Clinical trial NCT03736785
Conditions: Type 2 Diabetes Mellitus
Sponsor: Eli Lilly and Company
Start date: 2018-11-15; Completion date: 2020-02-18
Enrollment: 399 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The reason for this study is to see if the study drug LY3209590 is safe and effective in participants with type 2 diabetes that have already been treated with basal insulin.

Detailed description:

Arms: arm 1: Participants received loading dose followed by weekly dose of LY3209590 based on the prior randomization basal insulin dose for a period of 32 weeks by subcutaneous (SC) injection. Dose titration was done to maintain fasting blood glucose of \<140 milligram per deciliter (mg/dL). arm 2: Participants received loading dose followed by weekly dose of LY3209590 based on the prior randomization basal insulin dose for a period of 32 weeks by subcutaneous injection. Dose titration was done to maintain fasting blood glucose of \<120 mg/dL. arm 3: Participants received same dose of Degludec as the total basal insulin dose already administered prior to randomization. Dose was titrated to maintain fasting blood glucose of ≤100 mg/dL to achieve glycemic goal of HbA1C \<7%.
Interventions: intervention 1: LY3209590 intervention 2: Insulin Degludec
Intervention descriptions: intervention 1: Administered SC intervention 2: Administered SC

Protocol documents:
Prot_000.pdf: 
 
I8H-MC-BDCM Clinical Protocol 
 
 
A Phase 2, Randomized, Open-Label Trial to Evaluate the Safety and Efficacy of LY3209590 in 
Study Participants with Type 2 Diabetes Mellitus Previously Treated with Basal Insulin 
 
NCT03736785 
 
Date: 31-Aug-2018 
 
 


I8H-MC-BDCM Clinical Protocol
Page 1
LY3209590
Protocol I8H-MC-BDCM
A Phase 2, Randomized, Open-Label Trial to Evaluate the 
Safety and Efficacy of LY3209590 in Study Participants 
with Type 2 Diabetes Mellitus Previously Treated with 
Basal Insulin
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 
LY3209590, 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-Fc (LY3209590)
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly on date provided below.
Approval Date: 31-Aug-2018 GMT


I8H-MC-BDCM Clinical Protocol
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LY3209590
Table of Contents
Section
Page
Protocol I8H-MC-BDCM A Phase 2, Randomized, Open-Label Trial to 
Evaluate the Safety and Efficacy of LY3209590 in Study Participants 
with Type 2 Diabetes Mellitus Previously Treated with Basal Insulin..................................1
Table of Contents........................................................................................................................2
1.
Synopsis .............................................................................................................................9
2.
Schedule of Activities .......................................................................................................12
3.
Introduction ......................................................................................................................20
3.1.
Study Rationale............................................................................................................20
3.2.
Background..................................................................................................................20
3.3.
Benefit/Risk Assessment..............................................................................................21
4.
Objectives and Endpoints..................................................................................................22
5.
Study Design.....................................................................................................................24
5.1.
Overall Design .............................................................................................................24
5.1.1.
Study Visits..........................................................................................................25
5.2.
Number of Participants.................................................................................................27
5.3.
End of Study Definition ...............................................................................................27
5.4.
Scientific Rationale for Study Design...........................................................................27
5.5.
Justification for Dose ...................................................................................................28
6.
Study Population...............................................................................................................29
6.1.
Inclusion Criteria..........................................................................................................29
6.2.
Exclusion Criteria ........................................................................................................31
6.3.
Lifestyle Restrictions....................................................................................................33
6.4.
Screen Failures.............................................................................................................33
7.
Treatments........................................................................................................................34
7.1.
Treatments Administered .............................................................................................34
7.1.1.
Packaging and Labeling .......................................................................................34
7.2.
Method of Treatment Assignment ................................................................................35
7.2.1.
Selection and Timing of Doses.............................................................................35
7.2.1.1.
LY3209590 Algorithms..................................................................................35
7.2.1.2.
Insulin Degludec.............................................................................................36
7.3.
Blinding .......................................................................................................................37
7.4.
Dosage Modification....................................................................................................37
7.5.
Preparation/Handling/Storage/Accountability...............................................................37
7.6.
Treatment Compliance .................................................................................................38


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LY3209590
7.7.
Concomitant Therapy...................................................................................................38
7.7.1.
Antihyperglycemia Medications...........................................................................39
7.7.2.
Concomitant Antihyperglycemia Medication .......................................................40
7.7.3.
Medications that Promote Weight Loss ................................................................40
7.7.4.
Systemic Glucocorticoids.....................................................................................41
7.7.5.
Antihypertensive Medications..............................................................................41
7.7.6.
Dyslipidemia Medications....................................................................................41
7.8.
Treatment After the End of the Study...........................................................................41
7.8.1.
Treatment After Study Completion.......................................................................41
7.8.2.
Special Treatment Considerations ........................................................................42
7.8.2.1.
Standards of Medical Care..............................................................................42
7.8.2.2.
Management of Increased Hypoglycemia Risk ...............................................42
7.8.2.3.
Management of Study Participants with Severe, 
Persistent Hyperglycemia during the Treatment Period...................................43
7.8.2.4.
Emergency Situations .....................................................................................43
8.
Discontinuation Criteria ....................................................................................................44
8.1.
Discontinuation from Study Treatment.........................................................................44
8.1.1.
Permanent Discontinuation from Study Treatment ...............................................44
8.1.2.
Temporary Discontinuation from Study Treatment...............................................45
8.1.3.
Discontinuation of Inadvertently Enrolled Study Participants...............................45
8.2.
Discontinuation from the Study....................................................................................45
8.3.
Lost to Follow-Up........................................................................................................46
9.
Study Assessments and Procedures ...................................................................................47
9.1.
Efficacy Assessments...................................................................................................47
9.1.1.
Primary Efficacy Assessments .............................................................................47
9.1.2.
Secondary Efficacy Assessments..........................................................................47
9.1.3.
Appropriateness of Assessments ..........................................................................47
9.1.4.
Body Weight........................................................................................................47
9.2.
Adverse Events ............................................................................................................48
9.2.1.
Serious Adverse Events........................................................................................48
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................49
9.2.2.
Adverse Events of Special Interest .......................................................................50
9.2.2.1.
Hypoglycemia ................................................................................................50
9.2.2.2.
Allergic/Hypersensitivity Reactions................................................................51
9.2.3.
Adverse Event Monitoring with a Systematic Questionnaire ................................51
9.2.4.
Complaint Handling.............................................................................................51
9.2.4.1.
Device Complaint Handling............................................................................51
9.3.
Treatment of Overdose.................................................................................................51


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LY3209590
9.4.
Safety...........................................................................................................................51
9.4.1.
Cardiovascular Events..........................................................................................51
9.4.2.
Electrocardiograms ..............................................................................................52
9.4.3.
Vital Signs ...........................................................................................................52
9.4.4.
Self-monitoring of Blood Glucose Using CGM....................................................52
9.4.5.
Continuous Glucose Monitoring...........................................................................53
9.4.6.
Laboratory Tests ..................................................................................................54
9.4.7.
Immunogenicity Assessments ..............................................................................54
9.4.8.
Other Tests...........................................................................................................55
9.4.9.
Safety Monitoring ................................................................................................55
9.4.9.1.
Hepatic Safety Monitoring..............................................................................55
9.5.
Pharmacokinetics .........................................................................................................56
9.6.
Pharmacodynamics ......................................................................................................56
9.7.
Pharmacogenomics ......................................................................................................56
9.7.1.
Whole Blood Samples for Pharmacogenetic Research..........................................56
9.8.
Biomarkers...................................................................................................................57
9.9.
Health Economics ........................................................................................................57
10.
Statistical Considerations ..................................................................................................58
10.1. Sample Size Determination ..........................................................................................58
10.2. Analysis Sets................................................................................................................58
10.3. Statistical Analyses ......................................................................................................58
10.3.1.
General Statistical Considerations ........................................................................58
10.3.2.
Treatment Group Comparability...........................................................................59
10.3.2.1.
Study Participant Disposition..........................................................................59
10.3.2.2.
Study Participant Characteristics.....................................................................59
10.3.2.3.
Concomitant Therapy .....................................................................................59
10.3.2.4.
Treatment Compliance....................................................................................59
10.3.3.
Efficacy Analyses ................................................................................................60
10.3.3.1.
Primary Analyses ...........................................................................................60
10.3.3.2.
Secondary Analyses........................................................................................60
10.3.3.3.
Exploratory Analyses .....................................................................................61
10.3.4.
Safety Analyses....................................................................................................61
10.3.4.1.
Adverse Events...............................................................................................61
10.3.4.2.
Vital Signs......................................................................................................62
10.3.4.3.
Hypoglycemia Episodes .................................................................................62
10.3.4.4.
Laboratory Measures ......................................................................................62
10.3.4.5.
Electrocardiograms.........................................................................................63
10.3.4.6.
Adverse Events of Special Interest..................................................................63


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LY3209590
10.3.5.
Pharmacokinetic/Pharmacodynamic Analyses......................................................63
10.3.6.
Evaluation of Immunogenicity .............................................................................63
10.3.7.
Other Analyses.....................................................................................................64
10.3.7.1.
Health Economics...........................................................................................64
10.3.7.2.
Subgroup Analyses.........................................................................................64
10.3.8.
Interim Analyses..................................................................................................64
11.
References ........................................................................................................................65
12.
Appendices .......................................................................................................................66


I8H-MC-BDCM Clinical Protocol
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LY3209590
List of Tables
Table
Page
Table BDCM.1. Schedule of Activities....................................................................................13
Table BDCM.2. Objectives and Endpoints...............................................................................22
Table BCDM.3. Treatment Regimens......................................................................................34
Table BDCM.4. Criteria for Use of Concomitant Medications that may Interfere with 
Efficacy and Safety Assessments in Study BDCM.........................................39
Table BDCM.5
LY3209590 Loading Dose.............................................................................81
Table BDCM.6
LY3209590 Titration Algorithm....................................................................82


I8H-MC-BDCM Clinical Protocol
Page 7
LY3209590
List of Figures
Figure
Page
Figure BDCM.1. Illustration of study design for Clinical Protocol I8H-MC-BDCM. ................10
Figure BDCM.2. Illustration of study design for Clinical Protocol I8H-MC-BDCM. ................24


I8H-MC-BDCM Clinical Protocol
Page 8
LY3209590
List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................67
Appendix 2.
Clinical Laboratory Tests...............................................................................70
Appendix 3.
Study Governance Considerations..................................................................72
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................77
Appendix 5.
Methods of Contraception..............................................................................78
Appendix 6.
New York Heart Association Cardiac Disease Classification .........................79
Appendix 7.
Dosing Guidance ...........................................................................................80


I8H-MC-BDCM Clinical Protocol
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LY3209590
1. Synopsis
Title of Study:
A Phase 2, Randomized, Open-Label Trial to Evaluate the Safety and Efficacy of LY3209590 in 
Study Participants with Type 2 Diabetes Mellitus Previously Treated with Basal Insulin
Rationale: 
LY3209590 is a long-acting insulin receptor agonist being developed for the treatment of type 2 
diabetes mellitus (T2DM). This Phase 2 study of LY3209590 will evaluate the effects of 
LY3209590 on glycemic control using 2 different dose individualization strategies compared 
with insulin degludec in study participants previously treated with basal insulin.
Objective(s)/Endpoints:
Objectives
Endpoints
Primary

To investigate the efficacy of LY3209590 
arms in study participants with T2DM

HbA1c change from baseline to Week 32
Secondary
Efficacy:

To investigate the efficacy of LY3209590 
compared with insulin degludec in study 
participants with T2DM

HbA1c change from baseline to Week 12 and 
32

Fasting glucose change from baseline to 
Weeks 12 and 32

Insulin dose change from baseline to week 12 
and 32 
Safety:

To investigate the safety of LY3209590
compared with insulin degludec in study 
participants with T2DM

Incidence and Rate of nocturnal and 
documented symptomatic hypoglycemia 
events during the treatment period

Incidence of treatment-emergent serious 
adverse events

Body weight change from baseline at Weeks 
12 and 32
Pharmacokinetics:

To characterize the PK of LY3209590 in 
study participants with T2DM

LY3209590 population-based parameters, 
such as, AUC within dosing interval at Weeks 
12 and 32
Abbreviations:  AUC = area under the curve; HbA1c = hemoglobin A1c; PK = pharmacokinetics; T2DM = type 2 
diabetes mellitus


I8H-MC-BDCM Clinical Protocol
Page 10
LY3209590
Summary of Study Design:  
Study I8H-MC-BDCM (BDCM) is a multicenter, randomized, open-label, comparator-controlled 
Phase 2 study with 3 study periods:  2-week screening, 32-week treatment period, and 5-week 
safety follow-up period. The study is designed to evaluate the efficacy and safety of LY3209590 
compared to insulin degludec in study participants with T2DM. The primary endpoint will be 
hemoglobin A1c (HbA1c) change from baseline to 32 weeks.
Treatment Arms and Duration:  
Study participants will be randomized in a 1:1:1 ratio to one of two dosing algorithms of 
LY3209590 or insulin degludec.
Figure BDCM.1 illustrates the study design.
Figure BDCM.1.
Illustration of study design for Clinical Protocol I8H-MC-BDCM.
Number of Study Participants:
A total of 536 study participants with T2DM previously treated with basal insulin will be 
screened. Approximately 375 study participants will be randomized in a 1:1:1 ratio to 


I8H-MC-BDCM Clinical Protocol
Page 11
LY3209590
LY3209590 in one of two dosing algorithms (125 study participants in each treatment arm) or 
insulin degludec (125 study participants).
To ensure the safety of the screened study participants, a continuous glucose monitoring system 
will be used during the course of exposure to the investigational product, to alert study 
participants in case of expected or evident hypoglycemia.
Statistical Analysis:  
Efficacy Analysis:  
The primary efficacy outcome is HbA1c change from baseline to Week 32 for the LY3209590 
arms.  
Safety Analysis:  
The full analysis set (FAS), which includes all data, regardless of rescue medication use or early 
stop of study medication, will be used for safety analyses.  Both the overall and the pairwise 
comparisons of each LY3209590 arm versus insulin degludec will be reported for these safety 
analyses.
Safety measures include liver biomarkers alanine aminotransferase (ALT), hypoglycemia, vital 
signs (blood pressure [BP] and pulse rate), body weight, treatment-emergent adverse events 
(TEAEs including serious adverse events [SAEs] and adverse events of special interest [AESI]), 
laboratory measures (including anti-LY3209590 antibodies), and electrocardiograms (ECGs).
Summary statistics will be presented by treatment for the safety measures.
The summary statistics for continuous variables will be sample size, mean, standard deviation
(SD), median, minimum, and maximum.
The summary statistics for categorical variables will be sample size, frequency, and percentage.
Exposure to each therapy during the treatment period of the study will be calculated for each 
study participant and summarized by treatment group.
Additional pharmacokinetics (PK)/ pharmacodynamic (PD) analyses, such as concentration-
response for glucose and safety laboratory data, may be performed upon review of the data.


I8H-MC-BDCM Clinical Protocol
Page 12
LY3209590
2. Schedule of Activities


I8H-MC-BDCM Clinical Protocol
Page 13
LY3209590
Table BDCM.1.
Schedule of Activities
Procedure
Screening
and
Lead-in
Treatment Period
Follow-up
ET
Notesa
eCRF Visit 
Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16b
17
18b
19b
20
21
22b
801c
802c
803c
Weeks
-2
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
15
18
21
24
28
32
33
37
Visit window, 
days
±7
±3
±2
±2
±3
±2
±2
±3
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
Informed consent
X
Inclusion and 
exclusion criteria
X
Randomization
Xa
Study 
participants may 
resume  pre-
study insulin 
X
Clinical 
Assessments
Height
X
Body weighta
X
X
X
X
X
X
X
X
X
X
X
X
X
See Section 
9.1.4
Blood pressure 
and pulse ratea
X
X
X
X
X
X
X
X
X
X
X
X
X
See Section
9.4.3
Demography
X
Medical history 
(includes 
substance usagea
and history of 
CV disease)
X
Substances: 
(drugs, 
alcohol, 
tobacco and 
caffeine)


I8H-MC-BDCM Clinical Protocol
Page 14
LY3209590
Procedure
Screening
and
Lead-in
Treatment Period
Follow-up
ET
Notesa
eCRF Visit 
Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16b
17
18b
19b
20
21
22b
801c
802c
803c
Weeks
-2
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
15
18
21
24
28
32
33
37
Visit window, 
days
±7
±3
±2
±2
±3
±2
±2
±3
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
Pre-existing 
conditions
X
X
Concomitant 
medication 
review
X
X
X
X
X
X
X
X
X
X
X
X
Full physical 
examination
X
X
X
X
X
X
12-lead ECG
X
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
For screening 
visit, collect a 
single, local 
ECG
Hypoglycemia 
events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE/SAE review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Will include 
injection site 
inspections
Laboratory 
Assessments
LY3209590 PK
Xe
X
X
X
X
X
X
X
X
X
X
X
  
X
X
X
X
See Section
9.5
Fasting
X
X
X
X
X
X
X
X
X
X
X
X
Serum 
pregnancy test 
(WCBP only)a
X
See Section
5.1
Central lab


I8H-MC-BDCM Clinical Protocol
Page 15
LY3209590
Procedure
Screening
and
Lead-in
Treatment Period
Follow-up
ET
Notesa
eCRF Visit 
Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16b
17
18b
19b
20
21
22b
801c
802c
803c
Weeks
-2
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
15
18
21
24
28
32
33
37
Visit window, 
days
±7
±3
±2
±2
±3
±2
±2
±3
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
Urine pregnancy 
test (WCBP 
only)
X
X
X
X
X
Local lab
Urinalysis
X
X
X
X
X
X
Chemistry panela
X
X
X
X
X
X
X
X
X
X
X
X
Visit 2: 
glucose, AST, 
ALT, GGT 
only
Pancreatic 
Amylase
X
Lipase
X
Hepatitis B
X
HbA1c
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
FSH
X
Female study 
participants 
only
eGFR
X
X
X
X
HDL, LDL
X
X
X
X
X
X
X
X
Free fatty acid, 
triglycerides 
X
X
X
X
X
X
X
X
X
X
X
Collected in 
fasting state
C-peptide
X
X
X
X
X
X
X
X
X
Collected in 
fasting state
LY3209590 anti-
drug antibodiesa
X
X
X
X
X
X
X
X
X
See Section
9.4.7


I8H-MC-BDCM Clinical Protocol
Page 16
LY3209590
Procedure
Screening
and
Lead-in
Treatment Period
Follow-up
ET
Notesa
eCRF Visit 
Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16b
17
18b
19b
20
21
22b
801c
802c
803c
Weeks
-2
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
15
18
21
24
28
32
33
37
Visit window, 
days
±7
±3
±2
±2
±3
±2
±2
±3
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
Pharmaco-
genetic sample
X
Biomarker 
stored sample 
(plasma/
serum)
X
X
X
X
X
X
X
X
X 
Ancillary 
Supplies/
Diaries/
Investigational 
Product
Study participant
training/
educationa
X
Includes 
diabetes 
counseling, 
hypoglycemia 
(9.2.2.1), 
FPG profiles, 
diary 
completion, 
CGM sensor 
replacement
Study participant
CGM Training
X


I8H-MC-BDCM Clinical Protocol
Page 17
LY3209590
Procedure
Screening
and
Lead-in
Treatment Period
Follow-up
ET
Notesa
eCRF Visit 
Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16b
17
18b
19b
20
21
22b
801c
802c
803c
Weeks
-2
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
15
18
21
24
28
32
33
37
Visit window, 
days
±7
±3
±2
±2
±3
±2
±2
±3
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
CGM Sensor 
Insertion
X
Sensor 
inserted and 
system started 
by study 
participant
under site 
personal 
supervision
Distribute CGM 
sensorf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CGM data 
download
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense 
supplies and 
diary
X 
X
X
X
X
X
X
X
X
X
IWRS
X
X
X
X
X
X 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Record diary and 
CGM data 
(including FPGg, 
hypoglycemia)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Review diary 
and CGM data 
(including FPGg, 
hypoglycemia)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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LY3209590
Procedure
Screening
and
Lead-in
Treatment Period
Follow-up
ET
Notesa
eCRF Visit 
Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16b
17
18b
19b
20
21
22b
801c
802c
803c
Weeks
-2
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
15
18
21
24
28
32
33
37
Visit window, 
days
±7
±3
±2
±2
±3
±2
±2
±3
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
Record recent 
study drug 
dose/dose 
adjustment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense IP
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study personnel 
administer IP at 
site
X
X
X
X
X
X
X
X
X
Train study 
participant
in IP 
administration
X
X
X
X
X
X
X
X
Study participant
or study 
personnel 
administer at 
sitea
X
X
X
X
X
X
Weeks
13 - 31
(except Week 
18): study 
participants 
may self-
administer 
injection at 
home or have 
injection done 
at site


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LY3209590
Procedure
Screening
and
Lead-in
Treatment Period
Follow-up
ET
Notesa
eCRF Visit 
Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16b
17
18b
19b
20
21
22b
801c
802c
803c
Weeks
-2
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
15
18
21
24
28
32
33
37
Visit window, 
days
±7
±3
±2
±2
±3
±2
±2
±3
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
LY3209590 
accountability 
(collect used and 
unused IP)
X
X
X
X
X
Insulin degludec 
accountability 
(collect unused 
pens)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviations:  AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BG = blood glucose; CGM = continuous glucose 
monitoring; CV = cardiovascular; eCRF = electronic case report form; eGFR = estimated glomerular filtration rate; ECG = electrocardiogram; ET = early 
termination; FPG = fasting plasma glucose; FSH = follicle stimulating hormone; GGT = gamma-glutamyl transferase; HbA1c = glycated hemoglobin;
HDL = high density lipoprotein; IP = investigational product; IWRS = interactive web-response system; LDL = low density lipoprotein; LY = LY3209590;
PK = pharmacokinetics; SAE = serious adverse event; SMBG = self-monitoring of blood glucose; WCBP = women of child bearing potential.
a
Indicates that a relevant note is included in the last column.
b
Phone visit
c
Study activities at Visits 802 and 803 are identical to Week 32 (Visit 21) and Visit 801, respectively.
d
A triplicate, central ECG will be performed prior to the time of each PK sampling. These ECGs will be performed in a fasting state. 
e
Collect 2 PK samples: one predose and one approximately 2 hours postdose or as late as possible just prior to departure from the site.
f
Study participants will replace CGM sensor according to system label at home and will be trained for this procedure at Visit 3. At each visit study participants
will be supplied with the necessary sensors for the respective interval.
g
Occurs the week prior to the scheduled dose adjustment check. FPG should be collected daily for 
 prior to dose adjustment for calculating average 
FPG.
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3. Introduction
3.1.
Study Rationale
LY3209590 is a long-acting insulin receptor agonist with a half-life enabling weekly dosing 
developed for the treatment of type 2 diabetes mellitus (T2DM).  This Phase 2 study of 
LY3209590 will:
Evaluate the effects of LY3209590 on glycemic control using 2 different dose 
individualization strategies compared with insulin degludec in study participants 
previously treated with basal insulin.
3.2.
Background
LY3209590 was designed as a novel, once-weekly, long-acting insulin receptor agonist that is 
intended for the treatment of hyperglycemia in study participants with T2DM.  A once weekly 
insulin receptor agonist has the potential to increase willingness to initiate and compliance with 
an insulin therapy in study participants with T2DM. In real life only about a quarter of these 
study participants reach the target HbA1c of 7% (Blonde L et al. 2014) and a once weekly 
insulin receptor agonist could help to increase this number. The potential downside of such a 
long acting insulin receptor agonist could be a higher risk for hypoglycemic events or a longer 
duration of such events. The recently launched long acting insulin degludec has nevertheless 
shown a reduced potential to induce hypoglycemia as compared to insulin glargine while its 
half-life is twice as long as that of insulin glargine (Heise et al. 2012).  The current phase 2 study 
will therefore evaluate the safety and efficacy of LY3209590 as compared to insulin degludec 
while very closely monitoring glycemic profiles using continuous glucose monitoring.
Data from the single-ascending dose (SAD) study demonstrated clear evidence of glucose 
lowering in study participants with T2DM at single doses ranging from 
. The 
pharmacokinetics (PK) of LY3209590 following single doses demonstrated prolonged time-
action profile to support once-weekly administration.  LY3209590 reached maximum 
concentration approximately 
 after dosing, followed by a mean elimination half-life of 
approximately 
in study participants with T2DM. With a 
long elimination half-life, following a weekly fixed-dose regimen, PK steady-state is reached in 
approximately 
and results in approximately 
r concentration than after 
single dose. However, using a loading dose strategy that is 
, 
 on PK modeling. PK following a
single loading dose 
 during the first week was demonstrated to be 
comparable to concentration profile at Week 
 based on 
preliminary data in the multiple ascending dose (MAD) study.  No clinically significant 
persistence in hypoglycemia was observed in the study. Besides the known risk of
hypoglycemia, no relevant safety signals have been observed in the Phase 1 studies. Additional 
information about LY3209590 can be found in the Investigator’s Brochure.
The toxicity profile of LY3209590 has been characterized in 6-week and 6-month repeat-dose 
toxicology studies in rats and dogs, and reproductive toxicology studies in rats and rabbits.  
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These studies demonstrated a familiar spectrum of effects typically associated with changes 
secondary to hypoglycemia and/or hyperinsulinemia resulting from repeat dosing of exogenous 
insulin in normoglycemic test systems.  All findings were considered to be target-related with no 
evidence of off-target effects in any of the parameters assessed. Additional information about 
LY3209590 can be found in the Investigator’s Brochure.
3.3.
Benefit/Risk Assessment
The data from the SAD study and the ongoing MAD study (Studies BDCA and BDCB) have 
shown that LY3209590 was well tolerated and the adverse drug reactions are in line with those 
reported for long acting insulins.
Potential risks associated with LY3209590, derived from the known risks of long acting insulins 
are hypoglycemia, hypersensitivity reactions (localized allergy and/or systemic allergy), 
undesirable effects at the injection site (injection-site reactions and lipodystrophy), and 
peripheral edema. An additional risk based on preclinical data could be an elevation of liver 
aminotransferases. To date, this has not been observed in study participants or healthy 
volunteers exposed to LY3209590 for up to 6 weeks.
More information about the known and expected benefits, risks, Serious Adverse Events (SAE)
and reasonably anticipated AEs of LY3209590 are to be found in the Investigator’s Brochure.


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LY3209590
4.
Objectives and Endpoints
Table BDCM.2 shows the objectives and endpoints of the study.
Table BDCM.2.
Objectives and Endpoints
Objectives
Endpoints
Primary

To investigate the efficacy of LY3209590 arms 
in study participants with T2DM

HbA1c change from baseline to Week 32
Secondary
Efficacy

To investigate the efficacy of LY3209590 
compared with insulin degludec in study 
participants with T2DM.

HbA1c change from baseline to Week 12 and 
32

Fasting glucose change from baseline to Weeks 
12 and 32

Insulin dose change from baseline to week 12 
and 32
Safety

To investigate the safety of LY3209590
compared with insulin degludec in study 
participants with T2DM.

Incidence and rate of hypoglycemia 

Incidence and rate of nocturnal hypoglycemia

Incidence and rate of severe hypoglycemia

Incidence of treatment-emergent serious AEs

Body weight change from baseline at Weeks 12 
and 32
Pharmacokinetics 

To characterize the PK of LY3209590 in study 
participants with T2DM

LY3209590 population-based parameters, such 
as, AUC within dosing interval at Weeks 12 
and 32
Exploratory

To investigate the safety and tolerability of 
LY3209590 compared with insulin degludec in
study participants with T2DM.

Treatment-emergent AEs

Discontinuation of IP due to AEs

Clinical laboratory results

Systematic assessment of injection site 
reactions

Insulin dose during follow up period

Incidence and rate of hypoglycemia during 
treatment and follow-up period

Incidence and rate of daytime hypoglycemia

Liver aminotransferase change from baseline to 
Weeks 12 and 32

To explore quality of glycemic control 
compared with insulin degludec using CGM

Glucose time in target range, time in 
hyperglycemia, time in hypoglycemia

Duration and recurrence of hypoglycemic 
events 

To establish the relationships between 
dose/exposure and key safety and efficacy 
measures for LY3209590 

To evaluate dose/exposure and key safety and 
efficacy measures following different dosing 

LY3209590 exposure-response relationships 
with fasting glucose, SMBG, HbA1c, 
hypoglycemia, body weight, blood pressure, 
pulse rate, and QTc, 

Relationship of LY3209590 dose to efficacy 


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LY3209590
Objectives
Endpoints
regimens
(HbA1c, fasting glucose) and safety 
(hypoglycemia).

To characterize the effects of LY3209590 on 
exploratory PD biomarkers

To explore the development of LY3209590 
ADAs

Plasma lipids (cholesterol, LDL, HDL, 
triglycerides)

Biomarkers of lipolysis (FFA)

The frequency of antibody formation to 
LY3209590 will be determined.  
Abbreviations:  ADA = antidrug antibodies; AE = adverse events; AUC = area under the curve; CGM = continued 
glucose monitoring; FFA = free fatty acids; HbA1c = hemoglobin A1c; HDL = high density lipoprotein;
IP = investigational product; LDL = low density lipoprotein; PD = pharmacodynamics; PK = pharmacokinetics; 
QTc = corrected QT interval; SMBG = self-monitoring of blood glucose; T2DM = type 2 diabetes mellitus.


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5. Study Design
5.1.
Overall Design
Study I8H-MC-BDCM (BDCM) is a multicenter, randomized, open-label, comparator-controlled 
Phase 2 study with 3 study periods. A total of 536 study participants with T2DM, previously 
treated with basal insulin will be screened. Approximately 375 study participants will be 
randomized in a 1:1:1 ratio to LY3209590 in one of two dosing algorithms (Appendix 7) or 
insulin degludec (modified Riddle algorithm, Section 7.2.1.2). The study is designed to evaluate 
the efficacy and safety of LY3209590 compared with insulin degludec.
The study will consist of 3 periods:  2-week screening, 32-week treatment period, and 5-week 
safety follow-up period.
Study governance considerations are described in detail in Appendix 3.
Figure BDCM.2 illustrates the study design.
Figure BDCM.2.
Illustration of study design for Clinical Protocol I8H-MC-BDCM.


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LY3209590
5.1.1.Study Visits
Study Period 1: Screening and Lead-in
The purpose of procedures at screening is to establish eligibility for inclusion in the study (see 
Sections 6.1 and 6.2  During this period, study participants will be trained on disease monitoring 
and disease management procedures, study diaries and study procedures. Visit-specific subject 
diaries will be dispensed at Visit 2 and as specified in the Schedule of Activities (Section 2) for 
future visits.
During the lead-in period, study participants should continue the same formulation and dose of 
their previously used insulin therapy, as well as allowable oral antidiabetic medications (OAMs -
sulfonylureas [SU] and meglitinides, dipeptidyl peptidase-4 [DPP-IV] inhibitors, sodium-glucose 
cotransporter 2 [SGLT-2] inhibitors, biguanides, and alpha-glucosidase inhibitors) in order to 
allow reliable assessment of hemoglobin A1c (HbA1c) at randomization (see Section 7.7.2).
Continuing Glucose Monitoring:  
A standard system will be used for continuing glucose monitoring (CGM) in an unblinded mode. 
The study participants will wear this device beginning on Day 0 at randomization, as shown in 
the Schedule of Activities (Section 2). In addition, all study participants will be allowed to use 
their blood glucose meters for additional blood glucose testing or for calibration of the CGM 
system if deemed necessary, or for taking self-monitored plasma glucose (SMPG) measurements 
during the outpatient period.
At the randomization visit (Visit 3), study participants will be trained on the use of the CGM 
device, CGM sensor replacement, interpretation of CGM based blood glucose values and alarms, 
and the requirements for CGM.  For the first CGM session, study participants meeting all 
study-entry criteria will have the CGM sensor inserted as part of the Visit 3 activities.
Study Period 2: Treatment Period
Randomization (Week 0 [Visit 3])
Study participants who continue to be eligible for the study will be randomized to 1 of the 
treatment arms.  All measures to be performed at Visit 3 (see Schedule of Activities, Section 2)
should be done prior to injection of the study participant’s assigned investigational product (IP) 
to ensure that appropriate baseline measurements are obtained. Urine and serum pregnancy tests
will be done before IP administration.  The study participant will begin IP, if the urine pregnancy 
test is negative. If the result of the serum pregnancy test is positive, the study participant will be 
discontinued from the study (see Section 8.2).
Study personnel will inject the first dose of IP at the study site.  The PK samples and ECGs at 
randomization must be collected as described in the Schedule of Activities (Section 2).
Following randomization, study participants will participate in a 32-week treatment period. 
During Weeks 1 to 8, site personnel will administer IP, and study participants will receive 
education and training on how to self-administer IP. The training should include information on 
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LY3209590
symptoms of local adverse reactions, should that occur. During Weeks 9 to 12, IP will be 
reconstituted and administered at the site by the study participant, under supervision of trained
site personnel to assure that the study participant is capable of self-administration.  During 
Weeks 13 to 31 IP will be self-administered by the study participant at home, or optionally can 
be administered once weekly by site personnel. Information on self-injection can be reviewed as 
necessary throughout the study.
LY3209590 will be administered as one of two dose individualization algorithms (Appendix 7).
Insulin degludec will be self-administered daily by study participants after a training and first 
administration under site personnel supervision on Day 1 according to a modified Riddle 
algorithm (Section 7.2.1.2).
General considerations
Study procedures will be performed as listed in the Schedule of Activities (Section 2).
In order to allow timely sampling for PK assessments, visits for collection of the samples will be 
scheduled within the required time windows provided in the Schedule of Activities (Section 2).
Study participants will continue to use concomitant OAMs throughout the treatment period:  
discontinuation or changes to dose are not permitted, except in situations where dose adjustment 
or complete discontinuation is required per country-specific label or when allowed per study 
protocol (for further details see Section 7.7.2).
Study participants will be instructed to document fasting plasma glucose (FPG) each day by 
using the values displayed on their CGM device after wakening or using a finger-stick glucose 
measurement.  In addition, two 6-point SMPG profiles (prior to and 2 hours after the morning, 
midday, and evening meals) should be documented on non-consecutive days in the week prior to 
the required visits noted in the Schedule of Activities using CGM-based glucose values,
(Section 2). 
Study participants who develop severe, persistent hyperglycemia based on prespecified 
thresholds (see Section 7.8.2.3) will receive a new glucose-lowering intervention (or rescue 
therapy) based on clinical judgment of the investigator (see Table BDCM.4).  Study participants 
who need rescue therapy will continue on IP in the trial until they complete all study visits.
Study Period 3: End-of-Treatment and Safety Follow-Up, Visits 21, 801, 802, and 803
All randomized study participants should have a comprehensive efficacy and safety evaluation 
approximately 1 week after the last dose of IP and a safety follow-up visit approximately 
6 weeks after the last dose of IP.  During the safety follow-up study period, study participants
will continue CGM and may be treated with an appropriate glucose-lowering regimen (see Table 
BDCM.4) if necessary.  Study participants will also be required to return any remaining study 
diaries and used or unused IP to the investigative site.
Study participants who complete the treatment period will have a comprehensive
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LY3209590
after the last dose of IP and a safety follow-up assessment (Visit 801) approximately 6 weeks 
after the last dose of IP and 5 weeks after their End-of-Treatment assessment (Visit 801). During 
the safety follow-up study period, study participants will continue CGM, and may be treated with 
an appropriate glucose-lowering regimen (see Table BDCM.4) if necessary. Study participants 
will also be required to return any remaining study diaries and used or unused IP to the 
investigative site.
Study participants who discontinue IP prior to completion of the study for any reason should 
also have a comprehensive End-of-Treatment efficacy and safety assessment (Visit 802) 
approximately 1 week after the last dose of IP or as soon as reasonably possible thereafter, and 
should have a safety follow-up assessment (Visit 803) approximately 6 weeks after the last dose 
of IP. Study activities at Visits 802 and 803 are identical to Week 32 (Visit 21) and Visit 801, 
respectively.
Study participants who discontinue IP prior to study completion will be encouraged to remain in 
the study and to complete any scheduled study procedures that occur after their safety follow-up 
(Visit 803).  Study participants remaining in the study will receive an appropriate rescue 
glucose-lowering regimen.  Table BDCM.4 provides details on the use of glucose-lowering 
medications for rescue and for treatment of acute conditions.
Study participants who discontinue IP for any reason and are unwilling to return for a safety 
follow-up visit, will be asked to perform an early termination (ET) visit as their final study visit.  
At this visit, study participants will perform procedures listed in the Schedule of Activities 
(Section 2).
5.2.
Number of Participants
Approximately 536 participants will be screened to achieve 375 randomized and 300 evaluable 
participants for an estimated total of 100 evaluable participants per treatment group.
5.3.
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 study participant.
5.4.
Scientific Rationale for Study Design
This study will evaluate 2 dosing regimens of LY3209590 in study participants with T2DM who 
are already treated with a daily basal insulin. Study participants will take their last dose of daily 
basal insulin the day prior to randomization. Treatment will be initiated after randomization with 
either LY3209590 or insulin degludec as an active comparator. As LY3209590 has a long 
half-life, a weekly dosing regimen is expected to reach steady-state of PK in over 
 
of treatment.  Therefore, the withdrawal of a daily basal insulin would result in loss of glycemic 
control for several weeks after randomization. Therefore, a loading-dose regimen approach, by 
which an exposure to achieve comparable glycemic control to prior basal insulin dose can be 
achieved 
, followed by 
starting at Week 2 
to maintain steady-state exposure.  Subsequently, dose adjustments can be made in the initial 
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dose individualization phase of the study. See Appendix 7 and section 7.2.1.2 for dosing and 
administration details.  The 32-week treatment duration is planned as the slow dose escalation 
approach is necessary for LY3209590 to achieve near comparable glycemic efficacy to prior 
daily basal insulin.    
Insulin degludec is an unblinded active comparator in this study, and will be used to compare the 
effects of LY3209590 on glycemic control, hypoglycemia and weight gain with a daily basal 
insulin. 
5.5.
Justification for Dose
Following a once-weekly SC administration of LY3209590, the time to reach steady-state 
glucose level is estimated between 4 to 10 weeks based on the long half-life of LY3209590.  
Therefore, 
 weekly dose and gradual 
 
 dose adjustment is recommended for LY3209590 dosing regimen.
 
 
 of LY3209590 is based on prior basal insulin dose 
converting the dose in units into mg of LY3209590 and is based on PK/PD modeling of limited 
SAD and MAD data. Dose adjustments are based on average of prior 
) fasting 
glucose and hypoglycemia events. Alterations to the doses recommended by these dose 
adjustment algorithms are also under discretion of the investigator and will take hypoglycemia 
and other study participant safety concerns into account.
The starting dose for insulin degludec is the same dose as the basal insulin that the study 
participant used previously before entering the study. The study participant will start a titration 
phase based on fasting glucose achievements under this therapy and the presence of 
hypoglycemia or other safety concerns. The titration will be performed each week. The dose 
adjustment algorithm is adapted from the well-established Riddle algorithm (Section 7.2.1.2) 
under discretion of the investigator.
Guidance is provided for the two algorithms used in dosing LY3209590. There is also guidance 
for conversion of prior basal insulin dose to LY3209590 loading dose, as well as dosing 
suggestions for investigators based on fasting glucose and hypoglycemia of the study participant 
(Appendix 7).
Safety of study participants will be closely monitored during the early stages of dose titration to 
determine whether adjustments to the conversion and dose adjustment algorithms are needed. As 
additional data emerges, guidance from the Sponsor on these dosing algorithms may be modified
(Appendix 7).
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6.
Study Population
The study population will consist of study participants with T2DM previously treated with basal 
insulin.  Eligibility of study participants will be based on the results of the following assessments 
performed at screening (approximately Week -2) as described in the Schedule of Activities 
(Section 2).  The nature of any conditions present at the time of the initial screening and any 
pre-existing conditions will be documented in the electronic case report form (eCRF).
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Study participants are eligible to be included in the study only if they meet all of the following 
criteria at screening:
Type of Study Participant and Disease Characteristics
[1]
Have a diagnosis of T2DM according to the WHO criteria treated with basal 
insulin
[2]
Are receiving ≥10 units of insulin per day or ≤1.5 units per kilo of insulin 
per day
Study Participant Characteristics
[3a] Male study participants: 
Men with female partners of childbearing potential must agree to use at least 
one effective method of contraception (Appendix 5) for the duration of the 
study and for at least 15 weeks (approximately 3 half-lives plus 90 days)
following the last dose of IP.
[3b] Female study participants:  
Women not of child-bearing potential may participate and include those who are:  

Infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy, or 
tubal ligation), congenital anomaly such as Müllerian agenesis; or 

Postmenopausal, defined as:  
o
A woman at least 50 years of age with an intact uterus, not on hormone 
therapy, who has had either: 
a) Cessation of menses for at least 1 year, or 
b) At least 6 months of spontaneous amenorrhea with a follicle-
stimulating hormone >40 mIU/mL (local laboratory); or 
o
A woman 55 years or older not on hormone therapy, who has had at least 
6 months of spontaneous amenorrhea; or 
o
A woman at least 55 years of age with a diagnosis of menopause prior to 
starting hormone replacement therapy.


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Women of childbearing potential must agree to remain abstinent (if this is their 
preferred and usual lifestyle), use 1 highly effective method of contraception, or a 
combination of 2 effective methods of contraception (Appendix 5) starting at 
screening and continuing for 15 weeks (approximately 3 half-lives plus 90 days) 
after the last dose of IP:  

Test negative for pregnancy at screening based on serum pregnancy test, followed 
by a negative urine pregnancy test within 24 hours prior to randomization
(Visit 3)

Not be breastfeeding
[4]
Are at least 18 years of age at screening
[5]
Have a baseline HbA1c value of 6.5% to 10%, inclusive, at screening
[6]
Have been treated with a stable regimen of insulin glargine, insulin levemir
or insulin degludec with or without OAM therapy for 3 months prior to 
screening and be willing to continue stable dosing throughout the study. 
Acceptable OAMs include up to 3 of the following:

DPP-4 inhibitors

SGLT-2 inhibitors

biguanides

alpha-glucosidase inhibitors

sulfonlyureas
Note: All OAMs must be used in accordance with the corresponding local 
product label at the time of screening.
[7]
Have a body mass index (BMI) between 20 and 45 kg/m2, inclusive with no 
significant weight gain or loss in the past 3 months (≥5%)
[8]
In the investigator’s opinion, are well-motivated, capable, and willing to:

learn how to self-inject treatment, as required for this protocol; visually 
impaired persons who are not able to perform the injections must have the 
assistance of a sighted individual trained to inject the IP; persons with 
physical limitations who are not able to perform the injections must have 
the assistance of an individual trained to inject the IP;

maintain a study diary, as required for this protocol;

wear only the CGM device supplied for use in this study, without 
interruption, as required in the Schedule of Activities (Section 2) and 
Section 9.4.5; 

must have a normal wake/sleep pattern such that midnight to 0600 hours 
will reliably reflect a usual sleeping period.


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Informed Consent
[9]
Are able and willing to give signed informed consent 
6.2.
Exclusion Criteria
Medical Conditions
[10] Have a diagnosis of type 1 diabetes mellitus or latent autoimmune diabetes
[11] Are receiving prandial insulin, insulin mixtures, or twice daily basal insulin; 
also if receiving <10 units of insulin per day or >1.5 units per kilo of insulin 
per day
[12] Have a history of greater than 1 episode of ketoacidosis or hyperosmolar 
state/coma requiring hospitalization in the 6 months prior to screening
[13] Have had any episodes of severe hypoglycemia and/or hypoglycemia 
unawareness within the 6 months prior to screening
[14] Cardiovascular (CV):  have had any of the following CV conditions: acute 
myocardial infarction, New York Heart Association Class III or IV heart 
failure (Appendix 6), or cerebrovascular accident (stroke)
[15] Gastrointestinal:  have undergone gastric bypass (bariatric) surgery or 
restrictive bariatric surgery (e.g., Lap-Band®) prior to screening
[16] Hepatic:  have acute or chronic hepatitis, or obvious clinical signs or 
symptoms of any other liver disease except non-alcoholic fatty liver disease 
(NAFLD) (i.e., study participants with NAFLD are eligible for 
participation), and/or have elevated liver enzyme measurements, as 
determined by the central laboratory at screening and as indicated below:

Total bilirubin >2x the upper limit of normal (ULN), or

ALT/serum glutamic pyruvic transaminase (SGPT) >2.5x ULN, or

Aspartate aminotransferase (AST)/serum glutamic oxaloacetic 
transaminase (SGOT) > 2.5x ULN
[17] Renal:  have an estimated glomerular filtration rate (eGFR)
<30 mL/min/1.73 m2, calculated by the Chronic Kidney Disease-
Epidemiology equation, as determined by the central laboratory at screening
[18] Have experienced significant weight loss or gain (>5%) in body weight,
3 months prior to screening (Visit 1)
[19] Have active or untreated malignancy, or have been in remission from 
clinically significant malignancy (other than basal cell or squamous cell skin 
cancer) for less than 5 years or are at increased risk for developing cancer or 
a recurrence of cancer in the opinion of the investigator
[20] Have known hypersensitivity or allergy to any of the study medications or 
their excipients


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[21] Have any other serious disease or condition (for example, known drug or 
alcohol abuse or psychiatric disorder) that, in the opinion of the investigator, 
would pose a significant risk to the study participant, preclude the study 
participant from following and completing the protocol, or interfere with the 
interpretation of safety, efficacy, or PD data
[22] Have had a blood transfusion or severe blood loss within 3 months prior to 
screening or have any hematologic condition that may interfere with HbA1c 
measurement (e.g., hemoglobinopathy, hemolytic anemia, sickle-cell 
disease)
[23] Have a significant history of alcoholism or drug abuse as judged by the
investigator or consuming more than 24 g of alcohol per day for males or
more than 12 g of alcohol per day for females
[24] Have fasting Triglyceride levels above 400 mg/dl or non-fasting 
Triglycerides above 600 mg/dl at screening.
Prior/Concomitant Therapy
[25] Drugs which may significantly affect glycemic control (e.g., niacin [allowed 
if <1.0g/day], bile acid sequestrants)
[26] Are receiving chronic (>14 days) systemic glucocorticoid therapy (excluding 
topical, intraocular, intranasal, or inhaled preparations) or have received 
such therapy for >14 days within the month preceding screening
[27] Are currently taking or have taken within the 3 months preceding screening, 
prescription or over-the-counter medications to promote weight loss.  Study 
participants who participate must agree not to initiate a diet and/or exercise 
program during the study with the intent of reducing body weight other than 
the lifestyle and dietary measures for diabetes treatment
[28] Are using or have used blood pressure-lowering medication at a dose that 
has not been stable for 1 month prior to screening.
Prior/Concurrent Clinical Trial Experience
[29] Are currently enrolled in any other clinical study involving an IP or any 
other type of medical research, judged not to be scientifically or medically 
compatible with this study
[30] Have participated, within the last 30 days in a clinical trial involving an IP. 
If the previous IP has a long half-life, 3 months or 5 half-lives (whichever is 
longer) should have passed
[31] Have previously completed or withdrawn from this study or any other study 
investigating LY3209590.


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Other Exclusions
[32] Are investigator site personnel directly affiliated with this study and/or their 
immediate families.  Immediate family is defined as a spouse, parent, child, 
or sibling, whether biological or legally adopted
[33] Are Eli Lilly and Company (Lilly) employees or are employees of any 
third-party involved in the study who require exclusion of their employees
6.3.
Lifestyle Restrictions
Per the Schedule of Activities (Section 2), qualified medical staff will provide diabetes
management counseling, which will include instructions on diet and exercise and education 
about the signs, symptoms, and treatment of hypoglycemia, should it occur. Study participants 
should continue their usual exercise habits and generally follow a healthy meal plan (with 
consistent meal size and time of day) throughout the course of the study. Dietary counseling 
may be reviewed throughout the study, as needed.
Prescription or over-the-counter (OTC) medications that promote weight loss are exclusionary if 
used within 3 months prior to screening (study entry), or between screening and randomization at 
Visit 3 (see Section 2).  These medications are also not allowed at any time during the treatment 
period.  If started after randomization, they should be immediately withdrawn.  In addition, study 
participants should not receive an intensive diet/exercise program with the intent of reducing 
body weight at any time during the study, other than the lifestyle and dietary measures for 
diabetes treatment.
Study participants should be instructed not to donate blood or blood products during the study or 
for 4 weeks following the study.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened 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.


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7. Treatments
7.1.
Treatments Administered
LY3209590 will be administered once weekly as subcutaneous (SC) injections. Each study 
participant will receive 1 injection each week, as described in Table BCDM.3.  SC injections of 
LY3209590 will be administered rotating between left and right abdominal regions and upper 
and lower quadrants. During the first 8 weeks, treatment will be administered by the study staff,
while study participants receive education and training on how to reconstitute and self-administer 
LY3209590.  During Weeks 9 to 12, LY3209590 will be reconstituted and administered at the 
site by the study participant under supervision of the site personnel to assure that the study 
participant is capable of self-administration.  During Weeks 13 to 31, LY3209590 will be 
self-administered by the study participant at home, or optionally can be administered once 
weekly by site personnel.
Insulin degludec will be administered once daily at approximately the same time of day, rotating 
between left and right abdominal regions and upper and lower quadrants.
Study participants will receive treatment with LY3209590 by 1 of 2 algorithms.  Table BCDM.3
shows the treatment regimens.  See Section 7.2.1 for details on dosing algorithms and Section
7.8.1 for transitioning to treatment after study completion.
Table BCDM.3.
Treatment Regimens
Regimen
Dose
Randomization through Week 32
LY Dose Algorithm 1
LY injection
LY Dose Algorithm 2
LY injection
Insulin degludec
Insulin degludec injection
Abbreviations:  LY = LY3209590.
The investigator or his/her designee is responsible for the following:  

explaining the correct use of the investigational agent(s) to the study participant

verifying that instructions are followed properly

maintaining accurate records of IP dispensing and collection

at the end of the study, returning all unused medication to Lilly, or its designee, 
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 Labeling
LY3209590 will be provided as 
 of lyophilized powder in a vial. Reconstitution with 
sterile water or 0.9% sodium chloride will be required prior to dosing.
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Insulin degludec will be provided as a 100 U/mL solution in a 3-mL prefilled pen.
All IP materials must be stored at the investigative sites, according to the instructions provided 
on the product label, in a locked and secure place. Insulin must not be frozen. Unused study
treatments will remain in a locked and secured place at the investigative sites, according to
instructions provided on the product label, or according to written instruction from the Sponsor,
until returned to the Sponsor or destroyed.
Clinical study materials will be labeled according to the country’s regulatory requirements.
7.2.
Method of Treatment Assignment
Study participants who meet all criteria for enrollment will be randomized to open-label
treatment at Visit 3.  Assignment to treatment groups will be determined by a 
computer-generated random sequence using an interactive web-response system (IWRS).  The 
IWRS will be used to assign open-label IP to each study participant.  Site personnel will confirm 
that they have located the correct IP by entering a confirmation number found on the IP label 
into the IWRS.
To achieve between-group comparability for site factor, the randomization will be stratified by 
country, baseline HbA1c (<8.5%, ≥8.5%), country, SU (yes/no), and baseline BMI (<30, ≥30).  
The randomization scheme will be performed using IWRS, which will ensure balance between 
treatment arms.
7.2.1. Selection and Timing of Doses
Study participants will be randomly assigned to a LY3209590 dose via Algorithm 1 or 
Algorithm 2.  The doses will be administered at approximately the same time and day each week.  
The actual date and time of all dose administrations will be recorded in the subject’s diary (or 
study participant’s medical record when administered at the site) and in the eCRF. Insulin 
degludec will be administered same time each day, adjusted per modified Riddle algorithm
(Section 7.2.1.2).
If a study participant misses a scheduled dose of LY3209590, it should be administered as soon 
as possible, but no later than 3 days after the scheduled administration.  If more than 3 days have 
elapsed since the scheduled administration, the dose should be skipped and the next injection 
will occur at the next scheduled day and time. Study participants who miss a dose of insulin 
degludec should inject their daily dose during waking hours upon discovering the missed dose. 
Instruct study participants to ensure that at least 8 hours have elapsed between consecutive 
insulin degludec injections (Tresiba USPI). 
7.2.1.1.
LY3209590 Algorithms
Guidance is provided for conversion of prior basal insulin dose to LY3209590 loading dose and 
initial weekly dose (Appendix 7).  Dose adjustment is based on study participants’ prior fasting 
glucose and hypoglycemic events (Appendix 7).  Alterations to the doses recommended by these 
dose adjustment algorithms are allowed in situations where study participant safety is a concern 
or where adjustments do not show the desired therapeutic effect, after consultation with Lilly. 


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As additional data emerges, the guidance from the Sponsor on these dosing algorithms may be 
modified.
7.2.1.2.
Insulin Degludec
Insulin degludec will be initiated at the same dose as the total daily basal insulin dose already 
administered, or in accordance with the locally approved product labeling if different.  
Thereafter, a dosing algorithm adapted from Riddle et al. 2003 will be used by investigators for 
adjusting insulin degludec to target an FBG ≤100 mg/dL (<5.6 mmol/L) in order for study 
participants to achieve glycemic goals of an HbA1c value <7.0% and a pre-prandial capillary 
plasma glucose (PG) between 71 and 130 mg/dL (3.9 to 7.2 mmol/L; ADA 2011).  In situations 
where study participant safety is a concern or where dose adjustments have not had the desired 
therapeutic effect, investigators may only make increased adjustments to the dose of insulin 
degludec recommended by the dose-adjustment algorithm after consultation with Lilly.
At the time of site visit or telephone visit, the investigator will assess the study participant’s 
glycemic control for the previous week and, if necessary, inform the study participant about any 
needed dose adjustment.  The dose will be based on the study participant’s blood glucose value. 
Adherence to the dosing algorithm provided for this study is required from Visit 3 
(randomization) up to Visit 21 (Week 32, inclusive) and will be monitored periodically by the 
study team. Dose increases may be made at weekly intervals and no sooner than 5 days 
following the last dose increase.  In some cases, study participant visits could occur sooner than 
5 days apart due to the allowable visit window; however, there should be no dose increase if at 
least 5 days have not elapsed since the previous dose increase.  In contrast, the insulin degludec
dose may be reduced at any time on the judgment of the investigator. Any deviations from this 
guidance must be approved by Lilly.
The insulin dose increase algorithm is adapted from Riddle et al. 2003 and will be determined 
based on the definition of what is termed the “Algorithm FBG.”  The Algorithm FBG is the 
median of the FBG (determined from self-monitoring of blood glucose [SMBG]) of Days 5, 6,
and 7 since the last insulin dose increment.  If the interval since the last dose adjustment has been 
longer than 7 days, the dose increase is determined by the median of the FBG of the last 3 days. 
If the study participant only measured their FBG on 2 of the last 3 days, then the lesser of those 
2 FBG values should be used as the Algorithm FBG.  If only 1 FBG measurement is available 
for the last 3 days, then the investigator should use his/her discretion in determining whether 
there should be a dose adjustment based on that single FBG value.
As it is desired to achieve glycemic goals in as many study participants as possible, 
contingencies are provided to accommodate prespecified protocol visits and to increase the dose 
of insulin degludec in a timely manner.  Therefore, if the last dose increment was 5 days prior, 
then the dose increment is determined by the Algorithm FBG, which is the lesser of the 2 FBG 
values from Day 4 and Day 5. If the dose increment was 6 days prior, then the Algorithm FBG 
is the lesser of the 2 FBG values from Day 5 and Day 6.  In both of these cases, if only 1 of the 
2 FBG values is available, then the investigator should use his/her discretion in determining 
whether there should be a dose adjustment based on that single FBG value.


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The dose increase algorithm is defined as follows:

If the Algorithm FBG is 101 to 120 mg/dL (5.6 to 6.7 mmol/L), increase the dose 
by 2 U.

If the Algorithm FBG is 121 to 140 mg/dL (6.8 to 7.8 mmol/L), increase the dose 
by 4 U.

If the Algorithm FBG is 141 to 180 mg/dL (7.9 to 10.0 mmol/L), increase the 
dose by 6 U.

If the Algorithm FBG is 180 mg/dL (10.0 mmol/L), increase the dose by 8 U.
The treat-to-target FBG is ≤100 mg/dL (<5.6 mmol/L).  The insulin dose will not be increased if 
any SMBG was documented at ≤70 mg/dL (<3.9 mmol/L) at any time in the preceding week.  
Dose decreases of 2 to 4 U per adjustment may be permitted if multiple episodes of 
hypoglycemia with SMBG ≤70 mg/dL (<3.9 mmol/L) were recorded, if severe hypoglycemia 
(requiring assistance) occurred, or if any SMBG was documented at ≤54 mg/dL (≤3.0 mmol/L) 
in the preceding week.
7.3.
Blinding
This study is an open-label study. Investigators, site personnel and study participant will be 
aware of the treatment allocation. Due to the differences in administration of LY3209590 (once 
weekly) and the comparator (degludec given once daily) blinding the treatment assignment 
would be impossible for these titratable medications.
7.4.
Dosage Modification
Dosing will be individualized based on FBG. See Appendix 7 and section 7.2.1.2 for details of 
dose modification.
7.5.
Preparation/Handling/Storage/Accountability
The investigator or his/her designee is responsible for the following:

confirming 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.

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).
The study site must store LY3209590 and insulin degludec under refrigerated conditions (2°C to 
8°C) until use.  Insulin must not be frozen. In-use storage conditions must be followed  according 


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to the storage conditions provided on the label.  Study participants will be provided with cartons 
containing the required number of vials or pens at clinic visits as shown in the Schedule of 
Activities (Section 2).  They will receive insulated bags with cooling gel packs for use in 
transporting the cartons from the site to home.  Dry ice should not be used for cooling.
Unused medications will remain locked and securely stored under refrigerated conditions (2°C to 
8°C) at the investigative site until returned to the Sponsor or destroyed according to written 
instruction from the Sponsor.
7.6.
Treatment Compliance
The assessment of treatment compliance with IP (LY3209590 or insulin degludec) will be 
determined by the following:

Information about the once weekly IP injections will be entered into the study participant
diary by the study participant and reviewed by the site personnel at each study visit. This 
information will be collected in the eCRF;

IP accountability will be checked according to the Schedule of Activities (Section 2).  
Study participants will be instructed to return all dispensed vials, any unused pens and/or 
all empty cartons at the next visit to the study site for the purpose of performing drug 
accountability.  
Other aspects of compliance will also be assessed at each visit, including the study participant’s 
adherence to the visit schedule, compliance with the concomitant OAM requirements and other 
medication guidance (Section 7.7), completion of study diaries, results of SMBG, and any other 
parameters the investigator considers necessary.  Study participants considered to be poorly 
compliant with their medications and/or study procedures (for example, missed visits or specific 
diagnostic tests) will receive additional training and instructions, as required.
7.7.
Concomitant Therapy
Study participants will be permitted to use concomitant medications that they require during the 
study, except excluded medications described in Section 6.2 (Exclusion Criteria) and Section 
7.7.1 to Section 7.7.4 below. In addition, certain permitted medications (for example, treatments 
for blood pressure or dyslipidemia) described in Section 7.7.5 and Section 7.7.6 may be 
continued, but not changed, during the course of the study.
Investigative site staff will inform study participants that they must consult with the investigator 
or a designated site staff member upon being prescribed any new medications during the study, 
except when initiated for treatment of medical emergencies.  Any additional medication initiated 
during the course of the study (including OTC drugs, such as aspirin) must be documented, and 
the name of the drug and the date(s) of administration must be recorded in the study participant’s 
diary and on the “Concomitant Medications” section of the eCRF.  In addition, for permitted 
concomitant glucose-lowering agents, the dosage will also be documented and collected.


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Non-study medications taken by study participants who are screened but not randomized will not 
be reported to Lilly unless an SAE or AE occurs that the investigator believes may have been 
caused by a study procedure.
Table BDCM.4 provides a summary of criteria for use of concomitant medications that may 
interfere with planned assessments during the study.
Table BDCM.4.
Criteria for Use of Concomitant Medications that may Interfere with 
Efficacy and Safety Assessments in Study BDCM
Drug Class
Use During 
Screening/Lead-In
Conditions for Use After Randomization
Acute 
therapya
Rescue 
therapy 
During Safety 
Follow-up Period
Drugs with approved weight loss 
indicationb
Excluded
N
N/A
N
Systemic glucocorticoid therapyc
Excluded except for 
acute therapya
Y
N/A
N
Antihyperglycemia medications
GLP-1 RAs
Excluded
N
Y
Y
DPP-4 inhibitors
Permitted
N
Y
Y
SGLT2 inhibitors
Permitted
N/A
Y
Y
Insulins and insulin mixtures
Daily basal insulins 
Permitted. All 
others Excluded 
except for acute 
therapya
Y
Y
Y
Meglitinides
Excluded
N
N
Y
Alpha-glucosidase inhibitors
Permitted
N
Y
Y
Sulfonylureas
Permitted
N
N
Y
Thiazolidinediones
Excluded
N
N
N
Metformind
Permitted
N
Ye
Y
Abbreviations: DPP-4 = dipeptidyl peptidase-4; GLP-1 RA = glucagon-like peptide-1 receptor agonist; N = no;
N/A = not applicable; SGLT2 = sodium-glucose cotransporter 2; Y = Yes.
a
Acute therapy = treatment for up to 14 days.
b
Includes Saxenda® (liraglutide 3.0 mg), Xenical® (orlistat), Meridia® (sibutramine), Sanorex® (mazindol), 
Adipex-P® (phentermine), Belviq® (lorcaserin), Qsymia® (phentermine/topiramate combination), Contrave®
(naltrexone/bupropion) or similar other body weight loss medications including over-the-counter medications 
(e.g., allī® [orlistat 60 mg capsules]). 
c
Does not apply to topical, intraocular, intranasal, intra-articular, or inhaled preparations; 
d
Switching metformin manufacturers is allowed, as long as the dosage is the same.  Changing to a metformin 
formulation with a different action profile (i.e., from short-acting to long-acting metformin) is not permitted.
e
For rescue therapy, metformin dose may be increased if the dose is below maximum approved dose per country-
specific label.
7.7.1. Antihyperglycemia Medications
Insulin lispro as prandial treatment or insulin degludec are the preferred choice for rescue 
therapy in study participants randomized to LY3209590 or insulin degludec.  The only other
glucose-lowering agents allowed as rescue therapy during the study are concomitant metformin, 


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SLGT2 inhibitors, DPP-4 inhibitors, SU and alpha-glucosidase inhibitors.  In addition, insulins 
other than insulin degludec may be used for short-term (up to 14 days) management of medical 
emergencies prior to study entry and during the study.  Rescue therapy with other 
glucose-lowering agents, may be medically indicated in certain situations after randomization
(Table BDCM.4).  These situations are described in Section 7.8.2.3 (severe, persistent 
hyperglycemia) and in Section 8.1.1 (early discontinuation of IP).
If any new glucose-lowering medication is initiated after randomization at Visit 3, other than IP, 
rescue therapy, or short-term use of insulin for medical emergencies, the study participant will be 
required to immediately discontinue the medication and the appropriate study deviation report 
will be generated.  Any such violation of the protocol that lasts longer than 14 days will exclude 
the study participant from the per-protocol (PP) population for analyses.
7.7.2. Concomitant Antihyperglycemia Medication
Study participants treated with metformin in this study must be on a stable dose for at least 
3 months prior to screening.  The prescreening dose and formulation (short-acting or long-acting) 
must be maintained from the time of screening through the study participant’s last visit, except as 
required for rescue therapy (Section 7.8.2.3).
Where appropriate, allowable OAM therapy may be obtained locally by the Lilly affiliate in the 
participating country from local commercial supplies and distributed to sites.  It is acceptable for 
study participants to continue obtaining their OAM therapy by previous prescribing process.  In 
the United States and Puerto Rico, a prescription card will be available for study participants to 
obtain their OAM therapy with a prescription.
Dose adjustments of allowable OAM therapy are permitted after randomization (during the 
treatment period) under the following circumstances:

situations that require short-term treatment interruption in line with the product labeling 
for each respective country;

situations that require dose adjustment or discontinuation per country-specific label, for 
example, in the case of reduced eGFR;

in the case of increased hypoglycemia risk during the treatment period (as described in 
Section 7.8.2.2).
Dose reduction of allowable OAM therapy during the trial should be properly documented.
In study participants who require rescue therapy, dose increase of allowable OAM therapy is 
permitted, but the dose and the reason for change must be properly documented in the eCRF.
Guidance for treatment during the safety follow-up period is provided in Section 5.1.1 (Study 
Period 3: Safety Follow-up, Visit 801).
7.7.3. Medications that Promote Weight Loss
Prescription or OTC medications that promote weight loss are exclusionary if used within the 
3 months prior to screening, or any time after screening (see Section 7.7).  If started after 


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screening, these medications should be stopped immediately.  In addition, study participants 
should not receive an intensive diet/exercise program with the intent of reducing body weight at 
any time during the study, other than the lifestyle and dietary measures for diabetes treatment 
(see Section 6.3).
7.7.4. Systemic Glucocorticoids
Chronic systemic glucocorticoid therapy (excluding topical, intraocular, intranasal, or inhaled 
preparations) is exclusionary if used >14 consecutive days during the 1-month period before 
screening or between screening and randomization at Visit 3.  Study participants who require 
>14 consecutive days of therapy with these medications after randomization will be excluded 
from the PP population for analyses.
7.7.5. Antihypertensive Medications
If used, anti-hypertensive therapy should be kept stable throughout the trial to allow assessments
of the effect of randomized therapies on blood pressure.
7.7.6. Dyslipidemia Medications
If used, dyslipidemia therapy should be kept stable throughout the trial to allow assessments of 
the effect of randomized therapies on lipid endpoints.
7.8.
Treatment After the End of the Study
7.8.1. Treatment After Study Completion
Investigational Product will not be made available to study participants after conclusion of the 
study
Beginning on the evening of the last treatment visit (Visit 21 [Week 32] or ET visit), study 
participants will resume their previous basal insulin therapy. As washout of LY may take up to 
10 weeks to complete, previous basal insulin therapy will be instituted using the Riddle 
algorithm as need based on FBG (Section 7.2.1.2.). For example, no insulin would be required 
until the study participant’s blood glucose increases to >100 mg/dL, and then daily basal insulin 
would be initiated and adjusted based on weekly algorithm FBG.
Study Participants treated with LY3209590:
Study participants will receive the last injection of LY3209590 at Week 31 of the study and will 
switch back to their previously used basal insulin after Visit 21.  Since LY3209590 has a 
half-life of approximately 
 
 of the 
original insulin dose and 
 
 of the original insulin dose.  
Therefore, a slow up-titration of their previously used basal insulin is necessary to prevent 
hypoglycemia due to overlapping insulin action.  The pre-study basal insulin should be started at 
a dose of 10 I.U. at Visit 22 with a FBG of above 120 mg/dL for 3 consecutive days or as soon as 
the study participants FBG is above 180 mg/dL for 3 consecutive days.  Thereafter, an 
CCI
CCI
CCI
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up-titration according to the modified Riddle algorithm or any country specific label should be
applied.
Study Participants treated with Insulin Degludec:
Study participants assigned to the insulin degludec treatment arm will switch back to their 
pre-study basal insulin after Visit 21.  If their pre-study Basal insulin was insulin degludec they 
can continue with the same dose used until Visit 21 of the study.  If they switch back to another 
basal insulin (e.g. insulin Glargine), study participants should inject a daily dose, which is 20% 
lower than the last dose of insulin degludec used before Visit 21 and titrate under supervision of 
the investigator using the country-specific label for their pre-study basal insulin.
All study participants will continue to wear a continuous blood glucose monitor during the 
5-week follow-up period to ensure a safe transition back to their pre-study basal insulin.
7.8.2. Special Treatment Considerations
7.8.2.1.
Standards of Medical Care
Investigators and other study team members are expected to treat study participants according to 
the nationally established standards of care for diabetes management in respective participating 
countries, except where that treatment would be in conflict with the protocol-provided treatment 
requirements. If there are no local standards of care for diabetes, the investigators should follow 
current published standards of care from the American Diabetes Association (2016) and the 
European Association for Study of Diabetes (Inzucchi et al. 2015) during their study 
participants’ participation in this study.
This section provides guidance on management of episodes of hypoglycemic events and events 
of severe, persistent hyperglycemia. For effective implementation of measures described here, it 
is important that study participants, and their caregivers, if applicable, be well-educated about the 
signs and symptoms of hyperglycemia (for example, severe thirst, dry mouth, frequent 
micturition, or dry skin) and hypoglycemia (for example, intense hunger, sweating, tremor, 
restlessness, irritability, depression, headaches, disturbed sleep, or transient neurological 
disorders). Study participants should be instructed to contact the investigative site in the event of 
severe, persistent hyperglycemia or severe hypoglycemia between study visits.
7.8.2.2.
Management of Increased Hypoglycemia Risk
The risk associated with the allowable OAMs is low since all but the sulfonylureas are non-
secretagogues; therefore, clinically relevant increases in the risk of hypoglycemia due to the 
OAMs are not expected in this trial.  The effects of LY3209590 on hypoglycemia are not known 
and an objective of the study is to assess the risk of hypoglycemia in study participants receiving 
LY3209590.
The study uses real-time CGM to continuously monitor potential hypoglycemic events. In case 
of a hypoglycemic event, study participants will be proactively warned by an alarm and are 
instructed to immediately ingest rapidly absorbable carbohydrates. This safety measure 
minimizes the risk of severe hypoglycemic events during the complete study duration.


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In this study, increased risk of hypoglycemia is defined as having a single episode of severe 
hypoglycemia or having more than 1 episode of documented symptomatic hypoglycemia within 
a 1-week period at any time during the treatment period.
In cases where a study participant experiences hypoglycemia as described above, to confirm the 
increased risk, the study sites must ensure that the study participant has been fully compliant 
with the assigned therapeutic regimen and also that there is no evidence of other possible causes 
of hypoglycemia (e.g., omission of meal, unexpected increase in exercise).
Study participants fulfilling the definition of increased risk of hypoglycemia should first decrease 
their OAM dose (especially SU), followed by discontinuation of OAM therapy, if needed.  If the 
study participant continues to experience hypoglycemic events after the discontinuation of OAM 
therapy, the investigator should reduce the dose according to the appropriate algorithm 
(Section 7.2.1.2) or discontinue the study participant from IP.
7.8.2.3.
Management of Study Participants with Severe, Persistent 
Hyperglycemia during the Treatment Period
An additional therapeutic intervention should be considered in study participants who develop 
severe, persistent hyperglycemia after randomization based on the following criteria (reference 
FDA Draft Guidance 2016):  
a) average FPG >270 mg/dL (>15.0 mmol/L) over any 2-week period or longer during the 
first 6 weeks postrandomization; or
b) average FPG >240 mg/dL (>13.3 mmol/L) over any 2-week period or longer from 
Week 6 to Week 12 postrandomization; or
c) average FPG >200 mg/dL (>11.1 mmol/L) over any 2-week period or longer from 
Week 12 to Week 18 postrandomization.
Investigators should first confirm that the study participant does not have an acute condition 
causing severe hyperglycemia and, after the first 12 weeks of the study, that the study participant
is fully compliant with the assigned therapeutic regimen.  The investigator will decide, in 
collaboration with the responsible clinical research physician (CRP) and in consultation with the 
study participant, on an appropriate glucose-lowering intervention (rescue intervention) after 
considering relevant clinical criteria. In general, insulin degludec will be the preferred rescue 
therapy for study participants assigned to LY3209590. See Table BDCM.4 for allowed 
medications.  Study participants who receive a new intervention for hyperglycemia management 
should also continue administering IP for the remaining period in the trial.
7.8.2.4.
Emergency Situations
In emergency situations, it may be necessary for study participants to change their dose of OAM 
and/or be treated with a non-study insulin.  This will be allowed for up to 2 weeks total prior to 
Visit 21 (Week 32).  If multiple situations last longer than 2 weeks total prior to Visit 21
(Week 32), a decision to keep the study participant in the study should be made only after 
consultation between the investigator and the Lilly CRP.  The decision should be documented by 
a note to the investigator’s file.


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8.
Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
8.1.1. Permanent Discontinuation from Study Treatment
Possible reasons leading to permanent discontinuation of IP:  

Subject Decision
o
the study participant or the study participant’s designee, for example, parents or legal 
guardian requests to discontinue IP.

Discontinuation due to a hepatic event or liver test abnormality.  
o
Study participants who are discontinued from IP due to a hepatic event or liver test 
abnormality should have additional hepatic safety data collected via eCRF.
Discontinuation of the IP for abnormal liver tests should be considered by the 
investigator when a study participant meets one of the following conditions after 
consultation with the Lilly designated medical monitor:

ALT or AST >8X ULN

ALT or AST >5X ULN for more than 2 weeks

ALT or AST >3X ULN and total bilirubin level (TBL) >2X ULN or 
international normalized ratio >1.5

ALT or AST >3X ULN with the appearance of fatigue, nausea, vomiting, 
right upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(>5%)

alkaline phosphatase (ALP) >3X ULN

ALP >2.5X ULN and TBL >2X ULN

ALP >2.5X ULN with the appearance of fatigue, nausea, vomiting, right 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
In addition, study participants will be discontinued from the IP in the following 
circumstances:

if a study participant is inadvertently enrolled and it is determined that continued 
treatment with IP would not be medically appropriate (see Section 8.1.3)

if a study participant is diagnosed with an active or untreated malignancy (other than 
basal or squamous cell skin cancer, in situ carcinomas of the cervix, or in situ prostate 
cancer) after randomization

if a study participant is diagnosed by the investigator with acute or chronic pancreatitis

if a study participant is diagnosed with C-cell hyperplasia or medullary thyroid carcinoma
after randomization


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
if the investigator or sponsor decides that the study participant should be withdrawn from 
IP; if the investigator decides to permanently discontinue IP because of an SAE or a 
clinically significant laboratory value, Lilly or its designee should be alerted 
immediately.
Study participants discontinuing from the IP study treatment prematurely for any reason should 
complete AE and other follow-up procedures per Section 2 (Schedule of Activities), Section 9.2
(Adverse Events), and Section 9.4 (Safety) of this protocol.
Study participants who stop the IP permanently may receive another glucose-lowering 
intervention, if appropriate, and will continue participating in the trial according to the protocol 
to collect all planned efficacy and safety measurements.
8.1.2. Temporary Discontinuation from Study Treatment
In certain situations after randomization, the investigator may need to temporarily discontinue 
(interrupt) IP (for example, due to an AE or a clinically significant laboratory value).  If IP
interruption is due to an AE, the event is to be documented and followed according to the 
procedures in Section 9.2 of this protocol.  Investigators should inform the Sponsor that IP has 
been temporarily interrupted.  Every effort should be made by the investigator to maintain study 
participants on IP and to restart IP after any temporary interruption, as soon as it is safe to do so.  
The data related to temporary interruption of IP will be documented in source documents and 
entered in the eCRF.
8.1.3. Discontinuation of Inadvertently Enrolled Study Participants
If the sponsor or investigator identify a study participant who did not meet enrollment criteria 
and was inadvertently enrolled, then the study participant should be discontinued from study 
treatment unless there are extenuating circumstances that make it medically necessary for the 
study participant to continue on study treatment.  If the investigator and the sponsor CRP agree 
that it is medically appropriate to continue, the investigator must obtain documented approval 
from the sponsor CRP to allow the inadvertently enrolled study participant to continue in the 
study with or without treatment with IP. Safety follow up is as outlined in Section 2 (Schedule 
of Activities), Section 9.2 (Adverse Events), and Section 9.4 (Safety) of the protocol.
8.2.
Discontinuation from the Study
Study participants will be discontinued in the following circumstances:

if a study participant is diagnosed with any type of diabetes mellitus other 
than T2DM

if a female study participant becomes pregnant, enrollment in any other 
clinical study involving an IP or enrollment in any other type of medical 
research judged not to be scientifically or medically compatible with this 
study


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
participation in the study needs to be stopped for medical, safety, regulatory, 
or other reasons consistent with applicable laws, regulations, and good clinical 
practice (GCP)

investigator decision
o
the investigator decides that the study participant should be discontinued
from the study
o
if the study participant, 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

study participant decision
o
the study participant/study participant’s designee, for example, parents or 
legal guardian requests to be withdrawn from the study
Study participants discontinuing from the study prematurely for any reason should complete AE
and other safety follow-up per Section 2 (Schedule of Activities), Section 9.2 (Adverse Events),
and Section 9.4 (Safety) of this protocol.
8.3.
Lost to Follow-Up
A study participant 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 study participants 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.
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.  Certain samples may 
be retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1.
Efficacy Assessments
9.1.1. Primary Efficacy Assessments
The primary efficacy measure is HbA1c change from baseline to Week 32.
9.1.2. Secondary Efficacy Assessments

HbA1c change from baseline to Week 12

Fasting glucose change from baseline to Weeks 12 and 32

Insulin dose change from baseline to week 12 and 32
9.1.3. Appropriateness of Assessments
Efficacy and safety assessments included in this study are generally regarded as reliable and 
accurate with respect to the efficacy and safety assessments in individuals and populations with 
T2DM.
9.1.4. Body Weight
Body weight will be measured at prespecified time points (see Schedule of Activities, Section 2).  
Study participants will be weighed in a light hospital gown or standard clinical research site
scrubs at approximately the same time in the morning after an overnight fast and after evacuation 
of bowel and bladder contents, if possible.  Weight will be measured once at screening 
(non-fasting) and recorded in the source document and eCRF.  At lead-in and randomization 
(Visit 2 and Visit 3, respectively) and all subsequent visits indicated in the Schedule of Activities
(Section 2), weight will be measured twice, with the study participant stepping off the scale 
between measurements.  Both weight measurements will be recorded in the source document and 
the eCRF.  Calibrated (within 6 months prior to study start) scales should be used. The same 
scale should be used for all weight measurements throughout the study and should not be moved 
during the conduct of the study.


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9.2.
Adverse Events
Investigators are responsible for monitoring the safety of study participants who have entered 
this study and for alerting Lilly or its designee to any event that seems unusual, even if the event 
may be considered an unanticipated benefit to the study participant.
The investigator is responsible for the appropriate medical care of study participants during the 
study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the IP or the study, 
or that caused the study participant to discontinue the IP before completing the study.  The study 
participant should be followed until the event resolves, stabilizes with appropriate diagnostic 
evaluation, or is reasonably explained.  The frequency of follow-up evaluations of the AE is left 
to the discretion of the investigator.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect.
After the ICF is signed, study site personnel will record via eCRF the occurrence and nature of 
each study participant’s preexisting conditions, including clinically significant signs and 
symptoms of the disease under treatment in the study.  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, IP, via eCRF.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to IP, 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 IP, 
study device and/or study procedure and the AE.
The investigator answers yes/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 study participant’s IP is discontinued as a result of an AE, study site personnel must report 
this to Lilly or its designee via eCRF, 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 one of the following outcomes:

death

initial or prolonged instudy participant hospitalization


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
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 study participant or may require 
intervention to prevent one of the other outcomes listed in the definition above.  
Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in instudy participant hospitalization, or the 
development of drug dependency or drug abuse.
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 study participant has signed the ICF 
and has received IP.  However, if an SAE occurs after signing the ICF, but prior to receiving IP, 
the SAE should be reported to the sponsor as per 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. Study participants with a serious hepatic adverse event should have additional data 
collected using the eCRF.
Pregnancy (during maternal or paternal exposure to IP) does not meet the definition of an AE.  
However, to fulfill regulatory requirements, any pregnancy should be reported following the 
SAE process to collect data on the outcome for both mother and fetus.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued and/or completed the study (the study participant disposition CRF has been 
completed).  However, if the investigator learns of any SAE, including a death, at any time after 
a subject has been discharged from the study, and he/she considers the event reasonably possibly 
related to the study treatment or study participation, the investigator must promptly notify Lilly.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to IP or procedure.  United States 21 CFR 
312.32 and European Union Clinical Trial Directive 2001/20/EC and the associated detailed 
guidances or national regulatory requirements in participating countries require the reporting of 
SUSARs.  Lilly has procedures that will be followed for the identification, recording and 
expedited reporting of SUSARs that are consistent with global regulations and the associated 
detailed guidances.


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9.2.2. Adverse Events of Special Interest
9.2.2.1.
Hypoglycemia
Study participants will collect information on episodes of hypoglycemia starting from Visit 2 
until the last study visit (Visit 801 or ET visit).  For that purpose, study participants will be 
trained about signs and symptoms of hypoglycemia, how to treat hypoglycemia, and how to 
collect in study diary appropriate information for each episode of hypoglycemia according to the 
Schedule of Activities (Section 2).  Site personnel will enter this information into the eCRF at 
visits indicated in the Schedule of Activities (Section 2).
Investigators should use the following definitions and criteria when diagnosing and categorizing 
an episode considered to be related to hypoglycemia (the PG values in this section refer to values 
determined by a laboratory or International Federation of Clinical Chemistry and Laboratory 
Medicine plasma-equivalent glucose meters and strips) (American Diabetes Association 2005):

Documented symptomatic hypoglycemia is defined as any time a study 
participant feels that he/she is experiencing symptoms and/or signs associated 
with hypoglycemia, and has a PG level of ≤70 mg/dL (≤3.9 mmol/L).

Asymptomatic hypoglycemia is defined as any event not accompanied by typical 
symptoms of hypoglycemia but with a measured PG ≤70 mg/dL (≤3.9 mmol/L).

Probable symptomatic hypoglycemia is defined as an event during which 
symptoms of hypoglycemia are not accompanied by a PG determination (but that 
was presumably caused by a PG concentration ≤70 mg/dL [≤3.9 mmol/L]).

Severe hypoglycemia is defined as an episode requiring the assistance of another 
person to actively administer carbohydrate, glucagon, or other resuscitative 
actions.  These episodes may be associated with sufficient neuroglycopenia to 
induce seizure or coma.  Plasma glucose measurements may not be available 
during such an event, but neurological recovery attributable to the restoration of 
PG to normal is considered sufficient evidence that the event was induced by a 
low PG concentration.

Nocturnal hypoglycemia is defined as any hypoglycemic event that occurs 
between bedtime and waking.

Total hypoglycemia is defined as any event meeting the criteria for documented 
symptomatic hypoglycemia, asymptomatic hypoglycemia, or probable 
symptomatic hypoglycemia

Cases of relative hypoglycemia are defined as symptomatic events during which 
the person reports any of the typical symptoms of hypoglycemia and interprets 
those as indicative of hypoglycemia, but a measured PG concentration >70 mg/dL 
(>3.9 mmol/L) is collected.
For additional analysis, hypoglycemia defined as glucose <54 mg/dL (<3.0 mmol/L) will also be 
considered.


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If a hypoglycemic event meets the criteria of severe, it needs to be recorded as serious on the AE
eCRF and reported to Lilly as an SAE.
In each case of suspected or confirmed hypoglycemia, it is important that the event be properly 
categorized, the effect of the intervention be assessed, and the frequency and duration of 
hypoglycemia be evaluated.  The role of dietary changes and physical exercise (or any other 
contributing factor) in the development of an event should be established.  The study participant
should receive additional education, if deemed appropriate.  Management of increased risk of 
hypoglycemia is described in Section 7.8.2.2.
9.2.2.2.
Allergic/Hypersensitivity Reactions
All allergic or hypersensitivity reactions, including injection site reactions, will be reported by 
the investigator as either AEs or, if any serious criterion is met, as SAEs.  Additional data, such 
as type of reaction and treatment received, will be collected on any AEs or SAEs that the 
investigator deems related to IP via an eCRF created for this purpose.  IP should be temporarily 
interrupted in any individual suspected of having a severe or serious allergic reaction to IP
(Section 8.1.2).  IP may be restarted when/if it is safe to do so, in the opinion of the investigator.  
If IP is permanently discontinued, see Section 8.1.1 for procedures required in this situation.
9.2.3. Adverse Event Monitoring with a Systematic Questionnaire
Not applicable. 
9.2.4. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and to 
facilitate process and product improvements.
Study participants will be instructed to contact the investigator as soon as possible if he or she 
has a complaint or problem with the IP so that the situation can be assessed.
9.2.4.1.
Device Complaint Handling
Any CGM device complaint should be reported via the manufacturer’s instructions for device 
complaints.  A 24-hour toll-free number will be provided to the investigative site personnel in the 
event that either personnel or study participants have questions regarding the device.
9.3.
Treatment of Overdose
Study drug overdose (more than the specified number of injections) will be reported as an AE. In 
the event of an overdose, refer to the IB for LY3209590 and/or product label. 
9.4.
Safety
9.4.1. Cardiovascular Events
Deaths and nonfatal CV AEs will be adjudicated by a committee of physicians external to Lilly 
with cardiology expertise.  The nonfatal CV AEs to be adjudicated include:  myocardial 
infarction; hospitalization for unstable angina; hospitalization for heart failure; coronary 


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interventions (such as coronary artery bypass graft or percutaneous coronary intervention); and 
cerebrovascular events, including cerebrovascular accident (stroke) and transient ischemic 
attack.
9.4.2. Electrocardiograms
For each study participant, 12-lead digital ECGs, as well as single and triplicate safety ECGs,
will be collected according to the Schedule of Activities (Section 2).  Study participants must be 
supine for approximately 5 to 10 minutes before ECG collection and remain supine but awake 
during ECG collection. ECGs will be performed prior to collection of any blood samples.
ECGs will be interpreted by a qualified physician (the investigator or qualified designee) at the 
site as soon as possible after the time of ECG collection, and ideally while the study participant
is still present, to determine whether the study participant meets entry criteria at the relevant 
visit(s) and for immediate study participant management should any clinically relevant findings 
be identified.
Digital ECGs will be electronically transmitted to a central ECG laboratory designated by Lilly.  
The central ECG laboratory will perform a basic quality control check (for example, 
demographics and study details) then store the ECGs in a database.  At a future time, the stored 
ECG data may be overread at the central ECG laboratory for further evaluation of machine-read 
measurements or to meet regulatory requirements.
The machine-read ECG intervals and heart rate may be used for data analysis and report writing 
purposes unless an overread of the ECGs is conducted prior to completion of the final study 
report (in which case the overread data would be used).
9.4.3. Vital Signs
Sitting blood pressure (BP) and pulse rate will be measured using automated electronic 
sphygmomanometer according to the Schedule of Activities (Section 2). Vital sign 
measurements should be taken before obtaining an ECG tracing and before collection of blood 
samples for laboratory testing, at visits where required (see Schedule of Activities, Section 2). 
The participant should be required to sit quietly for 5 minutes before vital sign measurements are 
taken. An appropriately sized cuff (cuff bladder encircling at least 80% of the arm) should be 
used to ensure the accuracy of BP measurements.  The arm used for the BP measurement should 
be supported at heart level. Blood pressure should be measured consistently using the same arm 
throughout the study.  For each parameter (pulse rate, systolic BP, and diastolic BP), 
3 measurements will be taken using the same arm; the recordings should be taken at least 
1 minute apart, and each measurement of sitting pulse rate and BP will be recorded in the eCRF.
9.4.4. Self-monitoring of Blood Glucose Using CGM
A CGM system will be used in this study for self-measurement of plasma glucose equivalents. 
This system readings will be used for the purpose of monitoring study participant safety 
(hypoglycemia) and values shown by the system will be used for SMBG documentation.  The 
system will proactively warn study participants of low blood glucose values. Study participants


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should record all hypoglycemia related values read on the CGM device in the study diaries
provided.  Study participants with missing SMBG values may need to be retrained on the 
importance of SMBG monitoring.
Study participants will be instructed to take a pre-breakfast (fasting) SMBG reading every 
morning and 4-point SMBG measurements (consisting of fasting, pre-lunch, pre-dinner, and 
bedtime blood glucose measurements) once weekly throughout the study, and to record all 
results in diaries. Study participants will also measure FBG as needed to evaluate symptoms of 
hypoglycemia.
Study participants will be instructed to perform 6-point SMBG profiles over a 24-hour period on 
2 nonconsecutive days during the 7-day period prior to visits indicated in the Schedule of 
Activities (Section 2).  The 6-point profile consists of pre-meal and 2-hour postprandial SMBG 
measurements for the morning, midday, and evening meals in 1 day.  Pre-meal measurements 
should be taken before the study participant begins eating the meal.  Study participants should 
record their glucose measurements in their study diaries which are considered source documents 
and are to be returned to the investigator at each study visit.  Values from the 6-point SMBG 
profiles will be transferred from the diaries and recorded on the eCRFs. 
9.4.5. Continuous Glucose Monitoring
A CGM system will be provided to participating investigative sites.  Study-specific training will 
be provided to investigative site personnel and study participants.  The allowed range of the 
instrument recording is from 40 mg/dL to 400 mg/dL (2.2 mmol/L to 22.2 mmol/L) in the 
interstitial fluid (Gross et al. 2000).  The results of the continuous monitoring will be unblinded 
to study participants and investigative site personnel and will be downloaded for transfer to Lilly 
or designee.
The study participants will be thoroughly trained on sensor insertion and usage, and CGM 
data/alarm interpretation during the randomization visit. Study participants should self-insert the 
first sensor at Visit 3 and initiate the CGM system under supervision of the trained site personnel. 
Thereafter, study participants will be provided with the necessary CGM supplies and will 
self-insert new sensors when alerted by the system.
The CGM device and sensor will monitor study participant glucose levels.  Study participants 
will be unblinded to the real time CGM monitor readouts and alarms, so corrective action can be 
taken at the site regarding hypoglycemia prevention.
If problems occur with the CGM monitor or sensor, another sensor may be inserted or a 
replacement monitoring instrument may be used, as long as the CGM procedures and the 
subsequent visits continue to fall within the allowable time frames.  A sensor or monitoring 
instrument provided specifically for this study must be used when replacing another sensor or 
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9.4.6. Laboratory Tests
For each study participant, laboratory tests detailed in (Appendix 2) should be conducted 
according to the Schedule of Activities (Section 2). 
With the exception of laboratory test results that may unblind the study, Lilly or its designee will 
provide the investigator with the results of laboratory tests analyzed by a central vendor, if a 
central vendor is used for the clinical trial.
Any clinically significant findings from laboratory tests that result in a diagnosis, and that occur 
after the study participant receives the first dose of IP should be reported to Lilly or its designee 
as an AE via eCRF.
9.4.7. Immunogenicity Assessments
Venous blood samples of approximately 10 mL will be collected to determine antibody 
production against LY3209590 as specified in the Schedule of Activities (Section 2).  To 
interpret the results of immunogenicity, a PK sample will be collected at the same time points to 
determine the concentrations of LY3209590. All samples for immunogenicity should be taken 
predose when applicable and possible. In the event of drug hypersensitivity reactions 
(immediate or non-immediate), additional blood samples will be collected for anti-drug 
antibodies (ADA), PK and exploratory hypersensitivity analyses at the following time points, as 
close as possible to the onset of the event, at the resolution of the event, and 30 (±3) days
following the event. Exploratory hypersensitivity samples may be analyzed for markers of 
basophil/mast cell activation (e.g., tryptase), immune complex formation (e.g., C3 levels) and 
cytokine release (e.g., IL-6) as appropriate for the clinical presentation. Instructions for the 
collection and handling of blood samples will be provided by the sponsor. The actual date and 
time (24-hour clock time) of each sampling will be recorded.
Immunogenicity will be assessed by a validated assay designed to detect ADA in the presence of 
LY3209590 at a laboratory approved by the sponsor. For the detection of anti-LY3209590 
antibodies, study participant sera samples will be analyzed using a 3-tiered approach.  All 
samples will be assessed in Tier 1 (screening) for possible presence of ADA.  Samples found to 
produce a signal above or equal to the screening cut point will be assessed in Tier 2 to confirm 
specificity to LY3209590 (confirmation).  Any samples confirmed as specific for LY3209590
will be reported as “detected”.  All samples below the screening cut point in Tier 1 or not 
confirmed in Tier 2 will be reported as “not detected”.  All “detected” samples in Tier 2 will be 
assessed in Tier 3 (titer assessment). In vivo laboratory indicators for glycemic control (blood 
glucose and HbA1c) will be utilized to detect a potential neutralizing effect of ADA against 
LY3209590.
Treatment-emergent  antidrug antibodies (TE-ADA) are defined in Section 10.3.6. A risk-based 
approach will be used to monitor study participants who develop TE-ADA after treatment with 
LY3209590. Clinically significant TE-ADA will be defined as any TE-ADA at the follow-up 
visit with:
-
A titer ≥ 1:640 or increasing ADA titer at follow-up visit.
-
An association of TE-ADA with moderate to severe injection site reaction


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Study participants who have clinically significant TE-ADA will be followed with ADA testing 
(every 3 months for up to 1 year after dose) until the titer reaches a plateau/decreases (if 
increasing) or remains the same/decreases (if high). A PK sample will continue to be collected 
at each time point at the investigator’s discretion.
Samples will be retained for a maximum of 15 years after the last study participant visit, or for a 
shorter period if local regulations and Ethical Review Boards (ERBs) allow, at a facility selected 
by the sponsor.  The duration allows the sponsor to respond to future regulatory requests related 
to the LY3209590.  Any samples remaining after 15 years will be destroyed.
9.4.8. Other Tests
Not applicable.
9.4.9. Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods. Lilly will also review SAEs within the time frames mandated by company procedures.  
The Lilly CRP will, as appropriate, consult with the functionally independent Global Study 
participant Safety therapeutic area physician or clinical scientist.
9.4.9.1.
Hepatic Safety Monitoring
If a study participant 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 (GGT), and creatine kinase to confirm 
the abnormality and to determine if it is 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 baseline levels.
Hepatic Safety Data Collection
Additional safety data 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)

elevation of serum ALP to ≥2X ULN on 2 or more consecutive blood tests

study participant discontinued from treatment due to a hepatic event or 
abnormality of liver tests

hepatic event considered to be an SAE.


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9.5.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
will be collected to determine the plasma concentrations of LY3209590.  After Visit 3, PK 
samples can be taken at any time during the visit.
Instructions for the collection and handling of blood samples will be provided by the sponsor.  
The actual date and time (24-hour clock time) of each sampling will be recorded.
All the samples will be analyzed at a laboratory by the Sponsor, and stored at a facility 
designated by the Sponsor.
Plasma concentrations of LY3209590 will utilize a validated enzyme-linked immunosorbent 
assay method.
Bioanalytical samples collected to measure IP concentration will be retained for a maximum of 
1 year following last study participant visit for the study.
9.6.
Pharmacodynamics
In addition to PD parameters already discussed in the efficacy and safety sections, fasting plasma 
free fatty acids and fasting triglycerides will be evaluated as PD biomarkers of lipolysis, which is 
a sensitive measure of peripheral insulin activity.
9.7.
Pharmacogenomics
9.7.1. Whole Blood Samples for Pharmacogenetic Research
A whole blood sample will be collected for pharmacogenetic analysis as specified in the 
Schedule of Activities (Section 2) where local regulations allow.
All samples will be coded with the study participant number.  These samples and any data 
generated can be linked back to the study participant only by the investigator site personnel.
Samples will be retained at a facility selected by Lilly or its designee for a maximum of 15 years 
after the last study participant visit for the study, or for a shorter period if local regulations and/or 
ERBs/investigational review boards impose shorter time limits.  This retention period enables 
use of new technologies, response to regulatory questions, and investigation of variable response 
that may not be observed until later in the development of LY3209590 or after LY3209590 
becomes commercially available.
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome wide association studies, and candidate gene studies.  Regardless of 
technology utilized, genotyping data generated will be used only for the specific research scope 
described in this section.


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9.8.
Biomarkers
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, PD, mechanism of action, variability of study participant response (including 
safety), and clinical outcome.  Sample collection is incorporated into clinical studies to enable 
examination of these questions through measurement of biomolecules including DNA, RNA, 
proteins, lipids, and other cellular elements.
Serum and plasma samples for non-pharmacogenetic biomarker research will be collected at the 
times specified in the Schedule of Activities (Section 2) where local regulations allow.
Samples will be used for research on the drug target, disease process, variable response to 
LY3209590 pathways associated with T2DM, mechanisms of action of LY3209590 and/or 
research methods, or in validating diagnostic tools or assay(s) related to T2DM.
All samples will be coded with the study participant number.  These samples and any data 
generated can be linked back to the study participant only by the investigator site personnel.
Samples will be retained at a facility selected by Lilly or its designee for a maximum of 15 years 
after the last study participant visit for the study, or for a shorter period if local regulations and 
ERBs impose shorter time limits.  This retention period enables use of new technologies, 
response to regulatory questions, and investigation of variable response that may not be observed 
until later in the development of LY3209590 or after LY3209590 become(s) commercially 
available.
9.9.
Health Economics
No health economic outcomes are planned.


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10. Statistical Considerations
10.1. Sample Size Determination
Approximately 375 study participants will be randomized in a 1:1:1 ratio to LY3209590 in one 
of two dosing algorithms or insulin degludec treatment arms, assuming a 20% dropout rate 
resulting in approximately 300 total completers at 32 weeks (100 completers per treatment arm). 
The sample size was calculated based on the statistical power for the primary and liver safety
endpoints.

The 300 completers will provide 90% statistical power to demonstrate the noninferiority 
of the pooled LY3209590 arms versus insulin degludec for the change in HbA1c from 
baseline to 32 weeks (assuming non-inferiority margin is 0.4%, the SD is 1.1% and true
mean difference is 0%) using two sided t-test at alpha = 0.1.
10.2. Analysis Sets
For purposes of analysis, the following populations and analysis sets are defined:
Population and Analysis Set
Description
Enrolled 
All study participants who sign informed consent
All randomized study 
participants
All study participants who are randomly assigned a treatment arm
Efficacy analysis set (EAS)
Data for all randomized study participants who received at least one dose of 
study medication, excluding data after using rescue medication or stopping 
study medication (last dose date + xx days). In the event of a treatment error, 
participants will be analyzed according to the treatment they actually received.
Full analysis set (FAS)
Data for all randomized study participants, regardless of titration, stop of study 
medication, or rescue.
10.3. Statistical Analyses
10.3.1. General Statistical Considerations
Statistical analysis of this study will be the responsibility of Lilly or its designee.  Any change to 
the statistical methods described in the protocol will require an amendment only if it changes a 
principal feature of the protocol.  Any other change to the statistical analyses and the justification 
for the change will be described in the statistical analysis plan (SAP) and/or clinical study report.  
Additional exploratory analyses of the data may be performed as deemed appropriate.  Analyses 
will be fully detailed in the SAP.
Statistical analyses (including the primary analysis) will be conducted on the efficacy analysis
set population.  Safety analyses will be performed on the full analysis set.
No adjustments for multiplicity will be performed.
All tests of treatment effects will be conducted at a two-sided alpha level of 0.1 and/or two-sided 
90% confidence interval, unless otherwise stated.


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The baseline value used for the analyses will be the last scheduled baseline value obtained for 
each study participant prior to randomization. ALT, AST, and GGT will be average of 
3 assessments as baseline.
The analysis of the main secondary efficacy endpoint and possibly other Bayesian analyses may
be computed using Fixed and Adaptive Clinical Trial Simulator software.  Remaining summaries 
and analyses will be performed using the SAS System.
10.3.2. Treatment Group Comparability
10.3.2.1. Study Participant Disposition
Intention-to-treat population will be used for this analysis.  All study participants who 
discontinue the study will be identified, and the extent of their participation in the study will be 
reported.  If known, a reason for their discontinuation will be given.  The primary reasons for 
discontinuation will be listed and will be summarized by treatment.  The discontinuation due to 
AE will be summarized by adverse event and treatment. The percentage of study participants 
discontinuing from each treatment will be compared using the Fisher’s exact test.
10.3.2.2. Study Participant Characteristics
Intention-to-treat population will be used for this analysis. Demographic and baseline 
characteristics will be summarized by treatment group.  Categorical variables will be 
summarized by frequencies and percentages.  For categorical variables, comparisons between 
treatment groups will be assessed using a Pearson chi-square test.  Continuous variables will be 
summarized by mean and SD.  For continuous variables, comparisons between the treatment 
groups will be performed using a 1-way analysis of variance with treatment as the fixed effect.
10.3.2.3. Concomitant Therapy
Intention-to-treat population will be used for this analysis. Listings and summary of concomitant 
therapies will be provided by treatment group.
10.3.2.4. Treatment Compliance
Treatment compliance will be listed using all randomized study participants and summarized 
using the modified intention-to-treat population.  For a given study participant, overall 
compliance for treatment period is defined as, not missing 2 or more consecutive doses of the 
assigned treatment, or, missing 4 or more at any point in the study.  Study participants who miss 
4 or more doses at any point during the study will not be included in the efficacy analysis.
Adherence to the dosing algorithm is required from Visit 3 (Randomization) up to Visit 21
(Week 32, inclusive), although the last scheduled opportunity for dose adjustment will occur at
Week 31. Adherence to the dosing algorithm will be assessed based on the number and 
percentage of investigator-reported prescribed doses that do not follow the investigator-
calculated algorithm dose, which represent intentional deviation from the algorithm, and the 
number and percentage of investigator-calculated doses that are not equal to the sponsor-
calculated algorithm doses.


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10.3.3. Efficacy Analyses
10.3.3.1. Primary Analyses
The primary efficacy outcome is HbA1c change from baseline to Week 32 for LY arms.  The 
mixed-effect model repeated measures (MMRM) with BMI strata, treatment, visit, SU (Y/N),
and treatment-by-visit interaction as fixed effects, HbA1c baseline as a covariate will be used for 
the analysis. The within-study participant correlation will be modelled through a variance-
covariance structure.  The dependent variable will be the post-baseline change from baseline 
values.  The unstructured covariance matrix will be selected initially.  There will be no explicit 
missing data imputation as the missing values are handled implicitly by the MMRM model. 
10.3.3.2. Secondary Analyses
The secondary analysis will be performed on the efficacy analysis set. The main secondary
efficacy analysis aims to compare LY versus Insulin Degludec with regarding to HbA1c change 
from baseline at Week 12 and 32. The estimand of interest is the treatment differences in HbA1c 
at 12 and 32 weeks while the study participants are on study treatment.  The efficacy analysis set 
(EAS) will be used to calculate the mean difference between treatments.  Similar MMRM model 
will be used for the main secondary analysis. The least-squares (LS) mean differences and the 
standard errors from each imputed sample will be calculated based on the above model, and the 
final estimation for the means, standard errors, 90% confidence intervals, and p-values will be 
reported.
A supplementary analysis will be conducted to evaluate the “treatment policy” estimand, which 
is defined as the treatment differences in HbA1c at 32 weeks with the randomized treatment 
based on FAS.  The estimator is defined as the mean difference between treatments based on 
FAS.  The missing values will be imputed using multiple imputations. The similar MMRM 
model will be performed on imputed data and inferences will be drawn based on the framework 
of multiple imputations (Rubin, 1987). 
In addition to the main secondary efficacy analysis of HbA1c, the following secondary efficacy 
outcomes will be analyzed:

Body weight and change from baseline to 12 and 32 weeks

Fasting blood glucose and change from baseline at 12 and 32 weeks
The analyses of the HbA1c change, mean weight change, fasting blood glucose change and 
SMBG change from baseline will be conducted through MMRM similar to that of the primary 
efficacy outcome. The corresponding baseline will be used in the model instead of the baseline 
HbA1c levels.  The MMRM model will also include a term for the HbA1c stratification group.
The treatment p-value will be used as evidence of difference between LY3209590 and insulin 
degludec, while the comparison of LS means versus insulin degludec (unadjusted for multiple 
comparisons) and its 90% confidence interval will provide magnitude and significance of this 
difference.


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10.3.3.3. Exploratory Analyses
LY3209590 concentration data will be analyzed using standard nonlinear mixed-effects 
modeling implemented on the NONMEM software.  The relationships between LY3209590 dose
and/or concentration and efficacy, tolerability, and safety endpoints will be characterized, such 
as fasting glucose, SMBG, HbA1c, hypoglycemia, body weight, blood pressure, pulse rate, and 
corrected QT interval (QTc).
Additionally, the impact of intrinsic and extrinsic study participant factors such as age, weight, 
gender and renal function on PK and/or PD parameters may be examined as needed.  If ADA
titers are detected from immunogenicity testing, then the impact of immunogenicity titers on 
LY3209590 PK or any relevant PD parameters will also be examined.
10.3.4. Safety Analyses
The FAS will be used for safety analyses.  Both the overall and the pairwise comparisons of each 
LY3209590 arm versus insulin degludec will be reported for these safety analyses.
Safety measures include liver biomarkers (ALT), hypoglycemia, vital signs (BP and pulse rate), 
body weight, TEAEs (including SAEs and AEs of special interest), laboratory measures 
(including anti-LY3209590 antibodies), and ECGs. Summary statistics will be presented by 
treatment for the safety measures.
The summary statistics for continuous variables will be sample size, mean, SD, median, 
minimum, and maximum.
The summary statistics for categorical variables will be sample size, frequency, and percentage.
Exposure to each therapy during the treatment period of the study will be calculated for each 
study participant and summarized by treatment group.
In addition, the following safety outcomes will be analyzed on the efficacy analysis set
population:

ALT change from baseline to 12 and 32 weeks
The change from baseline of ALT will be analyzed using MMRM model. In addition, Bayesian
model will be used to conduct the same analysis. The corresponding baseline will be used in the 
model instead of the baseline HbA1c levels.  The MMRM model will also include a term for the 
HbA1c stratification group.
Additional analyses, such as concentration-safety laboratory plots, may be performed, if 
warranted upon review of the data.
10.3.4.1. Adverse Events
Adverse Events will be listed by study participant, actual term, preferred term, severity, and 
relationship to the treatment.  AEs will be summarized as TEAEs (defined as events that are 
newly reported after randomization or reported to worsen in severity from baseline).  The 
incidence of study participants with at least 1 TEAE and the incidence of TEAEs by preferred 
term and system organ class will be presented by treatment group.  The frequency and 


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percentage of TEAEs will be presented.  The incidence of study participants with at least 
1 TEAE assessed as possibly related to the investigational drug will be summarized by treatment 
group, in addition to the incidence of these possibly related TEAEs by preferred term.  In 
addition, a summary of TEAEs by severity will be presented descriptively by treatment group.
Reported and adjudicated CV AEs will be listed by study participant, and if there are a sufficient 
number of cases they may be summarized by treatment group.
All SAEs will be listed by study participant.  If a sufficient number of SAEs are reported, 
incidence summaries similar to incidence of TEAEs will be included.
Discontinuations due to AE and TEAEs will be listed by study participant and summarized by 
treatment group.
10.3.4.2. Vital Signs
Descriptive statistics for the actual measurements and changes from baseline for systolic and 
diastolic blood pressure and pulse rate will be presented by treatment arm and visit.  
Corresponding figures may be presented.
Vital signs will be analyzed using a similar MMRM-based model.
10.3.4.3. Hypoglycemia Episodes
The rate and incidence analyses will be analyzed. Details will be provided in the SAP. Statistical 
analysis will be performed for overall total hypoglycemia, documented symptomatic 
hypoglycemia and nocturnal hypoglycemia. Listing of hypoglycemic episodes and severe 
hypoglycemic episodes will be presented by visit for each study participant. If a sufficient 
number of severe hypoglycemic episodes are reported, then incidence summaries and analysis 
similar to incidence of hypoglycemic episodes will be included. 
10.3.4.4. Laboratory Measures
Summary statistics will be provided for laboratory measures, by treatment group and by visit.
A listing of laboratory measurements for individual study participants will be presented by visit.  
An additional listing will be presented for all laboratory measurements that are outside the 
normal range.
Descriptive statistics for the laboratory analyses will be presented by treatment group and visit, 
including safety off-treatment visits.
Laboratory analyses with categorical responses will be summarized by visit and treatment group 
using frequency and percentage.
The maximum/minimum post-baseline observation (as applicable for a laboratory) will be 
compared to the baseline observation by examining the proportion of study participants whose 
test values are within and outside the reference ranges.


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10.3.4.5. Electrocardiograms
A listing of the individual and averaged ECG measurements, by study participant, will be 
produced.  This will include the time elapsed between the onset of ventricular depolarization and 
the end of ventricular repolarization (QT) corrected values described below.
Descriptive statistics for the absolute measurements, outliers, and changes from baseline for 
selected ECG parameters will be presented by treatment arm.  These include the ECG heart rate, 
and the following intervals: QT and QT corrected for heart rate using Fridericia’s formula 
(QTcF).
In addition, LY3209590 concentration-response analysis of QTcF results will be performed as 
well as a categorical analysis of absolute and change from baseline QTc intervals. Any 
additional ECG analyses will be detailed in the SAP.
10.3.4.6. Adverse Events of Special Interest
Hypoglycemia, major adverse cardiovascular events, and injection site reaction are defined as 
AESIs.
Descriptive statistics for the AESIs will be presented by treatment group and visit.  Continuous 
responses will be summarized using sample size, mean, SD, median, minimum, and maximum, 
while categorical responses will be summarized using frequencies and percentages.
If necessary, continuous AESIs will be analyzed using a similar MMRM-based model.
Categorical AESIs will be analyzed using a logistic regression analysis with fixed effects of 
treatment, and HbA1c strata.
10.3.5. Pharmacokinetic/Pharmacodynamic Analyses
LY3209590 concentration data will be analyzed using a population PK approach via nonlinear 
mixed-effects modeling with the NONMEM software. The relationships between LY3209590
and/or concentration and efficacy, tolerability, and safety as well as biomarker endpoints will be 
characterized if exploratory analyses of the PD data warrant further PK/PD analyses upon 
review. Such analyses may include, but are not necessarily limited to, glucose, HbA1c, QTc, 
hypoglycemia, and vital signs.
In addition, if population PK and PK/PD models can be established, the impact of additional 
subject factors, such as age, weight, gender and renal function on PK and/or PD parameters, may 
be examined. Should ADA be detected from immunogenicity testing, its impact on LY3209590
PK or any relevant PD parameters will also be examined.
10.3.6. Evaluation of Immunogenicity
The frequency of antibody formation to LY3209590 will be determined. Treatment-emergent 
ADA are defined as those with a titer 2-fold (1 dilution) greater than the minimum required 
dilution if no ADAs were detected at baseline (treatment-induced ADA) or those with a 4-fold 
(2 dilutions) increase in titer compared to baseline if ADAs were detected at baseline (treatment-
boosted ADA). For the TE ADA+ study participants, the distribution of maximum titers will be 
described. 


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The relationship between the presence of antibodies, antibody titers, and clinical parameters (for 
example, AEs, efficacy measures) may be assessed.
10.3.7. Other Analyses
Detailed analysis plan for CGM will be documented in SAP.
10.3.7.1. Health Economics
Not applicable.
10.3.7.2. Subgroup Analyses
Subgroup analyses of important factors, including age, race, ethnicity, gender, duration of 
diabetes, baseline HbA1c (<8.5%, ≥8.5%), BMI, and other factors to be specified in the SAP are 
planned for the key outcomes of HbA1c, insulin dose and incidence and rate of hypoglycemia.
These will be conducted using the analysis of covariance model with strata, treatment, factor, 
treatment-by-factor interaction as fixed effects, and baseline as covariate.
Covariate analysis of PK and PK/PD may be performed.
Other exploratory subgroup analyses may be performed as deemed appropriate.
10.3.8. Interim Analyses
Interim analyses have been planned for this study.  The cancellation or addition of interim 
analysis will be determined at any time during the study and does not need protocol amendment.
An interim analysis of select safety, efficacy, and PK data is planned when approximately 50% 
of study participants complete 6 weeks of treatment.  Results of interim analysis might be used 
for adjusting LY3209590 dosing algorithm.   
A subsequent interim analysis of select safety, efficacy, and PK data is planned when all study 
participants complete 12 weeks of treatment. Results of interim analysis will be used to design 
subsequent studies.
In addition, the study team will perform periodic safety reviews during the study and if safety 
signals or concerns arise from these reviews, safety data may need to be in an unplanned interim 
analysis.
Study sites will receive information about interim results ONLY if they need to know for the 
safety of their study participants.


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11.
References
American Diabetes Association. Defining and reporting hypoglycemia in diabetes: a report from 
the American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care. 
2005;28(5):1245-1249.
American Diabetes Association. Standards of medical care in diabetes—2016. Diabetes Care. 
2016;39(suppl 1):S4-S108.
Blonde L, Brunton SA, Chava P, Dalal M, Zhou R, Meyers JL, Davis KL, Digenio A. 
Achievement of Goal A1C (<7 %) by U.S. Patients with T2DM on Basal Insulin in Both 
Randomized, Controlled Trials (RCTs) and in Clinical Practice. Diabetes. 2014;63(Suppl 1): 
A235. 
Food and Drug Administration (FDA) “Assay Development and Validation for Immunogenicity 
Testing of Therapeutic Protein Products: Guidance for Industry” April, (2016).
Gross TM, Bode BW, Einhorn D, Kayne DM, Reed JH, White NH, Mastrototaro JJ. 
Performance Evaluation of the MiniMed® Continuous Glucose Monitoring System During 
Patient Home Use. Diabetes Technology & Therapeutics. 2000;2(1):49-56.
Heise T, Nosek L, Bøttcher SG, Hastrup H, Haahr H. Ultra-long-acting insulin degludec has a 
flat and stable glucose-lowering effect in type 2 diabetes. Diabetes Obes Metab.
2012;14(10):944-950.
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas 
A, Wender R, Matthews DR. Management of Hyperglycemia in Type 2 Diabetes, 2015: A 
Patient-Centered Approach: Update to a Position Statement of the American Diabetes 
Association and the European Association for the Study of Diabetes. Diabetes Care. 
2015;38(1):140-149.
Riddle MC, Rosenstock J, Gerich J, Insulin Glargine 4002 Study Investigators. The Treat-to-
Target Trial: Randomized addition of glargine or human NPH insulin to oral therapy of type 2 
diabetic patients. Diabetes Care. 2003;26:3080–3086.
Rubin DB. Procedures with nonignorable nonresponse. Multiple Imputation for Nonresponse in 
Surveys. 1987:202-243.
Tresiba® prescribing information [USPI 2015]. Available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/203314lbl.pdf. Accessed January 
11, 2018.


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12.
Appendices


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Appendix 1.
Abbreviations and Definitions
Term
Definition
ADA
antidrug antibodies
AE
adverse event:  Any untoward medical occurrence in a study participant 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.
AESI
adverse event of special interest
ALP
alkaline phosphate
ALT/SGPT
alanine aminotransferase/ serum glutamic pyruvic transaminase
AST/SGOT
aspartate aminotransferase/ serum glutamic oxaloacetic transaminase
AUC
area under the curve
blinding/masking
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the study participant is not, or vice versa, or when the sponsor is aware of 
the treatment but the investigator and/his staff and the study participant are not.
A double-blind study is one in which neither the [study participant/subject] nor any of 
the investigator or sponsor staff who are involved in the treatment or clinical evaluation 
of the subjects are aware of the treatment received.
BMI
body mass index
BP
blood pressure
CGM
continuing glucose monitoring
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.
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
CV
cardiovascular
DPP-4
dipeptidyl peptidase-4


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ECG
electrocardiogram
eCRF
electronic case report form
Enroll
The act of assigning a study participant to a treatment.  Study participants who are 
enrolled in the trial are those who have been assigned to a treatment.
Enter
Study participants entered into a trial are those who sign the informed consent form 
directly or through their legally acceptable representatives.
ERB
Ethics Review Board
ET
early termination
FAS
full analysis set
FBG
fasting blood glucose
FBS
Fasting blood sugar
FPG
fasting plasma glucose
GCP
good clinical practice
GGT
gamma-glutamyl transferase
HbA1c
hemoglobin A1c
ICF
informed consent form
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigational 
product (IP)
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.
IWRS
interactive web-response system
LS
least squares
LY
LY3209590
MAD
multiple ascending dose
MMRM
mixed-effect model repeated measures
NAFLD
non-alcoholic fatty liver disease
OAM
oral antihyperglycemic medication
OTC
over the counter


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PD
pharmacodynamic
PG
plasma glucose
PK
pharmacokinetics
PP
per-protocol set: The set of data generated by the subset of study participants 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.
QTc
corrected QT interval
QTcF
QT corrected for heart rate using Fridericia’s formula
SAD
single-ascending dose
SAE
serious adverse event
SAP
Statistical analysis plan
SC
subcutaneous
SD
standard deviation
SGLT
sodium-glucose cotransporter
SMBG
self-monitoring of blood glucose
SMPG
self-monitored plasma glucose
SU
sulfonylureas
SUSARs
suspected unexpected serious adverse reactions
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. 
T2DM
type 2 diabetes mellitus
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, which and does not necessarily have to have a causal 
relationship with this treatment.
ULN
upper limit of normal


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Appendix 2.
Clinical Laboratory Tests
Hematologya
Clinical Chemistrya, b
Hemoglobin
Sodium
Hematocrit
Potassium
Erythrocyte count (RBC)
Chloride
Mean cell volume
Bicarbonate
Mean cell hemoglobin
Total bilirubin
Mean cell hemoglobin concentration
Direct bilirubin
Leukocytes (WBC)
Alkaline phosphatase (ALP)
Neutrophils, segmented
Alanine aminotransferase (ALT)
Lymphocytes
Aspartate aminotransferase (AST)
Monocytes
Gamma-glutamyltransferase (GGT)
Eosinophils
Blood urea nitrogen (BUN)
Basophils
Creatinine
Platelets
Uric acid
Calcium
Urinalysisa, c
Phosphorus
Protein
Glucose
Nitrite
Total protein
Blood
Albumin
Urine leukocyte esterase
Creatine kinase
Cholesterol
Pregnancy test serum and urine (females only)a, d
Triglycerides
Follicle stimulating hormone (females only, to confirm 
WCBP)
eGFR
Endocrine
C-peptide
Additional lipids
HDL cholesterol
Pancreas (Exocrine)
LDL cholesterol
Pancreatic amylase
Lipase
Hemoglobin A1c
Free Fatty Acid
Hepatitis B
Hepatitis B Core Antibody
Hepatitis B Surface Antigen
Hepatitis B Surface Antibody
Drug concentration
LY3209590
Immunogenicity
Anti-LY3209590
Pharmacogenetic sample
Non-pharmacogenetic samples


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Abbreviations:  HDL = high density lipoprotein; LDL = low density lipoprotein; RBC = red blood cells;
WBC = white blood cells; WCBP = women of child bearing potential.
a
Results will be confirmed by the Central Lab at the time of initial testing.
b
Refer to the Schedule of Activities.
c
All tests will be performed by a Lilly-designated central laboratory, unless otherwise noted.
d
Urine pregnancy tests (analyzed on-site) to be performed at Visits 3, 801, and ET and serum pregnancy test 
(analyzed by central laboratory) to be performed at Visit 1 for women of childbearing potential.  Additional 
pregnancy tests may be performed at the investigator’s discretion during the study.


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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 study participant/study participant’s legal representative 
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 study participant/study 
participant’s 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 study participant/study participant’s legal 
representative may have throughout the study and sharing in a timely manner 
any new information that may be relevant to the study participant/study 
participant’s legal representative’s 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.
A legal representative must give informed consent for a child to participate in this study.  In 
addition to informed consent given by the legal representative, the child may be required to give 
documented assent, if capable.
Appendix 3.1.2.Recruitment
Lilly or its designee is responsible for the central recruitment strategy for study participants.  
Individual investigators may have additional local requirements or processes.
Investigator(s) will be responsible for subject recruitment through local requirements or 
processes.  
Appendix 3.1.3.Ethical Review
The investigator or an appropriate local representative 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, 


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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 Investigator Brochure (IB)

informed consent form 

other relevant documents (for example, curricula vitae, advertisements)
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 (CIOMS) International Ethical Guidelines

applicable ICH GCP Guidelines

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 diabetes will participate as investigators in this clinical trial.
Physicians with a specialty in diabetes working in teaching or nonteaching hospitals or outstudy 
participant setting will participate as investigators in this clinical trial.
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 investigator will sign the final clinical study report (CSR) for this study, indicating 
agreement with the analyses, results, and conclusions of the report.
The CSR coordinating investigator will sign the final CSR for this study, indicating agreement 
that, to the best of his or her knowledge, the report accurately describes the conduct and results 
of the study.


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The investigator with the most analyzable study participants 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 CRFs, and 
study procedures.

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax

review and evaluate CRF data and use standard computer edits to detect errors in 
data collection

conduct a quality review of the database
In addition, Lilly or its representatives will periodically check a sample of the study participant
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
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor. 
An electronic data capture system (EDC) will be used in this study for the collection of the eCRF 
data.  The investigator maintains a separate source for the data entered by the investigator or 
designee into the sponsor-provided EDC system.  The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the eCRF.
Additionally, clinical outcome assessment (COA) data (questionnaires, scales, self-reported diary 
data, rating scales, etc.) will be collected by the study participant (investigator site personnel), 


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via a paper source document and will be transcribed by the investigator site personnel into the 
EDC system.
Data collected via the sponsor-provided data capture system(s) will be stored at third party.  The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture system(s).  Prior to decommissioning, the investigator will receive an archival 
copy of pertinent data for retention.
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system, and electronic transfers will be provided to the investigator 
for review and retention.  Data will subsequently be transferred from the central vendor to the 
Lilly data warehouse.
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.
Appendix 3.4.
Publication Policy
The publication policy for Study I8H-MC-BDCM is described in Clinical Trial Agreement.


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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 study participants in consultation with Lilly, or its designee,
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 cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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Appendix 5.
Methods of Contraception
Highly Effective Methods of Contraception:

Combined oral contraceptive pill or mini pill

NuvaRing

Implantable contraceptives

Injectable contraceptives (such as Depo-Provera®)

Intrauterine device (such as Mirena® and ParaGard®)

Contraceptive patch – ONLY women <198 pounds or 90 kg

Total abstinence

Vasectomy for men in clinical trials

Partner with vasectomy for women in clinical trials

Essure
Combination of 2 effective methods of contraception 

Male condom with spermicide

Female condom with spermicide

Diaphragm with spermicide

Cervical sponge with condom

Cervical cap with spermicide


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Appendix 6.
New York Heart Association Cardiac Disease 
Classification
Current classification can be found at 
https://manual.jointcommission.org/releases/TJC2016A/DataElem0439.html


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Appendix 7.
Dosing Guidance 
LY3209590 will be initiated at a loading dose
 estimated to 
be comparable to the total daily basal insulin dose already administered prior to randomization.  
The 
 dose are shown in Table BDCM.5.  New 
dosing algorithms developed specifically for LY3209590 will be used by investigators for 
adjusting fasting glucose to achieve glycemic goals (Table BDCM.6).  In situations where study 
participant safety is a concern or where dose adjustments have not had the desired therapeutic 
effect, investigators may only make adjustments to the dose of LY3209590 recommended by the 
dose-adjustment algorithm after consultation with Lilly.  
At the time of site visit or telephone visit, the investigator will assess the study participant’s 
glycemic control for the previous week and, if necessary, inform the study participant about any 
needed dose adjustment.  The dose will be based on the study participant’s blood glucose value.  
Adherence to the dosing algorithm provided for this study is required from Visit 3 
(randomization) up to Visit 21 (Week 32, inclusive) and will be monitored periodically by the 
study team.  Dose increases may be made no sooner than 
(algorithm #1) or 
(algorithm 
#2) 
 following the last dose increase.  There should be no dose increase or decrease if at 
least 
, respectively, have not elapsed since the previous dose increase.  Any 
deviations from this guidance must be approved by Lilly.
LY3209590 dose increase algorithm will be determined based on the mean of the FBG 
(determined from self-monitoring of blood glucose [SMBG]) 
.  Due to the long 
half-life of LY3209590, the change in fasting glucose response following dose adjustment may 
take several weeks to reach new level; therefore, less frequent dose adjustment is recommended 
to minimize prolonged variation in glycemic control.    
The insulin dose may not be increased if 
 
 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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Table BDCM.5
LY3209590 Loading Dose 
CCI


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Table BDCM.6
LY3209590 Titration Algorithm 
CCI


Leo Document ID = 918a14c6-c102-4f81-94a2-a4675ac3c540
Approver: 
)
Approval Date & Time: 31-Aug-2018 14:54:01 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 31-Aug-2018 16:06:36 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
 
I8H-MC-BDCM Statistical Analysis Plan Version 2 
 
 
A Phase 2, Randomized, Open-Label Trial to Evaluate the Safety and Efficacy of LY3209590 in 
Study Participants with Type 2 Diabetes Mellitus Previously Treated with Basal Insulin 
 
NCT03736785 
 
 Date: 16-Mar-2020 
 


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1.
Statistical Analysis Plan for Protocol I8H-MC-BDCM:
Evaluate the Safety and Efficacy of LY3209590 in Patients 
with Type 2 Diabetes Mellitus Previously Treated with 
Basal Insulin
Confidential Information
The information contained in this Statistical Analysis Plan (SAP) is confidential and the 
information contained within it may not be reproduced or otherwise disseminated without 
the approval of Eli Lilly and Company or its subsidiaries.  This document and its associated 
attachments or appendices are subject to United States Freedom of Information Act 
Exemption 4.
Basal Insulin-Fc (LY3209590) Diabetes Mellitus
This is a Phase 2, open-label, multicenter, multinational, randomized, controlled, parallel-
design trial comparing LY3209590 to insulin Degludec in approximately 375 patients with 
type 2 diabetes mellitus treated with basal insulin.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol I8H-MC-BDCM 
Phase 2
Statistical Analysis Plan Version 2 electronically signed and approved by Lilly on date 
provided below
Statistical Analysis Plan Version 1 electronically signed and approved by Lilly:  31-
January-2019. 
Approval Date: 16-Mar-2020 GMT


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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan for Protocol I8H-MC-BDCM:  Evaluate the 
Safety and Efficacy of LY3209590 in Patients with Type 2 Diabetes 
Mellitus Previously Treated with Basal Insulin....................................................................1
2.
Table of Contents................................................................................................................2
3.
Study Objectives.................................................................................................................6
3.1.
Primary Objective ..........................................................................................................6
3.2.
Secondary Objectives.....................................................................................................6
3.2.1.
Efficacy .................................................................................................................6
3.2.2.
Safety.....................................................................................................................6
3.3.
Exploratory Objectives...................................................................................................6
4.
A Priori Statistical Methods ................................................................................................8
4.1.
General Considerations ..................................................................................................8
4.2.
Patient Disposition .........................................................................................................9
4.3.
Patient Characteristics ....................................................................................................9
4.4.
Concomitant Medications.............................................................................................10
4.5.
Treatment Compliance .................................................................................................10
4.6.
Protocol Deviations......................................................................................................10
4.7.
Primary Outcome and Methodology.............................................................................11
4.8.
Secondary and Additional Efficacy Analyses ...............................................................11
4.9.
Pharmacokinetic/Pharmacodynamic Analyses..............................................................12
4.10. Safety Analyses............................................................................................................12
4.10.1.
Study Drug Exposure...........................................................................................13
4.10.2.
Adverse Events (AEs)..........................................................................................13
4.10.3.
Adverse Events of Special Interest (AESI) ...........................................................14
4.10.3.1.
Death and Nonfatal Cardiovascular Events .....................................................14
4.10.3.2.
Hypoglycemia Events.....................................................................................14
4.10.3.3.
Hepatobiliary Events ......................................................................................15
4.10.3.4.
Injection Site Reactions ..................................................................................16
4.10.3.5.
Systemic Hypersensitivity Reaction................................................................17
4.10.4.
Laboratory Measures............................................................................................18
4.10.4.1.
Lipid Measures...............................................................................................19
4.10.4.2.
Liver Enzyme Elevation Measures..................................................................19
4.10.5.
Vital Signs and Body Weight ...............................................................................20
4.10.6.
Antibodies............................................................................................................21
4.10.6.1.
Anti-LY3209590 Antibodies ..........................................................................21


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4.10.7.
Electrocardiograms ..............................................................................................22
4.11. Continuous Glucose Monitoring Analysis ....................................................................22
4.11.1.
General Consideration..........................................................................................22
4.11.2.
CGM Variable and Analysis.................................................................................22
4.11.2.1.
Hypoglycemia ................................................................................................23
4.11.2.2.
Hyperglycemia ...............................................................................................23
4.11.2.3.
Normal Range ................................................................................................23
4.11.2.4.
Glycemic Variability ......................................................................................23
4.11.3.
Definition of Variables.........................................................................................24
4.11.3.1.
Glucose in Target Ranges, Hypoglycemia or 
Hyperglycemia ...............................................................................................24
4.11.3.2.
Hypoglycemic Episode...................................................................................24
4.11.3.3.
Glycemic Variability ......................................................................................24
4.12. Subgroup Analyses.......................................................................................................27
4.13. Interim Analyses ..........................................................................................................27
5.
Unblinding Plan................................................................................................................29
6.
References ........................................................................................................................30


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Table of Contents
Table
Page
Table BDCM.1.
Hypoglycemia Event Related Analyses...................................................15
Table BDCM.2.
List of MedDRA Preferred Terms (PTs) to Search for Injection 
Site Reaction Adverse Events (AEs).......................................................17
Table BDCM.3.
Categorical Criteria for Abnormal Treatment-Emergent Blood 
Pressure and Pulse Measurement ............................................................21


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Revision History
Statistical Analysis Plan (SAP) Version 1 was approved on 31 January 2019.  Version 1 was 
based on the Protocol I8H-MC-BDCM approved on 31 August 2018. 
This SAP is the second version approved prior to the final database lock.  The main changes are 
listed below:

Correcting mistakes in the first version (for examples, MMRM model terms for the 
primary and secondary outcome, and significant level for treatment effect tests)

Removing duplicated information/analysis in the same section to avoid confusion

Updating analysis details to be consistent with other Phase 2 studies in the same program
(for example, the definition of Safety Population)

Replacing the multiple imputation method for the analysis of HbA1c meeting the target 
with longitudinal logistic regression

Adding required safety analyses which were missing in the first version (for example, 
analysis of body weight and analysis of treatment emergent antidrug antibody status)

Providing analysis details to clarify the analysis input data (for example, the SMQ search 
criteria for hepatobiliary events)

Modifying analyses to ensure using the collected data as the input data (for example, 
CGM analyses using available baseline variables as covariates)  
   


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3.
Study Objectives
3.1.
Primary Objective
To evaluate the efficacy of LY3209590, especially the change in hemoglobin A1c (HbA1c) from 
baseline to 32 weeks of treatment in patients with Type 2 diabetes mellitus (T2DM) treated with 
basal insulin alone or in combination with oral anti-hyperglycemic medication(s).
3.2.
Secondary Objectives
3.2.1. Efficacy
To compare the efficacy of LY3209590 versus insulin Degludec treatment groups for the 
following:
1. HbA1c change from baseline to Week 12 and 32;
2. Fasting glucose change from baseline to Week 12 and 32;
3. Insulin dose change from baseline to Week 12 and 32.
3.2.2. Safety
To compare the safety of LY3209590 versus insulin Degludec treatment groups for the 
following:
1. Documented, documented nocturnal and severe hypoglycemia incidence and rates during 
the treatment period (0-12, 12-32, and 0-32 weeks);
2. Treatment-emergent serious adverse events (SAEs) incidences;
3. Body weight change from baseline at Week 12 and 32.
3.3.
Exploratory Objectives
1. Fasting serum glucose (FSG) by laboratory and change from baseline to Weeks 6, 12, 18,
and 32 and all other scheduled visits;
2. Fasting blood glucose (FBG) by self-monitored blood glucose (SMBG) and change from 
baseline at Weeks 12 and 32 and all other available visits;
3. Fasting blood glucose (FBG) intra-patient variability (by SMBG) at Weeks 12 and 32 and 
all other available visits;
4. Six-point SMBG profile (pre-meal and 2-hour postprandial SMBG measurements for the 
morning, midday, and evening meals in 1 day.) at Visit 6, 9, 12, 15, 17, 20, 21;
5. Proportion of patients with HbA1c <7.0% at 12 and 32 weeks;
6. Proportion of patients with HbA1c ≤6.5% at 12 and 32 weeks;
7. Triglycerides, free fatty acid (FFA), liver aminotransferase (alanine aminotransferase 
[ALT]/aspartate aminotransferase [AST]) change from baseline to Weeks 6, 12, and 32;
8. Discontinuation of investigational product (IP) due to AEs;
9. Clinical laboratory results;


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10. Number of dose adjustments to steady-state;
11. Antibodies to LY3209590;
12. Incidence and rate of documented non-nocturnal hypoglycemia during the treatment 
period (0-12, 12-32, and 0-32 weeks);
13. Incidence and rate of hypoglycemia during the treatment period (0-12, 12-32, and 0-32 
weeks) by continuous glucose monitoring (CGM);
14. Glucose time in target range, time in hyperglycemia, time in hypoglycemia during the 
treatment period (0-12, 12-32, and 0-32 weeks) by CGM;
15. Total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein
cholesterol (HDL-C) and change from baseline to Weeks 6, 12, and 32.


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4.
A Priori Statistical Methods
4.1. General Considerations
All data will be entered, verified, and archived at a contract research organization (CRO) 
external to Eli Lilly and Company (Lilly) and/or at Lilly.  Data listings, summaries, and analyses 
will be performed by a CRO and/or by Lilly under the guidance and approval of statisticians at 
Lilly.
Statistical analysis of this study will be the responsibility of Lilly. Any change to the data 
analysis methods described in the protocol will require an amendment ONLY if it changes a 
principal feature of the protocol. Any other change to the data analysis methods described in the 
protocol, and the justification for making the change, will be described in this SAP and/or in the
clinical study report (CSR).  Additional exploratory analyses will be conducted, as deemed 
appropriate.
Unless otherwise specified, listings will be ordered by the patient ID nested within the 
investigator site.
The patient populations used for this study are described below:
Population and Analysis Set
Description
Entered/Enrolled Population
All study participants who sign informed consent
Randomized Population
All study participants who are randomly assigned a treatment arm
Efficacy analysis set (EAS)
Data for all randomized study participants who receive at least one dose of study 
medication, excluding data after using rescue medication(not acute therapy) or 
stopping study medication (last dose date + 10 days).  In the event of a treatment 
error, participants will be analyzed according to the treatment they actually 
received.
Safety Population
All randomized study participants who receive at least one dose of study 
medication.
CGM Population
All randomized study participants who receive at least 1 dose of study 
medication, and have CGM data from at least 1 collection period.
Abbreviations: CGM = continuous glucose monitoring.
Safety analyses will be conducted using the Safety Population with all data collected during the 
study including treatment and follow-up period regardless of the treatment disposition status.  
Efficacy analyses will be conducted on the efficacy analysis set (EAS), unless otherwise 
specified.  
Unless otherwise noted, all tests of treatment effects will be conducted at a 2-sided alpha level of 
0.10 and confidence intervals (CIs) will be calculated at 90%, 2-sided.  All tests of interactions 
between treatment groups and other factors will be conducted at a 2-sided alpha level of 0.10.  
Baseline value for a variable is defined as the last nonmissing value for this variable prior to or at 
randomization visit (Visit 3), unless otherwise specified.


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For continuous measurements, summary statistics will include sample size, mean, median, 
standard deviation (SD), minimum, and maximum.  For certain variables that are considered to 
be log-normally distributed, the geometric mean and coefficient of variation (CV) will be 
provided instead. 
For categorical measurements, summary statistics will include sample size, frequency, and 
percentages.  Fisher’s exact test will be used.  Chi-squared test will be used for multi-category 
variables.
A mixed-model repeated measures (MMRM) model will be used for continuous outcomes with 
repeated postbaseline measurements to compare treatment arms, unless otherwise noted.  
Treatment comparisons will be performed for the treatment difference in least-squares means 
(LS mean).  Means and LS mean by treatment group and visit, along with the standard error of 
LS mean, 90% CIs of the treatment differences along with the p-value for the treatment 
comparison will be displayed.  For the change from baseline, p-value for the within-treatment 
comparison will also be displayed.  For selected parameters, log-transformed values will be 
analyzed in the MMRM model instead.  The actual, change from baseline and percentage change 
from baseline will be presented using the derivation based on the output from the MMRM 
model. 
In this study, all negative binomial regression will estimate Group Mean instead of LS mean and 
use delta method to estimate the standard error of the Group Mean (Qu and Luo 2015).  Group 
Mean is defined as the mean response in the treatment group for the studied population. The 
difference between LS mean and the Group Mean is that LS mean estimates the response by 
taking the inverse link function on mean covariates, while the Group Mean takes the inverse link 
function on individual patient covariates first and then averages over all patients.
All analyses will be implemented using SAS Enterprise Guide Version 7.1 or above.  
4.2.
Patient Disposition
The reasons for discontinuation from the study and discontinuation of the study treatment will be 
summarized for the Randomized Population by treatment group and compared between the 
treatment groups using Fisher’s exact test.  Similar summary without treatment comparison will 
be provided for the discontinuation reasons prior to randomization.
A listing of the primary reason for patient discontinuation from the study or patient 
discontinuation of the treatment medication will be generated for the All Randomized 
Population.  
A listing of the randomization codes for this study will be provided. 
4.3. Patient Characteristics
Demographic and baseline characteristics including but not limited to age (years), age groups 
(<65 years, ≥65 years and <75 years, ≥75 years), sex, ethnicity, race, country, region, weight 
(kg), body mass index (BMI: kg/m2), BMI groups (<25, ≥25 and <30, ≥30 and <35, and ≥35 
kg/m2), eGFR groups (estimated glomerular filtration rate based on the modified Modification of 


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Diet in Renal Disease [MDRD] equation: ≥90, <90 and ≥60, <60 and ≥30, and <30 mL/min/1.73 
m2), duration of diabetes (years), baseline substance use (alcohol, drug, tobacco and caffeine 
baseline use status), baseline systolic blood pressure, baseline diastolic blood pressure, baseline 
HbA1c (% and mmol/mol), baseline HbA1c groups (<7%, ≥7% and <8.5%, ≥8.5% ), fasting 
serum glucose (FSG: mmol/L and mg/dL), lipid measures (triglycerides, FFA, total cholesterol, 
HDL-C, and LDL-C), liver enzymes (ALT, AST and total bilirubin), HbA1c strata (HbA1c 
,8.5% and ≥8.5% at Visit 1), and sulfonylureas [SU] use will be summarized by treatment group 
using the All Randomized Population. Continuous measures will be summarized using 
descriptive statistics and treatment difference will be analyzed using the analysis of variance.  
Categorical measures will be summarized using sample size, frequency, and percentage and 
treatment difference will be analyzed using Chi-squared test.  The by-patient listing of 
demographic and selected baseline characteristics will be provided for all randomized patients.
Number of randomized patients and number of patients discontinued per investigator within 
country for each treatment group will be summarized.  In addition, number of enrolled patients 
per investigator within each country will also be summarized.
4.4. Concomitant Medications
Concomitant medications will be summarized by treatment group and will be compared between 
treatment groups using Fisher’s exact test for all randomized patients. The percentages of 
patients who took concomitant medication will be summarized by treatment using Preferred 
Terms (PTs) nested within Anatomical Therapeutic Chemical (ATC) Level 3 codes.  The 
concomitant medications will be ordered by decreasing frequency within each ATC level.
Listing of concomitant medications will be provided.
4.5. Treatment Compliance
Treatment compliance will be summarized using the EAS.  For a given study participant, overall 
compliance for treatment period is based on the ratio of the total number of doses taken to the 
total number of required doses.  If the ratio is less than 80%, the participant will be considered as 
treatment non-compliant.  The compliance difference between treatment groups will be evaluated 
using Fisher’s exact test.  
Adherence to the dosing algorithm is required from Visit 3 (Randomization) up to Visit 21.  The 
number and percentage of investigator-calculated doses that are not equal to  patient actual dose 
will be provided.
4.6. Protocol Deviations
Important protocol deviations (IPDs) defined as deviations from the study protocol that may 
compromise the data integrity and patients’ safety will be summarized by treatment group for all 
randomized patients.  The listing of IPDs for all randomized patients will also be provided.
The list of pre-defined important protocol deviation was provided in the trial issue management 
plan.  The decision and rationale for not reporting certain protocol deviations as important in the 
CSR will be documented in the study decisions log.


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4.7.
Primary Outcome and Methodology
The primary efficacy measure of change in HbA1c at Week 32 (together with HbA1c measure at 
other postbaseline visits) will be summarized and analyzed using an MMRM approach on the 
EAS. This model implicitly adjusts for missing data through a variance-covariance structure.  
This model will include the fixed effects of treatment (LY3209590 Algorithm 1, LY3209590 
Algorithm 2, insulin degludec), stratification factors (country, BMI strata [BMI <30 or ≥30], 
sulfonylureas use[Y/N]), visit, treatment by visit interaction, and baseline value of the dependent 
variable as the fixed effects.  The HbA1c is reported in unit of % and will be converted to the 
unit of mmol/mol using the following formula: HbA1c in mmol/mol = 10.93*HbA1c in % -
23.5 (http://www.ngsp.org/ifccngsp.asp).  HbA1c analysis will be conducted based on both units.
In the MMRM model, the within-patient errors are modeled as an unstructured variance-
covariance matrix.  If the analysis fails to converge, the following variance-covariance matrix 
will be used (in order) until one converges: 
1. toeplitz with heterogeneity
2. autoregressive with heterogeneity
3. compound symmetry with heterogeneous variances
4. toeplitz
5. autoregressive
6. compound symmetry without heterogeneous variances
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom for 
the MMRM models.  The following is an example SAS code:
proc mixed data=DATA;
class TREATMENT STRATIFICATIONS VISIT PATIENT;
       model HbA1c=BASELINE TREATMENT STRATIFICATIONS VISIT     
                   VISIT*TREATMENT / solution ddfm=kr;
repeated VISIT / subject=PATIENT type=un;
lsmeans TREATMENT*VISIT/ pdiff cl alpha=0.1 om=DATA;
run;
The 2-sided 90% CI for the LS mean for the individual treatment arms, treatment LS mean 
difference (LY3209590 Algorithm 1 vs. insulin degludec, LY3209590 Algorithm 2 vs insulin 
degludec, and LY3209590 Algorithm 1 vs LY3209590 Algorithm 2) in the change in HbA1c at 
32 weeks will be constructed.  Similar summary will be provided for the comparison between 
pooled LY arm and insulin degludec based on the contrast from the above MMRM model.
4.8.
Secondary and Additional Efficacy Analyses
The analysis population for the secondary analysis on HbA1c reduction is the EAS.  Treatment 
comparison at 32 weeks will be used to assess the difference between the pooled LY arm and 
Degludec arm.  The 2-sided 90% CI for the LS mean of the difference between pooled LY arm 
and Degludec arm in the change in HbA1c at 32 weeks will also be constructed.
A sensitivity analysis will be conducted to evaluate the “treatment policy” estimand, which is 
defined as the treatment differences in HbA1c at 32 weeks with the randomized treatment based 


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on all randomized patients who took at least one dose of study medication, and have baseline and 
at least one postbaseline measurement.  In this analysis, all endpoint data regardless of treatment 
disposition status will be included and missing data will be imputed using multiple imputations
to assess sensitivity to departures from the missing at random assumption.  More specifically, the 
missing endpoint will be imputed multiple (for example, 100) times using the baseline data.  
Then, the inference based on the multiple imputations framework will be used (Rubin 1987).  
The following secondary and additional efficacy analyses will be performed based on the EAS
using the same MMRM model as the primary analysis with the addition term of HbA1c strata 
(<8.5% and ≥8.5%)  for non-HbA1c measures:
1. HbA1c change from baseline to Week 12;
2. Fasting blood glucose (FBG) by SMBG and change from baseline at Weeks 12 
and 32;
3. Fasting serum glucose (FSG) by laboratory and change from baseline at Weeks 6, 12, 18,
and 32;
4. Between-day glucose variability measured by the SD of the FBG (SMBG) at Week 12 
and 32;
5. Six-point SMBG profile (pre-meal and 2-hour postprandial SMBG measurements 
for the morning, midday, and evening meals in 1 day) at Weeks 12 and 32.  Since 
the baseline SMBG profile is not collected, the baseline FBG instead of baseline 
value of the dependent variable will be used as a covariate.
6. Within-day and between-day glucose variability measured by the standard 
deviation (SD) of 6-point SMBG.  Since the baseline SMBG profile is not 
collected, the baseline SD of FBG instead of baseline value of the dependent 
variable will be adjusted as a covariate.
The proportion of the patients with HbA1c <7.0% (or ≤6.5%) will be analyzed using a 
longitudinal logistic regression.  In the longitudinal logistic regression model, the independent 
variables of treatment, country, BMI strata (BMI <30 or ≥30), baseline SU use (yes or no), 
baseline HbA1c value, visit, and treatment by visit interaction will be used.
The insulin dose units are different between LY3209590 (mg) and insulin degudec (unit).  
Therefore, descriptive statistics will be provided for the insulin dose and the dose change from 
baseline.  No treatment comparison will be conducted.
4.9.
Pharmacokinetic/Pharmacodynamic Analyses
Pharmacokinetic/pharmacodynamics (PK/PD) analyses will be conducted by PK/PD group.
4.10. Safety Analyses
Safety measures will include AEs, vital signs, treatment exposure, adjudicated cardiovascular 
events, laboratory measures, and antibodies to LY3209590.  Safety analysis will be reported for 
Safety Population and data measured while on treatment and after study drug discontinuation 
will be included.


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4.10.1. Study Drug Exposure
Exposure in days in the study will be calculated for each patient and summarized by treatment 
group. The mean of exposure will be compared between treatment groups using 2-sample t- test.
Exposure during the treatment period will be calculated from date of first study basal insulin 
dose collected in the electronic case report form [eCRF] to date of discontinuation from study 
treatment (i.e., the last dose date for insulin degludec, and last dose date + 7 days for LY3209590
to account for the weekly injection).  The sum of exposure in total patient years will also be 
provided.
Frequency of subjects falling into the following different exposure ranges will also be 
summarized:  >0 days, ≥7 days, ≥14 days, ≥30 days (1 month), ≥60 days (2 months), ≥90 days 
(3 months), ≥120 days (4 months), ≥183 days (6 months) days.
In addition, the duration of follow-up in days for each individual patient is calculated from the 
date of last dose of study drug for insulin degludec/last dose of study drug + 7 days for 
LY3209590 to the last study visit date. The duration of the follow-up in days will be 
summarized (n, mean, standard deviation, median, sum in total patient years, minimum and 
maximum) by treatment group.  
The duration on study from date of first study drug to the last study visit date (including the 
follow-up visit) will also be summarized by treatment group, the following summary statistics 
will be provided: n, mean, standard deviation, median, sum in total patient years, minimum and 
maximum.
A by-patient listing of drug exposure data will be created to provide data for the CSR appendix 
of Compliance and/or Drug Concentration Data.
4.10.2. Adverse Events (AEs)
Adverse events will be summarized as treatment emergent AEs (TEAEs, defined as events that 
are newly reported after the first dose of study basal insulin or reported to worsen in severity 
from baseline) for the Safety Population and compared between treatments unless otherwise 
specified.  The Medical Dictionary for Regulatory Activities (MedDRA) Lowest Level Term 
(LLT) will be used in determination of the treatment-emergent status. The maximum severity 
for each LLT during the baseline period will be used as baseline severity.  All analysis will be 
performed on the data collected from the date of first dose of study drug to the end of the study 
(up to Visit 801).
The number and percentage of patients with TEAEs will be summarized by treatment using 
MedDRA PTs nested within System Organ Class (SOC). Events will be ordered by decreasing 
frequency within SOC. 
The number and percentages of patients with TEAEs (≥2% before rounding) will be summarized 
by treatment using MedDRA PT (without regard to SOC). Events will be ordered by decreasing 
frequency. 


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A TEAE considered possibly related to study drug will be summarized, separately, by treatment 
group using MedDRA PT nested within SOC. Events will be ordered by decreasing frequency 
within SOC. 
A by-patient listing of all AEs for the Safety Population will be created including, but not limited 
to, SOC, event PT, severity, and relationship to study drug for all randomized patients.
Discontinuations due to AEs will be summarized by PT and compared between treatment groups 
using Fisher’s exact test for the Safety Population.  
Summary of treatment emergent SAEs similar to summaries for the proportion of patients 
experiencing each reported TEAE by SOC will be included for the Safety Population. 
All SAEs (including death) will be listed for the Safety Population.  
4.10.3. Adverse Events of Special Interest (AESI)
Summary and analysis of TEAEs related to the following adverse events of special interest 
(AESIs) is specified in this section:

deaths and nonfatal cardiovascular events 

hypoglycemia events

hepatobiliary events

injection site reactions 

systematic hypersensitivity reactions
4.10.3.1. Death and Nonfatal Cardiovascular Events
Deaths and nonfatal cardiovascular AEs will be adjudicated by an independent Clinical Endpoint 
Committee. The following events will be adjudicated and listed by patient for all randomized 
population:  death due to cardiovascular events, myocardial infarction (MI), hospitalization for 
unstable angina, stroke, or transient ischemic attacks (TIA).  The actual term and PT of the event, 
date of first dose and last dose of study drug, result of adjudication, and time from first dose to 
event will be listed.  
4.10.3.2. Hypoglycemia Events 
Both the rate per 1 patient year and incidence of the following type of hypoglycemia events will 
be derived and analyzed:  documented hypoglycemia, documented nocturnal hypoglycemia
(occurs between bedtime and waking), and documented non-nocturnal hypoglycemia (occurs 
between waking and bedtime).  .
Table BDCM.1 provides the summary of statistical method for hypoglycemia event related 
analysis.  Additionally, severe hypoglycemia events will be listed, and incidence of severe 
hypoglycemia will be compared between treatments using Fishers’ exact test.


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Table BDCM.1.
Hypoglycemia Event Related Analyses
Endpoint
Time Point*
Statistical Method
Rate of hypoglycemia events defined by 
glucose <54 mg/dL (3.0 mmol/L) and ≤ 
70 mg/dL (3.9 mmol/L)

Documented 

Nocturnal

Non-Nocturnal
0-12, 0-32, 12-32 
weeks, post-treatment 
period (up to Visit 
801)*
Negative binomial regression with treatment, 
baseline SU use (yes/no), baseline 
HbA1c,baseline hypoglycemia event rate with 
the same category of the dependent variable, log 
(exposure in year) as the offset in the model. 
Incidence of hypoglycemia events 
defined by glucose <54 mg/dL(3.0 
mmol/L) and ≤ 70 mg/dL (3.9 mmol/L)

Documented

Nocturnal

Non-Nocturnal
0-12, 0-32, 12-32 
weeks, post-treatment 
period (up to Visit 
801)*
Logistic regression with treatment, baseline SU 
use (yes/no), baseline HbA1c, baseline 
hypoglycemia event rate with the same category 
of the dependent variable in the model. 
Note that the logistic regression will be 
conducted when ≥10 patients with this event.

Proportion of patients with HbA1c 
<7% without nocturnal 
hypoglycemia event 

Proportion of patients with HbA1c 
≤6.5% without nocturnal 
hypoglycemia event
0-32 weeks
Logistic regression with treatment, baseline 
SU/meglitinide use (yes/no), baseline 
HbA1c,and baseline nocturnal hypoglycemia 
event rate in the model. 
Abbreviations: HbA1c = hemoglobin A1c.
Note:  The hypoglycemia rate per year during defined period is calculated by the number of hypoglycemia within 
the period/number of days patient at risk within the period*365.25 days.  The hypoglycemia incidence during 
defined period indicates if the patient has at least 1 hypoglycemia events within the period (Yes/No).  The 
baseline hypoglycemia rate is the rate calculated between Visit 1 and Visit 3.
*Analyses for endpoint during post-treatment period (up to Visit 801) will include all of the data after study drug 
discontinued on Safety population; analyses for endpoints during other time points will include all data before 
study drug discontinued on Safety population.
The following is the example of the SAS code of the negative binomial regression for analyzing 
the rate of hypoglycemia events. 
proc glimmix empirical data=DATA;
class TREATMENT;
  model HYPO_FREQ=TREATMENT [BASELINE_HYPO_RATE]
      /dist=nb link=log offset=log(exposure in 
days/365.25);
  lsmeans TREATMENT/OM pdiff cl alpha=0.1 ilink;
        random _residual_;
run;
4.10.3.3. Hepatobiliary Events
The percentages of patients with treatment-emergent hepatic AEs will be summarized by 
treatment group using MedDRA PT nested within each SMQ ordered by decreasing frequency.  
The following SMQs based on MedDRA will be used to identify hepatic events:


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
Broad and narrow terms in the Liver related investigations, signs and 
symptoms SMQ (20000008)

Broad and narrow terms in the Cholestasis and jaundice of hepatic origin 
SMQ (20000009)

Broad and narrow terms in the Hepatitis non-infections SMQ (20000010)

Broad and narrow terms in the Hepatic failure, fibrosis and cirrhosis and other 
liver damage SMQ  (20000013) 

Narrow terms in the Liver-related coagulation and bleeding disturbances SMQ 
(20000015)
4.10.3.4. Injection Site Reactions
Injection site reactions will be evaluated using the spontaneous AE reporting of injection site 
reactions by the selected MedDRA PTs for the LY3209590 study program.
Table BDCM.2 contains a list of MedDRA PTs based on MedDRA that will be used to identify 
potential injection site reaction from the spontaneous reported AEs.
The number and percentage of patients experiencing treatment-emergent potential injection site 
reaction identified using the PTs in Table BDCM.2 will be summarized and compared by 
treatment group using Fisher’s exact test. The number and percentage of patients experiencing 
treatment-emergent potential injection site reactions that is judged to be related to study drug by 
the investigator will also be summarized and compared.


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Table BDCM.2.
List of MedDRA Preferred Terms (PTs) to Search for Injection Site 
Reaction Adverse Events (AEs)
Preferred Term
Preferred Term Code
Scope
Injection site abscess
10022044
Narrow
Injection site abscess sterile
10022045
Narrow
Injection site atrophy
10022048
Narrow
Injection site erythema
10022061
Narrow
Injection site hypertrophy
10022072
Narrow
Injection site induration
10022075
Narrow
Injection site infection
10022076
Narrow
Injection site inflammation
10022078
Narrow
Injection site irritation
10022079
Narrow
Injection site mass
10022081
Narrow
Injection site edema
10022085
Narrow
Injection site pruritus
10022093
Narrow
Injection site rash
10022094
Narrow
Injection site reaction
10022095
Narrow
Injection site warmth
10022112
Narrow
Injection site cellulitis
10050057
Narrow
Injection site swelling
10053425
Narrow
Injection site discomfort
10054266
Narrow
Injection site nodule
10057880
Narrow
Lipoatrophy
10024604
Narrow
Lipodystrophy acquired
10049287
Narrow
Partial lipodystrophy
10053857
Narrow
Lipohypertrophy
10062315
Narrow
Injection site bruising
10022052
Broad
Injection site haematoma
10022066
Broad
Injection site haemorrhage
10022067
Broad
Injection site pain
10022086
Broad
4.10.3.5. Systemic Hypersensitivity Reaction
The number and proportion of patients experiencing potential treatment-emergent systemic 
hypersensitivity reactions will be summarized and compared by treatment group using Fisher’s 
exact test.  The following MedDRA Standardized MedDRA Query (SMQ) will be used to 
identify potential systemic hypersensitivity reactions from all TEAEs:


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
Anaphylactic reaction (SMQ).  Besides using the narrow and broad terms designated 
within the SMQ, the following search algorithm will also be implemented as another 
approach to determine if a patient had an anaphylactic reaction:  if a patient (had at 
least 1 event in Category A) or (had at least 1 event that is in Category B and also had 
at least 1 event that is in Category C) or (had at least 1 event that is in Category D and 
[also had at least 1 event in Category B or at least 1 event in Category C])

Angioedema (SMQ)

Hypersensitivity (SMQ)
Specifically, need to perform the following:  (1) any narrow or algorithmic term from any 1 of 
the 3 SMQs indicated above (i.e., combined search across narrow and algorithmic portions of all 
3 SMQs); (2) any narrow scope term within each SMQ, separately (i.e., narrow SMQ search); (3) 
any term within each SMQ, separately (i.e., broad SMQ search); (4) narrow scope term search 
within each SMQ, report the PT nested within each SMQ.
Note that an individual patient may contribute multiple events.  Also, a single event may satisfy 
multiple SMQs, in which case the event contributes to every applicable SMQ.
4.10.4. Laboratory Measures
The data from laboratory testing will be summarized by treatment and visit.  Change from 
baseline (last nonmissing value up to Visit 3) to postbaseline value for laboratory tests (except 
for FSG, HbA1c, and Antibody) will be summarized for patients who have both a baseline and at 
least 1 postbaseline result.  Treatment differences in mean change for these laboratory tests will 
be evaluated using MMRM model.  The MMRM model will be used for the analysis during the 
treatment period and will contain the term for treatment, baseline value, visit, and visit-by-
treatment interaction as factors, patient as random effect, and compound symmetric as the 
variance-covariance structure.  Analyses will be provided in both international units (SI) and
conventional units (CN). The MMRM analysis will only include lab tests for the scheduled
visits specified in the protocol.  For selected lab measures, log-transformed value will be used in 
MMRM,  and the geometric LS means as well as the percentage change from baseline will be 
reported.
The percentages of patients with treatment-emergent abnormal laboratory results at any time
after randomization (including the treatment period and follow-up period) will be summarized 
and compared between treatment groups using Fisher’s exact test.  A treatment-emergent 
abnormal result is defined as a change from normal at baseline to abnormal at any time after 
randomization.  Covance reference ranges will generally be used to define the low and high 
limits.  Patients with missing baseline lab measures will be excluded from this analysis unless 
otherwise specified.  Scheduled visits, unscheduled visits, and retest measurements will be 
included in this analysis.


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A lab listing of patients in the safety population who had an abnormal laboratory value during 
the study will be provided, including the actual measurement (in both SI and CN unit), abnormal 
result, and reference low or high limits. 
4.10.4.1. Lipid Measures
Triglycerides, total cholesterol, LDL-C, and HDL-C (results from fasting samples) will take log-
transformation before being analyzed by MMRM model define above for the Safety population. 
A listing of patients with postbaseline fasting triglyceride value ≥400 mg/dL or non-fasting 
triglycerides >600 will be provided (scheduled visits, unscheduled visits, and repeat 
measurements will be included).  
4.10.4.2. Liver Enzyme Elevation Measures
The liver enzymes and biomarkers (alanine aminotransferase [ALT], aspartate aminotransferase
[AST], Alkaline phosphatase [ALP], total bilirubin[TBL], and Gamma glutamyl transferase
[GGT]) measures will take log-transformation before performing the MMRM analysis.  In 
addition, the percentage of patients with the following elevations in liver enzymes at any 
postbaseline visit after randomization including the treatment period and post-treatment follow-
up period will be summarized for subsest based on baseline categories.

The analysis of any postbaseline ALT (AST) ≥3 fold (3X) ULN will contain 4
baseline subsets:  
o
patients whose non-missing maximum baseline value is less than or equal to 
1X ULN, 
o
patients whose maximum baseline is greater than 1X ULN but less than 3X 
ULN, 
o
patients whose maximum baseline value is greater than or equal 3X ULN, and 
o
patients whose baseline values are missing.  

The analysis of any postbaseline ALT (AST)  ≥5X ULN will be contain 5 baseline 
subsets:  
o
patients whose non-missing maximum baseline value is less than or equal to 
1X ULN, 
o
patients whose maximum baseline is greater than 1X ULN but less than 3X 
ULN, 
o
patients whose maximum baseline is greater than or equal to 3X ULN but less 
than 5X ULN, 
o
patients whose maximum baseline value is greater than or equal to 5X ULN, 
and 
o
patients whose baseline values are missing.  

The analysis of any postbaseline ALT(AST)  ≥10X ULN will contain 6 baseline 
subsets:  


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o
patients whose non-missing maximum baseline value is less than or equal to 
1X ULN, 
o
patients whose maximum baseline is greater than 1X ULN but less than 3X 
ULN, 
o
patients whose maximum baseline is greater than or equal to 3X ULN but less 
than 5X ULN, 
o
patients whose maximum baseline is greater than or equal to 5X ULN but less 
than 10X ULN, 
o
patients whose maximum baseline value is greater than or equal to 10X ULN, 
and 
o
patients whose baseline values are missing.

The analysis of any postbaseline TBL ≥2X ULN will contain 4 baseline subsets: 
o
patients whose non-missing maximum baseline value is less than or equal to 
1X ULN,
o
patients whose maximum baseline is greater than 1X ULN but less than 2X 
ULN,
o
patients whose maximum baseline value is greater than or equal to 2X ULN, 
and 
o
patients whose baseline values are missing.
A listing of patients with any post randomization

elevation of serum ALT to ≥3-fold ULN on 2 or more consecutive blood tests

elevation of serum ALT to ≥5-fold ULN on 2 or more consecutive blood tests

elevation of serum AST to ≥3-fold ULN / 5-fold ULN on 2 or more 
consecutive blood tests

elevated serum TBL to ≥2-fold ULN (except for cases of known Gilbert’s 
syndrome)

elevation of serum ALP to ≥2-fold ULN on 2 or more consecutive blood tests

study participant discontinued from treatment due to a hepatic event or 
abnormality of liver tests

hepatic event considered to be an SAE
will be provided, including the actual measurement of ALT, AST, TBL, ALP, and the 
corresponding reference of high limits.
4.10.5. Vital Signs and Body Weight
Vital signs and weight will be summarized by treatment and visit.  Change from baseline (last 
nonmissing value up to Visit 3) to postbaseline value for vital signs and weight will be 
summarized for patients who have both a baseline and at least 1 postbaseline result.


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Treatment differences in mean change will be assessed using MMRM.  The MMRM model will 
be used for the analysis during the treatment period and will contain the terms for treatment, 
baseline value, visit, and visit-by-treatment interaction as factors; patient as random effect; and 
CS as the variance-covariance structure.  Only scheduled measures will be included in the 
MMRM analyses.
The percentages of patients with treatment-emergent high or low vital signs at any time after 
randomization will be summarized and compared between treatment groups using Fisher’s exact 
test. A treatment-emergent high result is defined as a change from a value less than or equal to 
the high limit (140 mm Hg for systolic blood pressure, 90 mm Hg for diastolic blood pressure, 
and 100 bpm for pulse) at baseline to a value greater than the high limit at any time that meets 
the specified change criteria after randomization. A treatment-emergent low result is defined as 
a change from a value greater than or equal to the low limit (90 mm Hg for systolic blood 
pressure, 50 mm Hg for diastolic blood pressure, and 50 bpm for pulse) at baseline to a value less 
than the low limit at any time that meets the specified change criteria after randomization.
Patients with missing baseline measures will be excluded from this analysis unless otherwise 
specified.  Scheduled visits, unscheduled visits, and retest measurements will be included in this 
analysis. Table BDCM.3 will be used to define the low and high limits and change thresholds.
Table BDCM.3.
Categorical Criteria for Abnormal Treatment-Emergent Blood 
Pressure and Pulse Measurement
Parameter
Low
High
Systolic BP (mm Hg) 
(Supine or sitting)
≤90 and decrease from baseline ≥20
≥140 and increase from baseline ≥20
Diastolic BP (mm Hg) 
(Supine or sitting)
≤50 and decrease from baseline ≥10
≥90 and increase from baseline ≥10
Pulse (bpm) 
(Supine or sitting)
<50 and decrease from baseline ≥15
>100 and increase from baseline ≥15
Abbreviations:  BP = blood pressure; bpm = beats per minute.
4.10.6. Antibodies
4.10.6.1. Anti-LY3209590 Antibodies
The sample to determine antibody against LY3209590 will be collected at protocol-specified 
visits.  Treatment emergent antidrug antibodies (TEADA) can be subclassified as either 
treatment induced (baseline antibody level is not detected) or treatment boosted (baseline 
antibody level is detected):

treatment induced response:  a titer 2-fold (1 dilution) greater than the minimum required 
dilution (1:20) if the baseline level is not detected (i.e., titer less than the minimum 
required dilution)

treatment boosted response:  a 4-fold (2dilution) increase in titer compared to baseline if 
the baseline level is detected.  For an example, 1:20 at baseline and 1:80 post baseline is 
treatment boosted.


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The TEADA status will be determined by all postbaseline data.  The number and percentage of 
patients with positive TEADA response any time after randomization including the treatment 
period and follow-up period will be summarized by treatment group.
A listing of anti-LY3209590 antibodies at each visit will be provided for the safety population.  
The listing will include anti-LY3209590 antibody status (detected/not detected), the titer for 
detected samples.
4.10.7. Electrocardiograms
Electrocardiograms (ECGs) will be collected at specific study visits.  For screening visit, a single 
ECG will be collected.  For the other scheduled visits, a triplicate ECG will be performed and the 
average values will be used in the analysis.
The actual and change from baseline for selected ECG parameters (heart rate, PR auto global 
beat, QRS, QT and QTcF) will be analyzed using the MMRM model.  The MMRM model will 
be used for the analysis during the treatment period and will contain the term for treatment, 
baseline value, visit, and visit-by-treatment interaction as factors, patient as random effect, and 
compound symmetric as the variance-covariance structure.
4.11. Continuous Glucose Monitoring Analysis
4.11.1. General Consideration
The continuous glucose monitoring system will be offered to all patients at selected sites in 
Study I8H-MC-BDCM.  Interstitial glucose (ISIG) values will be collected by the CGM at 5-
minute intervals.  Continuous glucose monitoring recordings will be obtained for all patients 
throughout the treatment phase of the study.  The device readings and alarms will not be blinded 
to the patients so that they can be warned of hypoglycemia and appropriately manage any 
hypoglycemic episodes.
All patients who are randomized to 1 of the study treatments (LY3209590 Algorithm 1, 
LY3209590 Algorithm 2, insulin degludec) receive at least 1 dose of study treatment, and have 
CGM data from at least 1 collection period which will be included in the analyses.  The data 
collected after permanent discontinuation of investigational product will be censored.  There will 
be no multiplicity adjustment.  Since the sensor takes about 2 hours to reach the steady state after 
insertion, it is recommended to only use the steady state data for analysis.
Summary statistics will include the number of observations, mean, median, maximum, 
minimum, and SD for all continuous measures.  For categorical measures, the number of 
observations, proportion, and frequencies will be included in summary statistics.  All analyses 
will be performed for data collected by visit and treatment.  
4.11.2. CGM Variable and Analysis
The following variables derived from CGM will be summarized and compared between 
treatment groups by visit using MMRM model.  The model will include the treatment, HbA1c 
stratum (<8.5% or >=8.5%), baseline FBG, visit, and treatment by visit interaction.  The LS 


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mean difference between treatment groups will be summarized.  We are missing CGM 
documentation if visit intervals are longer than 4 weeks due to storage limitation in the receiver.
4.11.2.1. Hypoglycemia
Percentage and Duration (in minutes) of time per day where glucose values are within a 
hypoglycemic range (defined as ≤70 mg/dL [3.9 mmol/L]) during the nighttime period 
(defined as midnight to 0600 hours).  
Percentage and Duration (in minutes) of time per day glucose values are within a 
hypoglycemic range (defined as ≤70 mg/dL [3.9 mmol/L]) during a 24-hour period.  
Percentage and Duration (in minutes) of time per day where glucose values are within a 
hypoglycemic range (defined as<54 mg/dL [3.0 mmol/L]) during the nighttime period.
Percentage and Duration (in minutes) of time per day where glucose values are within a 
hypoglycemic range (defined as <54 mg/dL [3.0 mmol/L]) during a 24-hour period.  
Incidence of hypoglycemic episodes during the nocturnal period and during a 24-hour 
period.
Rate of hypoglycemic episodes per patient per year during the nighttime period and during 
a 24-hour period.
Duration (in minutes) of each individual hypoglycemic episode.
4.11.2.2. Hyperglycemia
Percentage and Duration (in minutes) of time per day glucose values are within a 
hyperglycemic range (defined as >180 mg/dL [10.0 mmol/L] during a 24-hour period.
4.11.2.3. Normal Range
Percentage and Duration (in minutes) of time per day glucose values are within a normal 
glycemia range (defined as between 71 mg/dL and 180 mg/dL [3.9 and 10.0 mmol/L]) 
inclusive during a 24-hour period.  
Percentage and Duration (in minutes) of time per day glucose values are within a normal 
glycemia range (defined as between 71 mg/dL and 140 mg/dL [3.9 and 7.8 mmol/L]) 
inclusive during a 24-hour period.  
4.11.2.4. Glycemic Variability
Low Blood Glucose Index (LBGI) during the nighttime period and during a 24-hour 
period.
High Blood Glucose Index (HBGI) during the nighttime period and during a 24-hour 
period.
Combined blood glucose risk index (derived as LBGI + HBGI) during the nighttime period 
and during a 24-hour period.
Within-day and between-day glucose coefficient of variation during the nighttime period 
and during a 24-hour period.
Within-day and between-day glucose SD during the nighttime period and during a 24-hour 
period.


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4.11.3. Definition of Variables
In this section, we define the derived variables that are used for the analysis in Section 4.11.2 and 
some additional variables that may be used for exploratory analyses. 
4.11.3.1. Glucose in Target Ranges, Hypoglycemia or Hyperglycemia
The percentage of time within a glucose range (target, hypoglycemia or hyperglycemia ranges) 
will be calculated as the number of observations within the specified range divided by the 
number of observations in the time interval (for example, 24-hour period).  The duration (in 
minutes) within the glucose range will then be calculated as the percentage of time within the 
glucose range times the length of the period (24 hour, 18 hour, and 6 hour, for the periods of 24
hour, daytime or nighttime, respectively). 
4.11.3.2. Hypoglycemic Episode 
The CGM-determined hypoglycemic episode is defined as ISIG meeting the hypoglycemia range 
(e.g., <54 mg/dL or ≤ 70 mg/dL) for at least 15 minutes and the end of a hypoglycemic episode 
is defined as the absence of sensor readings ≥54 mg/dL for 15 minutes or more.  The linear 
interpolation method will be used to determine the start/end time when the patient’s glucose 
value crossed the glucose threshold. 
The duration of each episode will be calculated using the time difference between the 2 time 
points before the incidence starts and after the incidence ends.  
The CGM-determined nighttime hypoglycemic episode is defined as hypoglycemic episodes that 
occur between 2400 hours and 0600 hours.  To calculate the duration of nighttime hypoglycemic 
episode, the end date/time will be the end date/time when the patient passes outside the 
hypoglycemic range even if it is outside the interval of 2400 hours and 0600 hours. 
4.11.3.3. Glycemic Variability
Glycemic variability will be evaluated using the notation below:
i represents a time point within a time period (a 24-hour period, daytime or nighttime)
n represents the number of time points within the time period 
k represents a day within a visit
m represents number of days CGM is performed at a visit 
i
k ,
BG
represents the glucose value at time point i on day k unless otherwise specified.

Within-Day Variability
For variables assessing within-day variability, first determine the variability within each day, 
then average across days within a visit. 


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Within-day glucose SD (Rodbard 2009):
Within-day glucose CV (Clarke and Kovatchev 2009): 
Inter-quartile range (IQR) (Mazze et al. 2008):
                  






m
k
m
k
k
m
IQR
m
IQR
1
1
k)
day 
on 
BG values
all
of
percentile
25th 
  -
(75th 
1
1

Between-Day Variability
For variables assessing between-day variability, first determine the variability for each time point 
across days within a visit then average across all time points. 
Between-day glucose SD (Rodbard 2009):
Between-day glucose CV (Kovatchev et al. 2009):





















n
i
m
k
k
i
m
n
CV
n
CV
1
1
i,
n
1
i
i
100
BG
SD
1
1
























m
k
i
k
i
k
m
k
k
n
m
m
SD
1
2
n
1
i
,
n
1
i
,
1
1
)
n
BG
(BG
1
SD
1









m
k
i
k
k
m
k
k
SD
m
CV
m
CV
1
n
1
i
,
1
100
)
n
BG
(
1
1
























n
i
m
SD
1
2
m
1
k
i
k,
m
1
k
i
k,
n
1
i
i
1
m
)
BG
(BG
n
1
n
1
SD


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Mean of daily differences (MODD):  this parameter is calculated as the mean of absolute 
differences between glucose values at corresponding time points of consecutive days.

Overall Variability
The CV, SD, IQR, LBGI, HBGI, and BGRI will be calculated will be calculated using the 
standard formulas.

Risk for Hypo/Hyperglycemia
The LBGI has been developed to quantitate both frequency and severity of hypoglycemia.  The 
LBGI has been validated as a predictor of severe hypoglycemia, which is an SAE and could 
result in coma or death if unrecognized and untreated.  The HBGI quantifies both frequency and 
severity of hyperglycemia and has been related to HbA1c and risk for hyperglycemia (Kovatchev 
et al. 2006).  Additionally, both the LBGI and HBGI have a high sensitivity to changes in 
glycemic profiles and control (Kovatchev et al. 2006).  The LBGI is a non-negative number that 
increases as the number of low readings increases.  The HBGI is a non-negative number that 
increases as the number of high readings increases.
The LBGI, HBGI, and blood glucose risk index (BGRI) will be derived for each day of a visit 
and for overall in the following steps:
Step 1:  For each blood glucose (BG [mg/dL]) at the ith time point, compute the following:
f(BGi) = 1.509×[(ln(BGi))1.084-5.381]
This transforms the BG data using a nonlinear transformation that maps the BG range of 20 to 
600 mg/dL to a symmetric interval of

10
,
10

The center of the BG scale is 112.5 mg/dL and is mapped to 0
Step 2:  Compute BG risk for each reading




2
i
i
BG
f
10
BG
rl


if f(BG) < 0; otherwise rl(BGi) = 0




2
i
i
BG
f
10
BG
rh


if f(BG) > 0; otherwise rh(BGi) = 0
Assign the risk of each BG value by applying the above quadratic risk function
Value range from 0 (achieved when BG = 112.5, the center) to 100
Left side of the parabola is risk of hypoglycemia, and the right side is risk of hyperglycemia








1
1
n
1
i
,
1,
n
BG
BG
1
1
MODD
m
k
i
k
i
k
m


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Step 3:  Compute LBGI and HBGI



n
1
i
i)
rl(BG
n
1
LBGI



n
1
i
i)
rh(BG
n
1
HBGI
Step 4:  Compute BGRI 
BGRI = LBGI + HBGI
4.12. Subgroup Analyses
The subgroups will be defined as:

Body mass index (<30, ≥30)

Baseline HbA1c (<8.5% and >=8.5%)
The outcome measures included in the subgroup analyses are: 

HbA1c and change in HbA1c from baseline to up to 32 weeks

Documented hypoglycemia and nocturnal hypoglycemia rates (<54 mg/dL [3.0 mmol/L])
during 0-32 weeks.
Analyses for HbA1c and its change will be performed examining the 3-way interaction of the 
primary treatment arms, visit and the subgroup variable using the same MMRM model described 
for the primary analysis.  This model will include the same fixed effects given for the primary 
analysis model plus factors of subgroup, 2-way interaction of subgroup and treatment, 2-way 
interaction of subgroup and visit, and 3-way interaction of treatment, visit, and the subgroup.
The hypoglycemia rates will be analyzed using a negative binomial regression including the 
same fixed effects for hypoglycemia event analyses plus factors of subgroup, 2-way interaction 
of subgroup and treatment.
The interaction effects will be evaluated using a significance level of 0.1, unadjusted.  If the 
interaction effect is significant (p<0.1), separate analysis without the terms related with the 
subgroup will be performed for each subpopulation. 
4.13. Interim Analyses
Study team will conduct routine unblinded program-level safety reviews and some selected 
efficacy data reviews. 
An interim analysis of select safety, efficacy, and PK data is planned when approximately 50% 
of study participants complete 6 weeks of treatment.  Results of interim analysis might be used 
for adjusting LY3209590 dosing algorithm.  
A subsequent interim analysis of select safety, efficacy, and PK data is planned when all study 
participants complete 12 weeks of treatment.  The analyses for the primary objective and 


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secondary objectives, and some other key endpoints will be conducted at that time.  Results of 
interim analysis will be used to design subsequent studies.
Additional unplanned interim analyses may be performed as necessary, and the rationale for the 
interim analysis will be documented in the clinical study report. The analyses for the primary 
objective and secondary objectives, and some other key endpoints were conducted at that time.


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5.
Unblinding Plan
This is an open-label study where investigators and patients are aware of their assigned 
treatment.  


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6.
References
Clarke W, Kovatchev B. Statistical tools to analyze continuous glucose monitor data. Diabetes 
Technol Ther. 2009;11(Suppl. 1):S45–S54.
Kovatchev BP, Otto E, Cox D, Gonder-Frederick L, Clarke W. Evaluation of a new measure of 
blood glucose variability in diabetes. Diabetes Care. 2006;29:2433–2438.
Kovatchev BP, Shields D, Breton M.. Graphical and numerical evaluation of continuous glucose 
sensing time lag. Diabetes Technol Ther. 2009;11:139–143.
Mazze RS, Strock E, Wesley D, Borgman S, Morgan B, Bergenstal R, Cuddihy R. 
Characterizing glucose exposure for individuals with normal glucose tolerance using 
continuous glucose monitoring and ambulatory glucose profile analysis. Diabetes Technol 
Ther. 2008;10(3):149-159.
Qu Y, Luo J. Estimation of group means when adjusting for covariates in generalized linear 
models. Pharm Stat. 2015;14(1):56-62.
Rodbard D. New and improved methods to characterize glycemic variability using continuous 
glucose monitoring. Diabetes Technol Ther. 2009;11:551–565.
Rubin DB. Multiple Imputation for Nonresponse in Surveys. New York: Wiley; 1987.


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Approval Date & Time: 16-Mar-2020 16:59:37 GMT
Signature meaning: Approved
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