM with 4-week post-
treatment follow up. The study is designed to determine non-inferiority of LY2963016 to 
Lantus® in change in HbA1c from baseline in patients with T1DM. Patients will be screened at 
Visit 1, and eligible patients will be randomized to LY2963016 or Lantus® at Visit 2 to be 
treated for a total period of 24 weeks.
Patients must be administered with basal-bolus regimen or premixed insulins regimen before 
enrollment for at least 3 months (90 days) prior to Visit 1. For those patients with basal-bolus 
therapy before the study, bolus insulin includes mealtime injections of human regular insulin, or 
insulin analog lispro, or aspart, or glulisine; basal insulin can be QD injection of Lantus®, or 
either QD or twice daily (BID) injection of NPH or detemir. Twice-daily insulin glargine within 
6 months prior to Visit 1 will be excluded. For those patients with premixed therapy before the 
study, insulin regimens with any basal and bolus combination are administered at least BID.
At randomization, in the patients who were administered with basal-bolus therapies before 
enrollment with QD basal insulin and mealtime insulins, QD LY2963016 will be started at the 
same doses as the QD prestudy basal insulin. For those patients with BID prestudy basal insulin, 
the total daily prestudy basal insulin dose will be reduced by 20% at randomization to 
LY2963016 or insulin glargine (Product Information for Lantus®, 2007), therefore, the study 
basal insulin dose will be 80% of the prestudy basal insulin dose. Insulin lispro will be 
administered with meals at the same doses as the patient’s prestudy mealtime insulin dose while 
avoiding hypoglycemia, as determined by unit-to-unit conversion.
In the patients who were administered with pre-mixed insulin, the total daily dosage at 
randomization will be the average for the sum of all insulin doses taken in the 3 days prior to 
randomization. The total daily dosage will then be split between basal and bolus insulin doses at 
the discretion of the investigator. The initial basal insulin dose is recommended to be 
approximately 40% to 60% of the total daily dose (Retnakaran and Zinman 2010). Then the 
initial bolus insulin dose (insulin lispro, 60% to 40% of the total daily dose) will be divided into 
3 equal doses before 3 meals. The doses of initial bolus insulin can be adjusted at the discretion 
of investigators based on consideration of individual patient’s diet/physical activity/or insulin 
needs as reflected by SMBG pattern.
A total of 258 patients are planned to be enrolled in the study, with a target of 218 patients
completing the study. Patients will be screened at Visit 1, and eligible patients will be 
randomized at Visit 2 to receive LY2963016 or Lantus® QD with premeal insulin lispro for a
period of 24 weeks, at which time the efficacy endpoint of change in HbA1c levels from baseline 
will be assessed.
Patients will come to the investigator site for Visits 2, 4, 6, 8, 11, 12, 13, and 801 for various 
study assessments during the treatment period. Patients will be contacted over the telephone for 

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Visits 3, 5, 7, 9, and 10 (described as “Telephone Visits” in Section 7.2.2.3) to assess their 
response to study drug (including 4-point SMBG, AEs, and hypoglycemia) and/or to further 
adjust insulin doses, if needed. Insulin dose adjustments will be done in both treatment arms to 
help patients achieve glycemic targets (HbA1c <7%, preprandial capillary BGs 79 to 126 mg/dL
[4.4 to 7.0 mmol/L]) while minimizing/avoiding hypoglycemia. Patients will come for a clinic 
visit at Visit 13 for their final assessments at the completion of 24 weeks. At approximately 
4-weeks post-treatment endpoint, patients will have a final clinic visit (Visit 801), at which 
information will be collected according to the Study Schedule (Attachment 1).
End of study (trial) is the date of the last visit or last scheduled procedure shown in the Study 
Schedule for the last active patient in the study.
Figure ABES.7.1 illustrates the study design.
Abbreviations:  QD = once-daily administration; TID = thrice-daily administration;
* = telephone visit.
Figure ABES.7.1.
Study design for Clinical Protocol I4L-GH-ABES.
7.2.
Discussion of Design and Control
7.2.1. Introduction
The present study is a prospective, Phase 3, randomized, multicenter, 2-arm, active-control, 
open-label, parallel, 24-week treatment study in patients with T1DM on basal-bolus insulin 

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therapy, followed by a 4-week post-treatment follow-up. The trial is designed to allow a 
head-to-head comparison of the efficacy and safety of 2 basal insulin analogs with the same
primary amino acid sequence (LY2963016 and Lantus®) in patients with T1DM. The study 
design includes screening, randomization, treatment (24 weeks until primary endpoint 
assessment) and post-treatment follow-up periods. The Treatment Period is composed of a 
Titration Period and a Maintenance Period. It is expected that most of the basal and bolus insulin 
dose adjustments should occur during the initial titration period (Week 0 through Week 6); 
however, titration could extend up to Week 12 for patients who need more intensification to 
achieve glycemic targets. It is expected that insulin dose adjustments during the Maintenance 
Period would be for safety such as hypoglycemia or unacceptable hyperglycemia.
7.2.2. Study Visits
7.2.2.1.
Screening (Visit 1)
Approximately 2 weeks prior to the start of the study, all potential study patients eligible for 
randomization will be screened after signing the informed consent form (ICF) and will receive a 
patient number. The medical history and preexisting conditions, previous insulin exposure, 
physical examination, height, weight, vital signs, electrocardiogram (ECG) readings, 
concomitant medications, and adverse events will be recorded during this visit. Laboratory 
assessments will be performed to determine the eligibility of patients and to include pregnancy 
tests for women of child-bearing potential (performed at a central laboratory). The HbA1c, 
hematology and serum chemistry assays will be performed at a central laboratory (Attachment 1
and Attachment 2). Serum pregnancy tests will be performed on all females of childbearing 
potential at Visit 1 and when clinically indicated. Urine pregnancy tests at other visits can be 
accepted per local regulations. A urine pregnancy test may be repeated locally for any visits if 
considered necessary by the investigators and/or in compliance with local regulations. 
Each patient will be given a glucometer (and associated supplies) and will be trained on its use in 
monitoring their BG levels during the study (Section 7.2.3), including instructions on obtaining 
the 7-point SMBG profiles that will be collected at Visit 2.  Qualified medical staff will instruct 
patients about signs and symptoms of hypoglycemia and hyperglycemia and how to manage 
them. Patients will be provided study diaries and training to properly use the study diary at 
Visit 1 for recording BG values, corresponding insulin doses, hypoglycemic episodes, any AEs, 
and concomitant medications taken during the study (Attachment 1). If allowed by local law, 
patients may keep the study-provided blood glucose meter at the end of their study participation.
Patients who do not meet all the inclusion criteria at Visit 1 will be considered screen failures.  
As the patient’s eligibility for randomization may not be known at Visit 1 (for example, given 
that results of laboratory tests may not be available), the site could either provide a tentative 
schedule for Visit 2 or arrange for follow up with the patient to confirm eligibility, and then 
prepare for and schedule Visit 2 as they deem appropriate and efficient.

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7.2.2.2.
Randomization (Visit 2)
7.2.2.2.1. Patients Eligible for Randomization at Visit 2
At Visit 2, additional clinical assessments will occur, as outlined in the Study Schedule
(Attachment 1). More specifically, the following activities will also occur at this visit:

Eligible patients will be randomized to 1 of 2 treatment groups by a random assignment 
based on Visit 1 HbA1c, prestudy treatment with basal-bolus insulin or premixed insulin, 
and prestudy metformin or acarbose usage (metformin only, acarbose only, or neither).  
For patients with prestudy treatment of metformin or acarbose (excluding those taken 
both) prior to Visit 1, their concomitant OAM will be discontinued at Visit 2.

Study material (study insulins, diary, and blood glucose monitoring supplies) will be 
dispensed or distributed at Visit 2 as indicated in the Study Schedule (Attachment 1).

Study personnel will train patients on insulin pen injector use and proper injection 
technique, SMBG levels (Section 7.2.3), and proper use of the study diary for recording 
AEs, BG values and corresponding insulin doses, and hypoglycemia recognition and 
management.

Patients also will be instructed about diet and physical activity and encouraged to 
maintain healthful habits of diet/activity throughout the study.

Study diaries from Visit 1 will be collected, and patients will be given a study diary at
Visit 2 and each subsequent investigator-site visit. The diaries will be source documents 
for the patients with records of BG levels, insulin doses, and episodes of hypoglycemia 
that occur throughout the study. The diaries will be collected at each subsequent 
investigator-site visit to transfer data, and will be used by the investigator to determine 
any dose adjustments needed for a patient. As indicated in the Study Schedule 
(Attachment 1), baseline 7-point SMBG profiles will also be reviewed and transferred to 
an electronic case report form (eCRF).

Patient safety will be assessed, including body weight, vital signs, use of concomitant 
medications, and any AEs or hypoglycemic episodes that occurred since Visit 1.

A blood sample will be drawn to determine the baseline HbA1c level. Blood samples 
will be drawn during Visit 2 for immunogenicity tests and biomarker detection (as 
warranted) (Section 10.4.2). Patients will be administered questionnaires (ITSQ) to 
assess PROs at baseline with regard to insulin treatment satisfaction.
7.2.2.2.1.1.
Instructions for Insulin Self-administration
Patients will administer their basal insulin QD dose subcutaneously (in the abdomen, upper arm, 
or thigh) at any time of the day approximately the same time every day from the following day 
after Visit 2. Patients should be trained by the site personnel on how to inject study insulin and 
to rotate site injections, following good practices for insulin administration before the first 
injections (Visit 2).

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Patients will be instructed to monitor themselves for any signs and symptoms of immediate or 
delayed hypersensitivity or allergic reactions following their injections. Patients will be 
instructed to contact emergency medical services in case of severe reactions.
7.2.2.3.
Telephone Visits
Between each investigator-site visit, patients will have a telephone visit with the investigator or 
designee at Visit 3, 5, 7, 9, and 10.
The main purpose of telephone visits is to check SMBG values and ensure that patients are 
administering the appropriate insulin dose. Because the study diaries are considered to be source 
documents, applicable data from telephone visits will be included and entered in the eCRF from 
the patient diary as part of the next office visit. 
During telephone visits, the investigator or designee will inquire and/or perform the following:

Blood glucose readings from the 4-point SMBG from 3 separate days (preferably most 
recent readings) (Attachment 1) during the period prior to each telephone visit will be 
noted (see Section 7.2.3 for further explanation). Note that these values will need to be 
entered into the eCRF at the next office visit, once those values have been correlated with 
the study diary values.

Hypoglycemic episodes since last visit.

The previous day’s insulin dose.

Any AEs experienced, including any injection-site skin reactions, and any changes in 
medications since last visit

Titration of insulin/insulin dose adjustment, if indicated based on above (see also
Attachment 5).

Reeducation of the patient as needed.

Preparation for next office visit.
Patients will retrieve information about BG values and hypoglycemic episodes from entries in 
their study diaries.  Telephone visits can also be conducted as informal office visits at the study 
site if more practical.  Although 5 official telephone visits have been planned for this study, 
investigators may contact patients as frequently as necessary to adjust the insulin dose to achieve 
BG targets.  Specified data from telephone visits (Attachment 1) will be recorded in the eCRFs 
from the diaries once they are collected from the patient at the next office visit.  
7.2.2.4.
Study Visits (Visit 3 to Visit 13 or Early Discontinuation)
Patients will come to the investigator site at 2-week intervals between Visit 2 and Visit 8.  From 
Visit 8 to Visit 13, patients will come to the clinic at 6-week intervals.  Visit 801 is a 4-week 
follow-up clinic visit (Attachment 1).
Between Visit 2 and Visit 4 and Visit 4 and Visit 6, Visit 6 and Visit 8, Visit 8 and Visit 11, 
there are telephone visits (Visits 3, 5, 7, 9 and Visit 10), which are described separately 
(Section 7.2.2.3).
The following activities will occur during Visits 3 to Visit 13 or Early Discontinuation (ED):

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
study diaries collected and reviewed for BG levels, episodes of hypoglycemia, injection-
site skin reactions, and insulin self-administration (Section 7.2.2.2.1.1)

distribute study diaries (not completed at ED)

dispense glucose-meter supplies as needed (not completed at ED)

dispense study drug/device at Visits 8, 11, and 12 (not completed at Visit 13 or at ED)

collection of blood sample for HbA1c assessment to determine efficacy of treatment 
values for each patient at Visits 8, 11, 12, and Visit 13 (or ED)

transfer data from study diaries into eCRF (including previous day’s insulin dose from 
last telephone visit)

collect study drug at Visits 8, 11, 12, and Visit 13 (or ED)

the previous day’s insulin dose

titration of insulin/adjust insulin dose as needed during visits (See Attachment 5; not 
completed at Visit 13 or at ED)

assessment of vital signs and body weight

blood sampling for chemistry and hematology at Visit 13 or ED

inquiries of AEs

inquire about use of concomitant medications

collection of blood sample to determine generation of anti-glargine antibodies at Visits 4,
8, 11, and Visit 13 (or ED)

collection of serum samples for biomarker analyses during Visit 8 and Visit 13

Health outcomes of the study will be measured as reflected in responses to ITSQ 
administered to the patients during Visit 13, (or ED), as indicated in the Study Schedule 
(Attachment 1).
In addition to the daily BG monitoring, patients will be required to complete the following,
which are reviewed and/or transferred to eCRF during Visit 3 to Visit 13 or ED:

7-point SMBG profiles (described in Section 7.2.3) on 2 separate days in the 1-week 
period prior to all investigator-site visits (or at ED) (preferably most recent readings). 

4-point SMBG values (once before each meal and at bedtime, recorded before and 
reviewed during the telephone visit period) will be recorded in the eCRF during the next 
investigator-site visit.
Study treatment will be discontinued at Visit 13 if not discontinued beforehand, after which an 
appropriate diabetes treatment regimen will be initiated by the investigator or the patient’s 
treating physician in accordance with local standards of care.  

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7.2.2.5.
Follow-up Visit (Visit 801)
Patients will come to the investigator site approximately 4 weeks after the last treatment visit, at
which time information will be discussed and recorded according to the Study Schedule
(Attachment 1).  Patients who discontinue early from the study will undergo all end-of-study 
procedures and complete Visit 801 as outlined in Attachment 1. These data will be collected and 
stored for future reference/analyses, if needed. 
7.2.3. Blood Glucose Monitoring Plan
Patients will be provided with glucometers and corresponding glucose test strips so they can 
obtain SMBG values. Blood glucose values will be utilized to guide insulin titration dosing, to 
determine hypoglycemia (as specified in the protocol), and to ensure that uniform data are 
collected.
Throughout the study, patients will be expected to check their fasting blood glucose (FBG) 
values daily to assess the need for basal insulin-dose adjustments (Attachment 5). They will also 
be instructed to record results of 4- and 7-point SMBG values in the study diaries, as described 
below, so they can be shared and help inform the investigators who will direct insulin-dose 
adjustments, as needed, to help patients achieve glycemic targets (HbA1c <7%, preprandial BG 
79 to 126 mg/dL [4.4 to 7.0 mmol/L]) while minimizing/avoiding hypoglycemia. For 
consistency, the first recorded BG value for each profile should be a premorning meal value 
followed by the other specified BG values throughout the day.

Patients will be instructed to complete 3 separate 4-point SMBG values (once before each 
meal and at bedtime) (preferably most recent readings) during the period prior to each 
telephone visits. Four-point SMBG values will be reported during telephone visits and 
will be recorded at the subsequent office visit or Visit 801.

Patients will be instructed to complete 2 separate 7-point SMBG profiles in the 1-week 
period prior to each office visit from Visit 2 to Visit 13 (or at ED) (preferably most recent 
readings). At Visit 801, only 4-point SMBG is required to be collected.  The SMBG 
profiles will consist of:
o
before the morning meal, midday meal, and evening meal; 2-hour postprandial 
measurements for the morning, midday meal, at bedtime and 3 am.
Throughout the study, patients will be expected to routinely check their fasting, premeal, and 
bedtime BG values daily to help assess the need for dose adjustments and to guide dosing of the 
mealtime/fast-acting insulin lispro (Attachment 5). Patients may be requested by investigators 
(as they deem necessary) to perform more intensive self-monitoring, if clinically indicated. Both 
4-point and 7-point SMBG values will be recorded in the diaries and transcribed into the eCRF at 
the office visit (Attachment 1 and Attachment 5).
Missing values in SMBG profiles will not be considered protocol deviations unless, in the 
opinion of the investigator, they reflect noncompliance with the protocol.

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8. Study Population
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
8.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria:
[1]
Have T1DM based on the disease diagnostic criteria (World Health Organization 
[WHO] Classification) (Attachment 6).
[2]
If female patients, are women of child-bearing potential who test negative for 
pregnancy at the time of enrollment based on a serum pregnancy test and agree 
to use a reliable method of birth control during the study.
[3]
Aged ≥18 years.
[4]
Have duration of T1DM ≥1 year.
[5]
Have HbA1c ≤11 %.
[6]
Have been administered with basal-bolus insulins or pre-mixed insulins for at 
least 90 days prior to Visit 1 (see also Exclusion Criterion [33]):

for those patients with basal-bolus therapies, bolus insulin includes mealtime 
injections of human regular insulin, or insulin analog lispro, aspart, or 
glulisine; basal insulin can be QD injection of Lantus®, either QD or BID 
injection of NPH or detemir. 

for those patients with premixed insulin, insulin regimens with any 
NPH/NPL[neutral protamine lispro] (basal) and bolus combination are 
administered at least BID.
[7]
Have a body mass index (BMI) ≤35 kg/m2.
[8]
As determined by the investigator, are capable and willing to do the following:
o
perform SMBG measurements
o
complete patient diaries as instructed for this protocol
o
use the insulin injection device(s) according to the instructions provided
o
be receptive to diabetes education
o
comply with the required study insulins and study visits.
[9]
Have given written informed consent to participate in this study in accordance 
with local regulations.

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8.2.
Exclusion Criteria
Patients will be excluded from the study if they meet any of the following criteria:
[10] Exposure to an insulin glargine other than Lantus® within previous 30 days.
[11] Excessive insulin resistance at entry into the study (total daily insulin dose 
[TDID] ≥1.5 units [U]/kg).
[12] Have had more than one episode of severe hypoglycemia, as defined in 
Section 9.10 of the protocol, within 6 months prior to entry into the study.
[13] Have had more than one episode of diabetic ketoacidosis or emergency room
visits for uncontrolled diabetes leading to hospitalization within 6 months prior 
to entry into the study.
[14] Have known hypersensitivity or allergy to any of the study insulins (Lantus® or 
insulin lispro) or to excipients of the study insulins.
[15] Are pregnant, intend to become pregnant during the course of the study, or are 
sexually active women of childbearing potential not actively practicing birth 
control by a method determined by the investigator to be medically acceptable.
[16] Women who are breastfeeding.
[17] Have taken any oral antihyperglycemic medications (OAMs) within 3 months 
prior to Visit 1.  Except for those patients with metformin or acarbose at a stable 
dose for more than 90 days prior to Visit 1 (excluding those taken both), their 
concomitant OAM will be discontinued at randomization before the study 
treatment.
[18] Are currently taking traditional medicine (herbal medicine or patent medicine) 
with known/specified content of anti-hyperglycemic effects within 3 months 
before Visit 1.
[19] Have received treatment within the last 30 days with a drug that has not received 
regulatory approval for any indication at the time of study entry.
[20] Have received treatment with pramlintide or with continuous subcutaneous 
insulin infusion within 3 months prior to Visit 1.
[21] Have congestive heart failure Class III and IV.
[22] Have obvious clinical signs or symptoms, or laboratory evidence, of liver 
disease (alanine aminotransferase [ALT] or aspartate aminotransferase [AST] 
greater than 2.5 times the upper limit of the reference range, as defined by the 
central laboratory); or albumin value remarkably above or below the normal 
reference range, as defined by the central laboratory.  
[23] Have any active cancer, or a personal history of cancer within the previous 
5 years (except basal-cell cancer or carcinoma in situ).
[24] Have a history or diagnosis of human immunodeficiency virus (HIV) infection.

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[25] Have presence of clinically significant gastrointestinal disease (for example, 
clinically active gastroparesis associated with wide glucose fluctuations).
[26] Have a history of renal transplantation, or are currently receiving renal dialysis, 
or have creatinine greater than 2.0 mg/dL (177 mol/L).
[27] Have had a blood transfusion or severe blood loss within 3 months prior to 
Visit 1, or have known hemoglobinopathy, hemolytic anemia, or sickle cell 
anemia.
[28] Are receiving chronic (lasting longer than 14 consecutive days) systemic 
glucocorticoid therapy at pharmacological doses (excluding topical, intra-
articular, intraocular, or inhaled preparations, and physiologic replacement doses 
for Addison’s disease or adrenal deficiency) or have received such therapy 
within the 4 weeks immediately preceding Visit 1.
[29] Have an irregular sleep/wake cycle (for example, patients who sleep during the 
day and work during the night).
[30] Have any other condition (including known drug or alcohol abuse or psychiatric 
disorder) that precludes the patient from following and completing the protocol.
[31] Are investigator site personnel directly affiliated with this study and/or their 
immediate families.  Immediate family is defined as a spouse, parent, child, or 
sibling, whether biological or legally adopted.
[32] Are Lilly and Boehringer Ingelheim employees.
[33] Have previously completed or withdrawn from this study after having signed 
the ICF.
[34] Are currently enrolled in a clinical trial involving an investigational product or 
nonapproved use of a drug or device (other than the investigational product used 
in this study), or concurrently enrolled in any other type of medical research 
judged not to be scientifically or medically compatible with this study.
[35] Are using BID insulin glargine within 6 months (180 days) prior to Visit 1.
[36] Have evidence of a significant, active, uncontrolled endocrine or autoimmune 
abnormality, as judged by the investigator.
8.2.1. Rationale for Exclusion of Certain Study Candidates
Exclusion criterion [10] excludes patients because prior exposure to biosimilar insulin glargine 
may confound the interpretation of the study endpoints if anti-insulin glargine antibodies are 
present at baseline.
Exclusion criterion [11] excludes patients who may not have a physiological response to the 
study treatment, to meet the study objectives.

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Exclusion criteria [12] and [13] address the potential difficulty of distinguishing if severe 
hypoglycemia or diabetic ketoacidosis is related to study drugs or poor glycemic control in 
patients with recurring episodes.
Exclusion criteria [15] and [16] assure the safety of unborn and newborn children.
Exclusion criteria [17], [19], and [20] exclude medications that may cause HbA1c lowering not 
attributable to the regimens being studied, which could lead to misinterpretation of the results.  
Additionally, exclusion criterion [17] also precludes patients with unclear diagnosis of T1DM.
Exclusion criterion [18] excludes traditional medicine with anti-hyperglycemic effects due to 
safety concerns and leading to misinterpretation of the results.
Exclusion criteria [14] and [21 to 27] represent clinical situations that may prevent patients from 
completing the protocol, influence the effect or safety of study regimens, or are serious 
conditions that pose a risk for morbidity and mortality. Exclusion criterion [23] allows 
investigators to exclude patients in whom there may be a concern for cancer occurrence or 
recurrence consistent with the ADA-American Cancer Society (ACS) consensus report’s 
recommendation. According to this recommendation, patients with a very high risk of cancer 
occurrence (or for recurrence of specific cancer types) may require more careful consideration in 
choosing between available diabetes therapies (Giovannucci et al. 2010).
Exclusion criterion [28] relates to the negative effect of steroid therapy on the management of 
diabetes.
Exclusion criterion [29] avoids a situation where patients would need highly individualized
insulin regimens compared to the planned regimen for this study. Their schedule could also 
confound the results of the 7-point SMBG profiles.
Exclusion criterion [30] permits investigators to exclude patients who meet all other inclusion 
and exclusion criteria, but may not be appropriate study candidates.
Exclusion criteria [31] and [32] reduce potential bias due to conflict of interest.
Exclusion criterion [33] eliminates the possibility of duplicate participation by a patient.
Exclusion criterion [34] prevents a situation in which potential positive or negative outcomes 
may not be clearly attributable to the regimens in the study.
Exclusion criterion [35] excludes patients recently administrating twice daily insulin glargine, as 
the study design involves once-daily treatment with insulin glargine or LY2963016. Switching 
from twice- to once-daily insulin glargine dosing might not be beneficial to the patient given no 
guidance provided on twice-daily insulin glargine use in Lantus® label.
Uncontrolled endocrine or autoimmune restriction [36] excludes the clinical situation that may 
influence the efficacy or safety of study regimens. 

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8.3.
Discontinuations
8.3.1. Discontinuation of Inadvertently Enrolled Patients
The criteria for enrollment must be followed explicitly.  
If the investigator site identifies a patient who did not meet enrollment criteria and who was 
inadvertently enrolled, the sponsor must be notified. If the sponsor identifies a patient who did 
not meet enrollment criteria and who was inadvertently enrolled, the investigator site will be 
notified. A discussion must occur between the sponsor clinical research physician (CRP) and the 
investigator to determine whether the patient may continue in the study, with or without 
investigational product. Inadvertently enrolled patients may be maintained in the study and on 
investigational product when the Lilly CRP agrees with the investigator that it is medically 
appropriate for that patient. The patient may not continue in the study with or without 
investigational product if the Lilly CRP does not agree with the investigator’s determination it is 
medically appropriate for the subject to continue. The investigator must obtain documented 
approval from the Lilly CRP to allow the inadvertently enrolled patient to continue in the study 
with or without investigational product. 
8.3.2. Discontinuation of Investigational Product
Discontinuation of the investigational product for abnormal liver tests should be considered by 
the investigator when a study patient meets one of the following conditions after consultation 
with the Lilly designated medical monitor: 

ALT or AST >8X upper limit of normal (ULN)

ALT or AST >5X ULN for more than 2 weeks 

ALT or AST >3X ULN and total bilirubin level >2X ULN or prothrombin time >1.5X 
ULN

ALT or AST >3X ULN with the appearance of fatigue, nausea, vomiting, right upper-
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%).
Patients who discontinue the investigational product and/or study early will have ED procedures 
performed as shown in the Study Schedule (Attachment 1).
8.3.3. Patient Discontinuation from the Study
Patients will be discontinued from the study in the following circumstances:

If any of Exclusion Criteria [14 to 21] and [23 to 34] is observed or develops after 
study entry or enrollment.  In this case, the patient will be discontinued from the 
study at the next visit, or sooner if the patient safety is the rationale for the 
exclusion criterion.

If the patient is off study medication for more than 10 consecutive days’ study,
he/she will be discontinued from the study.  

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
If the investigator determines that the patient is noncompliant and should be 
discontinued from the study.  Patients who discontinue study drug early should 
have ED procedures performed, as shown in the Study Schedule (Attachment 1). 
Patients who discontinue after randomization will not be replaced.

Enrollment in any other clinical trial involving an investigational product or enrollment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study

Investigator Decision
o
the investigator decides that the patient should be discontinued from the study
o
if the patient, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent

Subject Decision 
o
the patient or the patient’s designee, for example, parents or legal guardian
requests to be withdrawn from the study

Sponsor Decision
o
Lilly or its designee stops the study or stops the patient’s participation in the study 
for medical, safety, regulatory, or other reasons consistent with applicable laws, 
regulations, and GCP

Adverse Event 
o
If the investigator decides that the patient should be withdrawn because of an 
SAE or a clinically significant laboratory value, the investigational product is to 
be discontinued and appropriate measures are to be taken.  Lilly or its designee is 
to be alerted immediately.  Refer to Safety Evaluations Section 10.3.
Randomized patients who discontinue the study early will have early discontinuation procedures 
performed as shown in the Study Schedule (Attachment 1).
8.3.4. Patients Lost to Follow-Up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.
8.3.5. Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the 
ethical review board (ERB) of the study site judges it necessary for medical, safety, regulatory, 
or other reasons consistent with applicable laws, regulations, and GCP.

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8.3.6. Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.

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9. Treatment
9.1.
Treatments Administered
All treatments will be administered in accordance with the product labeling in China, when 
applicable. This study involves a comparison of LY2963016 administered QD subcutaneously
with Lantus® QD along with thrice premeal insulin lispro to patients with T1DM. 
Study treatment will start on the second day of randomization.  
At randomization, patients who were administered with basal-bolus therapies before enrollment
with QD basal insulin and mealtime insulins will receive instruction to start new regimen with 
either QD LY2963016 or insulin glargine as basal insulin at the same doses next day. For those 
patients with BID prestudy basal insulin as part of basal-bolus regimen, the total daily prestudy 
insulin dose will be reduced by 20% therefore, the study basal insulin dose will be 80% of the 
prestudy basal insulin dose. Insulin lispro will be administered with meals at the same doses as 
the patient’s prestudy mealtime insulin dose while avoiding hypoglycemia, as determined by 
unit-to-unit conversion.
In the patients who were administered with premixed insulin will receive instruction to start new 
regimen on the next day. The total daily dosage of new regimen will be the average for the sum 
of all insulin doses taken in the 3 days prior to randomization. The total daily dosage will then 
be split between basal and bolus insulin doses at the discretion of the investigator. For the 
treatment regimen, the initial basal insulin dose should be approximately 40% to 60% of the total 
daily dose. Then the initial bolus insulin dose (insulin lispro, 60% to 40% of the total daily dose) 
will be divided into 3 equal doses before 3 meals. The doses of initial bolus insulin can be 
adjusted at the discretion of investigators based on consideration of individual patient’s 
diet/physical activity/or insulin needs as reflected by SMBG pattern. This conversion is 
consistent in the decrease of insulin dose with aforementioned scenario when switching from 
BID basal to once-daily insulin glargine, but relatively conservative. Physician could opt to use 
a once-daily basal insulin dose that is 20% less than the total basal insulin dose for the previous 
premix regimen at their discretion after evaluation of individual patient’s clinical conditions.
The investigator or his/her designee is responsible for the following:

explaining the correct use of the investigational agent(s) to the patient

verifying that instructions are followed properly

maintaining accurate records of investigational product dispensing and collection

returning all unused medication to Lilly or its designee at the end of the study
In some cases, sites may destroy the material if, during the investigator site selection, the 
evaluator has verified and documented that the site has the appropriate facilities and written 
procedures to dispose of clinical trial materials.
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.

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9.2.
Materials and Supplies
Clinical trial materials will be labeled and should be handled and stored according to the
respective country’s regulatory requirements.
The reference therapy (Lantus®) used in this clinical trial is approved for use in each respective
country.
At randomization, patients will be provided with insulin lispro as a prefilled pen injector to be 
used as premeal insulin. Study insulins (LY2963016, Lantus® and Lispro®) will be supplied by 
Lilly or its representative, in accordance with current good manufacturing practices (GMP) and 
will be supplied with lot numbers.
Patients randomized to LY2963016 will be provided with LY2963016 as a 100 U/mL solution 
for injection in a prefilled pen injector. Patients randomized to Lantus® will be provided with 
Lantus® as a 100 U/mL solution for injection in prefilled pen injector. In addition, a
commercially available glucometer will be provided with the necessary supplies.
9.3.
Method of Assignment to Treatment
At Visit 1, patients will be assigned a patient number, and at Visit 2, those who are eligible to 
participate in the study will be assigned by stratified randomization to 1 of the 2 treatment arms,
in a ratio of 1:1, via random assignment using the interactive web response system.  To achieve 
between-treatment group comparability, patients will be stratified by screening HbA1c stratum 
(<8.5%, ≥8.5%), pre-study treatment (Lantus®-bolus, other basal-bolus, premixed insulin), and 
pre-study metformin or acarbose usage (metformin only, acarbose only, or neither).
9.4.
Rationale for Selection of Doses in the Study
As supported by preclinical data demonstrating similar glucodynamics between Lantus® and 
LY2963016 (data on file), these insulins will be dosed in a similar fashion as described in the 
protocol (Section 9.5). 
For patients whose glycemic control is within desired levels on prestudy insulins, once they are 
switched from their prestudy insulins to LY2963016 or Lantus® and insulin lispro, the 
investigators and patients should continue to manage the patient’s insulin therapy to effectively 
maintain glycemic goals (HbA1c <7%, preprandial capillary BGs 79 to 126 mg/dL [4.4 to 
7.0 mmol/L], avoiding hypoglycemia). However, for patients with inadequate glycemic control, 
further insulin titration should be done (in conjunction with patient education, if needed) to 
improve glycemic control, as guided by general principles of intensive/flexible insulin therapy 
described below and in Attachment 5.
At randomization, in the patients who were administered with basal-bolus therapies before 
enrollment, QD LY2963016 will be started at the same doses as the QD prestudy basal insulin. 
For those patients with BID prestudy basal insulin as part of basal bolus regimen, the total daily 
prestudy insulin dose will be reduced by 20% at randomization to LY2963016 or insulin glargine, 
therefore, the study basal insulin dose will be 80% of the prestudy basal insulin dose. Insulin 
lispro will be administered with meals at the same doses as the patient’s prestudy mealtime 

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insulin dose while avoiding hypoglycemia, as determined by unit-to-unit conversion. Based on 
the patient’s prestudy mealtime insulin regimen relative to his/her lifestyle, the investigator could 
translate the patient’s previous mealtime insulin regimen so that the patient’s prestudy mealtime 
insulin is replaced with a similar dose of insulin lispro to be used during the study. During the 
course of the study, the patient’s mealtime insulin doses will be adjusted and optimized by the 
investigator. Study participants will administer mealtime insulin doses before meals to provide 
insulin coverage for the meal, as well as a correction dose if the premeal BG reading is above 
target.
Thus, a patient consuming 3 main meals will have a TDID consisting of the following:  
TDID = basal insulin dose + all mealtime insulin doses (including corrections). 
General guidance in determining how doses and any necessary dose adjustments will be made 
during the study is described in Attachment 5.
In the patients who were administered with premixed insulin, the total daily dosage at 
randomization will be the average for the sum of all insulin doses taken in the 3 days prior to 
randomization.  The TDID will then be split between basal and bolus insulin doses at the 
discretion of the investigator.  While adjusting the basal and premeal insulins, investigators may 
be cognizant that balancing the amount of basal and premeal insulin could help attain tighter 
glycemic control while minimizing hypoglycemia.  In general, the TDID for multiple daily 
insulin injections is distributed to approximately 50% basal and 50% premeal or mealtime 
insulin (Mecklenburg 1998; Skyler 1998).  However, this ratio may vary according to clinical 
practice.  The initial basal insulin dose is recommended to be approximately 40% to 60% of the 
total daily dose.  Then the initial bolus insulin dose (insulin lispro, 60% to 40% of the total daily 
dose) will be divided into 3 equal doses before 3 meals.  The doses of initial bolus insulin can be 
adjusted at the discretion of investigators based on consideration of individual patient’s 
diet/physical activity/or insulin needs as reflected by SMBG pattern.
The dose of LY2963016 or Lantus® will be titrated primarily based on FBG values, with 
algorithm-based treat-to-target titration described in Attachment 5. The dosing algorithm can be 
individualized at the discretion of the investigators due to medical reasons. To ensure that the 
HbA1c by Week 24 reflects glycemic control on the patient’s insulin regimen, most of the 
adjustments in the basal and bolus doses should be completed during the first 6 weeks of the 
Titration Period (or, for patients who need more intensification to better achieve glycemic 
targets, up to 12 weeks).  During the Maintenance Period, it is expected that adjustments to 
insulin dose would be for safety such as hypoglycemia or unacceptable hyperglycemia.
9.5.
Selection and Timing of Doses
All treatments will be administered according to the country-specific product labeling where 
applicable.  Insulin lispro should be administered subcutaneously within 15 minutes before meals
or immediately after the meal.  LY2963016 and Lantus® are to be administered QD by the 
patients at bedtime or anytime of the day (but approximately the same time of the day) every day
from the following day after Visit 2.  Investigators are advised to take into account patients’ 

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mealtimes and timing of the BG readings in making adjustment decisions on insulin dose or in 
requesting additional BG monitoring.  For example, if a patient’s evening meal is late and 
bedtime is only an hour later, the investigator should exercise caution in making insulin-dose 
adjustments to attain glycemic targets and to prevent nocturnal hypoglycemia.
The investigator will guide the patient in adjusting the insulin doses based on the SMBG profiles 
during the study to achieve preprandial BG targets of 79 to 126 mg/dL (4.4 to 7.0 mmol/L) while 
minimizing hypoglycemia.
9.5.1. Special Treatment Considerations
There is no plan for rescue therapy in this study. 
9.6.
Continued Access to Investigational Product
The sponsor will not provide patients with ongoing supplies of study medication after they have 
completed the study treatment period because LY2963016 is experimental, while Lantus®, 
insulin lispro, and the prestudy basal-bolus insulin therapy insulins are readily available.
9.7.
Blinding
This is an open-label study where investigators, patients, study-site personnel, and study 
monitors are aware of the treatment assignment. To minimize bias, an integrated summary of 
data will not be provided by the actual treatment group to the study team prior to the final 
database lock.  Unblinding of the patient study drug treatment assignment to the study team may 
occur in cases when an individual patient’s treatment assignment may need to be revealed for 
evaluation of the safety information or during review of SAEs or individual patient data.
9.8.
Concomitant Therapy
As described in Exclusion Criteria [10] and [17 to 20] (Section 8.2), patients should not take any 
other BG-lowering medications that are not allowed in the study.
Patients will be allowed to use any other concomitant medications they require during the study
except systemic glucocorticoid therapy longer than 14 consecutive days’ duration (with the 
exception of topical, intra-articular, intraocular, and inhaled preparations). Patients who receive 
excluded concomitant therapy will be discontinued from the study.
In emergencies, it may be necessary for patients to be treated with a nonstudy insulin. This will 
be allowed for up to 14 consecutive days. If such a situation occurs more than once during the 
study, or lasts longer than 14 consecutive days, a decision to keep the patient in the study should 
be made only after consultation between the investigator and the Lilly CRP or clinical research 
scientist. The decision should be documented by a note to the investigator’s file.
9.9.
Treatment Compliance
The investigator will assess the compliance of the patient at each visit, based on a review of the 
patient’s glycemic control, adherence to the visit and treatment schedule, completion of patient
diaries, and any other parameters the investigator deems necessary.  

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Patients who are deemed noncompliant will receive additional diabetes education and training, as 
required, and the importance of compliance with the protocol will be reinforced. Patients who, 
in the opinion of the investigator, are deemed consistently noncompliant may be discontinued 
from the study. Specific study data will not be collected for analysis of treatment compliance 
and, therefore, will not be assessed or reported.
9.10. Hypoglycemic Episodes
Patients should check their BG level whenever possible if they have symptoms suggestive of 
hypoglycemia. For each hypoglycemic episode, patients should record their BG level, associated 
symptoms, and treatment in the study diaries provided by the sponsor via the investigator. 
When instructing patients on recognition and management of hypoglycemic episodes, a
hypoglycemic episode is defined as any time a patient feels that he/she is experiencing a sign or 
symptom that is associated with hypoglycemia or has a BG level ≤70 mg/dL (≤3.9 mmol/L), 
even if it was not associated with signs, symptoms, or treatment consistent with current 
guidelines (ADA 2005).
Note: Episodes of severe hypoglycemia should also be recorded as SAEs (Section 10.3.1.1).
Severe hypoglycemia:  An event requiring assistance of another person to actively administer 
carbohydrate, glucagon, or other resuscitative actions. During these episodes, the subject has an 
altered mental status and cannot assist in his/her care, are semiconscious or unconscious, or 
experience coma with or without seizures, and may require parenteral therapy. Blood glucose 
measurements may not be available during such an event, but neurological recovery attributable 
to the restoration of BG concentration to normal is considered sufficient evidence that the event 
was induced by a low BG concentration (BG ≤70 mg/dL [3.9 mmol/L]).
Nocturnal hypoglycemia:  Any hypoglycemic event that occurs between bedtime and waking. 
Documented Hypoglycemia:

Documented symptomatic hypoglycemia: An event during which typical
symptoms of hypoglycemia are accompanied by plasma glucose (PG) ≤70
mg/dL (≤3.9 mmol/L).

Documented asymptomatic hypoglycemia: An event not accompanied by 
typical symptoms of hypoglycemia but with PG ≤70 mg/dL (≤3.9 mmol/L).

Documented unspecified hypoglycemia: An event during which PG ≤70
mg/dL (≤3.9 mmol/L) but no information relative to symptoms of 
hypoglycemia was recorded.
Probable symptomatic hypoglycemia: An event during which symptoms typical of
hypoglycemia are not accompanied by a plasma glucose determination but that was presumably
caused by a plasma glucose concentration ≤70 mg/dL (≤3.9 mmol/L).

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Relative hypoglycemia (also referred to as Pseudohypoglycemia): An event during which the 
person with diabetes reports any of the typical symptoms of hypoglycemia with a measured 
plasma glucose concentration >70 mg/dL (>3.9 mmol/L) but approaching that level.
Overall hypoglycemia: This optional category combines all cases of hypoglycemia
(documented hypoglycemia and probable symptomatic hypoglycemia, including severe
hypoglycemia) excluding the events of relative hypoglycemia.  Nocturnal and severe
hypoglycemia are special cases of documented or probable hypoglycemia. If an event of
hypoglycemia falls into multiple subcategories, that event should only be counted once in this
category.

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10.
Efficacy, Health Outcome/Quality of Life Measures, 
Safety Evaluations, Sample Collection and Testing, and 
Appropriateness of Measurements
Study procedures and their timing (including tolerance limits for timing) are summarized in the 
Study Schedule (Attachment 1).
10.1. Efficacy Measures
10.1.1. Primary Efficacy Measure
The primary efficacy measure is the change in HbA1c from baseline to 24 weeks.
10.1.2. Secondary Efficacy Measures
The following secondary efficacy measures will be considered for the comparison of other 
aspects of overall glycemic control:

change in HbA1c from baseline to 6, 12, and 18 weeks or LOCF

percentage of patients with HbA1c <7%, and the percentage of patients with 
HbA1c ≤6.5%

7-point SMBG measurements as listed in the Study Schedule (Attachment 1)
o
premeal for each meal
o
postmeal for breakfast and lunch
o
bedtime
o
3 am

intrapatient variability as measured by the standard deviation of the 7-point SMBG

total insulin, basal insulin, and mealtime insulin lispro doses in U/day and U/kg/day

weight change

patient-reported outcomes as reflected in responses to ITSQ
10.2. Health Outcome/Quality of Life Measures
Self-reported patient questionnaires will be used to compare the health outcomes for the 
2 insulins. This will be reflected in responses to ITSQ administered at baseline (Visit 2) and 
24 weeks (Visit 13) or ED if a patient received at least one dose of study insulin.
The ITSQ is a validated instrument containing 22 items that assesses treatment satisfaction for 
patients with diabetes on insulin (Anderson et al. 2004). Items are measured on a 7-point scale, 
where lower scores reflect better outcomes. In addition to an overall score, the items that make 
up the 5 domains of satisfaction are categorized as:

Inconvenience of Regimen (5 items)

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
Lifestyle Flexibility (3 items)

Glycemic Control (3 items)

Hypoglycemic Control (5 items)

Satisfaction with the Insulin Delivery Device (6 items)
All individual patient-domain scores will be calculated as the sum of the items in the domain. If 
an item score is missing for a patient and less than 20% of the items within the domain are 
missing for that patient, then the mean of all other patients’ scores for that item will be imputed 
for the item. Otherwise, the domain score will be missing for the patient.
10.3. Safety Evaluations
Investigators are responsible for monitoring the safety of patients 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 patient.
The investigator is responsible for the appropriate medical care of patients during the study.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious (SAEs), considered related to the study treatment or the study, or that caused 
the patient to discontinue before completing the study. The patient should be followed until the 
event is resolved or explained.  Frequency of follow-up evaluation is left to the discretion of the 
investigator.
10.3.1. Adverse Events
Lilly has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent.
Lack of drug effect is not an AE in clinical studies because the purpose of the clinical study is to 
establish drug effect.
Study site personnel will record the occurrence and nature of each patient’s preexisting 
conditions, including clinically significant signs and symptoms of the disease under treatment in 
the study.
After the ICF is signed, study-site personnel will record any change in the condition(s) and the 
occurrence and nature of any AEs. All AEs related to protocol procedures are reported to Lilly 
or designee.
In addition, all AEs, occurring after the patient receives the first dose of investigational product 
must be reported to Lilly or its designee via eCRF.
Any clinically significant findings from ECGs, labs, vital-sign measurements, or other 
procedures that result in a diagnosis should be reported to Lilly or its designee.

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Investigators will be instructed to report to Lilly or its designee their assessment of the potential 
relatedness of each AE to protocol procedure, studied disease state, investigational product, 
and/or drug delivery system via eCRF.
The investigator decides whether he or she interprets the observed AEs as either related to 
disease, to the study medication, study procedure, or other concomitant treatment or pathologies.  
To assess the relationship of the AE to the investigational product, the following terminologies 
are defined:

Related:  a direct cause and effect relationship between the study treatment and 
the AE is likely

Unrelated:  without question, the AE is definitely not associated with the study 
treatment
If a patient’s dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to Lilly or its designee via eCRF the circumstances and data 
leading to any such dosage reduction or discontinuation of treatment.
10.3.1.1. Serious Adverse Events
Serious adverse event collection begins after the patient has signed informed consent and 
received investigational product. If a patient experiences an SAE after signing informed consent, 
but prior to receiving investigational product, the event will NOT be reported as serious unless 
the investigator feels the event may have been caused by a protocol procedure.
Planned surgeries should not be reported as SAEs unless the underlying medical condition has 
worsened during the course of the study.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method. If alerts issued via telephone, they are to 
be immediately followed with official notification on study-specific SAE forms. This 24-hour 
notification requirement refers to the initial SAE information and all follow-up SAE information.
An SAE is any AE from this study that results in one of the following outcomes:

death 

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

considered significant by the investigator for any other reason.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse drug events when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.

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For the purposes of this protocol, all episodes of severe hypoglycemia will be considered 
an SAE. If the investigator believes that a reported SAE of hypoglycemia does not fit any of the 
specific criteria outlined above (that is, death, initial or prolonged inpatient hospitalization, a life-
threatening experience, persistent or significant disability/ incapacity, or congenital 
anomaly/birth defect), then the investigator should select “Other” as the outcome (that is, 
considered significant by the investigator for a reason other than those specified). 
When a condition related to LY2963016 or Lantus® necessitates medical or surgical intervention 
to preclude either permanent impairment of a body function or permanent damage to a body 
structure, the serious outcome of “required intervention” will be assigned.
Serious adverse events occurring up to and including the patient’s last visit will be collected, 
regardless of the investigator’s opinion of causation, in the clinical data collection database and 
the pharmacovigilance system at the sponsor.
Pregnancy (during 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.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued and/or completed the study (the patient 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.
Information on SAEs expected in the study population independent of drug exposure and that 
will be assessed by the sponsor in aggregate periodically during the course of the trial may be 
found in the IB.
10.3.1.1.1.Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are not listed in the IB 
and that the investigator identifies as related to the investigational product or procedure. Lilly 
has procedures for the recording and expedited reporting of SUSARs that are consistent with 
global regulatory regulations and detailed guidances and will be followed.
10.3.2. Other Safety Measures
Hypoglycemic events, vital signs, and weight will be collected as indicated in the Study 
Schedule (Attachment 1). Twelve-lead ECGs will be collected locally according to the Study 
Schedule (Attachment 1).
The ECG will be interpreted by a qualified physician (the investigator or qualified designee) at 
the site as soon after the time of ECG collection as possible, and ideally while the patient is still 
present, for immediate patient management and to determine whether the patient meets entry 
criteria. 

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10.3.3. Safety Monitoring
The Lilly CRP will monitor safety data throughout the course of the study.
Lilly will review SAEs within time frames mandated by company procedures. The Lilly CRP
will, as is appropriate, consult with the functionally independent GPS therapeutic area physician 
or clinical scientist, and periodically review:

trends in safety data

laboratory analytes 

adverse events
If a study patient experiences elevated ALT or AST ≥3X ULN or elevated total bilirubin ≥2X
ULN, clinical and laboratory monitoring should be initiated by the investigator. Details for 
hepatic monitoring depend upon the severity and persistence of observed laboratory test 
abnormalities. To ensure patient safety and comply with regulatory guidance, the investigator is 
to consult with the Lilly designated medical monitor regarding collection of specific 
recommended clinical information and follow-up laboratory tests. See Attachment 2 and
Attachment 4. 
10.3.4. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and to 
facilitate process and product improvements.
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. Sample Collection and Testing
Attachment 1 lists the schedule for sample collections in this study.
Attachment 2 lists the specific laboratory tests that will be performed for this study.  
Attachment 3 provides a summary of the estimated maximum number and volume of samples, 
for all sampling, during the study.
10.4.1. Samples for Study Qualification and Health Monitoring
Blood samples will be collected at the times specified in the Study Schedule (Attachment 1). 
Standard laboratory tests, including chemistry and hematology, will be performed. The clinical 
laboratory tests including a serum pregnancy test will be analyzed by a central laboratory. A 

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urine pregnancy test may be repeated locally for any visits if considered necessary by the 
investigators and/or in compliance with local regulations.  
Investigators must document their review of each laboratory safety report.
Samples collected for specified laboratory tests will be destroyed within 60 days of receipt of 
confirmed test results. Tests are run and confirmed promptly whenever scientifically 
appropriate.  When scientific circumstances warrant, however, it is acceptable to retain samples 
to batch the tests run, or to retain the samples until the end of the study to confirm that the results 
are valid.  Certain samples may be retained for a longer period, if necessary, to comply with 
applicable laws, regulations, or laboratory certification standards.
10.4.2. Samples for Biomarker Research
10.4.2.1. Nonpharmacogenetic Biomarker Evaluations
This study will employ sample collection.  Samples will be collected for nonpharmacogenetic 
biomarker investigation where local regulations allow.  Fasting serum samples will be collected 
at the times specified in the Study Schedule (Attachment 1).
Fasting samples being collected will be used to measure C-peptide to support trial interpretation. 
Samples will be coded with the patient number and may be stored for a maximum of 1 year 
following last patient visit for the trial at a facility selected by the Sponsor to enable further 
analysis of responses to the investigational products.  The duration allows the Sponsor to respond 
to regulatory requests related to the investigational products.
10.4.3. Samples for Immunogenicity Research
Blood samples for immunogenicity testing will be collected to determine antibody production 
against LY2963016 or Lantus®. Immunogenicity will be assessed by a validated assay designed 
to detect antidrug antibodies in the presence of the investigational product. Antibodies may be 
further characterized and/or evaluated for their ability to neutralize the activity of the 
LY2963016 or Lantus®.
Samples may be stored for a maximum of 1 year following last patient visit for the trial at a 
facility selected by the sponsor to enable further analysis of immune responses to LY2963016 or 
Lantus®. The duration allows the sponsor to respond to regulatory requests related to the 
investigational product.
10.5. Appropriateness of Measurements
All efficacy and safety assessments included in this study are generally regarded as reliable and 
accurate with respect to diabetes mellitus.

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11.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

Provide instructional material to the study sites, as appropriate.

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 use standard computer edits to detect errors in data 
collection.

Conduct a quality review of the database.
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site. The study may be audited by Lilly or its 
representatives and/or regulatory agencies at any time. Investigators will be given notice before 
an audit occurs.
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the investigator will keep records of laboratory tests, clinical notes, and patient medical 
records in the patient files as original source documents for the study. If requested, the 
investigator will provide the sponsor, applicable regulatory agencies, and applicable ERBs with 
direct access to original source documents.
11.1. Data Capture System
An electronic data capture system will be used in this study. The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
Case report form data will be encoded and stored in a clinical trial database. Data managed by a 
central vendor, such as laboratory test data, will be stored electronically in the central vendor’s 
database system. Data will subsequently be transferred from the central vendor to the Lilly 
generic labs system.
Any data for which the paper documentation provided by the patient will serve as the source 
document will be identified and documented by each site in that site’s study file. Paper 
documentation provided by the patient may include, for example, a paper diary to collect PRO 
measures (for example, a rating scale), a daily dosing schedule, or an event diary.
Data from study-specific product-complaint forms submitted to Lilly will be encoded and stored 
in the global product-complaint management system.

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12.
Sample Size and Statistical Methods
12.1. Determination of Sample Size
Based on the primary objective, to show noninferiority of LY2963016 to Lantus® at the 0.40% 
noninferiority margin (NIM), 109 completers per arm (218 total) are needed at 24 weeks. This 
calculation assumes no treatment difference in HbA1c between LY2963016 and Lantus®, a 
common standard deviation (SD) of 1.05% for change from baseline in HbA1c, a two-sided 
significance level of 0.05, and over 80% power. Assuming a 15% dropout rate at 24 weeks, the 
required number of randomized patients is 129 per arm (258 total).  
Blinded sample-size reestimation may be performed when approximately 40% of the subjects 
have been enrolled in the study and finished 24-weeks of treatment, or about 6 months prior to 
the completion of enrollment, depending on which occur first by team assessment. This 
reestimation will use a statistical model to estimate the variability in the change in HbA1c from 
baseline to 24 weeks using all available patient HbA1c values at the time of data cutoff.  The 
estimate of variability will then be used to recalculate the sample size that would be needed to 
have 80% conditional power for a NIM of 0.4%, assuming no difference between treatments. 
The sample size from the study is constrained by a predefined maximum sample size of
400 patients.  If the recalculated sample size is smaller than sample size planned (258), the study 
will enroll to the sample size planned.  If the recalculated sample size is larger than the planned
sample size, the team will make a decision whether to increase sample size to the reestimated 
sample size. If the reestimated sample size is larger than the predefined maximum sample size, 
the team will increase the sample size to 400 subjects.
12.2. Statistical and Analytical Plans
12.2.1. General Considerations
All data will be entered, verified, and archived at a contract research organization (CRO) 
external to Lilly and/or at Lilly. Data listings, summaries, and analyses will be performed by a 
CRO and/or by Lilly under the guidance and approval of statisticians at Lilly. Statistical analysis 
of this study will be the responsibility of Lilly.
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol. Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the statistical analysis plan and/or in the clinical study report (CSR). Additional exploratory 
analyses will be conducted, as deemed appropriate.
The patient populations used in the study are described below:  
1. All Patients Entered - all patients who entered this study and completed Visit 1.
2. All Randomized - all patients who were randomized to a treatment arm.

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3. Full Analysis Set (FAS) - based on the intent to treat (ITT) principle, all patients 
who were randomized and who have taken at least one dose of study medication. 
Patients are assigned to the treatment arm to which they were randomized.
4. Per-protocol (PP) - patients in the FAS/ITT population who also meet the 
following criteria:
a.
violate no inclusion or exclusion criteria
b. have not discontinued from the study prior to 24 weeks
c.
have not been off study medication for more than 10 consecutive days 
during the treatment period
d. have not received chronic (lasting longer than 14 consecutive days) 
systemic glucocorticoid therapy (excluding topical, intra-articular, 
intraocular, and inhaled preparations)
Efficacy and safety analyses will be conducted using the FAS population. Selected analyses will 
be conducted using the All Randomized population and the PP population.  
Unless otherwise noted, all tests of treatment effects will be conducted at a 2-sided alpha level 
of 0.05, and confidence intervals (CIs) will be calculated as 2-sided 95% CIs. All tests of 
interactions between treatment groups and other factors will be conducted at a 2-sided alpha 
level of 0.05. No adjustments for multiplicity will be performed.  
The baseline is Visit 2. If baseline data are missing, the last measurement taken prior to this visit 
will be used for the baseline measurement.
The analysis of the continuous secondary efficacy and safety measurements will use the same 
mixed model repeated measure (MMRM) model for the primary efficacy analyses with the 
baseline value of the response as a covariate with the FAS patient population. Continuous 
laboratory measures will be analyzed using an analysis of covariance (ANCOVA) model. For 
categorical measures, Fisher’s exact test or Pearson’s Chi-square test will be used.
All analyses will be implemented using SAS Version 8.2® or higher.
12.2.2. Patient Disposition
All patients 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.
A listing of the primary reason for patient discontinuation will be presented for All Randomized 
patients. Summary analyses will be conducted for the All Randomized and FAS populations. 
Frequency counts and percentages will be presented for each treatment group and compared 
across treatment groups using Fisher’s Exact Test or Pearson’s Chi-square test.

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12.2.3. Patient Characteristics
The patient’s age, sex, weight, height, BMI, or other demographic characteristics will be 
recorded.
Demographic and baseline characteristics will be summarized by treatment group for the FAS 
and PP populations. For continuous measures, summary statistics will include sample size, 
mean, median, maximum, minimum, and SDs. The treatment groups will be compared using a 
2-sample t-test. For categorical measures, summary statistics will include sample size, 
frequency, and percent. Analysis will use Fisher’s Exact test or Pearson’s Chi-square test.
12.2.4. Concomitant Therapy
Concomitant medications, including previous therapies for diabetes, will be summarized by 
different categories and treatment group using the FAS population. All concomitant therapies 
that originally mapped using the WHODRUG dictionary in the Clintrial database will be further 
classified using anatomical, therapeutic chemical code for reporting purpose. Analyses will use 
test Fisher's Exact Test or Pearson’s Chi-square test.
12.2.5. Treatment Compliance
No specific study data will be collected for analysis of treatment compliance.
12.2.6. Primary Efficacy Outcome and Methodology
The primary efficacy outcome will be the change in HbA1c level from baseline to 24 weeks.  
The primary analysis will be a likelihood-based, MMRM approach, treating the data as missing 
at random (MAR) for the FAS population.  The MMRM model will evaluate the change from 
baseline to each postbaseline visit in HbA1c level as the dependent variable with treatment 
(LY2963016, Lantus®), pre-study treatment (Lantus®-bolus, other basal-bolus, premixed 
insulin), and pre-study metformin or acarbose usage (metformin only, acarbose only, or neither),
visit, and interaction between visit and treatment as fixed effects; the baseline value of HbA1c as 
a covariate; and a random effect for patient.  The MMRM model will be carried out using the 
observed margins (OM) option in SAS.  Using this option weights the levels of the independent 
or stratification variables according to the observed marginal distribution. This will provide 
least-squares means (LSMeans) for these outcomes that are more representative of the patient 
population recruited in this study.
The primary treatment comparison is to compare LY2963016 versus Lantus® at the NIM
of +0.4%. If the upper limit of the 95% CI on the change from baseline to 24-week endpoint 
HbA1c for LY2963016 versus Lantus® is below +0.4%, then LY2963016 will be declared 
noninferior to Lantus®. The LSMean and standard error derived from the MMRM model for 
each treatment will be used to test noninferiority. Type III sums of squares will be used to make 
the treatment comparisons.  

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
If the +0.4% NIM is met, a key secondary treatment comparison is to compare 
Lantus® versus LY2963016 at the NIM of -0.4%. If the lower limit of the 
95% CI on the change in HbA1c from baseline to the 24-week endpoint for 
LY2963016 versus Lantus® is above -0.4%, then Lantus® will be declared 
noninferior to LY2963016. The LSMean and standard error derived from the 
MMRM model for each treatment will be used to test noninferiority. This 
gate-keeping procedure controls the family-wise Type 1 error rate at a 1-sided 
0.025 level.

If LY2963016 is declared noninferior to Lantus® in the primary treatment 
comparison, and Lantus® is declared noninferior to LY2963016 in this 
secondary treatment comparison, then LY2963016 will be considered to have 
equivalent efficacy as Lantus®.
A first secondary analysis of the primary efficacy outcome will use the same MMRM model 
described above with the PP patient population. Significance tests will be based on LSMeans
using the Type III sum of squares, and testing for noninferiority will occur as described above.
A second secondary analysis of the primary efficacy outcome will use an ANCOVA model with 
FAS population. The ANCOVA model will include treatment, pre-study treatment, and pre-
study metformin or acarbose usage (metformin only, acarbose only, or neither) as fixed effects 
and the baseline value of HbA1c as a covariate.  The ANCOVA model will be carried out using 
the OM option in SAS. If the 24-week HbA1c value is missing, the last postbaseline value will 
be carried forward and used in the analysis.  This creates the 24-week endpoint value for HbA1c
using the LOCF methodology.  If there are no HbA1c data after the date of randomization, the 
endpoint will be considered missing and the patient will not be included in the analysis.
The analyses of the primary efficacy outcome will only be conducted for patients with both 
nonmissing baseline value and at least 1 nonmissing postbaseline value.
12.2.7. Secondary Efficacy Outcomes and Methodology
The continuous secondary efficacy outcomes include:

7-point SMBG measurements as listed in the Study Schedule (Attachment 1)
o
premeal for each meal
o
postmeal for breakfast and lunch
o
bedtime
o
3 am

intrapatient variability as measured by the SD of the 7-point SMBG

change in HbA1c from baseline to 6, 12, and 18 weeks or LOCF 

total insulin, basal insulin, and mealtime insulin lispro doses in U/day and U/kg/day

weight change

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The analysis of the continuous secondary efficacy variables will be performed using the same 
MMRM model for the primary efficacy analysis with the baseline value of the response variable 
added as a covariate with the FAS population. The proportions of subjects achieving HbA1c
target values (HbA1c <7.0% and ≤6.5%) at any point during the study will be analyzed using 
Fisher’s Exact test or Pearson’s Chi-square test.
12.2.8. Health Outcome/Quality of Life Analyses
The ITSQ will be completed at baseline (Visit 2), prior to randomization and at Week 24
(Visit 13 or ED). Change from baseline to Week 24 or end of study will be analyzed using the 
ANCOVA model for the FAS population. 
All individual patient-domain scores will be calculated as the sum of the items in the domain. If 
an item score is missing for a patient and less than 20% of the items within the domain are 
missing for that patient, then the mean of all other patients’ scores with nonmissing value for that 
item will be imputed for the item. Otherwise, the domain scores will be missing for the patient.
12.2.9. Safety Analyses
12.2.9.1. Immunogenicity Test
The proportion of patients with detected anti-glargine antibodies will be summarized as counts 
and percentages at baseline, at Visits 4, 8 and 11, at the 24-week endpoint (last observation 
carried forward [LOCF]), and overall for the 24-week treatment period. At each of these time 
points, the proportion of patients with detected antibodies will be compared between treatment 
groups using Fisher’s exact test. The level of anti-glargine antibodies (percentage binding) will 
be summarized by descriptive statistics (mean, median, SD, standard error, minimum, and 
maximum) at baseline, indicated visits, and endpoint (LOCF). At each of these time points, the 
level of percentage binding will be compared between treatment groups using the Wilcoxon rank 
sum test. The relationship between the level of anti-glargine antibodies detected and clinical 
outcomes (HbA1c, total hypoglycemia, basal dose [U/day, U/kg/day]) will be investigated.
12.2.9.2. Adverse Events
Adverse events will be listed by patient, system organ class, Medical Dictionary for Regulatory 
Activities® (MedDRA) preferred term, severity, and relationship to the study disease, drug, 
device, or procedure for all patients. Adverse events will be summarized as treatment-emergent 
adverse events (TEAEs) for the FAS. Treatment-emergent adverse events are defined as events 
that are newly reported after first study treatment following randomization, or reported to worsen 
in severity from baseline. The proportion of patients experiencing each TEAE will be presented 
by preferred term, system organ class, and treatment group. The proportion of patients 
experiencing each TEAE that are assessed as possibly related to the study disease, drug, device, 
or procedures will also be summarized. The number and proportion of patients will be presented 
and compared by treatment using Fisher’s exact test or Pearson’s chi-square test for the FAS. 
Injection site AEs will be evaluated for pain, pruritus, and rash associated with the injection, as 
well as the characteristics of the injection site (abscess, nodule, lipoatrophy, lipohypertrophy, or 

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induration). The incidences of both injection site AEs and allergic events by treatment group will 
be compared using Fisher’s exact test or Pearson’s chi-square test for the FAS population.
All SAEs will be listed by patient. If a sufficient number of SAEs are reported, they will be 
summarized by treatment for all randomized patients. Discontinuations due to TEAEs will be 
listed by patient. If a sufficient number of discontinuations are reported, they will be 
summarized by treatment.
12.2.9.3. Hypoglycemic Events
The incidence, rate per 30 days and rate per year of hypoglycemic episodes (total, severe, and 
nocturnal as defined in Section 9.10) will be summarized by treatment at baseline, titration, 
maintenance, and overall study periods and at endpoint. The rate per 30 days between 2 visits is 
defined as the total number of episodes between the visits divided by the actual number of days 
between the visits, and then multiplied by 30 days.
The proportion of patients (with at least 1 hypoglycemic event (total, severe, nocturnal, and 
others) or incidence during the study will be summarized (counts and percentages) and analyzed 
using Fisher’s exact test or the Pearson’s chi-square test for the FAS population.
The rate of hypoglycemic episodes per 30 days and per year (total, severe, nocturnal, and others) 
will be analyzed at baseline, titration, maintenance, and overall study periods and at endpoint
using the Wilcoxon test. In addition, the hypoglycemia rates will also be analyzed using a 
negative binomial model for the FAS population with terms for treatment, baseline HbA1c, 
prestudy treatment, and prestudy metformin or acarbose usage. The offset variables are log of 
patient’s treatment duration/30 and log of patient’s treatment duration/365.25 for the models 
analyzing hypoglycemia rate per 30 days and per year, respectively.
In addition, the total number of patients with at least 1 hypoglycemic episode divided by the total 
extent of exposure in patient-years will be calculated for the overall study period and 
summarized descriptively for each treatment group for total, severe, nocturnal, documented 
symptomatic, and asymptomatic hypoglycemia definitions only.  Listings of hypoglycemic 
episodes will be presented by visit for each subject.
12.2.9.4. Laboratory Measures
Continuous measures in the chemistry and hematology panels for the FAS population will be 
summarized at baseline.
Chemistry and hematology laboratory measures will be summarized as change from baseline to 
each postbaseline visit. The continuous measures and change from baseline values to 24 weeks 
will be analyzed using the ANCOVA model with treatment, prestudy treatment, and prestudy 
metformin or acarbose usage as fixed effects and the baseline value of HbA1c and the baseline of 
the response variable as covariates.  The ANCOVA model will be carried out using the OM 
option in SAS.

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12.2.9.5. Vital Signs
Systolic blood pressure, diastolic blood pressure, and heart rate will be summarized by 
descriptive statistics (mean, median, SD, standard error, minimum, and maximum) by visit for 
the FAS population.  Additionally, change from baseline to each postbaseline visit will be 
summarized.  Change from baseline values to each postbaseline visit will be analyzed for the 
FAS population using the same MMRM model as in the primary efficacy analyses.
12.2.10.
Subgroup Analyses
The consistency of the treatment effect will be assessed in the following subgroups in the FAS if 
there are a sufficient number of patients in each treatment by subgroup:

entry HbA1c levels (<7%, ≥7%) 

entry HbA1c levels (<8.5%, ≥8.5%)

prestudy treatment (Lantus®-bolus, other basal-bolus, premixed insulin)

entry BMI (<30, ≥30) 

entry age (<65, ≥65)

Prestudy metformin or acarbose use (metformin only, acarbose only or neither)

Renal function, as estimated by estimated glomerular filtration rate (EGFR). The 
following EGFR categories will be used:
o
normal or increased GFR: EGFR (≥90 mL/min/1.73 m2)
o
mild reduction in GFR: EGFR (60 to 89 mL/min/1.73 m2)
o
Moderate reduction in GFR: EGFR (30 to 59 mL/min/1.73 m2)
o
Severe reduction in GFR: EGFR (15 to 29 mL/min/1.73 m2)
o
Kidney failure: EGFR (<15 mL/min/1.73 m2).
The change in HbA1c from baseline to 24-week endpoint will be analyzed using MMRM with 
treatment, visit, prestudy treatment, prestudy metformin or acarbose usage, subgroup, subgroup-
by-treatment interaction, subgroup-by-visit interaction, treatment-by-visit interaction, and 
treatment-by-visit-by-subgroup interaction as fixed-effects, the baseline value of HbA1c as a 
covariate, and a random effect for patient for the FAS. If the subgroup is one of the stratification 
variables, then the subgroup will only be included once in the model. A significant treatment-
by-subgroup interaction (p<.05) may be indicative of a differential treatment effect across levels 
of the subgroup, necessitating further exploration of the nature of the interaction. 
Other subgroup analyses may be performed if deemed appropriate as exploratory analyses.
12.2.11.
Interim Analyses
A single interim analysis on both efficacy and safety data may be performed to allow interaction 
with regulatory authorities. Analyses on both interim and final data will be performed using the 
same statistical methods, as described in this protocol and the SAP. The study will not stop for 

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early efficacy at the interim analysis therefore no adjustment of Type I error is needed. If there 
are significant safety concerns arising from the interim analyses, the study team may decide to 
stop the trial early for safety concerns. The study team will decide, based on the trial operation 
and blinded safety information, whether and when the interim analyses will be performed.
If any unplanned interim analysis is deemed necessary, the appropriate Lilly regulatory scientist 
will be consulted to determine whether it is necessary to amend the protocol.

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13.
Informed Consent, Ethical Review, and Regulatory 
Considerations
13.1. Informed Consent
The investigator is responsible for ensuring:

that the patient understands the potential risks and benefits of participating in 
the study

that informed consent is given by each patient or legal representative.  This 
includes obtaining the appropriate signatures and dates on the ICF prior to the 
performance of any protocol procedures and prior to the administration of 
investigational product

answering any questions the patient may have throughout the study and 
sharing in a timely manner any new information that may be relevant to the 
patient’s willingness to continue his or her participation in the trial
13.2. Ethical Review
The investigator must give assurance that the ERB was properly constituted and convened as 
required by ICH guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s). Lilly or its representatives must approve the ICF, 
including any changes made by the ERBs, before it is used at the investigative site(s). All ICFs 
must be compliant with the ICH guideline on GCP.
The study site’s ERB(s) should be provided with the following:

the current IB or package insert and updates during the course of the study

ICF

relevant curricula vitae
13.3. Regulatory Considerations
This study will be conducted in accordance with:

consensus ethics principles derived from international ethics guidelines, including 
the Declaration of Helsinki and Council for International Organizations of
Medical Sciences (CIOMS) International Ethical Guidelines

applicable ICH GCP Guidelines

applicable laws and regulations
All or some of the obligations of the sponsor will be assigned to a third-party organization.

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13.3.1. Investigator Information
Physicians with a specialty in family practice, internal medicine, or endocrinology, who are 
experienced in treating patients with diabetes mellitus, may participate as investigators in this 
clinical trial. 
13.3.2. Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.  
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
13.3.3. Final Report Signature
The investigator will sign the final CSR for this study indicating agreement with the analyses, 
results, and conclusions of the report.
The CSR coordinating investigator will sign the final CSR for this study, indicating agreement 
that, to the best of his or her knowledge, the report accurately describes the conduct and results 
of the study. 
The investigator with the most enrolled patients will serve as the CSR coordinating investigator.  
If this investigator is unable to fulfill this function, another investigator will be chosen by Lilly to 
serve as the CSR coordinating investigator.
The sponsor’s responsible medical officer and statistician will approve the final CSR for this 
study, confirming that, to the best of his or her knowledge, the CSR 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. 
[ADA] American Diabetes Association. Standards of medical care in diabetes–2011. Diabetes 
Care. 2011;34(Suppl 1):S11-S61.
Anderson RT, Skovlund SE, Marrero D, Levine DW, Meadows K, Brod M, Balkrishnan R. 
Development and validation of the insulin treatment satisfaction questionnaire. Clin Ther. 
2004;26(4):565-578.  
Bennett PH. Classification and diagnosis of diabetes mellitus and impaired glucose tolerance. In: 
Pickup J, Williams G, editors. Textbook of Diabetes, Vol 1. Oxford:  Blackwell Scientific 
Publications; 1991:p 37-44.
DeWitt DE, Hirsch IB. Outpatient insulin therapy in type 1 and type 2 diabetes mellitus: 
scientific review. JAMA. 2003;289(17):2254-2264.
Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, Pollak M, 
Regensteiner JG, Yee D. Diabetes and cancer: a consensus report. CA Cancer J Clin.
2010;60(4):207-221.
Lantus [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2010.
Mecklenburg RS. Insulin-pump therapy. In: Lebovitz H., editor. Therapy for Diabetes Mellitus 
and Related Disorders. 3rd ed. Alexandria, VA: American Diabetes Association; 1998:p 204-
210.
Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ, Raskin P, Zinman B.
Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and 
Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and 
cardiovascular disease in patients with type 1 diabetes. N Engl J Med.
2005;353(25):2643-2653.
Product information for Lantus: Sanofi-Aventis U.S. LLC. Bridgewater. NJ 08807. March 2007.
Raskin P, Klaff L, Bergenstal R, Hallé JP, Donley D, Mecca T. A 16-week comparison of the 
novel insulin analog insulin glargine (HOE 901) and NPH human insulin used with insulin 
lispro in patients with type 1 diabetes. Diabetes Care. 2000;23(11):1666-1671. 
Ratner RE. Hirsch IB, Neifing JL, Garg SK, Mecca TE, Wilson CA. Less hypoglycemia with 
insulin glargine in intensive insulin therapy for type 1 diabetes. U.S. Study Group of Insulin 
Glargine in Type 1 Diabetes. Diabetes Care. 2000;23(5):639-643.
Retnakaran R, Zinman B. Treatment of type 1 diabetes mellitus in adults. In: Jameson JL, De
Groot LJ, editors. Endocrinology: adult and pediatric. Philadelphia (PA): Saunders Elsevier, 
Inc.;2010:p 840-857.
Skyler JS. Insulin treatment. In: Lebovitz H., editor. Therapy for Diabetes Mellitus and Related 
Disorders. 3rd ed. Alexandria, VA: American Diabetes Association; 1998:p 186-210.

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The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment 
of diabetes on the development and progression of long-term complications in insulin-
dependent diabetes mellitus. N Engl J Med. 1993;329(14):977-986.

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Attachment 1.Protocol ABES Study Schedule

LY2963016
I4L-GH-ABES(a) Clinical Protocol
Page 59
Study Schedule, Protocol I4L-GH-ABES
Visit
Description of Event
1
2
3*
4
5*
6
7*
8
9*
10*
11
12
13
801
ED#
Week of Study
-2
0
1
2
3
4
5
6
8
10
12
18
24
28
Allowable Deviation (Days)a
±7a
±2a
±3a
±3a
±7a
±7a
±7a
±7a
±7a
±7a
±7a
±7a
±7a
Telephone Visit
X
X
X
X
X
Clinic Visit
X
X
X
X
X
X
X
X
X
X
Screen Inclusion
Screening
X
Informed Consent Obtained
X
Patient Number Assigned
X
Randomization
X
Clinic Assessments
Medical History and Pre-existing 
Conditions
X
Previous Insulin Exposure
X
Physical Exam
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
Vital Signs (Sitting SBP, DBP, 
and HR)
X
X
X
X
X
X
X
X
X
Concom. Medsb
X
X
Xb
X
Xb
X
Xb
X
Xb
Xb
X
X
X
X
X
Adverse Eventsb
X
X
Xb
X
Xb
X
Xb
X
Xb
Xb
X
X
X
X
X
Hypoglycemic Episodesb
X
Xb
X
Xb
X
Xb
X
Xb
Xb
X
X
X
X
X
7-point SMBG Profilec
Xc
Xc
Xc
Xc
Xc
Xc
Xc
Xc
4-point SMBGb
Xb
Xb
Xb
Xb
Xb
X

LY2963016
I4L-GH-ABES(a) Clinical Protocol
Page 60
Visit
Description of Event
1
2
3*
4
5*
6
7*
8
9*
10*
11
12
13
801
ED#
Week of Study
-2
0
1
2
3
4
5
6
8
10
12
18
24
28
Allowable Deviation (Days)a
±7a
±2a
±3a
±3a
±7a
±7a
±7a
±7a
±7a
±7a
±7a
±7a
±7a
Telephone Visit
X
X
X
X
X
Clinic Visit
X
X
X
X
X
X
X
X
X
X
Study Drug/Device/Training 
and Educationd
Dispense Glucose Meter and 
Suppliese
X
Xe
Xe
Xe
Xe
Xe
Xe
Xe
Glucometer Training
X
Dispense Study Drug/Device
X
X
X
X
Injection Technique/Device use 
training
X
Training on Signs/Symptoms of 
Hypo/hyperglycemia
X
BG Level Monitoring Training
X
X
Diet and Exercise Counseling
X
Distribute Study Diary 
X
X
X
X
X
X
X
X
X
Diary Use Training
X
X
Adjust Insulin Dose (if 
Applicable)
X
X
X
X
X
X
X
X
X
X
Collect Study Drug
X
X
X
X
X
Collect Study Diaryf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Transfer Diary Data to eCRF 
(InForm)
Insulin Therapy Dose (day prior 
to visit)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
7-point SMBG Profilec,g
Xc
Xc
Xc
Xc
Xc
Xc
Xc
Xg

LY2963016
I4L-GH-ABES(a) Clinical Protocol
Page 61
Visit
Description of Event
1
2
3*
4
5*
6
7*
8
9*
10*
11
12
13
801
ED#
Week of Study
-2
0
1
2
3
4
5
6
8
10
12
18
24
28
Allowable Deviation (Days)a
±7a
±2a
±3a
±3a
±7a
±7a
±7a
±7a
±7a
±7a
±7a
±7a
±7a
Telephone Visit
X
X
X
X
X
Clinic Visit
X
X
X
X
X
X
X
X
X
X
Telephone Visit 4-point SMBG
X
X
X
X
Lab Assessments
Chemistry
X
X
X
Hematology
X
X
X
Pregnancy Screenh
Xh
ECG (local)
X
HbA1c
X
X
X
X
X
X
X
Serum Samples for Biomarkers
(Fasting)i
Xi
Xi
Xi
Xi
Anti-Glargine Antibody Titer 
X
X
X
X
X
X
Fasting Serum Glucosei
Xi
Xi
Xi
Other Transfer Data to eCRF 
(InForm)
Administer the ITSQj,k
Xj
Xj
Xj,k

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I4L-GH-ABES(a) Clinical Protocol
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Abbreviations:  BG = blood glucose; DBP = diastolic blood pressure; ECG = electrocardiogram; eCRF = electronic case report form; ED = early discontinuation; 
HbA1c = hemoglobin A1c; HR = heart rate; ITSQ = Insulin Treatment Satisfaction Questionnaire; SBP = systolic blood pressure; SMBG = self-monitored blood 
glucose.
* Telephone visit.
#
Patients who discontinue early from the study will complete Visit 801.
a
For visit window purposes, the visit will end on the last day when the patient completes a study procedure or assessment. Visits should occur within the visit 
intervals indicated. The timing of visits (including allowable deviations) should be based on time postrandomization.
b
Adverse events, hypoglycemic episodes, concomitant medications, and the last three available 4-point SMBG profiles reported at telephone visits should be 
recorded on the eCRF at the next office visit. The 4 points are: before morning, mid-day, evening meals, and at bedtime.
c
Patients should perform two 7-point SMBG profiles during the 1-week period prior to these visits. The 7 points are:  before the morning meal, midday meal, 
and evening meal; 2-hour postprandial measurements for the morning, midday meal, at bedtime and 3 am. In some instances (for example, between Visit 2 
and Visit 3), some readings of the 7-point SMBG could overlap with those taken for the 4-point SMBG.
d
Training should include instruction on glucose self-monitoring and the use of the glucose meter, record-keeping, hypoglycemia/marked hyperglycemia 
recognition and treatment, injection technique and device use, diet, and exercise. Additional training activity should be provided as needed throughout the 
study. 
e
Dispense glucose meter supplies as needed; may not be at every visit. 
f
Study sites will retain study diaries.
g
Transfer values from the study diary if available.
h
Serum pregnancy tests will be performed on all females of childbearing potential at Visit 1 (and when clinically indicated) and will be analyzed by the central
laboratory. Urine pregnancy tests at other visits can be accepted per local regulations. A urine pregnancy test may be repeated locally for any visits if 
considered necessary by the investigators and/or in compliance with local regulations.
i
The measurements should be done fasting before breakfast.
j
Study sites will retain questionnaires.
k
Administer this questionnaire only if the patient has received at least 1 dose of study medication.

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Attachment 2.Protocol ABES Clinical Laboratory Tests
Hematologya
Clinical Chemistrya
Hemoglobin
Serum Concentrations of:
Hematocrit
Sodium
Erythrocyte count (RBC)
Potassium
Leukocytes (WBC)
Total bilirubin
Direct bilirubin
Platelets
Indirect bilirubin
Neutrophils, segmented
Alkaline phosphatase
Lymphocytes
Alanine aminotransferase (ALT)
Monocytes
Aspartate aminotransferase (AST)
Eosinophils
Blood urea nitrogen (BUN)
Basophils
Other
Pregnancy Testb
Creatinine
Albumin
Hemoglobin A1ca
Anti-glargine Antibodiesa
Fasting serum glucose
Serum for nonpharmacogenetic
biomarkers (C-peptide)
.
Abbreviations:  RBC = red blood cells; WBC = white blood cells.
a
All laboratory tests to be performed at the central laboratory, unless specified otherwise
b
Serum pregnancy tests will be performed on all females of childbearing potential at Visit 1 (and when clinically 
indicated) and will be analyzed by the central laboratory. Urine pregnancy tests at other visits can be accepted 
per local regulations. A urine pregnancy test may be repeated locally for any visits if considered necessary by the 
investigators and/or in compliance with local regulations.

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Attachment 3.Protocol ABES Estimated Sampling Summary
This table summarizes the purpose for sampling, sample types, estimated volume per sample, 
number of samples, and estimated total volume during the study.    
Protocol I4L-GH-ABES Sampling Summary
Purpose
Sample 
Type
Estimated Amount 
per Sample 
Number Samples
Estimated
Total Amount
Screening testsa
Blood
3mL
2
6 mL
Standard laboratory testa
Blood
3 mL
7
21 mL
Immunogenicity samples
Blood
8 mL
5
40 mL
Nonpharmacogenetic 
biomarkers (C-peptide)
Blood
6 mL
3
18 mL
Total 
85 mL
Hepatic Monitoringb
Blood
-
-
3 - 30
Abbreviation:  
a
Additional samples may be drawn if needed for safety purposes.
b
Based on laboratory safety values, unscheduled hepatic monitoring testing may be performed as part of patient 
follow-up, in consultation with Lilly Designated Medical Monitor

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Attachment 4. Protocol ABES Hepatic Monitoring Tests for
Treatment Emergent Abnormality
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils, segmented
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
GGT
CPK 
Anti-smooth muscle antibodya
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; 
GGT = gamma-glutamyl transpeptidase; IgG = immunoglobulin G; IgM= immunoglobulin M; INR = international 
normalized ratio; RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated central laboratory
b
Reflex/confirmation dependent on regulatory requirement and /or testing availability.

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Attachment 5. ABES General Rules and Guidance for 
Intensive Insulin Therapy for ABES Study
1.  Target glycemic goals would be the same for all patients (HbA1c <7%, preprandial capillary 
BGs: 79 to 126 mg/dL ([4.4 to 7.0 mmol/L], avoiding hypoglycemia).
2.  Study treatment will start on the second day of randomization (Visit 2).  At randomization, in 
the patients who were administered with basal-bolus therapies before enrollment with QD basal 
insulin and mealtime insulins will receive instruction to start new regimen with either QD 
LY2963016 or insulin glargine as basal insulin at the same doses next day.  For  those patients 
with BID prestudy basal as a part of basal-bolus regimen, the total daily prestudy basal insulin 
dose will be reduced by 20%, therefore, the study basal insulin dose will be 80% of the prestudy 
basal insulin dose.  Insulin lispro will be administered with meals at the same doses as the 
patient’s prestudy mealtime insulin dose while avoiding hypoglycemia, as determined by unit-to-
unit conversion.
In the patients who were administered with premixed insulin will stick to prestudy regimen on 
the day of randomization, the total daily dosage at randomization will be the average for the sum 
of all insulin doses taken in the 3 days prior to randomization.  The total daily dosage will then 
be split between basal and bolus insulin doses at the discretion of the investigator.  For the 
treatment regimen, the initial basal insulin dose should be approximately 40% to 60% of the total 
daily dose.  Then the initial bolus insulin dose (insulin lispro, 60% to 40% of the total daily dose) 
will be divided into 3 equal doses before 3 meals (or appropriate adjustment at investigator’s 
discretion).  The group of patients will be instructed by the investigators for receiving treatment 
with basal-bolus insulins in the trial.
The following examples are provided as a dose calculation tool of conversion from prestudy 
insulins to trial drugs.

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Examples:
Patients will stick to pre-study insulin regimen at Visit 2, and new insulin regimen will start on 
the next day after visit 2.
a.
Prestudy basal-bolus insulin regimen (QD basal + TID premeal) (1:1 conversion of basal-
bolus insulin): 
Lantus® 12U QD + Humulin R 6U (breakfast), 4U (lunch), 5U (dinner)
Will switch to:
LY2963016 (or Lantus®) 12U QD (same dosing time as previous) + Lispro 6U
(breakfast), 4U (lunch), 5U (dinner)
b. Prestudy basal-bolus insulin regimen (BID basal + TID premeal) (1:1 conversion of bolus 
insulin and 80% of pre-study basal insulin):
NPH 10U (breakfast), 10U (dinner) + Lispro 6U (breakfast), 6U (lunch), 6U (dinner)
Will switch to:
LY2963016 (or Lantus®) (10U+10U)*80%=16U QD (daytime or evening/bedtime at the 
discretion of investigator) + Lispro 6U (breakfast), 6U (lunch), 6U (dinner).
c.
Prestudy premixed insulin BID
In past 3 days, Humulin 70/30 18U (breakfast), 12U (dinner), total daily insulin dose: 
30U
Will switch to:
LY2963016 (or Lantus®) 30U*40%=12U QD (daytime or evening/bedtime at the 
discretion of investigator) +6U for each meal (30U*60%=18U, equally divided into 3
meals), or appropriate adjustment at discretion of the investigators.
3.  Insulin dose adjustments are mostly based upon SMBG levels.  Four-point SMBG values will 
be reviewed during the telephone visit period and be recorded in the eCRF during the next 
investigator-site visit.  In addition, 7-point SMBGs are also recorded during the 1-week period 
preceding office visits.  The patient’s SMBG results are to be used by the investigator to inform 
dose adjustments for a particular insulin dose (that is, adjustment based on glucose pattern or 
trends), as represented in Table A5.1. 

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Table A5.1.
Overview of Scenarios with Different Blood Glucose Levels and 
Corresponding Insulin-dose Adjustments*
Time
BG <80 mg/dL (<4.4 mmol/L)
BG >140 mg/dL (>7.8 mmol/L)
AM 
Decrease Basal or Bedtime insulin 
Increase Basal or Bedtime insulin 
Pre-midday 
meal
Decrease AM lispro 
Increase AM lispro 
PM
Decrease Pre-midday meal lispro 
Increase Pre-midday meal lispro 
Bedtime BG <100 mg/dL (<5.5 mmol/L)
Bedtime BG >160 mg /dL (>8.9 mmol/L)
BEDTIME
Decrease PM lispro 
Increase PM lispro 
Abbreviations:  BG = blood glucose.
*
Adapted from Staged Diabetes Management.
Additional BG monitoring may be requested by the investigator while optimizing insulin doses.  
The investigator may adjust the insulin dose every 3 to 4 days (twice per week, [for example, via 
instructions to patient]) when appropriate, based on the patient’s glycemic needs as reflected by 
SMBG measurements, and after the investigator has evaluated the role of diet and exercise on the 
resulting BG measurements.  
4.  All patients will have adjustments of basal insulin (LY2963016 or Lantus®) that are primarily 
investigator-driven during the phone and office visits, following Table A5.2. Based on the Study 
Schedule, these could occur every 7 days during the first 6 weeks, then every 2 to 6 weeks; but 
the investigator may also provide instructions to patients about increasing dose after 3 days or 
during the interval between visits until the dose is stable or the FBG goal has been achieved.  To 
provide sufficient time for the HbA1c at Week 24 to be representative of a patient’s glycemic 
control on their basal-bolus insulin regimen, most of the insulin titration should occur during the 
first 6 weeks of the Titration Period (Figure ABES.7.1.) or up to 12 weeks for patients who may 
need even more aggressive insulin intensification from their prestudy insulin regimen in order to 
achieve glycemic targets.  During the Maintenance Period, it is expected that adjustments to 
insulin dose would be for safety such as hypoglycemia or unacceptable hyperglycemia.

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Table A5.2.
Dose Adjustment for LY2963016 or Lantus®a
FBG mg/dL
FBG mmol/L
Dose Change (Units)b
<50 
<2.8
see belowc
50-90
2.8-5.0
see belowc
91-108
5.1-6.0
0
109-180
6.1-10
+2
181-270
10.1-15.0
+4
>270
>15.0
+6
Abbreviations:  FBG = fasting blood glucose; TDID = total daily insulin dose.
a
Fasting (morning) blood glucose values should be considered for adjusting the basal insulin.
b
Based on most values during the last 1 to 2 weeks or the median of 3 most recent/applicable FBGs.  In general, 
the change in TDID should not exceed more than 10 U per day or 10% of the current basal insulin dose, 
whichever is greater.  If the dose adjustment needed is >10 U or 10% of basal insulin dose, the investigator 
should make a dosing decision based on the patient's highest BG level of the day.
c
Based on most values during the 1 to 2 weeks or the median of 3 most recent/applicable FBGs.  If glucose value 
is <5.0 mmol/L (<90 mg/dL) or the patient has symptoms consistent with hypoglycemia, the investigator will use 
their clinical judgment to decrease the insulin dosage appropriately.
5.  Patients, in general, are to be instructed with their bolus insulin administration to achieve 
glycemic targets.  Adjustments in the patients’ bolus insulin intended to cover the meal are based 
upon a 2-day (corresponding premeal) pattern.  Such adjustments to the bolus insulin intended to 
cover the meals are primarily investigator-driven and done during the office/phone visits in the 
course of the study (weekly for 6 weeks then every 2 to 6 weeks).  In addition, the patients 
should also be encouraged to do daily SMBGs (before meals and at bedtime) and educated 
about/instructed on administering additional insulin if pre-meal BGs are above target at time of 
testing (that is, in addition to the dose intended to cover their meal).  For patients who have 
relatively consistent carbohydrate intake from day to day, they may be provided with a pre-meal 
insulin algorithm described in 5a below.  Patients who do carbohydrate counting alternatively 
may do pre-meal bolus calculation that includes insulin to cover the anticipated carbohydrate 
intake, and additional insulin if pre-meal BG happens to be above target, as described in 5b
below. 
The investigator could also consider keeping close to the 50:50 general guidance regarding basal 
mealtime insulin distribution in adjusting the insulin doses.  However, it should be noted that this 
ratio may vary and the initial basal insulin dose is recommended to be approximately 40% to 60% 
of the total daily dose.
When BG is not determined before a meal, then the mealtime insulin dose administered would be 
the dose as if the BG were at target (79 to 126 mg/dL).  Patients should be encouraged to 
regularly check pre-meal SMBG levels to optimize glycemic control.  
5a. Adjustment of insulin doses for patients not using carbohydrate counting:

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At Visit 2 (randomization), patients with basal-bolus regimen are switched to insulin lispro at 
each meal using a unit-to-unit conversion from prestudy mealtime bolus insulin doses.  For those 
patients with premixed insulins before the study, the initial bolus insulin dose (insulin lispro) is 
recommended to be approximately 60% to 40% of the total prestudy insulin dose and will be 
divided into 3 equal doses before 3 meals or appropriate adjustment at investigator’s discretion.  
For patients who have relatively constant carbohydrate per meal, each mealtime dose will have 
to be adjusted based on a 3-day glucose pattern for corresponding meals (for example, for the 
morning meal insulin dose, the midday meal glucose levels from 3 days, preferably the 3 most 
recent days, or from the available 4- or 7-point SMBGs, if applicable) according to Table A5.3.  
Table A5.3.
Mealtime Insulin Lispro Adjustments to Cover Patients Not 
Carbohydrate Countinga
BG mg/dL based on 3-day pattern for corresponding meal
BG mmol/L
Dose Change (Units)
b
< 50 (<80 mg/dL at bedtime)
<2.8 (<4.4 at bed time)
-3 to -4
50-80 (80-100 mg/dL at bedtime)
2.8-4.4 (4.4-5.5 at bed time)
-1 to -2
81-140 (101-160 at bedtime)
4.5-7.8 (5.6-8.8 at bed time)
0
141-180 (161-200 at bedtime)
7.9-10.0 (8.9-11.1 at bed time) +1 to +2
>180 (>200 at bedtime)
>10.0 (11.1 at bed time)
+2 to +4
Abbreviations:  BG = blood glucose
a
Adapted from Staged Diabetes Management. Pre-midday meal BG values in the past 3 to 14 days are considered 
for dose adjustment of insulin lispro at the morning meal, pre-evening meal BG values for dose adjustment of 
insulin lispro at midday meal, and bedtime BG for dose adjustment of insulin lispro given at the evening meal.  
Note that the target BG for bedtime is between 100 and 160 mg/dL (5.5 and 8.9 mmol/L).
b
Based on glucose pattern from BG readings on 3 separate days from previous 1 to 2 weeks (preferably most 
recent readings).
The insulin adjustments in Table A5.3address the mealtime insulin dose intended to cover the 
patient’s carbohydrate intake during the meal (presumed consistent from day to day), and are 
primarily investigator-driven based on patient’s previous glucose trends as described above.  A 
mealtime insulin dose directed to cover a meal could only bring a patient’s BG level back to 
target if the patient started off with BG levels that are right on target.  If the patient’s pre-meal 
BG level is elevated at time of testing, additional insulin should also be given to bring the BG 
level closer to target using a “correction bolus,” which allows the patient to bring down high 
blood glucose levels closer to their target blood glucose level after the meal.  The investigator 
may determine the appropriate “correction bolus” for the patient to administer when pre-meal 
BG levels are above target, based on clinical judgment, taking into account the patient’s 
performance with previous/current insulin regimen and recent glucose profiles, and appropriate 
patient education should be provided when needed.  Alternatively, the correction bolus may 
initially be calculated as follows:  
Correction Bolus = 1800/TDID = estimated drop in BG (mg/dL) level per unit of Humalog®
administered. 
Fine-tuning the patient’s correction bolus may be done based on the investigator’s clinical 
assessment and guided by the patient’s SMBG results or clinical presentation.  While the patient 

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may keep in mind this correction bolus and use it to calculate their insulin lispro dose before 
each meal, a mealtime insulin algorithm may also be offered to patients to incorporate the 
correction bolus with the mealtime insulin dose intended to cover the meal as illustrated in 
example below.
Example 1: Patient with prestudy insulin regimen consisting of 20 U Lantus
® and insulin lispro 
given as 4 U at the morning meal, 6 U at the midday meal, and 6 U at the evening meal (and, 
thus, started on similar regimen at randomization) would have:  
correction bolus = 1800/ TDID = 1800/36 = 50
(that is, each unit of insulin could decrease BG level by approximately 50 mg/dL).
If the patient reports that their individualized glucose targets are between 70 and 140 mg/dL (for 
example, a tendency to develop hypoglycemia occurs if patient administers additional 
“correction” insulin if BG is <140 mg/dL), a mealtime insulin algorithm could be constructed 
from the information below, using the correction bolus as the increment between the upper limit 
of the range from one BG range to the next (for example, 140 + 50 = 190, 190 + 50 = 240, etc.).  
(NOTE:  If a patient has not been experiencing hypoglycemia or does not appear to be too 
sensitive to insulin, one could use 79 to 126 mg/dL as the range at which no correction dose is 
applied.)  Each day then, the patient would administer the doses indicated for respective meals 
based on results of SMBG values at mealtime.
If the premeal BG 
is:
The pre-morning meal dose of 
insulin lispro is:
The pre-midday meal dose of 
insulin lispro is:
The pre-evening meal dose of 
insulin lispro is:
<70 mg/dL
3
5
5
70-140 mg/dL
4
6
6
141-190 mg/dL
5
7
7
191-240 mg/dL
6
8
8
>240 mg/dL
7
9
9
Note also that a patient’s insulin doses that are intended to cover meals (derived from prestudy 
doses) are plugged in the “base case,” where pre-meal BG is assumed to be at target as a start 
(for example, 70 to 140 mg/dL in the example above).  If a patient has elevated HbA1c, then it 
could be expected that the patient will likely have to increase “base case” dose.  An example is 
provided below to illustrate how this mealtime insulin algorithm is refined during follow up, 
when the pre-meal insulin doses at “base case” need to be adjusted.
Example 2:  Upon follow up of the patient in the example above, it was noted that there was a 
consistent elevation in bedtime values averaging approximately 260 mg/dL.  (Thus, the patient 
has been administering an extra 2 U of insulin every bedtime to correct this high reading.)  
Guided by Table A5.3, the investigator instructs the patient to increase the pre-evening meal 
dose by 3 U (thus, 6 + 3 = 9 U to be administered at the evening meal when BG are within 
target).  Adjustments to the mealtime insulin algorithm, considering the same correction bolus 
calculated earlier, will result in refinements below (changes bolded):

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If the premeal 
BG is:
The pre-morning meal dose of 
insulin lispro is:
The pre-midday meal dose of 
insulin lispro is:
The pre-evening meal dose of 
insulin lispro is:
<70 mg/dL
3
5
5
70-140 mg/dL
4
6
9
141-190 mg/dL 5
7
10
191-240 mg/dL 6
8
11
>240 mg/dL
7
9
12
(In the next few days, if the adjustments reflected above are effective and sufficient, then the 
patient’s bedtime BG levels would be expected to fall within or closer to target such that patient 
does not need to give any extra insulin at bedtime as the hyperglycemic episodes have been 
averted by the increased pre-evening meal insulin dose.) 
5b. Adjustment of mealtime insulin doses of patients doing carbohydrate counting.
For patients who practice carbohydrate counting, the patient’s pre-meal insulin dose 
administered is based on the amount of carbohydrate they are about to consume with the meal 
(for example, 0.5 to 2.0 units of insulin /10 to 15 g carbohydrate [that is, per fruit exchange]) and 
a correction bolus (similar calculation as 5a) if their pre-meal PG is above target. 
6.  The investigator may provide guidance on bolus insulin adjustments, based on the projected 
exercise pattern and level of stress during the period of insulin action, when applicable.  
Anticipated exercise adjustment:  50% reduction in insulin dose with anticipated exercise.  
Adjustment when under increased stress is approximately a 10% increase in dose.

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Attachment 6.Protocol ABES World Health Organization
(WHO)
Classification of Diabetes
Type 1 Diabetes Mellitus:  Type 1 diabetes mellitus is judged to be present when the classical 
symptoms of diabetes (thirst, polyuria, wasting and stupor, or coma) are associated with readily 
detectable concentrations of glucose and ketone bodies in the blood and urine.  Insulin treatment 
is necessary, not only to control hyperglycemia, but to prevent spontaneous ketosis and death.
Type 2 Diabetes Mellitus:  Type 2 diabetes mellitus, although often asymptomatic, may also 
present with classical hyperglycemic symptoms (thirst, polyuria, weight loss), but despite 
hyperglycemia, ketone bodies are present in only low concentrations in the blood and urine.  
Coma is rare in type 2 diabetes, but may result from extreme hyperglycemia and 
hyperosmolarity; lactic acidosis or ketoacidosis can also occur in fulminating illness (for 
example, severe infection or mesenteric artery thrombosis) due to an acute increase in insulin 
requirements, but spontaneous ketosis does not occur.  Some patients with type 2 diabetes later 
progress to a state of absolute insulin deficiency (Bennett 1991).

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Attachment 7.Protocol Amendment I4L-GH-ABES(a)
Summary: A Prospective, Randomized, Open-Label 
Comparison of a Long-Acting Basal Insulin Analog, 
LY2963016, to Lantus® in Combination with Mealtime 
Insulin Lispro in Adult Chinese Patients with Type 1 
Diabetes Mellitus
Overview
Protocol I4L-GH-ABES has been amended.  The new protocol is indicated by amendment (a) 
and will be used to conduct the study in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:

Estimated first patient visit date and last patient visit date in synopsis were updated.

For acarbose usage, 1) inclusion criteria was expanded to include patients with previous 
treatment of acarbose only as oral antihyperglycemic medication; 2) it was added as a 
stratification factor, and 3) discontinuation of acarbose at randomization was added in 
exclusion criterion [17], Section 8.2.

Visit 801 was changed from telephone visit to clinic visit to mitigate the risk of source 
data inaccuracy.

For patients who discontinue from the study, completion of Visit 801 was added to avoid 
missing of Visit 801.

Sentence related to patients’ self-titration of mealtime insulin dose based on SMBG 
readings in Section 9.4 was modified to clarify that insulin dose titration will be driven by 
the investigator.

Tests of fasting serum glucose at Visit 2, Visit 13, or ED were added in study schedule 
(Attachment 1) as a complementation of self-monitored blood glucose (SMBG) pre-
morning value and c-peptide in data interpretation. And in Attachment 2, fasting serum 
glucose was added.

For serious adverse events after study completion or patient discontinuation in 
Section 10.3.1.1, related paragraph was updated according to current protocol template 
(version 11.0).

InFuse database is no longer in use, so it was replaced by Clintrial.

For treatment-emergent adverse event, the definition was revised from events newly 
reported or worsened after randomization to those after first study treatment to exclude 
events occurred or worsened after randomization and prior to first dose.  Definition of 
TEAE in Section 4 was also updated per current clinical protocol template (version 11.0).

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
Added an abbreviation of SD (standard deviation) in Section 4.

In Attachment 3, estimated sampling for standard laboratory test was updated, and total 
amount was changed accordingly.

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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
2.
Synopsis
Length of Study:  
Estimated first patient visit:  Mar 20178               Estimated last patient visit:  Sep 201920
Statistical Methods:
Sample Size:
Based on the primary objective, to show noninferiority of LY2963016 to Lantus® at the 0.40% noninferiority 
margin (NIM), 109 completers per arm (218 total) are needed at 24 weeks. This calculation assumes no treatment 
difference in HbA1c between LY2963016 and Lantus®, a common standard deviation (SD) of 1.05% for change 
from baseline in HbA1c, a two-sided significance level of 0.05, and over 80% power. Assuming a 15% dropout 
rate at 24 weeks, the required number of randomized patients is 129 per arm (258 total).  
Blinded sample-size reestimation may be performed when approximately 40% of the subjects have been enrolled 
in the study and finished 24-week of treatment, or about 6 months prior to the completion of enrollment, depending 
on which occur first by team assessment.
Statistical: 
The primary efficacy outcome is the change in HbA1c level from baseline to 24 weeks.  The primary analysis will 
be a likelihood-based, mixed model repeated measure (MMRM) approach, treating the data as missing at random 
(MAR) for the full analysis set (FAS) population.  The MMRM model will evaluate the change from baseline in 
HbA1c level as the dependent variable with treatment (LY2963016, Lantus®), stratification factors screening 
HbA1c Stratum, prestudy treatment, and prestudy metformin or acarbose usage (yes or nometformin only, acarbose 
only, or neither), visit, and interaction between visit and treatment as fixed effects; the baseline value of HbA1c as 
a covariate; and a random effect for patient.  Supportive analyses will be performed with the same MMRM model 
on per-protocol (PP) population and with an analysis of covariance (ANCOVA) model on FAS population.
4.
Abbreviations and Definitions
SD
standard deviation
TEAE (treatment-
emergent adverse 
event)
Any untoward medical occurrence that either occurs or worsens at any time after 
treatment baseline and that does not necessarily have a causal relationship with this 
treatment. Treatment-emergent adverse event:  An untoward medical occurrence that 
emerges during a defined treatment period, having been absent pretreatment, or worsens 
relative to the pretreatment state, and does not necessarily have to have a causal 
relationship with this treatment.
7.1.
Summary of Study Design
Patients will come to the investigator site for Visits 2, 4, 6, 8, 11, 12, and 13, and 801 for various 
study assessments during the treatment period.  Patients will be contacted over the telephone for 
Visits 3, 5, 7, 9, and 10, and 801 (described as “Telephone Visits” in Section 7.2.2.2) to assess 
their response to study drug (including 4-point SMBG, AEs, and hypoglycemia) and/or to further 

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adjust insulin doses, if needed. Insulin dose adjustments will be done in both treatment arms to 
help patients achieve glycemic targets (HbA1c <7%, preprandial capillary BGs 79 to 126 mg/dL 
[4.4 to 7.0 mmol/L]) while minimizing/avoiding hypoglycemia. Patients will come for a clinic 
visit at Visit 13 for their final assessments at the completion of 24 weeks. At approximately 
4-weeks post-treatment endpoint, patients will have a final telephoneclinic visit (Visit 801), at 
which information will be collected according to the Study Schedule (Attachment 1).
End of study (trial) is the date of the last visit or last scheduled procedure shown in the Study 
Schedule for the last active patient in the study.
Figure ABES.7.1 illustrates the study design.

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7.2.2.2.1.
Patients Eligible for Randomization at Visit 2

Eligible patients will be randomized to 1 of 2 treatment groups by a random assignment 
based on Visit 1 HbA1c, prestudy treatment with basal-bolus insulin or premixed insulin, 
and prestudy treatment with metformin or not metformin or acarbose usage (metformin 
only, acarbose only, or neither).  For patients with prestudy treatment of metformin or 
acarbose (excluding those taken both) prior to Visit 1, their concomitant OAM will be 
discontinued at Visit 2.
7.2.2.3.
Telephone Visit 1
Between each investigator-site visit, patients will have a telephone visit with the investigator or 
designee at Visit 3, 5, 7, 9, and 10, and 801.
7.2.2.4.
Study Visits (Visit 3 to Visit 13 or Early Discontinuation)
Patients will come to the investigator site at 2-week intervals between Visit 2 and Visit 8.  From 
Visit 8 to Visit 13, patients will come to the clinic at 6-week intervals.  Visit 801 is a 4-week 
follow-up telephoneclinic visit (Attachment 1).
7.2.2.5.
Follow-up Visit (Visit 801)
Patients will receive a telephone callcome to the investigator site approximately 4 weeks after the 
last treatment visit, at which time information will be discussed and recorded according to the 
Study Schedule (Attachment 1).  Patients who discontinue early from the study will undergo all 

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end-of-study procedures and complete Visit 801 as outlined in Attachment 1.  These data will be 
collected and stored for future reference/analyses, if needed. 
7.2.3.
Blood Glucose Monitoring Plan

Patients will be instructed to complete 2 separate 7-point SMBG profiles in the 1-week 
period prior to each office visit from Visit 2 to Visit 13 (or at ED) (preferably most recent 
readings). At Visit 801, only 4-point SMBG is required to be collected.  The SMBG 
profiles will consist of:
o
before the morning meal, midday meal, and evening meal; 2-hour postprandial 
measurements for the morning, midday meal, at bedtime and 3 am.
Throughout the study, patients will be expected to routinely check their fasting, premeal, and 
bedtime BG values daily to help assess the need for dose adjustments and to guide dosing of the 
mealtime/fast-acting insulin lispro (Attachment 5).  Patients may be requested by investigators 
(as they deem necessary) to perform more intensive self-monitoring, if clinically indicated. Both 
4-point and 7-point SMBG values will be recorded in the diaries and transcribed into the eCRF at 
the office visit and at Visit 801 (Attachment 1 and Attachment 5). 
8.2.
Exclusion Criteria
[17] Have taken any oral antihyperglycemic medications (OAMs) within 3 months 
prior to Visit 1.  Except for those patients with metformin or acarbose at a stable 
dose for more than 90 days prior to Visit 1 (excluding those taken both), 
theytheir concomitant OAM will be discontinued metformin at randomization 
before the study treatment.
9.3.
Method of Assignment to Treatment
At Visit 1, patients will be assigned a patient number, and at Visit 2, those who are eligible to 
participate in the study will be assigned by stratified randomization to 1 of the 2 treatment arms, 
in a ratio of 1:1, via random assignment using the interactive web response system.  To achieve 
between-treatment group comparability, patients will be stratified by screening HbA1c stratum 
(<8.5%, ≥8.5%), pre-study treatment (Lantus®-bolus, other basal-bolus, premixed insulin), and 
pre-study metformin usage (yes or no) or acarbose usage (metformin only, acarbose only, or 
neither).
9.4.
Rationale for Selection of Doses in the Study
At randomization, in the patients who were administered with basal-bolus therapies before 
enrollment, QD LY2963016 will be started at the same doses as the QD prestudy basal insulin. 
For those patients with BID prestudy basal insulin as part of basal bolus regimen, the total daily 
prestudy insulin dose will be reduced by 20% at randomization to LY2963016 or insulin glargine, 
therefore, the study basal insulin dose will be 80% of the prestudy basal insulin dose. Insulin 
lispro will be administered with meals at the same doses as the patient’s prestudy mealtime 
insulin dose while avoiding hypoglycemia, as determined by unit-to-unit conversion. Based on 
the patient’s prestudy mealtime insulin regimen relative to his/her lifestyle, the investigator could 

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translate the patient’s previous mealtime insulin regimen so that the patient’s prestudy mealtime 
insulin is replaced with a similar dose of insulin lispro to be used during the study. During the 
course of the study, the patient’s mealtime insulin does will be adjusted and optimized by 
investigators. During the course of the study, the patient’s mealtime insulin doses will be
adjusted and optimized by the investigator., as he or she is encouraged to do SMBG readings 
before meals and instructed to titrate his or her mealtime insulin dose as guided by those premeal 
readings, in addition to investigator –directed insulin dose adjustments guided by the previous 
days’ glucose patterns.  Study participants will administer mealtime insulin doses before meals to 
provide insulin coverage for the meal, as well as a correction dose if the premeal BG reading is 
above target.
10.3.1.1.
Serious Adverse Events
The investigator does not need to actively monitor patients for adverse events once the trial has 
ended, unless provided otherwise in the protocol.  However, if an investigator becomes aware of 
SAEs occurring to a patient after the patient’s participation in the trial has ended, the investigator 
should report the SAEs to the sponsor, regardless of the investigator’s opinion of caucation, and 
the SAEs will be entered in the pharmacovigilance system at the sponsor. Investigators are not 
obligated to actively seek AEs or SAEs in subjects once they have discontinued and/or 
completed the study (the patient 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.
10.4.2.1.
Nonpharmacogenetic Biomarker Evaluations
This study will employ sample collection.  Samples will be collected for nonpharmacogenetic 
biomarker investigation where local regulations allow.  Blood Fasting serum samples will be 
collected at the times specified in the Study Schedule (Attachment 1).
Samples Fasting samples being collected will be used to measure C-peptide to support trial
interpretation. 
12.1.
Determination of Sample Size
Based on the primary objective, to show noninferiority of LY2963016 to Lantus® at the 0.40% 
noninferiority margin (NIM), 109 completers per arm (218 total) are needed at 24 weeks. This 
calculation assumes no treatment difference in HbA1c between LY2963016 and Lantus®, a 
common standard deviation (SD) of 1.05% for change from baseline in HbA1c, a two-sided 
significance level of 0.05, and over 80% power. Assuming a 15% dropout rate at 24 weeks, the 
required number of randomized patients is 129 per arm (258 total).  
12.2.4.
Concomitant Therapy
Concomitant medications, including previous therapies for diabetes, will be summarized by 
different categories and treatment group using the FAS population. All concomitant therapies 
that originally mapped using the WHODRUG dictionary in the InFuseClintrial database will be 

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further classified using anatomical, therapeutic chemical code for reporting purpose. Analyses 
will use test Fisher's Exact Test or Pearson’s Chi-square test.
12.2.6.
Primary Efficacy Outcome and Methodology
The primary efficacy outcome will be the change in HbA1c level from baseline to 24 weeks.  
The primary analysis will be a likelihood-based, MMRM approach, treating the data as missing 
at random (MAR) for the FAS population.  The MMRM model will evaluate the change from 
baseline to each postbaseline visit in HbA1c level as the dependent variable with treatment 
(LY2963016, Lantus®), pre-study treatment (Lantus®-bolus, other basal-bolus, premixed 
insulin), and pre-study metformin usage (yes or no) or acarbose usage (metformin only, acarbose 
only, or neither), visit, and interaction between visit and treatment as fixed effects; the baseline 
value of HbA1c as a covariate; and a random effect for patient.  The MMRM model will be 
carried out using the observed margins (OM) option in SAS.  Using this option weights the 
levels of the independent or stratification variables according to the observed marginal 
distribution. This will provide least-squares means (LSMeans) for these outcomes that are more 
representative of the patient population recruited in this study.
A second secondary analysis of the primary efficacy outcome will use an ANCOVA model with 
FAS population. The ANCOVA model will include treatment, pre-study treatment, and pre-
study metformin or usage (yes or no) or acarbose usage (metformin only, acarbose only, or 
neither) as fixed effects and the baseline value of HbA1c as a covariate.  The ANCOVA model 
will be carried out using the OM option in SAS. If the 24-week HbA1c value is missing, the last 
postbaseline value will be carried forward and used in the analysis.  This creates the 24-week 
endpoint value for HbA1c using the LOCF methodology.  If there are no HbA1c data after the 
date of randomization, the endpoint will be considered missing and the patient will not be 
included in the analysis.
12.2.9.2.
Adverse Events
Adverse events will be listed by patient, system organ class, Medical Dictionary for Regulatory 
Activities® (MedDRA) preferred term, severity, and relationship to the study disease, drug, 
device, or procedure for all patients.  Adverse events will be summarized as treatment-emergent 
adverse events (TEAEs) for the FAS.  Treatment-emergent adverse events are defined as events 
that are newly reported after first study treatment following randomization, or reported to worsen 
in severity from randomizationbaseline. The proportion of patients experiencing each TEAE 
will be presented by preferred term, system organ class, and treatment group. The proportion of 
patients experiencing each TEAE that are assessed as possibly related to the study disease, drug, 
device, or procedures will also be summarized. The number and proportion of patients will be 
presented and compared by treatment using Fisher’s exact test or Pearson’s chi-square test for 
the FAS. 
12.2.9.3.
Hypoglycemic Events
The rate of hypoglycemic episodes per 30 days and per year (total, severe, nocturnal, and others) 
will be analyzed at baseline, titration, maintenance, and overall study periods and at endpoint

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using the Wilcoxon test. In addition, the hypoglycemia rates will also be analyzed using a 
negative binomial model for the FAS population with terms for treatment, baseline HbA1c, 
prestudy treatment, and prestudy metformin or acarbose usage. The offset variables are log of 
patient’s treatment duration/30 and log of patient’s treatment duration/365.25 for the models 
analyzing hypoglycemia rate per 30 days and per year, respectively.
12.2.9.4.
Laboratory Measures
Chemistry and hematology laboratory measures will be summarized as change from baseline to 
each postbaseline visit. The continuous measures and change from baseline values to 24 weeks 
will be analyzed using the ANCOVA model with treatment, prestudy treatment, and prestudy 
metformin or acarbose usage as fixed effects and the baseline value of HbA1c and the baseline of 
the response variable as covariates.  The ANCOVA model will be carried out using the OM 
option in SAS.
12.2.10.
Subgroup Analyses

Prestudy metformin or acarbose use: (metformin only, acarbose only or neither)
The change in HbA1c from baseline to 24-week endpoint will be analyzed using MMRM with 
treatment, visit, prestudy treatment, prestudy metformin or acarbose usage, subgroup, subgroup-
by-treatment interaction, subgroup-by-visit interaction, treatment-by-visit interaction, and 
treatment-by-visit-by-subgroup interaction as fixed-effects, the baseline value of HbA1c as a 
covariate, and a random effect for patient for the FAS.  If the subgroup is one of the stratification 
variables, then the subgroup will only be included once in the model. A significant treatment-
by-subgroup interaction (p<.05) may be indicative of a differential treatment effect across levels 
of the subgroup, necessitating further exploration of the nature of the interaction. 

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Attachment 1.
Protocol ABES Study Schedule
Visit
Description of Event
1
2
3*
4
5*
6
7*
8
9*
10*
11
12
13
801*
ED#
Week of Study
-2
0
1
2
3
4
5
6
8
10
12
18
24
28
Allowable Deviation (Days)a
±7a
±2a
±3a
±3a
±7a
±7a
±7a
±7a
±7a
±7a
±7a
±7a
±7a
Telephone Visit
X
X
X
X
X
X
Clinic Visit
X
X
X
X
X
X
X
X
X
X
Clinic Assessments
Concom. Medsb,i
X
X
Xb
X
Xb
X
Xb
X
Xb
Xb
X
X
X
Xi
X
Adverse Eventsb,i
X
X
Xb
X
Xb
X
Xb
X
Xb
Xb
X
X
X
Xi
X
Hypoglycemic Episodesb,i
X
Xb
X
Xb
X
Xb
X
Xb
Xb
X
X
X
Xi
X
4-point SMBGb,i
Xb
Xb
Xb
Xb
Xb
Xi
Study Drug/Device/Training 
and Educationd
Distribute Study Diary
X
X
X
X
X
X
X
X
X
Transfer Diary Data to eCRF 
(InForm)
Insulin Therapy Dose (day prior 
to visit)i
X
X
X
X
X
X
X
X
X
X
X
X
Xi
X
Telephone Visit 4-point SMBGi
X
X
X
X
Xi
Lab Assessments
Serum Samples for Biomarkers
(Fasting)i
Xi
Xi
Xi
Xi
Anti-gGlargine aAntibody tTiter 
X
X
X
X
X
X
Fasting Serum Glucosei
Xi
Xi
Xi

LY2960316
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Page 84
#
Patients who discontinue early from the study will complete Visit 801.
b
Adverse events, hypoglycemic episodes, concomitant medications, and the last three available 4-point SMBG profiles reported at telephone visits should be 
recorded on the eCRF at the next office visit or at Visit 801. The 4 points are: before morning, mid-day, evening meals, and at bedtime.
i
Information will be collected during a telephone visit and will be recorded on the eCRF.  Site documentation will serve as the source for this telephone visit, 
as the patient will not be returning the paper diary to the site.The measurements should be done fasting before breakfast.

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Attachment 2.
Protocol ABES Clinical Laboratory Tests
Hematologya
Clinical Chemistrya
Hemoglobin
Serum Concentrations of:
Hematocrit
Sodium
Erythrocyte count (RBC)
Potassium
Leukocytes (WBC)
Total bilirubin
Direct bilirubin
Platelets
Indirect bilirubin
Neutrophils, segmented
Alkaline phosphatase
Lymphocytes
Alanine aminotransferase (ALT)
Monocytes
Aspartate aminotransferase (AST)
Eosinophils
Blood urea nitrogen (BUN)
Basophils
Other
Pregnancy Testb
Creatinine
Albumin
Hemoglobin A1ca
Albumin
Anti-glargine Antibodiesa
Fasting serum glucose
Serum for nonpharmacogenetic
biomarkers (C-peptide)
.
Attachment 3.
Protocol ABES Estimated Sampling Summary
Purpose
Sample 
Type
Estimated Amount 
per Sample 
Number Samples
Estimated  
Total Amount
Screening testsa
Blood
3mL
2
6 mL
Standard laboratory testa 
Blood
3 mL
67
1821 mL
Immunogenicity samples
Blood
8 mL
5
40 mL
Nonpharmacogenetic 
biomarkers (C-peptide)
Blood
6 mL
3
18 mL
Total 
825 mL
Hepatic Monitoringb
Blood
-
-
3 - 30
LY2960316

Leo Document ID = 791af027-9537-40d9-a476-8efda92cfa02
Approver: 
Approval Date & Time: 02-Mar-2017 02:47:52 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 02-Mar-2017 14:41:53 GMT
Signature meaning: Approved