Conditions: Type 2 Diabetes Mellitus
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 304
Healthy volunteers: no

Brief summary:
The reason for this study is to see if insulin glargine is safe in participants with type 2 diabetes mellitus (T2DM) in India.

Detailed description:

Arms:
arm 1: Participants received insulin glargine once a day (QD) subcutaneously (SC) with a starting dose of 10 units. Participants self-titrated once or twice weekly until fasting blood glucose level was lowered to \<100 milligrams per deciliter (mg/dL). Dose was reduced by 4 units in case of hypoglycemia.

Interventions: intervention 1: Insulin Glargine
Intervention descriptions: intervention 1: Administered SC

Protocol document:
Prot_000.pdf: 
 
 
 
Protocol I4L-IN-ABEX(b) 
 
 
A Multicenter, Open-Label, Single-Arm, Phase 4 Study to Assess the Safety of Basaglar in 
Subjects with Type 2 Diabetes Mellitus in India 
 
  
NCT04153981 
 
Approval Date: 04-Oct-2019 
 
 


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LY2963016
Protocol I4L-IN-ABEX(b)
A Multicenter, Open-Label, Single-Arm, Phase 4 Study to 
Assess the Safety of Basaglar in Subjects with Type 2 
Diabetes Mellitus in India
Confidential Information
The information contained in this document is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of
basal insulin glargine (LY2963016; Basaglar), unless such persons are bound by a 
confidentiality agreement with Eli Lilly and Company or its subsidiaries.
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure. Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
Basal Insulin Glargine (LY2963016; Basaglar)
Eli Lilly and Company
Gurugram, Haryana-122001, India
Protocol Electronically Signed and Approved by Lilly: 03 June 2019.
Amendment (a) Electronically Signed and Approved by Lilly:  12 July 2019.
Amendment (b) Electronically Signed and Approved by Lilly on approval date provided 
below.
Approval Date: 04-Oct-2019 GMT


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Table of Contents
Section
Page
Protocol I4L-IN-ABEX(b) A Multicenter, Open-Label, Single-Arm, Phase 
4 Study to Assess the Safety of Basaglar in Subjects with Type 2 
Diabetes Mellitus in India ...................................................................................................1
Table of Contents........................................................................................................................2
1.
Synopsis .............................................................................................................................8
2.
Schedule of Activities .......................................................................................................12
3.
Introduction ......................................................................................................................17
Study Rationale............................................................................................................17
Background..................................................................................................................17
Benefit/Risk Assessment..............................................................................................18
4.
Objectives and Endpoints..................................................................................................19
5.
Study Design.....................................................................................................................20
Overall Design .............................................................................................................20
5.1.1.
Study Visits..........................................................................................................21
Number of Participants.................................................................................................22
End of Study Definition ...............................................................................................22
Scientific Rationale for Study Design...........................................................................22
Justification for Dose ...................................................................................................23
6.
Study Population...............................................................................................................24
Inclusion Criteria..........................................................................................................24
Exclusion Criteria ........................................................................................................24
6.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................25
Lifestyle Restrictions....................................................................................................25
Screen Failures.............................................................................................................25
7.
Treatments........................................................................................................................26
Treatments Administered .............................................................................................26
7.1.1.
Packaging and Labelling ......................................................................................26
7.1.2.
Medical Devices...................................................................................................27
Method of Treatment Assignment ................................................................................27
7.2.1.
Selection and Timing of Doses.............................................................................27
Blinding .......................................................................................................................27
Dosage Modification....................................................................................................27
Preparation/Handling/Storage/Accountability...............................................................27
Treatment Compliance .................................................................................................28


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Concomitant Therapy...................................................................................................28
Treatment after the End of the Study............................................................................29
7.8.1.
Study Extensions..................................................................................................29
7.8.2.
Treatment after Study Completion........................................................................29
7.8.3.
Special Treatment Considerations ........................................................................29
8.
Discontinuation Criteria ....................................................................................................30
Discontinuation from Study Treatment.........................................................................30
8.1.1.
Permanent Discontinuation from Study Treatment ...............................................30
8.1.2.
Temporary Discontinuation from Study Treatment...............................................30
8.1.3.
Discontinuation of Inadvertently Enrolled Subjects..............................................30
Discontinuation from the Study....................................................................................31
Lost to Follow-Up........................................................................................................31
9.
Study Assessments and Procedures ...................................................................................32
Efficacy and Safety Assessments..................................................................................32
9.1.1.
Primary Safety Assessments.................................................................................32
9.1.2.
Secondary Safety and Efficacy Assessments ........................................................33
9.1.3.
Appropriateness of Assessments ..........................................................................33
Adverse Events ............................................................................................................33
9.2.1.
Serious Adverse Events........................................................................................34
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................35
9.2.2.
Adverse Event Monitoring with a Systematic Questionnaire ................................35
9.2.3.
Complaint Handling.............................................................................................36
Treatment of Overdose.................................................................................................36
Safety...........................................................................................................................36
9.4.1.
Electrocardiograms ..............................................................................................36
9.4.2.
Vital Signs ...........................................................................................................36
9.4.3.
Laboratory Tests ..................................................................................................37
9.4.4.
Immunogenicity Assessments ..............................................................................37
9.4.5.
Other Tests...........................................................................................................37
9.4.6.
Safety Monitoring ................................................................................................37
9.4.6.1.
Hepatic Safety Monitoring..............................................................................37
Subject-Reported Outcomes .........................................................................................38
Pharmacokinetics .........................................................................................................38
Pharmacodynamics ......................................................................................................38
Pharmacogenomics ......................................................................................................39
9.8.1.
Sample for Pharmacogenetic Research.................................................................39
Biomarkers...................................................................................................................39
Health Economics and Medical Resource Utilization ...................................................39


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10.
Statistical Considerations ..................................................................................................40
Sample Size Determination ..........................................................................................40
Populations for Analyses..............................................................................................40
Statistical Analyses ......................................................................................................40
10.3.1.
General Statistical Considerations ........................................................................40
10.3.1.1.
Subject Characteristics....................................................................................41
10.3.1.2.
Disposition .....................................................................................................41
10.3.1.3.
Concomitant Therapy .....................................................................................41
10.3.1.4.
Treatment Compliance....................................................................................41
10.3.2.
Safety Analyses....................................................................................................41
10.3.2.1.
Hypoglycemic Events.....................................................................................41
10.3.2.2.
Laboratory Measurements ..............................................................................42
10.3.2.3.
Vital Signs......................................................................................................42
10.3.2.4.
Adverse Events Analyses................................................................................43
10.3.3.
Efficacy Analyses ................................................................................................43
10.3.3.1.
Actual and Change from Baseline HbA1c.......................................................43
10.3.3.2.
Subjects Reaching HbA1c Targets (≤6.5% or <7%) at 
Week 24 .........................................................................................................43
10.3.3.3.
Other Efficacy Parameters ..............................................................................44
10.3.4.
Analyses of Subject-Reported Outcomes..............................................................44
10.3.5.
Pharmacokinetic/Pharmacodynamic Analyses......................................................44
10.3.6.
Evaluation of Immunogenicity .............................................................................44
10.3.7.
Subgroup Analyses ..............................................................................................44
10.3.8.
Interim Analyses ..................................................................................................44
11.
References ........................................................................................................................45
12.
Appendices .......................................................................................................................46


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List of Tables
Table
Page
Table ABEX.1.
Schedule of Activities....................................................................................13
Table ABEX.2.
Objectives and Endpoints...............................................................................19
Table ABEX.3.
Estimated Precision Rates..............................................................................22
Table ABEX.4.
Recommendations for Dose Titrations ...........................................................26


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List of Figures
Figure
Page
Figure ABEX.1. Illustration of study design for clinical protocol I4L-IN-ABEX......................21


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................47
Appendix 2.
Clinical Laboratory Tests...............................................................................50
Appendix 3.
Study Governance Considerations..................................................................51
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................56
Appendix 5.
Sampling Summary .......................................................................................57
Appendix 6.
World Health Organization Classification of Diabetes ...................................58
Appendix 7.
Protocol Amendment 14L-IN-ABEX(b) Summary – A Multicenter, 
Open-Label, Single-Arm, Phase 4 Study to Assess the Safety of 
Basaglar in Subjects with Type 2 Diabetes Mellitus in India .........................59


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1. Synopsis
Title of Study:
A Multicenter, Open-Label, Single-Arm, Phase 4 Study to Assess the Safety of Basaglar in 
Subjects with Type 2 Diabetes Mellitus in India
Rationale:
Basaglar® (LY2963016; Eli Lilly and Company [Lilly], Indianapolis, IN, USA, and Boehringer 
Ingelheim, Ingelheim Rheim, Germany) is an insulin glargine product which received marketing 
approval in India in 2017 as a biosimilar of LANTUS® (Sanofi Aventis, Paris, France) insulin
glargine.  It is approved for the treatment of patients with type 1 and type 2 diabetes mellitus 
(T2DM) above 2 years of age. As a clause towards marketing approval, the Drug Controller 
General of India, in accordance to the biosimilar guidelines for India, recommended that 
Basaglar be studied in a minimum of 200 additional local subjects without specific guidance 
towards objective of the study from an efficacy or safety perspective.
Patients with T2DM who are unable to meet glycemic targets in spite of being on oral 
antihyperglycemic medications and/or glucagon-like peptide-1 receptor agonist and need to 
initiate basal insulin, are usually preferred for treatment with Basaglar.  Hence, it was decided to 
conduct the study in these patients.  The efficacy of the drug is well established based on results 
from 3 randomized controlled trials in patients with type 1 diabetes and T2DM. In this study, we
would seek to understand the safety of this drug in the local Indian population in accordance with 
the biosimilar guidelines of India.


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Objectives/Endpoints:
Objectives
Endpoints
Primary

To assess risk of hypoglycemia in 
adult subjects with T2DM in India 
who will be administered Basaglar

Incidence of total (symptomatic or asymptomatic,
with FBG level ≤54 mg/dL [3.0 mmol/L])
hypoglycemic events at Week 24
Secondary

To assess adverse events and other 
safety parameters in adult subjects 
with T2DM in India

SAEs and TEAEs

Rates per 30 days and per subject year of total 
(symptomatic or asymptomatic) hypoglycemic events

Incidence and rates per 30 days and per subject-year 
of nocturnal, severe, documented symptomatic and 
asymptomatic hypoglycemic events

Basal insulin dose (U/day and U/kg/day)

Change in weight and BMI at Week 24 from baseline 

To assess efficacy of Basaglar in adult 
subjects with T2DM in India

Change in HbA1c at Week 12 and Week 24 from 
baseline

Percentage of subjects reaching HbA1c targets ≤6.5% 
or <7%

Change in FBG levels at Weeks 4, 8, and 12 from 
baseline

Self-monitored 7-point SMBG levels at baseline, 
Weeks 4, 8, 12, and 24

Change in 7-point SMBG levels at Weeks 4, 8, 12, 
and 24 from baseline 

Intrasubject variability, as measured by SD of 7-point 
SMBG levels

To assess outcomes reported by adult 
subjects with T2DM in India

Change in Insulin Treatment Satisfaction 
Questionnaire score at Week 24 from Week 4
Abbreviations:  BMI = body mass index; FBG = fasting blood glucose; HbA1c = glycated hemoglobin; 
SAE = serious adverse event; SD = standard deviation; T2DM = type 2 diabetes mellitus; TEAE = 
treatment-emergent adverse event; SMBG = self-monitored blood glucose.
Summary of Study Design:
Study I4L-IN-ABEX is a multicenter, open-label, single-arm study, that will enroll insulin-naïve 
subjects with T2DM.  The study period consists of a screening period (Week -2 to Week 0), a 
treatment period (Week 0 to Week 24), and a safety follow-up visit at Week 28.
Treatment Arms:
This is a single-arm study.  Enrolled subjects will be treated with Basaglar using a self-titration 
scheme as outlined below.  


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Fasting Blood Glucose
(mg/dL)
Fasting Blood Glucose 
(mmol/L)
Dose Adjustments (Units)
<80
<4.4
-2
80-100
4.4-5.6
0
101-130
5.6-7.2
+2
131-160
7.3-8.9
+4
161-190
8.9-10.6
+6
>190
>10.6
+8
Number of Subjects:
Indian regulatory authorities have recommended the study to be done in a minimum of 200 local
subjects. Assuming a 15% screen failure rate, approximately 295 subjects will be screened, so 
that 250 subjects can be enrolled.  Assuming a drop-out rate of 20%, the target is to have a 
minimum of 200 subjects completing the present study.
In the India subpopulation of ELEMENT 5 study, 5 of the 46 insulin-naïve subjects experienced 
at least 1 hypoglycemic event (total hypoglycemia incidence with glucose levels ≤54 mg/dL [3.0 
mmol/L]) during the overall study period.  When considering the total ELEMENT 5 population, 
146 out of 489 subjects (30%) experienced at least 1 hypoglycemic event during the overall 
study period.  Based on these estimates, the precision with 250 and 200 subjects would be as 
follows (95% confidence interval for proportion shown based on normality assumption):
Sample 
Size
Estimated 
Proportion
Standard 
Error
Width of 
Proportion to 
95% 
Confidence 
Limit
Width of 
Interval 
(2 Sides)
95% Lower 
Confidence 
Limit
95% Upper 
Confidence Limit
250
11%
2.0%
3.9%
7.80%
7.1%
14.9%
250
30%
2.9%
5.7%
11.40%
24.3%
35.7%
200
11%
2.2%
4.3%
8.60%
6.7%
15.3%
200
30%
3.2%
6.4%
12.80%
23.6%
36.4%
Statistical Analysis:
No randomization will be performed as this is a single-arm study.  The sample size was 
calculated assuming a 15% screen failure rate, with a target to have a minimum of 200 subjects 
completing the study.  No interim analyses and/or sample size re-estimation are planned to be 
performed.


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Statistical Methodology:
Primary endpoint:  Incidence of the total (symptomatic and asymptomatic) hypoglycemic events 
at Week 24 will be assessed as number and percentage of subjects experiencing at least 1 event 
over the study period. 
Secondary outcomes:  Actual values and change in glycated hemoglobin (HbA1c) level from 
baseline to Week 12 and Week 24 will be analyzed in a descriptive manner on non-missing 
values and last observation carried forward-imputed values.  Additionally, a general linear model
will be performed on the full analysis set (FAS), with change from baseline in HbA1c level as 
the dependent variable and the baseline value of HbA1c as a covariate.
The number of hypoglycemic events per subject, the rate of hypoglycemic events per 30 days, 
and the rate per year, that is, the number of hypoglycemic events per subject year (365.25 days) 
will be assessed using a negative binomial model, with baseline HbA1c as a covariate and the 
log of the study treatment exposure time as an offset variable.
The analysis for other continuous secondary efficacy and safety measurements and continuous 
laboratory measures will use the general linear model for the FAS population with the baseline 
value of the response variable as a covariate.


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2. Schedule of Activities


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Table ABEX.1.
Schedule of Activities
Procedure
Screening
Treatment Period
Follow-up
Notes
Visit
1
2
3
4
5
6a
7a
8
9/ET
Week of Study
-2
0
4
8
12
16
20
24
28
Allowable Deviation 
+/- (days)
3
7
7
7
7
7
7
Informed consent
X
Subject number assigned
X
Inclusion and exclusion 
criteria
X
Clinical Assessments
Demography
X
Full physical 
examination 
X
Height and weight
X
X
X
Height will be measured only at 
screening.
Vital signsb
X
X
X
X
X
X
X
SBP, DBP, and PR
Medical history and 
family history of CV 
disease
X
History of substance 
usage
X
Substances:  drugs, alcohol, 
tobacco, and caffeine
12-lead ECG
X
To be recorded in a resting supine 
state
Concomitant medication 
review
X
X
X
X
X
X
X
X
X
AE/SAE/complaint 
handling
X
X
X
X
X
X
X
X
Hypoglycemic events
X
X
X
X
X
X
X
X
Completion or
discontinuation of
investigation
X
X
X
X
X
X
X
FBGc
X
X
X
X


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Procedure
Screening
Treatment Period
Follow-up
Notes
Visit
1
2
3
4
5
6a
7a
8
9/ET
Week of Study
-2
0
4
8
12
16
20
24
28
Allowable Deviation 
+/- (days)
3
7
7
7
7
7
7
7-point SMBG 
measurementd
X
X
X
X
X
Laboratory 
Assessments
Hematology, clinical 
chemistry, and urinalysis 
tests
X
X
X
See Appendix 2 for details.
Estimated glomerular filtration rate 
will be measured only in subjects 
with a history of severe chronic 
kidney disease.
Pregnancy test (for 
WCBP only)
X
X
Serum pregnancy test at Visit 1 
and urine pregnancy test at Visit 2 
prior to being given the study drug
HIV, hepatitis B and C
X
HbA1c measurement
X
X
X
X
Subject-reported 
outcomes
ITSQ
X
X
Ancillary 
Supplies/Diaries/Study 
Drug
Trainings on 
signs/symptoms of
hypo/hyperglycemia and 
insulin reactions
X
X
X
X
X
X
X
This training is given at baseline 
and reinforced at every visit of the 
treatment period
Trainings on injection 
technique, use of 
glucometer and 7-point 
SMBG measurement
X
X
X
X
X
X
This training is given during 
screening and reinforced at every 
face-to-face visit of the treatment 
period


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Procedure
Screening
Treatment Period
Follow-up
Notes
Visit
1
2
3
4
5
6a
7a
8
9/ET
Week of Study
-2
0
4
8
12
16
20
24
28
Allowable Deviation 
+/- (days)
3
7
7
7
7
7
7
Self-titration traininge
X
X
X
X
X
X
X
This training is given at baseline 
and reinforced at every visit of the 
treatment period
Dispense study diary
X
X
Pretreatment study diary will be 
dispensed at Visit 1 and 
comprehensive study diary will be 
dispensed at Visit 2
Dispense study drug
X
X
X
X
Review study diary
X
X
X
X
X
Pretreatment study diary will be 
collected at Visit 2 and 
comprehensive study diary will be 
collected at Visit 8
Collect unused study 
drug
X
X
X
X
Dispense glucometer 
X
Compliance to study 
drug administration
X
X
X
X
X
X
X
Adjust insulin dose (if 
required)
X
X
X
X
Site personnel will review the 
Basaglar dose and FBG levels
recorded in the subject diary. 
They may recommend change in 
dose of Basaglar if required.


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Abbreviations:  AE = adverse event; CV = cardiovascular; DBP = diastolic blood pressure; ECG = electrocardiogram; ET = early termination; FBG = fasting 
blood glucose; HbA1c = glycated hemoglobin; HIV = human immunodeficiency virus; ITSQ = Insulin Treatment Satisfaction Questionnaire; PR = pulse rate; 
SAE = serious adverse event; SBP = systolic blood pressure; SMBG = self-monitored blood glucose; WCBP = women of child-bearing potential.
a
Telephone visit.
b
All vital signs should be recorded in the subject in a resting state.  If there is a suspicion of postural hypotension or autonomic instability, the investigators at 
their discretion might decide to record the blood pressure in a supine state and then after standing for 2 minutes to detect any postural hypotension.  Blood 
pressure measurements should be done in the left arm with sphygmomanometer held at the level of the heart.  Blood pressure recording in both arms is at the 
investigators’ discretion in selective cases of pulse volume inequality or pulse being absent in either of the arms.
c
Subjects will be instructed to daily measure the FBG levels mandatorily using glucometer before the morning meal till Week 12 and record in the subject 
diary.  Also, subjects will be instructed to measure and record the blood glucose levels using glucometer if they have symptoms of hypoglycemia (including 
nocturnal hypoglycemia) at any time of the day or night.
d
Subjects will be instructed to perform 7-point SMBG level monitoring (glucose measurements before breakfast, lunch, and dinner; 2 hours after breakfast, 
lunch, and dinner; and at 3 am [± 1 hour]) 2-3 days in the week prior to Visits 2, 3, 4, 5, and 8, and record the values in the subject diary.  Subjects will be 
instructed to carry the glucometers to the sites on Visits 2, 3, 4, 5, and 8.
e
Subjects will be instructed to record the actual time and dose of Basaglar administration in the subject diary.


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3. Introduction
Study Rationale
Basaglar® (LY2963016; Eli Lilly and Company [Lilly], Indianapolis, IN, USA, and Boehringer 
Ingelheim, Ingelheim Rheim, Germany) and LANTUS® (Sanofi Aventis, Paris, France) are basal 
insulin glargine analogs that have identical amino acid sequence and similar pharmacological 
profiles.  Basaglar received marketing approval in India on 21 August 2017 for the treatment of 
patients with type 1 diabetes and type 2 diabetes mellitus (T2DM) above 2 years of age.  As a 
clause towards marketing approval, the Drug Controller General of India (DCGI), in accordance 
to the biosimilar guidelines for India, recommended that Basaglar be studied in a minimum of 
200 additional local subjects (there were 100 subjects from India in the ELEMENT 5 study) 
without specific guidance towards objective of the study from an efficacy or safety perspective.
Patients with T2DM who are unable to meet glycemic targets in spite of being on oral 
antihyperglycemic medications (OAMs) and/or glucagon-like peptide-1 receptor agonist (GLP-1 
RA) and need to initiate basal insulin, are usually preferred for treatment with Basaglar.  Hence, 
it was decided to conduct the study in these patients.  The efficacy of the drug is well established 
based on results from 3 randomized controlled trials in patients with type 1 diabetes and T2DM. 
In this study, we would seek to understand the safety of this drug in the local Indian population 
in accordance with the biosimilar guidelines of India.
Background
Diabetes and its comorbidities present major health challenges to individuals and society at large 
by imposing an economic burden. Diabetes often turns fatal, thus, it has a detrimental impact on 
the economic burden of the society (Wild et al. 2004).  The number of patients with T2DM is
increasing rapidly.  Of the current population burdened with T2DM, 60% are Asians (Hu 2011).  
Currently, India has an estimated 73 million people with diabetes, the second largest number for 
any individual country in the world.  The projected growth between the period 2017 and 2045 in 
India is one of the highest in the world.  By the year 2045, approximately 134 million people in 
India are projected to be suffering from diabetes as against 120 million in China (IDF 2017).
Insulins play an important role in the treatment of T2DM.  Recent guidelines highlight the 
importance of initiation of basal insulin in patients with T2DM who fail to attain glycemic 
targets with non-insulin therapeutic options (Davies et al. 2018).  Insulin initiation in India is 
often delayed, by almost a decade after diagnosis of diabetes.  During this period, subjects are 
recommended various combinations of available OAMs and/or GLP-1 RA. Often, subjects are 
not able to achieve the glycemic targets in spite of these OAMs.
ELEMENT 5, a Phase 3, prospective, randomized, multinational, 2-arm, active-controlled, 
open-label, parallel-design study conducted in subjects with T2DM, showed that efficacy and 
safety profiles of Basaglar and LANTUS were similar (Pollom et al. 2019).


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Benefit/Risk Assessment
There are different ways of insulin initiation in India – twice-daily neutral protamine Hagedorn 
insulin or once-daily LANTUS or premixed insulin.  It is increasingly becoming easier to initiate
subjects on long acting insulins due to its once-in-a-day dose.  Evidence from several large 
randomized controlled trials showed that self-titration of insulin can help to reduce levels of 
glycated hemoglobin (HbA1c) and fasting blood glucose (FBG) without increasing the risk of 
hypoglycemia.  This study involving glucometer-based blood glucose measurement can further 
substantiate the fact that subjects can self- titrate basal insulin in India without increased risk of 
hypoglycemia.
More detailed information about the known and expected benefits and risks of Basaglar may be 
found in the Patient Information Leaflet, Package Insert, or Summary of Product Characteristics.


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4.
Objectives and Endpoints
Table ABEX.2 shows the objectives and endpoints of the study.
Table ABEX.2.
Objectives and Endpoints
Objectives
Endpoints
Primary

To assess risk of hypoglycemia in 
adult subjects with T2DM in India 
who will be administered Basaglar

Incidence of total (symptomatic or asymptomatic with 
FBG level of ≤54 mg/dL [≤3.0 mmol/L])
hypoglycemic events at Week 24
Secondary

To assess adverse events and other 
safety parameters in adult subjects 
with T2DM in India

SAEs and TEAEs

Rates per 30 days and per subject year of total 
(symptomatic or asymptomatic) hypoglycemic events 

Incidence and rates per 30 days and per subject-year of 
nocturnal, severe, documented symptomatic and 
asymptomatic hypoglycemic events

Basal insulin dose (U/day and U/kg/day)

Change in weight and BMI at Week 24 from baseline

To assess efficacy of Basaglar in 
adult subjects with T2DM in India 

Change in HbA1c at Week 12 and Week 24 from
baseline

Percentage of subjects reaching HbA1c targets ≤6.5% 
or <7%

Change in FBG levels at Weeks 4, 8, and 12 from 
baseline

Self-monitored 7-point SMBG levels at baseline, 
Weeks 4, 8, 12, and 24 

Change in 7-point SMBG levels at Weeks 4, 8, 12, and 
24 from baseline 

Intrasubject variability, as measured by SD of 7-point 
SMBG levels

To assess outcomes reported by adult 
subjects with T2DM in India

Change in Insulin Treatment Satisfaction 
Questionnaire scores at Week 24 from Week 4
Abbreviations: BMI = body mass index; FBG = fasting blood glucose; HbA1c = glycated hemoglobin; SAE = 
serious adverse event; SD = standard deviation; SMBG = self-monitored blood glucose; T2DM = type 2 diabetes 
mellitus; TEAE = treatment-emergent adverse event.


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5. Study Design
Overall Design
Study I4L-IN-ABEX (ABEX) is a multicenter, open-label, single-arm, Phase 4 study to assess 
the safety of Basaglar in subjects with T2DM in India.
The study design includes the following periods:  

Screening (Week -2 to Week 0)

Treatment 
o
Titration period (Week 0 to Week 12)
o
Maintenance period (Week 12 to 24)

Safety Follow-up (Week 28)
Week 0 to Week 12 will be the titration phase followed by the maintenance phase till Week 24.  
Approximately 295 subjects will be screened as per the inclusion and exclusion criteria 
mentioned in Sections 6.1 and 6.2, respectively, so that 250 subjects can be enrolled in the study, 
with a target to have a minimum of 200 subjects completing the present study.  Subjects will be 
screened at Visit 1 and eligible subjects will be administered with Basaglar once daily (QD) from 
Visit 2 for a period of 24 weeks.
The starting dose will be 10 units QD.  All subjects will be trained at Screening (Visit 1) on
insulin injection administration technique, use of glucometer, and 7-point SMBG measurement.  
These trainings will be reinforced at every face-to-face visit of the treatment period.  Subjects
will self-administer Basaglar at bedtime.  The doses may be titrated by 2-4 units once or twice in 
a week until FBG levels are lowered to <100 mg/dL (5.6 mmol/L).
Study governance considerations are described in detail in Appendix 3.
Figure ABEX.1 illustrates the study design.


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*Telephone visit
Abbreviations:  GLP-1 RA = glucagon-like peptide-1 receptor agonist; OAM = oral antihyperglycemic medications; 
QD = once daily.
Figure ABEX.1.
Illustration of study design for clinical protocol I4L-IN-ABEX.
5.1.1. Study Visits
Screening period (Week -2 to Week 0)
Multiple procedures will be done during the screening period to assess eligibility of subjects for 
inclusion in the study (Sections 6.1 and 6.2) as specified in the Schedule of Activities 
(Section 2).  Subjects will be provided glucometers and study diaries at Screening (Visit 1).
Treatment period (Week 0 to Week 24)
Study participants found eligible during the screening period will begin their treatment at Visit 2. 
All measures to be performed at Visit 2 will be done prior to administration of Basaglar. All 
necessary trainings will be imparted at Visits 1 and 2 and will be reinforced at subsequent visits 
as outlined in Section 2.
Subjects will be instructed to carry the glucometers to the sites at Visits 2, 3, 4, 5, and 8. 
Subjects will be instructed to measure and record the FBG levels daily before the morning meal
till Week 12.  Also, subjects will be instructed to measure and record the blood glucose levels if 
they have symptoms of hypoglycemia at any time of the day or night. Subjects will be instructed 
to perform 7-point self-monitored blood glucose (SMBG) level monitoring (glucose 
measurements before breakfast, lunch, and dinner; 2 hours after breakfast, lunch, and dinner; and 
at 3 am [± 1 hour]) 2 to 3 days in the week prior to Visits 2, 3, 4, 5, and 8 and record the values 
in the subject diary (Section 2).
Subjects will self-administer Basaglar QD at bedtime. They will self-titrate once or twice in a 
week until FBG levels are lowered to <100 mg/dL (5.6 mmol/L).


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Follow-up Visit (Week 28)
All subjects will have a follow-up visit 4 weeks after the last dose of Basaglar. Assessments at 
this visit will be done as detailed in Section 2. Subjects who withdraw from the study will also 
have assessments done similar to those at the follow-up visit.
Number of Participants
Assuming a 15% screen failure rate, approximately 295 subjects will be screened, so that 250 
subjects can be enrolled. Assuming a drop-out rate of 20%, the target is to have a minimum of 
200 subjects completing the present study.
In the India subpopulation of ELEMENT 5 study, 5 of the 46 insulin-naïve subjects experienced 
at least 1 hypoglycemic event (total hypoglycemia incidence with glucose levels ≤54 mg/dL
[3.0 mmol/L]) during the overall study period. When considering the total ELEMENT 5 
population, 146 out of 489 subjects (30%) experienced at least 1 hypoglycemic event during the 
overall study period. Based on these estimates, the precision with 250 and 200 subjects would be 
as outlined in Table ABEX.3 (95% confidence interval for proportion shown based on normality 
assumption).
Table ABEX.3.
Estimated Precision Rates
Sample 
Size
Estimated 
Proportion
Standard 
Error
Width of 
Proportion to 
95% 
Confidence 
Limit
Width of 
Interval 
(2 sides)
95% Lower 
Confidence 
Limit
95% Upper 
Confidence 
Limit
250
11%
2.0%
3.9%
7.80%
7.1%
14.9%
250
30%
2.9%
5.7%
11.40%
24.3%
35.7%
200
11%
2.2%
4.3%
8.60%
6.7%
15.3%
200
30%
3.2%
6.4%
12.80%
23.6%
36.4%
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last subject.
Scientific Rationale for Study Design
The ELEMENT 5 study has proven the noninferiority of Basaglar administered QD to LANTUS 
administered QD, as measured by change in HbA1c level from baseline to 24 weeks, when used 
in combination with OAMs.  Basaglar received marketing approval as a basal insulin for the 
treatment of type 1 diabetes and T2DM in India in 2017 in subjects above 2 years of age.  
Biosimilar guidelines (effective August 2016) recommend the safety of the biosimilar to be


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evaluated in at least 300 subjects.  There were 100 subjects from India in the ELEMENT 5 study.  
As a clause towards marketing approval, the DCGI recommended that Basaglar be studied in a 
minimum of 200 additional local subjects without specific guidance towards objective of the 
study from an efficacy or safety perspective.
Patients with T2DM who are unable to meet glycemic targets in spite of being on OAMs and/or 
GLP-1 RA and need to initiate basal insulin, are usually preferred for treatment with Basaglar.  
Hence, it was decided to conduct the study in these patients.
Thus we designed a multicenter, open-label, single-arm, Phase 4 study to assess the safety and 
efficacy of Basaglar in subjects with T2DM who are on ≥2 OAMs and/or GLP-1 RA and are 
insulin-naïve with inadequate glycemic control.
Justification for Dose
The American Diabetes Association (2018) recommends initiation of basal insulin at 10 units or 
0.1 to 0.2 unit/kg/day depending on the degree of hyperglycemia.  Subjects can self-titrate once 
or twice in a week by 2 to 4 units or 10% to 15% to reach the target FBG level of <100 mg/dL
(5.6 mmol/L).  In case of hypoglycemia, the dose can be reduced by 4 units or 10% to 20%.  The 
American Association of Clinical Endocrinologists consensus statement of 2018 recommends 
initiation of basal insulin based on HbA1c level of 8% (total daily insulin dose: 0.2 to 0.3
unit/kg).  Thus, in this study the starting dose will be 10 units QD and the dose may be titrated 
every 2 to 3 days to reach the glycemic goal.


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6.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
Inclusion Criteria
Subjects are eligible to be included in the study only if they meet all of the following criteria at 
screening:
[1] have T2DM based on the disease diagnostic criteria from the World Health Organization 
(WHO) classification (Appendix 6) for at least 6 months before screening
[2] men or non-pregnant women aged more than 18 years and less than 75 years at the time 
of screening
[3] have been receiving GLP-1 RA or ≥2 OAMs at stable doses for 90 days prior to Visit 1 
[4] have an HbA1c level ≥7.0% and <11.0%
[5] have never been treated with insulins except for short term treatment of acute conditions 
up to a maximum of 14 days
[6] are able and willing to provide signed informed consent to participate in this study in 
accordance with local regulations
Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria at
screening:
[7] have any form of diabetes other than T2DM
[8] have hypersensitivity to the active substance of Basaglar or to any of the excipients
[9] have any clinically significant disorder, other than T2DM, that in the investigator’s 
opinion, would preclude participation in the trial
[10]are receiving systemic glucocorticosteroids therapy or have excessive insulin resistance 
(total insulin dose >2 U/kg)
[11]have a history or diagnosis of human immunodeficiency virus infection, hepatitis B and 
C
[12]have comorbidities of unstable angina, cardiac failure (Stage III or IV as per New York 
Heart Association guidelines) or renal failure (estimated glomerular filtration rate <30 
mL/min/m2)
[13]are pregnant or intend to become pregnant during the course of the study; or are sexually 
active women of child-bearing potential not actively practicing birth control by a 
medically acceptable method as determined by the investigator 
[14]is a woman who is breastfeeding
[15]are investigator site personnel directly affiliated with this study and/or their immediate 
families.  Immediate family is defined as spouse, parent, child, or sibling, whether 
biological or legally adopted
[16]are Lilly employees or are employees of third party organizations involved in the study 
who require exclusion of their employees


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[17]have participated within the last 30 days in a clinical trial involving an investigational 
product other than the Basaglar.  If the previous investigational product has a long 
half-life, 3 months or 5 half-lives (whichever is longer) should have passed
[18]have previously completed or withdrawn from this study or any other study investigating 
Basaglar.  This exclusion criterion does not apply to subjects who are rescreened prior to 
baseline visit
[19]are currently enrolled in any other clinical study involving an investigational product or 
any other type of medical research judged not to be scientifically or medically 
compatible with this study
[20]are unwilling or unable to comply with the use of a glucometer
6.2.1. Rationale for Exclusion of Certain Study Candidates
Exclusion criteria [7], [8], [10], and [12] exclude medications or conditions that may cause 
HbA1c lowering not attributable to the regimens being studied or which could lead to
misinterpretation of the results.
Exclusion criterion [9] permits investigators to exclude subjects who meet all other inclusion and 
exclusion criteria but may not be appropriate for this study.
Exclusion criterion [11] may prevent subjects from completing the protocol, may influence the 
effect or safety of study regimens.
Exclusion criteria [13] and [14] ensure the safety of unborn and newborn children.
Exclusion criteria [15] and [16] reduce potential bias due to conflict of interest.
Exclusion criteria [17], [18], [19], and [20] prevents a situation in which potential positive or 
negative outcomes may not be clearly attributable to the regimens in the study.
Lifestyle Restrictions
Patients will be suggested to continue their usual exercise habits and generally follow a healthy 
meal plan throughout the course of the study.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) at the 
initial visit may be later rescreened only once. The interval between screening and rescreening 
should be at least 4 weeks. A new informed consent form (ICF) must be signed at the time of 
rescreening and the study participant will be assigned a new identification number. A single 
repeat testing of suspected erroneous/spurious central laboratory results is allowed without 
rescreening the study participant.  These will be done in consultation with the Lilly clinical 
research physician (CRP).


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7. Treatments
Treatments Administered
Subjects will receive Basaglar QD at bedtime.  The starting dose will be 10 units.  Subjects can 
self-titrate as outlined in Table ABEX.4 once or twice weekly until FBG is lowered to 
<100 mg/dL (5.6 mmol/L).  In case of hypoglycemia, the dose can be reduced by 4 units.  
Subjects will continue their pre-study anti-diabetic medications at the prescribed dosage 
throughout the study except for risks described in Section 7.7. It is recommended that doses of
anti-diabetic medications being taken by the subjects is stable for 90 days prior to enrolling them 
in this study. However, the investigator can recommend that these doses be optimized to 
maximum tolerated dose during 2 weeks of the screening period. If the target FBG levels are not 
achieved at Visit 2, the subjects are included in the study and Basaglar is initiated.
Table ABEX.4.
Recommendations for Dose Titrations
Fasting Blood Glucose
(mg/dL)
Fasting Blood Glucose 
(mmol/L)
Dose Adjustments (Units)
<80
<4.4
-2
80-100
4.4-5.6
0
101-130
5.6-7.2
+2
131-160
7.3-8.9
+4
161-190
8.9-10.6
+6
>190
>10.6
+8
The investigator or his or her designee is responsible for

explaining the correct use of the investigational agent to the subject

verifying that instructions are followed properly

maintaining accurate records of investigational product dispensing and collection, 
and

returning all unused medication to Lilly or its designee at the end of the study, 
unless the sponsor and sites have agreed all unused medication is to be destroyed 
by the site, as allowed by local law.
7.1.1. Packaging and Labelling
Clinical study materials will be labeled according to the country’s regulatory requirements.


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7.1.2. Medical Devices
Glucometers, test strips, and lancets will be provided to patients. Patients will be trained to use 
glucometers to self-monitor the blood glucose levels as specified in the Schedule of Activities 
(Section 2).
Method of Treatment Assignment
Patients who meet all criteria for enrollment will be assigned to Basaglar treatment.  
7.2.1. Selection and Timing of Doses
Subjects will self-administer the insulin every day at bedtime after dinner.  Patients will record 
the actual time and dose of all administrations of Basaglar in the subject diary. Later, these data 
will be recorded in the subjects’ electronic case report form (eCRF).  
Blinding
This is an open-label study. The investigational product will be procured from commercially 
available Basaglar in India. The investigational product will be adequately labeled to indicate 
that it is only for use in the clinical study and is not for sale. 
Dosage Modification
The doses may be titrated by 2 to 4 units once or twice in a week until FBG levels are lowered to 
<100 mg/dL (5.6 mmol/L) as tabulated in Table ABEX.4.
Investigators will be trained to assess when they need to intervene the treatment regimen of 
subjects who do not reach glycemic targets.  If any of the FBG values for 2 consecutive weeks 
exceed the limits outlined below with no other possible cause of hyperglycemia, rescue 
medication (more OAMs or GLP-1 RA or bolus insulin; switching to a different basal insulin is 
not permitted as decided by the investigator) will be prescribed in addition to the ongoing
treatment.  

FBG >270 mg/dL (>15.0 mmol/L) from baseline to Week 6 (4 values/week)

FBG >240 mg/dL (>13.3 mmol/L) from Week 6 to Week 12 (4 values/week)

FBG >200 mg/dL (>11.1 mmol/L) from Week 12 to end of trial (4 values/week)

HbA1c ≥8.5% (≥69.4 mmol/mol) by and after Week 24
The dose and name of rescue medication must be properly documented in the eCRF. Subjects 
who had to use rescue medication during the study period will be excluded from the per protocol 
set (PPS) population.
Preparation/Handling/Storage/Accountability
The investigator or his or her designee is responsible for


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
confirming that appropriate temperature conditions have been maintained during 
transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment. The drug product should be stored at 
room temperature for no more than 28 days or under refrigerated conditions (2oC 
to 8oC) for long-term storage.

ensuring that only participants enrolled in the study may receive study treatment 
and only authorized site staff may supply or administer study treatment. All study 
treatments must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions,
with access limited to the investigator and authorized site staff.

the investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (such as receipt, reconciliation and final disposition records).
Treatment Compliance
Subject compliance with study medication will be assessed at each visit of the treatment period.  
Compliance will be assessed by 

subject’s glycemic control

adherence to the visit schedule

dosing-titration algorithm

administration of study insulin, and 

any other parameters the investigator deems necessary.  
Deviations from the prescribed dosage regimen should be recorded in the eCRF.
The subject will be considered significantly noncompliant if during the study he or she misses 

more than 3 consecutive days of study medication (full doses), or 

more than 15 cumulative days of study medication (full doses).  
Similarly, a subject will be considered significantly noncompliant if he or she is judged by the 
investigator to have intentionally or repeatedly taken more than the prescribed amount of 
medication. All such subjects will be considered to have withdrawn from the study.  The last 
observation carried forward (LOCF) replacement of these subjects will be taken under the 
supervision of Lilly or its designee if the target number of subjects (a minimum of 200) is at risk 
to be achieved.
Concomitant Therapy
All combination of OAMs or GLP-1 RAs are allowed in the protocol and can be continued with 
Basaglar.  Subjects need to be on GLP-1 RA or at least 2 OAMs at the time of entering the study.  
For subjects on thiazolidinediones, the investigator may consider reducing the dose or 
discontinuing it, if there is risk of fluid retention in the subject or complaint of shortness of 
breath during rest. For subjects on sulphonylureas, the investigator may consider to modify the 
dose in cases of hypoglycemia.


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Treatment after the End of the Study
7.8.1. Study Extensions
Not applicable.
7.8.2. Treatment after Study Completion
Basaglar will not be made available to subjects from the study team after conclusion of the study.  
The subject can continue to take commercially available Basaglar or any other basal insulin 
analog as recommended by the investigator.  The access of the drug to the subjects can be 
confirmed in the follow-up visit.
7.8.3. Special Treatment Considerations
Following an event of severe hypoglycemia or in cases where subjects require assistance to 
recover from hypoglycemia, the subject may continue in the study depending on the decision of 
the investigator in consultation with Lilly CRP.  This may require a reduction in dosage of basal 
insulin being administered and titration algorithm provided above can be referred to or at the 
discretion of the investigator.


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8.
Discontinuation Criteria
Discontinuation from Study Treatment
8.1.1. Permanent Discontinuation from Study Treatment
Following are the possible reasons leading to permanent discontinuation of investigational 
product:

Subject decision
o
The subject requests to discontinue investigational product.

Discontinuation due to a hepatic event or liver test abnormality
Subjects who are discontinued from the investigational product due to a hepatic event or 
liver test abnormality should have additional hepatic safety data collected in the eCRF.
Discontinuation of the investigational product due to abnormal liver tests should be
considered by the investigator when a subject meets 1 of the following conditions after 
consultation with the Lilly-designated medical monitor:
o
alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8X upper limit 
of normal (ULN)
o
ALT or AST >5X ULN for more than 2 weeks
o
ALT or AST >3X ULN and total bilirubin level (TBL) >2X ULN or international 
normalized ratio >1.5
o
ALT or AST >3X ULN, with the appearance of fatigue, nausea, vomiting, right 
upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
o
alkaline phosphatase (ALP) >3X ULN
o
ALP >2.5X ULN and TBL >2X ULN
o
ALP >2.5X ULN, with the appearance of fatigue, nausea, vomiting, right quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%)
Subjects discontinuing from the investigational product prematurely for any reason should 
complete adverse events (AEs) and other safety follow-up as per Section 2 (Schedule of 
Activities), Section 9.2 (Adverse Events), and Section 9.4 (Safety) of this protocol.
8.1.2. Temporary Discontinuation from Study Treatment
Not applicable.
8.1.3. Discontinuation of Inadvertently Enrolled Subjects
If the sponsor or investigator identifies a subject who did not meet enrollment criteria and was 
inadvertently enrolled, then the subject should be discontinued from study treatment, unless there 
are extenuating circumstances that make it medically necessary for the subject to continue on 
study treatment.  If the investigator and Lilly CRP agree it is medically appropriate to continue, 
the investigator must obtain documented approval from Lilly CRP to allow the inadvertently 
enrolled subject to continue in the study with or without treatment with Basaglar.  Safety 


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follow-up is as outlined in Section 2 (Schedule of Activities), Section 9.2 (Adverse Events), and
Section 9.4 (Safety) of the protocol.
Discontinuation from the Study
Subjects will be discontinued from the study in the following circumstances:

enrollment in any other clinical study involving an investigational product or enrollment 
in any other type of medical research judged not to be scientifically or medically 
compatible with this study

participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice

investigator decision
o
the investigator decides that the subject should be discontinued from the study
o
if the subject, for any reason, requires treatment with another therapeutic agent that 
has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent
o
if the subject has persistent hypoglycemia or increased risk of hypoglycemia

subject decision
o
the subject or the subject’s designee requests to be withdrawn from the study
Subjects discontinuing from the study prematurely for any reason should complete AEs and 
other safety follow-up per Section 2 (Schedule of Activities), Section 9.2 (Adverse Events), and
Section 9.4 (Safety) of this protocol.
Lost to Follow-Up
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact subjects who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.


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9.
Study Assessments and Procedures
Section 2 lists the Schedule of Activities, with the study procedures and their timing (including 
tolerance limits for timing).
Appendix 2 lists the laboratory tests that will be performed for this study.
Appendix 5 provides a summary of the maximum number and volume of invasive samples, for 
all sampling, during the study.
Unless otherwise stated in the subsections below, all samples collected for specified laboratory 
tests will be destroyed within 60 days of receipt of confirmed test results.  
Efficacy and Safety Assessments
9.1.1. Primary Safety Assessments
Hypoglycemia
Information on treatment-emergent hypoglycemic events starting from Visit 2 until the last study 
visit (Visit 9 or early termination [ET] visit) will be collected. Subjects will be trained about 
signs and symptoms of hypoglycemia. Subjects will be trained to check and record their blood 
glucose levels if they experience symptoms suggestive of hypoglycemia.  For each 
hypoglycemic event, subjects should record the following data in the study diaries provided by 
the sponsor via the investigator:

blood glucose levels

associated symptoms

treatment, and 

other pertinent information.
A hypoglycemic event is defined as any time a subject feels that he or she is experiencing a sign 
or symptom that is associated with hypoglycemia or has a FBG level of ≤54 mg/dL 
(3.0 mmol/L), even if it was not associated with signs, symptoms, or treatment consistent with 
current guidelines.
Severe hypoglycemia:  An event requiring assistance of another person to actively administer 
carbohydrates or glucagon or taking other corrective actions.  Blood glucose concentrations may 
not be available during an event, but neurologic recovery following the return of blood glucose 
to normal levels is considered sufficient evidence that the event was induced by a low blood 
glucose concentration.
Nocturnal hypoglycemia: Any total hypoglycemic event that occurs after bedtime and prior to
the first meal in the morning.  
Documented symptomatic hypoglycemia: An event during which typical symptoms of 
hypoglycemia are accompanied by a blood glucose level of ≤54 mg/dL (≤3.0 mmol/L) as 
confirmed by blood glucose measurement.


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Asymptomatic hypoglycemia: Any event not accompanied by typical symptoms of 
hypoglycemia but a measured a blood glucose level of ≤54 mg/dL (≤3.0 mmol/L) was observed.
9.1.2. Secondary Safety and Efficacy Assessments

Serious adverse events (SAEs) and treatment-emergent adverse events (TEAEs)

Rates per 30 days and per subject year of total hypoglycemic events (symptomatic or 
asymptomatic)

Incidence and rates per 30 days and per subject-year of nocturnal, severe, documented 
symptomatic and asymptomatic hypoglycemic events

Change in HbA1c levels at Weeks 12 and 24 from baseline

Percentage of subjects reaching HbA1c targets ≤6.5% or <7%

Change in FBG levels at Weeks 4, 8, and 12 from baseline

Self-monitored 7-point SMBG levels at baseline, Weeks 4, 8, 12, and 24

Change in 7-point SMBG levels at Weeks 4, 8, 12, and 24 from baseline 

Intrasubject variability, as measured by the standard deviation (SD) of 7-point SMBG
levels

Basal insulin dose (U/day and U/kg/day)

Change in weight and body mass index at Week 24 from baseline 

Change in Insulin Treatment Satisfaction Questionnaire (ITSQ) score at Week 24 from
Week 4
9.1.3. Appropriateness of Assessments
All safety and efficacy assessments included in this study are generally regarded as reliable and 
accurate with respect to diabetes mellitus.
Adverse Events
Investigators are responsible for monitoring the safety of subjects who have entered this study 
and for alerting Lilly or its designee of any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the subject.
The investigator is responsible for the appropriate medical care of subjects during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that

are serious or otherwise medically important

are considered related to the investigational product or the study, or 

cause the subject to discontinue the investigational product before completing the study.  
The investigator will record all relevant AE/SAE information in the eCRF.  The subject should 
be followed until the event 

resolves

stabilizes with appropriate diagnostic evaluation, or 


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
is reasonably explained.  
The frequency of any additional follow-up evaluations of AEs between site and telephonic visits
is left at the discretion of the investigator.
After the ICF is signed, study site personnel will record the occurrence and nature of each 
subject’s preexisting conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study in eCRFs.  In addition, site personnel will record any change 
in the condition(s) and any new conditions as AEs. Investigators should record their assessment 
of the potential relatedness of each AE to protocol procedure and investigational product in the 
eCRFs.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account the 
disease, concomitant treatment, or pathologies.
A “reasonable possibility” means that there is a cause and effect relationship between the 
investigational product, study device, and/or study procedure and the AE.
The investigator answers yes or no when making this assessment.
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.
If a subject’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via eCRFs clarifying, if possible, the circumstances 
leading to any dosage modifications or discontinuations of treatment.  
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in 1 of the following outcomes:

death

initial or prolonged insubject hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in 
death or hospitalization, but may jeopardize the subject or may require 
intervention to prevent 1 of the other outcomes listed in the definition above.  
Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency department or at home, blood dyscrasias or 
convulsions that do not result in insubject hospitalization, or the development of 
drug dependency or drug abuse.

severe hypoglycemia


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If the investigator believes that a reported SAE of hypoglycemia does not meet any of the 
specific criteria outlined above, the investigator should select the outcome of “considered
significant by the investigator for any other reason” in the eCRF.
All AEs occurring after signing the ICF are recorded in the eCRF and assessed for serious 
criteria.  The SAE reporting to the sponsor begins after the subject has signed the ICF and has 
received investigational product.  However, if an SAE occurs after signing the ICF, but prior to 
receiving investigational product, the SAE should be reported to the sponsor according to the 
SAE-reporting requirements and timelines (see Section 9.2) if it is considered reasonably 
possibly related to study procedure.
Study-site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms.  This 
24-hour notification requirement refers to the initial SAE information and all follow-up SAE 
information. Subjects with a serious hepatic AE should have additional data collected using 
eCRFs (Appendix 4).
Pregnancy 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 after they have 
discontinued (ET visit) and/or completed the study (follow-up visit), that is, the subject
disposition eCRF 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.
Serious AEs occurring up to and including the subject’s last study visit (or ET visit) will be 
collected, regardless of the investigator’s opinion of causation, in the clinical data collection 
database and the pharmacovigilance system at the sponsor.  The investigator will make a note of 
the relationship of the event with the drug.  This information will be included in the narrative.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) 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.  United States 21 CFR 312.32 and European Union Clinical Trial Directive 
2001/20/EC, and the associated detailed guidance or national regulatory requirements in 
participating countries require the reporting of SUSARs. Lilly has procedures that will be 
followed for the identification, recording, and expedited reporting of SUSARs that are consistent 
with global regulations and the associated detailed guidance.
9.2.2. Adverse Event Monitoring with a Systematic Questionnaire
Not applicable.


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9.2.3. 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 

facilitate process and product improvements.
Subjects will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product or glucometer so that the situation can be 
assessed. A replacement instrument may be used as long as the procedures and the subsequent 
visits continue to fall within the allowable time frames.
The investigator or his or 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, and 

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.
Treatment of Overdose
Refer to Section 6.2.2.9 of the IB for information on management of insulin overdose.
Safety
9.4.1. Electrocardiograms
For each subject, 12-lead electrocardiograms (ECGs) should be collected according to the 
Schedule of Activities (Section 2).
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
subject receives the first dose of the investigational product should be reported to Lilly or its 
designee as an AE via eCRF/electronic data entry/designated data transmission methods.
9.4.2. Vital Signs
For each subject, vital signs measurements will be conducted as mentioned in the Schedule of 
Activities (Section 2).
Any clinically significant findings from vital signs measurement that result in a diagnosis and 
that occur after the subject receives the first dose of study treatment should be reported to Lilly 
or its designee as an AE via eCRFs.


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9.4.3. Laboratory Tests
For each subject, laboratory tests detailed in (Appendix 2) will be conducted according to the 
Schedule of Activities (Section 2).  
Lilly or its designee will provide the investigator with the results of laboratory tests analyzed by 
a central vendor.
Any clinically significant findings from laboratory tests that result in a diagnosis, and that occur 
after the subject receives the first dose of investigational product should be reported to Lilly or 
its designee as an AE via eCRFs.
9.4.4. Immunogenicity Assessments
Not applicable.
9.4.5. Other Tests
Not applicable.
9.4.6. Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.
9.4.6.1.
Hepatic Safety Monitoring
If a study subject experiences elevated ALT ≥3X ULN, ALP ≥2X ULN, or elevated TBL ≥2X 
ULN, liver testing (Appendix 4) should be repeated within 3 to 5 days, including 

ALT

AST

ALP

TBL

direct bilirubin

gamma-glutamyl transferase, and 

creatine kinase.
These tests are performed to confirm the abnormality and to determine if the levels are
increasing or decreasing.  If the abnormality persists or worsens, clinical and laboratory 
monitoring should be initiated by the investigator and in consultation with the study medical 
monitor. Monitoring of ALT, AST, TBL, and ALP should continue until levels normalize or 
return to approximate screening visit (Week -2) levels.  
Hepatic Safety Data Collection
Additional safety data as mentioned in Appendix 4 should be collected via the eCRF if 1 or more 
of the following conditions occur:

elevation of serum ALT to ≥5X ULN on 2 or more consecutive blood tests

elevated serum TBL to ≥2X ULN (except for cases of known Gilbert’s syndrome) 


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
elevation of serum ALP to ≥2X ULN on 2 or more consecutive blood tests

subject discontinued from treatment due to a hepatic event or abnormality of liver 
tests, and/or

hepatic event considered to be a SAE.
Subject-Reported Outcomes
Subject-reported outcomes will be measured using the ITSQ at Week 4 and Week 24.
The ITSQ is a validated instrument containing 22 items that assesses treatment satisfaction for
subjects taking insulin. Items are measured on a 7-point scale, in which lower scores reflect 
better outcomes. The items that constitute the 5 domains of satisfaction are categorized as:

Inconvenience of Regimen (IR – 5 items)

Lifestyle Flexibility (LF – 3 items)

Glycemic Control (GC – 3 items)

Hypoglycemic Control (HC – 5 items), and

Insulin Delivery Device (DD – 6 items).
The individual raw and transformed domain scores are calculated as follows:

Step 1: Calculate the raw domain score as the mean of the items in the domain for that 
subject.

Step 2: Use the following formula to transform the raw domain scores on a scale from 0 
to 100, where higher scores indicate better treatment satisfaction:
Transformed domain score = 100*[(7- raw domain score)/(6)]
The individual raw and transformed overall scores are then calculated as follows: 

Step 1: Calculate the raw overall score as the mean of the items for that subject.

Step 2: Use the following formula to transform the raw overall score on a scale from 0 to 
100, where a higher score indicates better treatment satisfaction:
Transformed overall score = 100*[(7- raw overall score)/(6)]
If an item score is missing for a subject and ≤20% of the items within the domain (or overall) are 
missing for that subject, then the mean of the items in the domain (or overall) will be imputed for 
the missing item score(s). If there are >20% missing items, the individual subject domain (or 
overall) score will be set to missing. Change at Week 24 from Week 4 will be analyzed using 
the general linear model, with the Week 4 value of the response variable as covariate.
Pharmacokinetics
Not applicable.
Pharmacodynamics
Not applicable.


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Pharmacogenomics
9.8.1. Sample for Pharmacogenetic Research
Not applicable.
Biomarkers
Not applicable.
Health Economics and Medical Resource Utilization 
Health Economics and Medical Resource Utilization parameters will not be evaluated in this 
study.


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10. Statistical Considerations
Sample Size Determination
As a clause towards marketing approval, the DCGI in accordance with the biosimilar guidelines 
for India recommended that Basaglar be studied in a minimum of 200 additional local subjects.  
Assuming a 15% screen failure rate, approximately 295 subjects will be screened so that 250 
subjects can be enrolled. Assuming a drop-out rate of 20%, the target is to have a minimum of 
200 subjects complete the present study.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All participants who sign informed consent form
Full Analysis Set (FAS)
All enrolled participants who take at least 1 dose of study treatment
Safety
Identical to FAS, as no randomization occurs (single arm trial)
Per Protocol Set (PPS)
All FAS subjects, who also meet the following criteria:
a) have no violations of inclusion/exclusion criteria
b) have not discontinued from the study prior to 24 weeks
c) have not been off study medication for more than 14 consecutive days 
during the treatment period
d) have not received chronic (lasting longer than 14 consecutive days) 
systemic glucocorticoid therapy (excluding topical, intra-articular, 
intra-ocular, and inhaled preparations)
Statistical Analyses
10.3.1. General Statistical Considerations
All data will be entered, verified, and archived by a contract research organization (CRO)
external to Lilly and/or at Lilly.  Data listings, summaries, and analyses will be performed by a
CRO 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.  Additional exploratory analyses 
will be conducted as deemed appropriate.
Safety and efficacy analyses will be conducted on the full analysis set (FAS) or safety set.  These
sets include all data from all enrolled subjects who take at least 1 dose of study treatment.
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, unless otherwise 
stated.


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The planned statistical method for the primary analysis is the calculation of the estimate and the 
95% confidence interval for the incidence of total (symptomatic or asymptomatic with FBG level 
≤54 mg/dL [3.0 mmol/L]) hypoglycemic events at Week 24.
10.3.1.1. Subject Characteristics
The demographic and baseline characteristics will be recorded and summarized for the FAS and 
PPS populations.  For continuous measures, summary statistics will include 

sample size

mean

median

maximum

minimum

interquartile range

SDs, and

number with missing values.  
For categorical measures, summary statistics will include 

sample size

frequency

percentage, and 

number with missing values.  
10.3.1.2. Disposition
A detailed description of subject disposition will be provided at the end of the study.  
10.3.1.3. Concomitant Therapy
Concomitant medications, including previous therapy for diabetes, will be summarized by 
different categories and treatment group using the FAS population.  All concomitant therapies 
that was originally mapped using the WHO Drug Dictionary in the ClinTrial database will be 
further classified using Anatomical Therapeutic Chemical codes for reporting purposes.  
10.3.1.4. Treatment Compliance
Subject compliance with study medication will be assessed at each visit of treatment period as 
mentioned in Section 7.6.
10.3.2. Safety Analyses
10.3.2.1. Hypoglycemic Events
The primary endpoint of this study is the incidence of total (symptomatic or asymptomatic with 
FBG level ≤54 mg/dL [3.0 mmol/L]) hypoglycemic events at Week 24.  The events will be 
analyzed as following as number and percentage of subjects experiencing at least 1 event over 
the study period.  A 95% confidence interval for the rate will be calculated using the normality 
assumption.


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The rate of total (symptomatic or asymptomatic with FBG level ≤54 mg/dL [3.0 mmol/L]) 
hypoglycemic events will be analyzed as follows:

Number of hypoglycemic events per subject over the study period will be analyzed as 
continuous variables as per Section 10.3.1 (mean, median, SD, standard error [SE], 
minimum, and maximum)

The rate of hypoglycemic events per 30 days, and the rate per year, that is the number of 
hypoglycemic events per subject year (365.25 days), will be calculated. 
o
The rate per 30 days between 2 time points (end of treatment/study vs. baseline) is 
defined as the total number of events between the time points divided by the 
actual number of days between the time points, and then multiplied by 30. A 
similar approach is then used for the number of events per subject-year (365.25 
days).  
o
These measures will be summarized for the overall study period and will be 
assessed using a negative binomial model with baseline HbA1c as covariate and 
the log of the study treatment exposure time as offset variable.
The following types of hypoglycemia (see Section 9.1.1) will be analyzed similarly (incidence 
and rates) as specified for total hypoglycemia:

nocturnal hypoglycemia

severe hypoglycemia 

documented symptomatic hypoglycemia, and

asymptomatic hypoglycemia
All analyses for the hypoglycemic events will be repeated for the PPS population.
10.3.2.2. Laboratory Measurements
Continuous chemistry and hematology measures will be summarized by descriptive statistics at 
screening visit (Week -2) and at different visits (Section 2) for the FAS population.  
Continuous chemistry and hematology measures will be summarized as change from screening 
visit (Week -2) to Week 24 using the general linear model, with the screening visit (Week -2)
value of the response variable as covariate.  
All laboratory measurements analyses will be repeated for the PPS population.
10.3.2.3. Vital Signs
Systolic blood pressure, diastolic blood pressure, and pulse rate will be summarized by 
descriptive statistics (mean, median, SD, SE, minimum, and maximum) by visit for the FAS 
population.  Additionally, change from baseline to each post baseline face-to-face visit for each 
parameter will be summarized by means of descriptive measures as described in Section 10.3.1.  
Change from baseline values to Week 24 will be analyzed using the general linear model, with 
the baseline value of the response variable as covariate after applying the LOCF method to 
missing values.
All vital signs analyses will be repeated for the PPS population.


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10.3.2.4. Adverse Events Analyses
Adverse events will be listed by 

subject

system organ class (SOC)

Medical Dictionary for Regulatory Activities® preferred term (PT)

severity, and 

relationship to the study disease, drug, device, or procedure for all subjects. 
Adverse events (including injection site reactions and neoplasms) will be summarized as TEAEs 
for the FAS population. Treatment-emergent AEs are defined as events that are newly reported 
after the first study drug treatment or are reported to have worsened in severity after the first 
study drug treatment. The proportion of subjects experiencing each TEAE will be presented by 
PT, SOC, and treatment group. The proportion of subjects experiencing each TEAE that is 
assessed as possibly related to the study disease, drug, or procedures will also be summarized. 
Treatment-emergent AEs will be summarized by PT within SOC and by PT by decreasing 
frequency.
All SAEs will be listed by subject and summarized by treatment as counts and percentages. 
Similar analyses will be performed for discontinuations due to AEs.
All AEs analyses will be repeated for the PPS population.
10.3.3. Efficacy Analyses
10.3.3.1. Actual and Change from Baseline HbA1c
The actual and change in HbA1c level from baseline to Week 12 and Week 24 will be analyzed 
using descriptive statistics (mean, median, SD, SE, minimum, maximum, and number with 
missing values). For subjects requiring rescue medication (see Section 7.4), HbA1c values 
recorded after the first administration of rescue medication will not be considered for analysis, 
and these values will be considered as missing. In addition, for the actual value and change from 
baseline, a descriptive analysis using LOCF will be performed, using the baseline or 12-week 
value, if the 24-week value is missing or occurred after use of rescue medication.
Additionally, the change in HbA1c level from baseline to Week 24 will be analyzed using the
general linear model for the FAS population.  The general linear model will evaluate the change 
from baseline in HbA1c level as the dependent variable and the baseline value of HbA1c as 
covariate.
All the HbA1c analyses described will be repeated for the PPS population.
10.3.3.2. Subjects Reaching HbA1c Targets (≤6.5% or <7%) at Week 24
Subjects reaching HbA1c levels of ≤6.5% and <7% at Week 24 will be analyzed descriptively as 
binary variable, using number and percentage. The HbA1c values used to calculate this binary 
variable will be the LOCF value, that is, in case the Week 24 value is missing, the Week 12
value will be used. The denominator will be the total FAS population. Subject with missing 
HbA1c data at Week 12 and Week 24 will be considered as not having reached the target.


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These analyses will be repeated for the PPS population.
10.3.3.3. Other Efficacy Parameters
The following parameters (actual values and change from baseline will be summarized by 
descriptive statistics (mean, median, SD, SE, minimum, and maximum) by visit for the FAS 
population and for the PPS population:

7-point SMBG levels (mg/dL and mmol/L)

body mass index (kg/m2)

body weight (kg), and

basal insulin dose (U/day and U/kg/day).
Additionally, the change from baseline to the Week 24 for 7-point SMBG levels, body mass 
index, and body weight will be analyzed using the general linear model for the FAS population.  
The model will evaluate the change from baseline in HbA1c level as the dependent variable, with 
the baseline value of the variable as covariate, after applying the LOCF method to missing 
values.
All analyses will be repeated for the PPS population.
10.3.4. Analyses of Subject-Reported Outcomes
Subject responses to the ITSQ will be reported as overall and domain scores at Weeks 4 and 24.
These scores will be summarized by descriptive statistics (mean, median, SD, SE, minimum, and 
maximum) by visit for the FAS population.  Change at Week 24 from Week 4 will be analyzed 
using the general linear model, with the Week 4 value of the response variable as covariate, after 
applying the LOCF method to missing values.
These analyses will be repeated for the PPS population.
10.3.5. Pharmacokinetic/Pharmacodynamic Analyses
Not applicable.
10.3.6. Evaluation of Immunogenicity 
Not applicable.
10.3.7. Subgroup Analyses
Not applicable.
10.3.8. Interim Analyses
No interim analyses and/or sample size re-estimation are planned for this study.  If an unplanned 
interim analysis is deemed necessary, the appropriate Lilly Medical Director, or designee, will be 
consulted to determine whether it is necessary to amend the protocol.


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11.
References
American Diabetes A. 8. Pharmacologic Approaches to Glycemic Treatment: Standards of 
Medical Care in Diabetes-2018. Diabetes Care. 2018;41(Suppl 1):S73-S85.
Hu FB. Globalization of diabetes: the role of diet, lifestyle, and genes. Diabetes Care. 
2011;34(6):1249-1257.
Davies MJ, D’Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, Rossing P, Tsapas 
A, Wexler DJ, Buse JB. Management of hyperglycemia in type 2 diabetes, 2018. A Consensus 
Report by the American Diabetes Association (ADA) and the European Association for the 
Study of Diabetes (EASD). Diabetes Care. 2018;41(12):2669-2701.
[IDF] International Diabetes Federation. IDF Diabetes Atlas Eighth Edition. Available at: 
http://diabetesatlas.org/resources/2017 atlas.html. 2017. Accessed July 2018.
Pollom RK, Ilag LL, Lacaya LB, Morwick TM, Ortiz Carrasquillo R. Lilly insulin glargine 
versus Lantus® in insulin-naïve and insulin-treated adults with type 2 diabetes: a randomized, 
controlled trial (ELEMENT 5). Diabetes Ther. 2019;10(1):189-203.
Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the 
year 2000 and projections for 2030. Diabetes Care. 2004;27(5):1047-1053.


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12.
Appendices


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Appendix 1.
Abbreviations and Definitions
Term
Definition
AE
adverse event:  Any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
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 study-related, good clinical practice (GCP), and applicable regulatory 
requirements.
CRO
contract research organization
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
DCGI
Drug Controller General of India
ECG
electrocardiogram
eCRF
electronic case report form
ERB
Ethical Review Board
enroll
The act of assigning a subject to a treatment.  Subjects who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Subjects entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ET
early termination
FAS
full analysis set


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FBG
fasting blood glucose
GCP
Good Clinical Practice
GLP-1 RA
glucagon-like peptide-1 receptor agonist
HbA1c
glycated hemoglobin
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
informed consent
A process by which a subject voluntarily confirms his or her willingness to participate 
in a particular study, after having been informed of all aspects of the study that are 
relevant to the subject’s decision to participate.  Informed consent is documented by 
means of a written, signed and dated informed consent form
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
ITSQ
Insulin Treatment Satisfaction Questionnaire
LOCF
last observation carried forward
OAM
oral antihyperglycemic medication
PPS
per-protocol set:  The set of data generated by the subset of subjects who sufficiently 
complied with the protocol to ensure that these data would be likely to exhibit the 
effects of treatment, according to the underlying scientific model
PT
Preferred Term, as per Medical Dictionary for Regulatory Activities (MedDRA)
QD
once daily
SAE
serious adverse event
screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study. 
SD
standard deviation
SMBG
self-monitored blood glucose
SOC
system organ class, as per Medical Dictionary for Regulatory Activities (MedDRA)
SUSARs
suspected unexpected serious adverse reactions
T2DM
type 2 diabetes mellitus


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TBL
total bilirubin level
TEAE
Treatment-emergent adverse event:  An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment
ULN
upper limit of normal
WHO
World Health Organization


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Appendix 2.
Clinical Laboratory Tests
Clinical Laboratory Tests
Hematologya,b
Clinical Chemistrya,b,c
Hemoglobin
Serum Concentrations of:
Hematocrit
Sodium
Erythrocyte count (RBC)
Potassium
Mean cell volume
Total bilirubin
Mean cell hemoglobin concentration
Direct bilirubin
Leukocytes (WBC)
Alkaline phosphatase
Neutrophils, segmented
Alanine aminotransferase (ALT)
Lymphocytes
Aspartate aminotransferase (AST)
Monocytes
Blood urea nitrogen (BUN)
Eosinophils
Creatinine
Basophils
Uric acid
Platelets
Calcium
Fasting blood glucose
Urinalysisa,b,d
Albumin
Specific gravity
Cholesterol
pH
Creatine kinase (CK)
Protein
Glucose
Pregnancy Test (females only)e
Ketones
Blood
Urine leukocyte esterase
Abbreviations:  CRO = contract research organization; RBC = red blood cell; WBC = white blood cell.
a
Assayed by CRO-designated laboratory agreed by Lilly.
b
Screening visit (Week -2) and Week 24 results will be confirmed by the Central Laboratory.
c
Refer to the Schedule of Activities:  Abbreviated chemistry includes total bilirubin, direct bilirubin, ALT, BUN, 
and serum creatinine.
d
Estimated glomerular filtration rate may also be measured but only in subjects with a history of severe chronic 
kidney disease
e
Local- or investigator-designated laboratory.


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Appendix 3.
Study Governance Considerations


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Appendix 3.1. Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Appendix 3.1.1.
Informed Consent
The investigator is responsible for:

ensuring that the subject understands the nature of the study, the potential risks 
and benefits of participating in the study, and that their participation is voluntary

ensuring that informed consent is given by each subject or legal representative.  
This includes obtaining the appropriate signatures and dates on the informed 
consent form (ICF) prior to the performance of any protocol procedures and prior 
to the administration of investigational product.

answering any questions the subject may have throughout the study, and sharing 
in a timely manner any new information that may be relevant to the subjects’ 
willingness to continue his or her participation in the study

ensuring that a copy of the ICF is provided to the participant or the participant’s 
legal representative and is kept on file

ensuring that the medical record includes a statement that written informed 
consent was obtained before the participant was enrolled in the study and the date 
the written consent was obtained. The authorized person obtaining the informed 
consent must also sign the ICF.  
Appendix 3.1.2.
Recruitment
Eli Lilly and Company (Lilly) or its designee is responsible for the central recruitment strategy 
for subjects.  Individual investigators may have additional local requirements or processes.
Appendix 3.1.3.
Ethical Review
The investigator must give assurance that the ethical review board (ERB) was properly 
constituted and convened as required by International Council for Harmonisation (ICH) 
guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  Lilly or its representatives must approve the ICF, 
including any changes made by the ERBs, before it is used at the investigative site(s).  All ICFs 
must be compliant with the ICH guideline on Good Clinical Practice (GCP).
The study site’s ERB(s) should be provided with the following:

the protocol and related amendments and addenda, current IB or Patient 
Information Leaflet, Package Insert, or Summary of Product Characteristics
and updates during the course of the study

ICF, and

other relevant documents (for example, curricula vitae, advertisements).


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Appendix 3.1.4.
Regulatory Considerations
This study will be conducted in accordance with the protocol and with the

consensus ethics principles derived from international ethics guidelines, including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences International Ethical Guidelines

applicable ICH GCP guidelines, and

applicable laws and regulations.
Some of the obligations of the sponsor will be assigned to a third party.
Appendix 3.1.5.
Investigator Information
Physicians with a specialty in family practice, internal medicine, or endocrinology, who are 
experienced in treating subjects with diabetes mellitus with basal insulin may participate as 
investigators in this clinical trial, provided they can demonstrate adequate experience in the 
conduct of clinical research studies.
Appendix 3.1.6.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Appendix 3.1.7.
Final Report Signature
The coordinating investigator will sign the final clinical study report (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 qualified/analyzable/enrolled subjects 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 report accurately describes the 
conduct and results of the study.
Appendix 3.2.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

sponsor start-up training to instruct the investigators and study coordinators.  This 
training will give instruction on the protocol, the completion of the electronic case 
report forms (eCRFs), and study procedures.


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
make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax

review and evaluate eCRF data and use standard computer edits to detect errors in 
data collection, and

conduct a quality review of the database.
In addition, Lilly or its representatives will periodically check a sample of the subject data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives, and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents.
Appendix 3.2.1.
Data Capture System
An electronic data capture system will be used in this study. The site will maintain a separate 
source for the data entered by the site into the sponsor-provided electronic data capture system. 
Electronic case report form data will be encoded and stored in a clinical trial database.  Data 
managed by a central vendor will be stored electronically in the central vendor’s database 
system.  Data will subsequently be transferred from the central vendor to the Lilly data 
warehouse.
Any data, for which paper documentation provided by the subject will serve as the source 
document, will be identified and documented by each site in that site’s study file.  Paper 
documentation provided by the subject may include subject diary and Insulin Treatment 
Satisfaction Questionnaires to collect patient-reported outcome measures.  Data from these paper
documentations will be transcribed to eCRFs at the sites.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
Appendix 3.3.
Study and Site Closure
Appendix 3.3.1.
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.
Appendix 3.3.2.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee, judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.


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Appendix 3.4.
Publication Policy
In accordance with the sponsor’s publication policy, the results of this study will be submitted 
for publication to a peer-reviewed journal.


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Appendix 4.
Hepatic Monitoring Tests for 
Treatment-Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with subjects in consultation with Lilly’s or its designee’s clinical 
research physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin time
WBC
Prothrombin time, INR
Neutrophils, segmented
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
GGT
Alkaline Phosphatase Isoenzymesa
CPK
Anti-smooth muscle antibody (or anti-actin antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspirate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized 
ratio; RBC = red blood cell; WBC = white blood cell.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.
Note:  These tests will be implemented in accordance with the most current guidance provided by the Eli Lilly Liver
and Gastrointestinal Safety Advisory Committee with respect to the assessment of hepatic safety and collection 
of hepatic safety data.


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Appendix 5.
Sampling Summary
This table summarizes the approximate number of blood samples and volumes for all sampling 
and tests during the study.  
Protocol ABEX Sampling Summary
Purpose
Sample 
Type
Maximum Amount 
per Sample
Maximum 
Number of 
Samples
Maximum 
Total Amount
Screening testsa
Blood
4.5 mL
1
4.5 mL
Standard laboratory testsa
Blood
2 mL
1
2 mL
Total [rounded to nearest 10]
6.0 mL
-
6.0 mL
Hepatic Monitoringb
Blood
3-30 mL
-
-
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 subject
follow-up, in consultation with Lilly-designated Medical Monitor.


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Appendix 6.
World Health Organization Classification 
of Diabetes
Type 2 Diabetes Mellitus:  Type 2 diabetes mellitus, although often asymptomatic, may also 
present with classical hyperglycemic symptoms (thirst, polyuria, and weight loss); 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) because of an acute increase in 
insulin requirements, but spontaneous ketosis does not occur.  Some subjects with type 2 
diabetes later progress to a state of absolute insulin deficiency.


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Appendix 7. Protocol Amendment 14L-IN-ABEX(b)
Summary – A Multicenter, Open-Label, Single-Arm, Phase 
4 Study to Assess the Safety of Basaglar in Subjects with 
Type 2 Diabetes Mellitus in India
Overview
Protocol I4L-IN-ABEX – A Multicenter, Open-Label, Single-Arm, Phase 4 Study to Assess the 
Safety of Basaglar in Subjects with Type 2 Diabetes Mellitus in India has been amended.  The 
new protocol is indicated by amendment (b) and will be used to conduct the study in place of any 
preceding version of the protocol.
The overall changes and the rationale for the changes made to this protocol are as follows:
1. The protocol title was changed from “Safety Evaluation of Basaglar in Adult Subjects 
with Type 2 Diabetes Mellitus in India:  A Postmarketing Study” to “A Multicenter, 
Open-Label, Single-Arm, Phase 4 Study to Assess the Safety of Basaglar in Subjects 
with Type 2 Diabetes Mellitus in India” per request from Indian Ministry of Health.
2. The statistical analysis model was changed from “ANCOVA” to “general linear”
model to match the statistical analysis plan.
3. Typographical errors with respect to the study identifier were corrected.


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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
Cover Page: Protocol Title
Protocol I4L-IN-ABEX(ba)
A Multicenter, Open-Label, Single-Arm, Phase 4 Study to Assess the Safety of Basaglar in 
Subjects with Type 2 Diabetes Mellitus in IndiaSafety Evaluation of Basaglar in Adult Subjects 
with Type 2 Diabetes Mellitus in India:  A Postmarketing Study
1. Synopsis
Title of Study:
A Multicenter, Open-Label, Single-Arm, Phase 4 Study to Assess the Safety of Basaglar 
in Subjects with Type 2 Diabetes Mellitus in IndiaSafety Evaluation of Basaglar in Adult 
Subjects with Type 2 Diabetes Mellitus in India:  A Postmarketing Study
Summary of Study Design:
Study I4L-INMC-ABEX is a multicenter, open-label, single-arm study, that will enroll 
insulin-naïve subjects with T2DM.  The study period consists of a screening period (Week -2 to 
Week 0), a treatment period (Week 0 to Week 24), and a safety follow-up visit at Week 28.
Statistical Analysis:
Statistical Methodology:
Secondary outcomes:  Actual values and change in glycated hemoglobin (HbA1c) level from 
baseline to Week 12 and Week 24 will be analyzed in a descriptive manner on non-missing 
values and last observation carried forward-imputed values.  Additionally, a general linear model
analysis of covariance (ANCOVA) model will be performed on the full analysis set (FAS), with 
change from baseline in HbA1c level as the dependent variable and the baseline value of HbA1c 
as a covariate.
The number of hypoglycemic events per subject, the rate of hypoglycemic events per 30 days, 
and the rate per year, that is, the number of hypoglycemic events per subject year (365.25 days) 
will be assessed using a negative binomial model, with baseline HbA1c as a covariate and the 
log of the study treatment exposure time as an offset variable.
The analysis for other continuous secondary efficacy and safety measurements and continuous 
laboratory measures will use the ANCOVA general linear model for the FAS population with the 
baseline value of the response variable as a covariate.


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5.1. Overall Design
Study I4L-INMC-ABEX (ABEX) is a multicenter, open-label, single-arm, Phase 4 study to 
assess the safety of Basaglar in subjects with T2DM in India.
9.5. Subject-Reported Outcomes
If an item score is missing for a subject and ≤20% of the items within the domain (or overall) are 
missing for that subject, then the mean of the items in the domain (or overall) will be imputed for 
the missing item score(s). If there are >20% missing items, the individual subject domain (or 
overall) score will be set to missing.  Change at Week 24 from Week 4 will be analyzed using 
the analysis of covariance (ANCOVA)general linear model, with the Week 4 value of the 
response variable as covariate.
10.3.2.2. Laboratory Measurements
Continuous chemistry and hematology measures will be summarized by descriptive statistics at 
screening visit (Week -2) and at different visits (Section 2) for the FAS population.  
Continuous chemistry and hematology measures will be summarized as change from screening 
visit (Week -2) to Week 24 using the ANCOVA general linear model, with the screening visit 
(Week -2) value of the response variable as covariate.  
10.3.2.3. Vital Signs
Systolic blood pressure, diastolic blood pressure, and pulse rate will be summarized by 
descriptive statistics (mean, median, SD, SE, minimum, and maximum) by visit for the FAS 
population.  Additionally, change from baseline to each post baseline face-to-face visit for each 
parameter will be summarized by means of descriptive measures as described in Section 10.3.1.  
Change from baseline values to Week 24 will be analyzed using the ANCOVA general linear 
model, with the baseline value of the response variable as covariate after applying the LOCF 
method to missing values.
10.3.3.1. Actual and Change from Baseline HbA1c
Additionally, the change in HbA1c level from baseline to Week 24 will be analyzed using the 
ANCOVA general linear model for the FAS population.  The ANCOVA general linear model 
will evaluate the change from baseline in HbA1c level as the dependent variable and the baseline 
value of HbA1c as covariate.
10.3.3.3. Other Efficacy Parameters
Additionally, the change from baseline to the Week 24 for 7-point SMBG levels, body mass 
index, and body weight will be analyzed using the ANCOVA general linear model for the FAS 
population.  The model will evaluate the change from baseline in HbA1c level as the dependent 
variable, with the baseline value of the variable as covariate, after applying the LOCF method to 
missing values.


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10.3.4. Analyses of Subject-Reported Outcomes
Subject responses to the ITSQ will be reported as overall and domain scores at Weeks 4 and 24.  
These scores will be summarized by descriptive statistics (mean, median, SD, SE, minimum, and 
maximum) by visit for the FAS population.  Change at Week 24 from Week 4 will be analyzed 
using the ANCOVA general linear model, with the Week 4 value of the response variable as 
covariate, after applying the LOCF method to missing values. 
Appendix 1.
Abbreviations and Definitions
Term
Definition
ANCOVA
analysis of covariance


Leo Document ID = 947ebaaa-f87c-4575-8b4a-47b259b9d1b1
Approver: 
Approval Date & Time: 04-Oct-2019 11:56:10 GMT
Signature meaning: Approved
Approver:
Approval Date & Time: 04-Oct-2019 11:58:40 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
 
 
 
Statistical Analysis Plan Version 1 I4L-IN-ABEX(b) 
 
 
A Multicenter, Open-Label, Single-Arm, Phase 4 Study to Assess the Safety of Basaglar in 
Subjects with Type 2 Diabetes Mellitus in India 
 
  
NCT04153981 
 
Approval Date: 02-Dec-2019 
 
 


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